Myocardial Function

The influence of volatile anesthetics on contractile function has been investigated extensively in several animal species and in humans using various in vitro and in vivo models.^4–11 In general, it is now widely agreed that volatile agents cause dose-dependent depression of contractile function (Box 9-1). Moreover, different volatile agents are not identical in this regard and the preponderance of information indicates that halothane and enflurane exert equal but more potent myocardial depression than do isoflurane, desflurane, or sevoflurane. This reflects, in part, reflex sympathetic activation with the latter agents. It is also widely accepted that in the setting of preexisting myocardial depression, volatile agents have a greater effect than in normal myocardium.^12,13 Early studies indicating that volatile agents may not have a deleterious effect on function in the setting of acute myocardial infarction (AMI) likely reflected the fact that the limited infarction did not compromise overall myocardial function.^14,15 At the cellular level, volatile anesthetics exert their negative inotropic effects, mainly by modulating sarcolemmal (SL) L-type Ca⁺⁺ channels, the sarcoplasmic reticulum (SR), and the contractile proteins. L-type Ca⁺⁺ currents are decreased and, secondarily, SR Ca⁺⁺ release is depressed (Figures 9-1 and 9-2).¹⁶ Moreover, the contractile response to lower Ca⁺⁺ levels is further attenuated in the presence of volatile agents in that the response is decreased by volatile agents at any given Ca⁺⁺ level; that is, volatile agents also decrease Ca⁺⁺ sensitivity (Figure 9-3).¹⁶ However, the mechanisms whereby anesthetic agents modify ion channels are not completely understood. Ion channels usually are studied in ex vivo circumstances in which, by definition, multiple modulating influences of the specific channel under study may be altered. Moreover, these studies frequently are undertaken in nonhuman tissue. Well-recognized species differences make extrapolation to humans difficult.¹⁷ Nitrous oxide causes direct mild myocardial depression but also causes sympathetic activation.¹⁸

Figure 9-1 Sites of action of volatile anesthetics in a ventricular myocyte. Dark spots indicate inhibitory actions; light spots indicate stimulatory actions.

(From Hanley PJ, ter Keurs HEDJ, Cannell MB: Excitation-contraction in the heart and the negative inotropic action of volatile anesthetics, Anesthesiology 101:999, 2004.)

Figure 9-2 Fura-2 fluorescence (top trace), an index of Ca⁺⁺, and cell length (bottom trace), an index of contraction, were measured simultaneously in an electrically stimulated rat ventricular myocyte. Application of halothane initially induced a transient increase in the Ca⁺⁺ transient and twitch force before both the Ca⁺⁺ signals and contraction decreased.

(From Harrison SM, Robinson M, Davies LA, et al: Mechanisms underlying the inotropic action of halothane on intact rat ventricular myocytes,Br J Anaesth 82:609, 1999.)

Figure 9-3 Simultaneous measurement of force and fluo-3 fluorescence, an index of Ca⁺⁺, in a rat cardiac trabecula. Application of isoflurane decreased force and Ca⁺⁺. Restoration of the Ca⁺⁺ transient amplitude by increase of external Ca⁺⁺ did not recover force, indicating that, in addition to decreasing Ca⁺⁺ availability, the anesthetic decreased Ca⁺⁺ responsiveness of the contractile proteins.

(From Hanley PJ, Loiselle DS: Mechanisms of force inhibition of halothane and isoflurane in intact rat cardiac muscle, J Physiol 506:231, 1998.)

It is well recognized that even in the setting of normal systolic function, diastolic dysfunction occurs with increasing frequency in the elderly and is an important cause of congestive heart failure (CHF).^19–25 Diastolic dysfunction and its more severe clinical counterpart, diastolic heart failure, have protean causative factors and can be mechanistically complex²³ (Table 9-1). However, the mechanisms underlying these conditions can be categorized into those involving alterations in myocardial relaxation (e.g., SR Ca⁺⁺ handling, phospholamban), those related to intrinsic properties of myocardial tissue (e.g., myocyte cytoskeletal elements), and those that are extramyocardial (e.g., loading conditions). Indices of diastolic function were not readily and reliably measured noninvasively in the past; hence the relatively more recent recognition and description of diastolic dysfunction and diastolic heart failure compared with perturbations in systolic function. This likely also explains the relative paucity of literature detailing the modulating effects of volatile agents on diastolic function. There is reasonable agreement in the literature that volatile agents prolong isovolumic relaxation and do so in a dose-dependent manner.^{21,22,26–30} The effects of volatile agents on chamber stiffness are more controversial; for example, halothane has been reported to both decrease compliance and have no effect on myocardial stiffness.^{21,22,26,28–31} The effect of nitrous oxide on diastolic function has not been investigated in a manner that critically rules out confounding variables. At a molecular level, alterations in relaxation likely reflect modulation of Ca⁺⁺ currents, including SR Ca⁺⁺ reuptake mechanisms. Paradoxically, in the setting of reperfusion injury and Ca⁺⁺ overload, the volatile agent sevoflurane improves indices of diastolic relaxation and attenuates myoplasmic Ca⁺⁺ overload.³²

TABLE 9-1 Diastolic Heart Failure: Mechanisms and Causes

Cardiac Electrophysiology

Volatile anesthetic agents reduce the arrhythmogenic threshold for epinephrine. Moreover, not all volatile agents are similar, with the order of sensitization being: halothane > enflurane > sevoflurane > isoflurane = desflurane.

The molecular mechanisms underlying this effect of volatile anesthetics are poorly understood. Anesthetic agent–induced modulation of ion channels is important mechanistically in excitation-contraction coupling (vide supra), in preconditioning (vide infra), and in modulating automaticity and arrhythmia generation¹⁷ (Table 9-2). Although the effects of any particular volatile agent on a specific cardiac ion channel may have been characterized, this does not allow a ready extrapolation into clinical situations. This partly reflects those issues already discussed (species differences, ex vivo studies) but also the recognition that it is impossible to predict the arrhythmogenic effect that might ensue after modulation with a particular volatile agent. This should be one of the lessons garnered from the experience with the antiarrhythmic drugs such as encainide and flecainide.³³ Moreover, even in the clinical setting, not all volatile agents have the same effect.³⁴

Coronary Vasoregulation

Volatile anesthetic agents modulate several determinants of both myocardial oxygen supply and demand. Moreover, it is now established that volatile agents also directly modulate the myocytes’ response to ischemia. Thus, studies investigating the effects of volatile agents on coronary vasoregulation should be interpreted in this context.

Animal studies indicate that halothane has little direct effect on the coronary vasculature.^35–37 Likewise, clinical studies investigating the effect of halothane indicate that it has either minimal or mild coronary vasodilator effects.^38–41 The effect of isoflurane on coronary vessels was controversial and dominated much of the literature in this area in the 1980s and early 1990s. The current assessments of the effects of isoflurane have been succinctly detailed by Tanaka et al.⁴² Several reports have indicated that it caused direct coronary arteriolar vasodilatation in vessels of 100 μm or less, and that isoflurane could cause “coronary steal” in patients with “steal-prone” coronary anatomy; that is, in patients with significant coronary stenosis in a vessel subserving a region of ischemic myocardium, when, presumably, vessels were maximally dilated because of local metabolic autoregulation, and in whom isoflurane-induced vasodilatation in adjacent vessels resulted in diversion of coronary flow away from the ischemic region.^43,44 Several animal and human studies in which potential confounding variables were controlled indicated clearly that isoflurane did not cause coronary steal.^45–51 Studies of sevoflurane and desflurane showed similar results and are consistent with a mild direct coronary vasodilator effect of these agents.^52,53

Ultimately, CBF (in the setting of normal systemic hemodynamics) is controlled by coronary vascular smooth muscle tone, which can be modulated directly (endothelium-independent) or indirectly via the endothelium (endothelium-dependent). Teleologically, it can be predicted that in vital organs, control of blood flow is predominantly local, acting through either endothelium-dependent or -independent mechanisms. Thus, volatile agents have the capacity to modulate mechanisms underlying vascular tone: (1) Halothane and isoflurane have been shown to attenuate endothelial-dependent tone (by receptor-dependent and receptor-dependent plus -independent mechanisms, respectively) in coronary microvessels⁵⁴; (2) several volatile agents cause coronary vasodilation via K⁺_ATP-channel–dependent mechanisms^54–57; and (3) sevoflurane induced K⁺– and Ca⁺⁺-channel–mediated increases in coronary collateral blood flow.⁵⁸ The effects in vivo are likely to be modest because local control mechanisms are likely to predominate.

Systemic Regional and Pulmonary Vascular Effects

Vascular tone can be modulated by volatile agents. However, the specific result can be influenced not only by the agent under study but by the vascular bed being investigated, the vessel size/type within that vascular bed, the level of preexisting vascular tone, age, and indirect effects of the agents, such as anesthesia-induced hypotension and reflex autonomic nervous system (ANS) activation.

All volatile anesthetic agents decrease systemic blood pressure (BP) in a dose-dependent manner. With halothane and enflurane, the decrease in systemic BP primarily is due to decreases in stroke volume (SV) and cardiac output (CO), whereas isoflurane, sevoflurane, and desflurane decrease overall systemic vascular resistance (SVR) while maintaining CO. However, these overall effects belie the multiple effects in the various regional vascular beds. Within the systemic noncoronary vasculature, aortic and mesenteric vessels have been the best studied.

Reversible inhibition of endothelium-dependent relaxation in aortic and femoral vessels was first demonstrated for halothane and also has been demonstrated for enflurane, isoflurane, and sevoflurane in both capacitance and resistance vessels.^54,59–63 However, these observations mask the differential effects of volatile agents on underlying endothelium-dependent mechanisms. Halothane and enflurane decrease agonist (bradykinin) and ATP-induced Ca⁺⁺ increases in bovine endothelial cells, whereas isoflurane does not.⁶⁴ In contrast, isoflurane does attenuate histamine-induced Ca⁺⁺ influx into human endothelial cells.⁶⁵ Alterations in endothelium-dependent mechanisms by volatile agents are not confined to attenuation of agonist-dependent and -independent activation of endothelial nitric oxide synthase (eNOS) and nitric oxide (NO) release but also may extend to other mechanisms. For example, the effects of sevoflurane on endothelial cell function may be partially because of sevoflurane-induced changes in endothelin-1 (ET-1) production and in the redox milieu of the endothelial cells (i.e., increased superoxide anion production).⁶⁶

The effect of volatile agents on vascular smooth muscle mechanisms is equally complex and varies among agents. In endothelial cell–denuded aortic rings, halothane decreases both SL Ca⁺⁺ influx via voltage-dependent calcium channels and SR Ca⁺⁺ release, but sevoflurane does not.⁶⁷ Sevoflurane also inhibits angiotensin II–induced vascular smooth muscle contraction in aortic rings.⁶⁸ In mesenteric vessels, sevoflurane accentuates endothelium-dependent mechanisms and attenuates endothelium-independent mechanisms in the presence of norepinephrine.⁶⁹ Studies of the influence of volatile agents on vascular smooth muscle Ca⁺⁺ currents indicate that both halothane and enflurane stimulate SR release and reuptake from the caffeine-sensitive pool. In contrast, halothane, enflurane, and isoflurane all increase calcium-induced calcium release (CICR) mechanisms, but sevoflurane decreases CICR mechanisms.⁷⁰ Finally, volatile agents also have been demonstrated to modulate Ca⁺⁺ sensitivity. In mesenteric vessels, halothane relaxation is largely mediated by Ca⁺⁺ and myosin light-chain desensitizing mechanisms.⁷¹

The pulmonary circulation has unique features that must be taken into account when interpreting studies of this vascular bed. In addition to those issues that also apply to systemic vascular beds (vessel size, etc.), the pulmonary vasculature is a low-resistance bed (requiring preconstriction to access vasoactive effects), is not rectilinear (thus, changes in flow per se can change certain parameters used to calculate resistance), is contained within the chest (and thus subject to extravascular pressures, which are not atmospheric and change during the respiratory cycle), and exhibits the unique vascular phenomenon of hypoxia-induced vasoconstriction. It is clear that volatile agents modulate not only the baseline pulmonary vasculature but also multiple vasoactive mechanisms that control pulmonary vascular tone. Moreover, the effect of volatile agents is agent specific. For example, halothane causes flow-independent pulmonary vasoconstriction.⁷² In contrast, the hypoxic pulmonary vasoconstrictor response does not appear to be altered by at least two currently used volatile agents: sevoflurane and desflurane.⁷³ The pulmonary vascular endothelial response appears to be impaired by the volatile agents halothane and isoflurane.^74,75 Finally, pulmonary vascular smooth muscle regulatory mechanisms also can be modified by volatile agents. Halothane, enflurane, and isoflurane all attenuate pulmonary vasodilatation induced by K⁺_ATP channel activation.^76,77 Although the effects of the different volatile agents on K⁺_ATP-channel activation are similar, β-adrenergic receptor–induced pulmonary vasodilatation is differently modulated. Halothane and isoflurane potentiate the vasodilatory response, but enflurane has no effect.⁷⁸

Baroreceptor Reflex

All volatile agents attenuate the baroreceptor reflex. Baroreceptor reflex inhibition by halothane and enflurane is more potent than that observed with isoflurane, desflurane, or sevoflurane, each of which has a similar effect.^79,80 Each component of the baroreceptor reflex arc (afferent nerve activity, central processing, efferent nerve activity) is inhibited by volatile agents. Inhibition of afferent nerve traffic results, in part, from baroreceptor sensitization,^81,82 whereas attenuation of efferent activity is due, in part, to ganglionic inhibition as manifest by differential preganglionic and postganglionic nerve activity.^81–83

Reversible Myocardial Ischemia

Prolonged ischemia results in irreversible myocardial damage and necrosis (Box 9-2). Shorter durations of myocardial ischemia can, depending on the duration and sequence of ischemic insults, lead to either preconditioning or myocardial stunning (Figure 9-4).⁸⁴ Stunning, first described in 1975, occurs after brief ischemia and is characterized by myocardial dysfunction in the setting of normal restored blood flow and by an absence of myocardial necrosis.⁸⁵ Ischemic preconditioning (IPC) was first described by Murry et al⁸⁶ in 1986 and is characterized by an attenuation in infarct size after sustained ischemia, if this period of sustained ischemia is preceded by a period of brief ischemia (Figure 9-5). Moreover, this effect is independent of collateral flow. Thus, short periods of ischemia followed by reperfusion can lead to either stunning or preconditioning with a reduction in infarct size (Figure 9-6).⁸⁴

Figure 9-4 Effects of ischemia and reperfusion on the heart based on studies in anesthetized canine model of proximal coronary artery occlusion. Brief periods of ischemia of less than 20 minutes followed by reperfusion are not associated with development of necrosis (reversible injury). Brief ischemia/reperfusion results in the phenomenon of stunning and preconditioning. If duration of coronary occlusion is extended beyond 20 minutes, a wavefront of necrosis marches from subendocardium to subepicardium over time. Reperfusion before 3 hours of ischemia salvages ischemic but viable tissue. (This salvaged tissue may demonstrate stunning.) Reperfusion beyond 3 to 6 hours in this model does not reduce myocardial infarct size. Late reperfusion may still have a beneficial effect on reducing or preventing myocardial infarct expansion and left ventricular (LV) remodeling.

(From Kloner RA, Jennings RB: Consequences of brief ischemia: stunning, preconditioning, and their clinical implications, Part I, Circulation 104:2981, 2001.)

Figure 9-5 Infarct size and collateral blood flow in the 40-minute study.

Left, Infarct size, as a percentage of the anatomic area at risk, in the control (striped bar) and preconditioned (stippled bar) hearts. Infarct size in control animals averaged 29.4% of the area at risk. Infarct size in preconditioned hearts averaged only 7.3% of the area at risk (preconditioned vs. control, P < 0.001). Transmural mean collateral blood flow (right) was not significantly different in the two groups. Thus, the protective effect of preconditioning was independent of the two major baseline predictors of infarct size, area at risk and collateral blood flow. Bars represent group mean ± standard error of the mean.

(From Warltier DC, al-Wathiqui MH, Kampine JP, et al: Recovery of contractile function of stunned myocardium in chronically instrumented dogs is enhanced by halothane or isoflurane, Anesthesiology 69:552, 1988.)

Figure 9-6 Schematic of stunning and preconditioning.

Short coronary artery occlusions result in stunning, in which there is prolonged regional wall motion abnormality, despite presence of reperfusion and viable myocardial cells. Brief episodes of ischemia/reperfusion also precondition the heart. When the heart is then exposed to a longer duration of ischemia and reperfusion, myocardial infarct size is reduced.

(From Kloner RA, Jennings RB: Consequences of brief ischemia: stunning, preconditioning, and their clinical implications, Part I, Circulation 104:2981, 2001.)

As discussed previously, work in the 1970s indicated that volatile anesthetic agents attenuated ST-segment elevations in the setting of short-duration ischemia and limited infarct size and lactate production after prolonged ischemia.^87,88 Moreover, these effects seemed to be independent of the main determinants of myocardial oxygen supply and demand, and suggested that the volatile agents may be exerting a beneficial effect at the level of the myocyte. On resolution of the isoflurane “coronary steal” controversy, the first description of the salutary effects of volatile agents on the consequences of brief ischemia was made in 1988. Warltier and coworkers⁸⁹ described the beneficial effects of halothane and isoflurane in facilitating the recovery of contractile function in stunned myocardium (Figure 9-7). However, it was almost a decade later before the effects of volatile agents on preconditioning were outlined^2,3 and the term APC was used¹ (Figure 9-8).

Figure 9-7 Segment shortening data (expressed as a percentage of control mean ± standard error of the mean during coronary artery occlusion (OCC) and at various times after reperfusion in conscious dogs (Group 1, diamonds) and in those dogs anesthetized with isoflurane (Group 7, dark squares). Comparisons are made at various time points with those animals anesthetized with isoflurane but not undergoing coronary artery occlusion and reperfusion (Group 6, light squares). ^aSignificant (P < 0.05) difference, Group 6 (anesthetized without occlusion) versus 1 (conscious occlusion) or 7 (occlusion during anesthesia). ^bSignificant (P < 9.95) difference, Group 1 (conscious occlusion) versus 7 (occlusion during anesthesia). Note that the control state (C) indicates either the awake, unsedated state (Group 1) or after a stable hemodynamic state after 2 hours of isoflurane anesthesia (Groups 6 and 7).

(From Warltier DC, al-Wathiqui MH, Kampine JP, et al: Recovery of contractile function of stunned myocardium in chronically instrumented dogs is enhanced by halothane or isoflurane, Anesthesiology 69:552, 1988.)

Figure 9-8 A, Infarct size (mean ± standard deviation) expressed as a percentage of area at risk in rabbit hearts that were not pretreated (control: N = 13), exposed to 5 minutes of preconditioning (ischemic preconditioned: N = 8), or exposed to 15 minutes of 1.1% isoflurane (isoflurane: N = 15) before 30 minutes of anterolateral coronary occlusion. ^#,*,⁺Statistical analysis showed that the relation between infarct size and area at risk was different in each group (P < 0.05). B, Relation between infarct size and myocardium at risk for the three groups. All three regression lines were statistically different because of differences in line elevation.

(From Cason BA, Gamperi AK, Slocum RE, et al: Anesthetic-induced preconditioning: previous administration of isoflurane decreases myocardial infarct size in rabbits, Anesthesiology 87:1182, 1997.)

The phenomenon of and the mechanisms underlying IPC are the focus of extensive investigation. IPC has the following characteristics: (1) results in two periods (termed windows) of protection—the first (termed early or classic) occurs at 1 to 3 hours, and the second (termed late or delayed) occurs 24 to 96 hours after the preconditioning stimulus; (2) occurs also in noncardiac tissue, such as brain and kidney; (3) is ubiquitous across species; (4) is most pronounced in larger species with lower metabolism and slower heart rates (HRs); (5) seems to be important clinically because angina within the 24-hour period preceding an AMI is associated with an improved outcome (Figure 9-9)⁹⁰; and (6) is mediated by multiple endogenous signaling pathways⁹¹ (Figure 9-10).⁹² As might be predicted from the time frame of delayed IPC, it is mediated, at least in part, by transcriptional and posttranslational mechanisms⁹¹ (Figure 9-11). Finally, and of the utmost importance, preconditioning can be triggered by events other than ischemia (cellular stress of various forms, pharmacologic agonists, anesthetic agents; see Figure 9-11).⁹¹ Moreover, the benefits of IPC are not necessarily confined to and may not include limitation of infarct size, and depend on the specific trigger for IPC, the species under study, and classic versus delayed IPC. For example, rapid pacing affords protection against arrhythmias but not against infarct evolution. In contrast, cytokine-induced IPC limits infarct size but has no effect on arrhythmias.⁹¹ Different triggers of IPC modulating different end points suggest that, although there are fundamental mechanisms common to various triggers of IPC, there also exist mechanistic differences across triggers. Thus, APC may not be identical to IPC mechanistically.

Figure 9-9 Five-year survival curves for patients with [angina < 24 hours (+)] versus those without [angina < 24 hours (−)] prodromal angina in the 24 hours before infarction.

(From Ishihara M, Sato K, Tateishi H, et al: Implications of prodromal angina pectoris in anterior wall acute myocardial infarction: acute angiographic findings and long-term prognosis, J Am Coll Cardiol 30:970, 1997.)

Figure 9-10 Investigated signaling pathways (full lines).

During early reperfusion, multiple signaling cascades inhibit the master switch kinase glycogen synthase kinase-3β (GSK-3β), which converges the prosurvival pathways and prevents permeability transition (PT) in mitochondria. Beside other kinases, protein kinase B (PKB)/Akt represents a key enzyme in the reperfusion injury salvage kinase cascade requiring phosphorylation at Ser473 for full activation. Phosphorylated PKB/Akt subsequently inactivates its downstream target GSK-3β by phosphorylation at Ser9. LY294002 specifically inhibits phosphatidylinositol 3-kinase (PI3K). Atractyloside induces opening of the mitochondrial permeability transition pore (mPTP). Arrows indicate positive activity; lines with blunted ends indicate inhibition. DAG, diacylglycerol; GPCR, G-protein–coupled receptor; IP₃, inositol triphosphate; MAPK, mitogen-activated protein kinases; NAD⁺, nicotinamide adenine dinucleotide; PDK2, phosphatidylinositol-dependent kinase 2, also called Ser473 kinase; PKC, protein kinase C; PLC/D, phospholipase C/D.

(From Feng J, Lucchinetti E, Ahuja P, et al: Isoflurane postconditioning prevents opening of the mitochondrial permeability transition pore through inhibition of glycogen synthase kinase 3β, Anesthesiology 103:987–995, 2005.)

Figure 9-11 Schematic representation of the cellular mechanisms underlying late preconditioning (PC).

A nonlethal cellular stress (such as reversible ischemia, heat stress, ventricular pacing, or exercise) causes release of chemical signals (nitric oxide [NO], reactive oxygen species [ROS], adenosine, and possibly opioid receptor agonists) that serve as triggers for the development of late PC. These substances activate a complex signal transduction cascade that includes protein kinase C (PKC) (specifically, the ε isoform), PTKs (specifically, Src and/or Lck), and probably other as yet unknown kinases. A similar activation of PKC and downstream kinases can be elicited pharmacologically by a wide variety of agents, including naturally occurring, and often noxious, substances (such as endotoxin, interleukin-1, tumor necrosis factor-α [TNF-α], TNF-β, leukemia inhibitor factor, or ROS), as well as clinically applicable drugs (NO donors, adenosine A1- or A3-receptor agonists, endotoxin derivatives, or δ₁-opioid receptor agonists). The recruitment of PKC and distal kinases leads to activation of nuclear factor (NF)-κB and almost certainly other transcription factors, resulting in increased transcription of multiple cardioprotective genes and synthesis of multiple cardioprotective proteins that serve as comediators of protection 2 to 4 days after the PC stimulus. The mediators of late PC identified thus far include inducible nitric oxide synthase (iNOS), cyclooxygenase-2 (COX-2), aldose reductase, and manganese superoxide dismutase (MnSOD). Among the products of COX-2, prostaglandin E₂ (PGE₂) and/or PGI₂ appear to be the most likely effectors of COX-2–dependent protection. Increased synthesis of heat shock proteins (HSPs) is unlikely to be a mechanism of late PC, although the role of post-translational modification of preexisting HSPs remains to be determined. In addition, the occurrence of cardioprotection on days 2 to 4 requires the activity of PTKs and possibly p38 mitogen-activated protein kinases (MAPKs), potentially because iNOS and other mediators need to undergo post-translational modulation to confer protection against ischemia. Opening of K⁺_ATP channels is also essential for the protection against infarction (but not against stunning) to become manifest. The exact interrelationships among iNOS, COX-2, aldose reductase, MnSOD, and K⁺_ATP channels are unknown, although recent evidence suggests that COX-2 may be downstream of iNOS (i.e., COX-2 is activated by NO). AP-1, activator protein 1; PTK, protein tyrosine kinases.

(From Bolli R: The late phase of preconditioning, Circ Res 87:972, 2000.)

Anesthetic Agents: Pre- and Post-Conditioning

This is an area of intense investigation as reflected by two issues of Anesthesiology being devoted predominantly to the subject.^93,94 After the initial description of APC,^1–3 subsequent investigations have indicated that volatile agents can elicit delayed (late), as well as classic (early), preconditioning.^95,96 Moreover, APC is dose dependent,^97–99 exhibits synergy with ischemia in affording protection,^100,101 and perhaps not surprisingly, in view of differential uptake and distribution of volatile agents, has been demonstrated to require different time intervals between exposure and the maintenance of a subsequent benefit that is agent dependent⁴² (see Chapters 6 and 7).

The contributions of both SL and mitochondrial K⁺_ATP channels in IPC have been extensively investigated, and it is now widely agreed that mitochondrial K⁺_ATP channels play a critical role in this process. Volatile agents that exhibit APC activate mitochondrial K⁺_ATP channels, and this effect is blocked by specific mitochondrial K⁺_ATP channel antagonists. However, the precise relative contributions of SL versus mitochondrial K⁺_ATP channel activation to APC remain to be elucidated (Figure 9-12).⁴² The original descriptions of APC indicated that volatile agents can trigger preconditioning without concurrent ischemia during the “triggering” period^1–3 (see Figure 9-8). However, studies of mitochondrial activation (via mitochondrial K⁺_ATP channels) indicate that volatile agents on their own do not activate mitochondria but do potentiate the effects of direct mitochondrial K⁺_ATP channel openers⁹⁹ (Figure 9-13). These apparent inconsistencies are likely explained by the presence of multiple parallel and redundant pathways activated during APC (and IPC)⁹⁶ (see Figure 9-12). For example, it is now well established that the adenosine A-1 and δ₁ opioid G-coupled receptors can trigger IPC. Moreover, pharmacologic blockade of these receptors attenuates the positive effects of volatile agents.^98,102 Protein kinase C (PKC) and the nuclear signaling pathway, mitogen-activated protein kinase (MAPK), are important signaling pathways in preconditioning, and volatile agents have been shown to modulate at least PKC translocation.¹⁰³ Oxidant stress is a central feature of reperfusion and, depending on the specific moiety, the enzymatic source and, most importantly, the oxidant stress load may trigger preconditioning on the one hand or mediate reperfusion injury on the other. Both indirect and direct evidence indicate that volatile agents can increase oxidant stress to levels that trigger preconditioning.^104–106

Figure 9-12 Multiple endogenous signaling pathways mediate volatile anesthetic-induced myocardial activation of an end-effector that promotes resistance against ischemic injury. Mitochondrial K⁺_ATP channels have been implicated as the end-effector in this protective scheme, but sarcolemmal K⁺_ATP channels may also be involved in this mechanism of protection. A trigger initiates a cascade of signal transduction events, resulting in the protection. Volatile anesthetics signal through adenosine and opioid receptors, modulate G proteins, stimulate protein kinase C (PKC) and other intracellular kinases, or have direct effects on mitochondria to generate reactive oxygen species (ROS) that ultimately enhance K⁺_ATP channel activity. Volatile anesthetics may also directly facilitate K⁺_ATP channel opening. Dotted arrows delineate the intracellular targets that may be regulated by volatile anesthetics; solid arrows represent potential signaling cascades.

(From Tanaka K, Ludwig LM, Kersten JR, et al: Mechanisms of cardioprotection by volatile anesthetics, Anesthesiology 100:707, 2004.)

Figure 9-13 Effect of sevoflurane (SEVO; 2.8% [vol/vol]) on diazoxide (DIAZO)-induced flavoprotein oxidation in myocytes excited at 480 nm. Similar results were obtained for isoflurane. An artificial color scale was used to visualize the relative intensity of emitted fluorescence at 530 nm (dark blue indicates reduced flavoproteins; red indicates fully oxidized flavoproteins). A, At baseline. B, At 100 μm DIAZO (same cells). C, At 2 minimal alveolar concentration (MAC) SEVO. D, At 100 μm DIAZO preceded by 2 MAC SEVO. Red color indicates intense local oxidation by mitochondrial clusters. E, At 100 μm 2,4-dinitrophenol (DNP). F, Mean percentages of peak flavoprotein fluorescence depending on the drugs exposed to myocytes. *P < 0.0001 versus baseline or SEVO + DIAZO versus DIAZO alone. ^#P value not significantly different from DIAZO; ^†P value not significantly different from baseline. SEVO/CHE indicates concomitant treatment of myocytes with SEVO and chelerythrine (CHE) at 2 μm before exposure to DIAZO. G, Time-lapse analysis of alterations in fluorescence intensity in individual myocytes expressed as percentage of DNP-induced fluorescence. Blue squares and red circles indicate values from eight different experiments. H, Latency to peak activation of mitoK⁺_ATP channels in response to the various treatment regimens. *P < 0.001 versus DIAZO; ^#P value not significant versus DIAZO. Data are mean ± standard deviation.

(From Zaugg M, Lucchinetti E, Spahn DR, et al: Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial KATP channels via multiple signaling pathways, Anesthesiology 97:4, 2002.)

Activation of eNOS also has been shown to play a role, as has depolarization of the mitochondrial internal membrane.¹⁰⁷ This may prevent the opening of the mitochondrial permeability transition pore (MPTP) and inhibit Na⁺-H⁺ exchange, attenuating Ca⁺² overload and cell edema.¹⁰⁷ Inhibition of mitochondrial permeability by APC has been suggested to decrease myocyte death, and PKC also has been thought to play a role in IPC-induced delay of MPTP opening.^108,109 For the first time, a recent study demonstrates that isoflurane has been shown to activate PKC-dependent signaling pathways resulting in the delay of MPTP opening,¹¹⁰ suggesting a possible mechanism for isoflurane in APC. With respect to postconditioning, Ge et al¹¹¹ demonstrated that NO may, in fact, act as both a trigger and a mediator for isoflurane-induced cardiac protection in mouse hearts. This implies that an eNOS-dependent mechanism prevents the opening of the MPT pore, although other pathways including glycogen synthase kinase-3β also have been implicated (Figure 9-14).^92,111

Figure 9-14 Concentration-dependent decreases in myocardial infarct size by isoflurane postconditioning (IsoPC) in wild-type mice subjected to 30 minutes of coronary occlusion followed by 2 hours of reperfusion. A, Area at risk expressed as a percentage of left ventricle area. B, Myocardial infarct size expressed as a percentage of area at risk. IsoPC was produced by 0.5, 1.0, or 1.5 minimum alveolar concentration of isoflurane (ISO_0.5, ISO_1.0, or ISO_1.5) administered during the last 5 minutes of ischemia and first 3 minutes of reperfusion. *P < 0.05 versus control (n = 8–10 mice/group).

(From Ge Z, Pravdic D, Bienengraeber M, et al: Isoflurane postconditioning protects against reperfusion injury by preventing mitochondrial permeability transition by an endothelial nitric oxide synthase-dependent mechanism. Anesthesiology 112:73–85, 2010.)

It is clear that mitochondrial activation attenuates ischemia-induced oxidant stress, favorably modulates mitochondrial energetics, decreases cytochrome c egress into the cytoplasm, and attenuates mitochondrial and cytoplasmic Ca⁺⁺ overload. Mitochondrial cytochrome c release is one of the important mechanisms underlying caspase activation, and thus the apoptotic process¹¹² (Figure 9-15). Whether by Ca⁺⁺-mediated or by apoptotic mechanisms, or both, volatile agents clearly attenuate cell death in models of APC¹⁰¹ (Figure 9-16). Although the mechanisms underlying mitochondrial activation have been aggressively studied, they remain incompletely understood. Finally, these salutary effects of volatile agents seem to have a clinical correlate¹⁰¹ (Figure 9-17).

Figure 9-15 Center stage in apoptosis.

In this view, numerous cell-death stimuli work through the mitochondria. They cause proapoptotic members of the BCL-2 family, such as BAX and BAK, to either open new pores or modify existing channels in the mitochondrial membrane, releasing cytochrome c (Cyt c) and other proteins that lead to caspase activation and cell death. BCL-2 itself, which is antiapoptotic, somehow blocks the pore or channel opening. AIF, apoptosis-inducing factor; IAP, inhibitors of apoptosis.

(Reprinted from Finkel E: The mitochondrion: is it central to apoptosis? Science 292(5517):624–626, 2001. Illustration: C. Slayden, Copyright 2001 AAAS.)

Figure 9-16 Effects of the specific mitochondrial K⁺_ATP (mitoK⁺_ATP) channel blocker 5-hydroxy-decanoate (5HD) and the specific sarcolemmal K⁺_ATP (sarcK⁺_ATP) channel blocker HMR-1098 on sevoflurane (SEVO)- and isoflurane (ISO)-mediated protection at 1 minimal alveolar concentration (MAC) against 60 or 120 minutes of ischemia in myocytes as assessed by trypan blue staining. A, Control myocytes after 60 minutes of ischemia. Myocytes staining dark blue indicate irreversible cell damage. B, Myocytes exposed to SEVO before ischemia. Most myocytes retain their rod-shaped morphology. C, Myocytes exposed to 5HD and SEVO before ischemia. The protective effect of SEVO is abolished. D, Myocytes exposed to HMR-1098 and SEVO before ischemia. The protection by SEVO is unaffected. E, Representative trypan blue–positive and –negative myocytes after exposure to ischemia seen at higher magnification. F, Trypan blue–positive myocytes are indicated as percentage of total viable myocytes before ischemia. CTL indicates control group and represents myocytes exposed to 60 or 120 minutes of ischemia alone. Data are mean ± standard deviation. *P < 0.0001 versus respective CTL; ^#P value not significant versus respective CTL.

(From Zaugg M, Lucchinetti E, Spahn DR, et al: Volatile anesthetics mimic cardiac preconditioning by priming the activation of mitochondrial KATP channels via multiple signaling pathways, 97:4, 2002.)

Figure 9-17 Cardiac troponin I concentrations in the propofol and sevoflurane groups before surgery (control), at arrival in the intensive care unit (T0), and after 3 (T3), 12 (T12), 24 (T24), and 36 (T36) hours. Top panels, Median values (green) with 95% confidence intervals (purple). Bottom panels, Evolution of the individual values. Concentrations were significantly greater with propofol. In the propofol group, all patients had troponin concentrations greater than the cutoff value of 2 ng/mL (gray line).

(From de Hert S, ten Broecke PW, Mertens E, et al: Sevoflurane but not propofol preserves myocardial function in coronary surgery patients, Anesthesiology 97:42, 2002.)

The use of volatile anesthetics also can alter outcomes after cardiac surgery. A meta-analysis by Landoni et al¹¹³ demonstrated a significant reduction in postoperative myocardial infarction after cardiac surgery, as well as significant advantages with respect to postoperative cardiac troponin release, inotrope requirements, time to extubation, intensive care unit stay, hospital stay, and survival. Furthermore, another meta-analysis by Bignami et al¹¹⁴ demonstrated that the use of volatile anesthetics may, in fact, have a beneficial role with respect to mortality after cardiac surgery. The duration of the volatile anesthetic exposure seemed to have some impact—the longer the exposure, the greater the effect. De Hert et al¹¹⁵ demonstrated the cardioprotective effects of volatile anesthetics if used throughout the surgical procedure rather than only before and after cardiopulmonary bypass (CPB).

Further studies are necessary to delineate the role of the anesthetic regimen on outcomes after cardiac surgery and elucidate the mechanisms behind this protection. Whether it involves mechanisms that are associated with APC continues to remain unclear.

Myocardial Contractility

To understand the effect of intravenous anesthetics on integrated cardiovascular responses is to understand the effect on the different factors that regulate the force of contraction of the heart. If the heart in isolation is considered (not coupled to the vasculature and not regulated by the autonomic system), the best methodologies for examining the effects of anesthetic agents involve using isolated myocytes and muscle tissue preparations in which the effect of the anesthetic drugs on contractile force/tension or myocyte/sarcomere shortening can be determined. With regard to propofol, the studies remain controversial whether there is a direct effect on myocardial contractile function at clinically relevant concentrations. However, the weight of evidence suggests that the drug has a modest negative inotropic effect, which may be mediated by inhibition of L-type Ca⁺⁺ channels or modulation of Ca⁺⁺ release from the SR. Thus, the effect of propofol may be mediated at multiple sites in the cardiac myocytes.

The effect of the agents may be species dependent, thus further confounding the literature regarding mechanism. For instance, van Klarenbosch et al¹¹⁷ demonstrated that in contrast with rat, propofol directly depresses myocardial contractility in isolated muscle preparations from guinea pig, probably by decreasing trans-SL Ca⁺⁺ influx. However, there was little influence of propofol on Ca⁺⁺ handling by the SR or on the contractile proteins in rat. In one of the few human studies using isolated atrial muscle tissue (Figure 9-18), no inhibition of myocardial contractility was found in the clinical concentration ranges of propofol, midazolam, and etomidate. In contrast, thiopental showed strong negative inotropic properties, whereas ketamine showed slight negative inotropic properties (Figure 9-19). Thus, negative inotropic effects may explain, in part, the cardiovascular depression on induction of anesthesia with thiopental but not with propofol, midazolam, and etomidate. Improvement of hemodynamics after induction of anesthesia with ketamine cannot, therefore, be explained by intrinsic cardiac stimulation but is a function of sympathoexcitation.¹¹⁸

Figure 9-18 Typical experiment showing the force traces of an isometric twitch of human atrial tissue during exposure to increasing concentrations of propofol (15 to 1500 μmol/L).

(From Gelissen HP, Epema AH, Henning RH, et al: Inotropic effects of propofol, thiopental, midazolam, etomidate, and ketamine on isolated human atrial muscle, Anesthesiology 84:397, 1996.)

Figure 9-19 Comparative effects of increasing concentrations of anesthetic on isometric contractions of human atrial tissue induced by field stimulation. Data are mean ± standard error of the mean. Curves were plotted using logistic regression. Squares indicate the clinical concentration range during anesthesia. Tan hatching (left) represents the total concentration and white hatching (right) shows the free fraction. A, Propofol (n = 16). B, Thiopental (n = 7). C, Midazolam (n = 7). D, Ketamine (n = 9). E, Etomidate (n = 9). F, Combined plot showing the concentration–response curve of the five anesthetics.

(From Gelissen HP, Epema AH, Henning RH, et al: Inotropic effects of propofol, thiopental, midazolam, etomidate, and ketamine on isolated human atrial muscle, Anesthesiology 84:397, 1996.)

The effect of drugs such as propofol also may be affected by the underlying myocardial pathology.^119,120 For instance, Sprung et al¹²⁰ determined the direct effects of propofol on the contractility of human nonfailing atrial and failing atrial and ventricular muscles obtained from the failing human hearts of transplant patients or from nonfailing hearts of patients undergoing coronary artery bypass graft surgery (CABG). They concluded that propofol exerts a direct negative inotropic effect in nonfailing and failing human myocardium, but only at concentrations larger than typical clinical concentrations. Negative inotropic effects are reversible with β-adrenergic stimulation, suggesting that propofol does not alter the contractile reserve but may shift the dose responsiveness to adrenergic stimulation. The negative inotropic effect of propofol is at least partially mediated by decreased Ca⁺⁺ uptake into the SR; however, the net effect of propofol on contractility is insignificant at clinical concentrations because of a simultaneous increase in the sensitivity of the myofilaments to activator Ca⁺⁺.¹²⁰

Molecular Mechanisms: Adrenergic Signaling, Ca⁺⁺ Influx, and Ca⁺⁺ Sensitivity

There are a number of suggested molecular mechanisms by which a drug such as propofol may alter cardiac contractility. Propofol may inhibit cardiac L-type calcium current by interacting with the dihydropyridine-binding site¹²¹ (Figure 9-20A), with resultant alteration in developed tension (see Figure 9-20B). Furthermore, as mentioned earlier, propofol may alter adrenergic signaling in cardiac myocytes. Experiments in membranes and cardiac preparations isolated from rat heart demonstrate that relatively high concentrations of propofol (25 to 200 μmol/L) are required to antagonize β-adrenoceptor binding and tissue responsiveness.¹²² Kurokawa et al¹²³ observed that clinically relevant concentrations of propofol attenuated β-adrenergic signal transduction in cardiac myocytes via inhibition of cyclic adenosine monophosphate (cAMP) production (Figure 9-21). The inhibitory site of action of propofol appears to be upstream of adenylyl cyclase and involves activation of PKCα.

Figure 9-20 A, Representative current traces of I_Ca,L in response to depolarizing pulses to 0 μmol/L from a holding potential of −70 μV. These traces were obtained before exposure to propofol (light squares), during treatment with 25 (dark squares) and 50 μmol/L (circles) propofol, and after recovery (triangles). B, Current-voltage (I-V) relation of peak I_Ca,L as monitored before and during exposure to propofol. Cultured rat ventricular myocytes were clamped at −70 μV. I_Ca,L was elicited by 200-millisecond pulses from the holding potential of −70 μV to potentials between −60 and +80 μV in 10-μV increments. Propofol dose-dependently decreases calcium current. C, Effects of propofol on developed tension in papillary muscle isolated from the rat heart. Preparations (n = 4) were bathed in an oxygenated Krebs–Henseleit solution at 37°C and paced electrically at 1 Hz. The anesthetic was added to the bathing solution cumulatively. Vertical bars represent standard error of the mean. Values on the ordinate are presented as a percentage of the developed tension recorded immediately before adding propofol (0.64 ± 0.15 g). Propofol dose-dependently decreases twitch tension.

Buy Membership for Anesthesiology Category to continue reading. Learn more here