Chapter 8. Treatment of Acute Myocardial Ischemia

Chapter 8.

Treatment of Acute Myocardlal lschemla

Melvin J. Yu and Paul J. Simpson Lilly Research Laboratories, Eli Lilly and Company Indianapolis, IN 46285 I n t r o d u c m - Early reperfusion during acute myocardial infarction represents an effective means to limit tissue necrosis and preserve myocardial function (1,2). Restoring blood flow to ischemic tissue, however, may paradoxically have deleterious effects on reversibly injured cells within the region of the myocardium at risk of infarction (3,4). Consequently, with the development of thrombolytic agents and mechanical methods such as percutaneous transluminal coronary angioplasty (PTCA) for emergency revascularization, there is intense interest in identifying potential adjunctive pharmacotherapies which could limit the progression of tissue injury during reperfusion and enhance functional recovery of the postischemic myocardium. A number of important advances have been made toward understanding the mechanisms underlying ischemia-induced myocardial damage since the last review in this series on antiischemic agents eight years ago (5). The primary focus of investigation in this area over the past few years has been concerned with the importance of oxygen-derived free radicals, ion fluxes and the inflammatory response, in particular the role of the neutrophil. in mediating ischemia-induced cell injury and cardiac dysfunction. This chapter will summarize the important pharmacological approaches and agents reported in the recent literature for limiting acute myocardial ischemia and reperfusion injury. Free Radicals - A brief period (C 20 min) of coronary artery occlusion followed by reperfusion results in a prolonged and eventually reversible depression of contractile function (myocardial stunning) (6). Although a number of causative mechanisms have been proposed, myocardial stunning is generally believed to be mediated in part by reactive oxygen species (7,8). The evidence for free radical involvement in postischemic contractile dysfunction and its clinical implications have been reviewed (9). A longer period of ischemia (20 to 60 minutes or longer) results in irreversible cell injury where the extent of tissue necrosis is related to the severity and duration of the ischemic episode. There is ample evidence to suggest that reoxygenation of the ischemic myocardium is accompanied by free radical generation from a variety of intracellular andfor extracellular sources, and that oxygen-derived free radicals may contribute to tissue injury. The role of free radicals and their possible contribution to reperfusion injury was reviewed in this series three years ago (lo),and a number of reviews have since appeared in the literature (1 1-18). A review on coenzyme Q as a possible therapeutic agent in myocardial ischemia has alSO appeared (19). Superoxide dismutase (SOD) was reported to reduce infarct size in an occlusionreperfusion model of myocardial damage in the anesthetized dog (20), and was the first antioxidant or free radical scavenger to undergo clinical trials for treatment of acute myocardial infarction (21). Significant controversy exists, however, regarding the efficacy of SOD i n experimental models of myocardial infarction (22-24). Since there may be a time window during which neutrophil-suppressive therapy must be administered for containment of ultimate infarct size quantitated several days after reperfusion (25), a potential complication in these models may be the relatively short pharmacologic half-life of both human recombinant and bovine erythrocyte SOD. Consequently, a short treatment period may not provide a sustained beneficial effect (26). Conjugation of SOD to PEG, however, was demonstrated to prolong the pharmacologic half-life of the enzyme from less than 10 minutes to greater than 30 hours, to provide sustained protection after 4 days of reperfusion, and to prevent rather than simply delay irreversible myocardial damage in canine models of myocardial infarction (27,28). Thus, effective therapy may be dependent on assuring that an appropriate concentration of the pharmacological agent be present in the circulation during the critical time period of reperfusion. A number of agents have been described which exhibit beneficial effects in experimental models of myocardial stunning. These include the antioxidant cyanidanol-3 (1)and the iron

ANNUAL REPORTS IN MEDICINAL CHEMISTRY-25

Copyright 0 1989 by Academic Press, Inc. All rights of reproduction in any form reserved.

7a

Section 11-Cardiovascularand Pulmonary Agents

Robertson, Ed

(a,

chelator 1,2-dimethyl-3-hydroxy-4-pyridone both of which enhanced recovery of contractile function in postischemic buffer-perfused isolated rat hearts (29). Hydroxyethyl starch conjugated desferal also enhanced recovery of stunned myocardium in anesthetized dogs (30). In addition, captopril attenuated postischemic contractile dysfunction perhaps through a sulfhydryl-mediated free radical scavenging mechanism that was independent of ACE inhibition (31,32). A series of imidazol-2-thiones (e.g. 3 structurally related to the positive ionotropes enoximone and piroximone reportedly improved contractility in stunned canine myocardium independent of ionotropic activity (33). OH

HO Me OH

SMe

S

Me

I

2

3

Since cell membrane phospholipids are particularly vulnerable to free radical mediated damage which results in increased membrane fluidity and permeability, agents which protect cell membrane structure and function during oxidative stress may limit ischemia-inducedcellular injury enhanced functional recovery of stunned (34). The lipid peroxidation inhibitor U74006F canine myocardium, without affecting systemic hernodynamics or myocardial blood flow (35).

(a

h

CHO OH

OH

CHO

Other lipid peroxidation inhibitors recently described include a series of 2-0-alkylascorbic acids (36). A free 3-hydroxyl group and a straight alkyl chain consisting of 11-20 methylene units on the 2-hydroxyl moiety were optimal for inhibiting lipid peroxidation h y & ~One . of the most potent representatives from this series, 2-0-octadecylascorbicacid (CV-3611, decreased the incidence and duration of ventricular fibrillation following oral administration to a rat model of myocardial ischemia and reperfusion. This agent also reduced ultimate infarct size orally in dogs subjected to 60 minutes of coronary artery occlusion followed by 14 days of reperfusion (37). When administered intravenously just prior to reperfusion, CV-3611 also reduced infarct size and neutrophil infiltration in the area of myocardium at risk of infarction (38).

s),

(a,

a polyphenolic component of cottonseed oil, was also recently reported to Gossypol inhibit peroxidation of myocardial membrane phospholipid (39,40). Increasing endogenous myocardial defense mechanisms against oxidative stress has been reported to reduce postischemic abnormalities in isolated rat hearts. For example, exposure to elevated temperatures is known to induce both cultured cells and whole animals to synthesize a

Yu,Smpson 73

Acute Myocardml Ischemia

Chap 8

number of highly conserved proteins (heat-shock response) (41). Although the precise function of these heat-shock proteins is not completely understood, cells that synthesize and accumulate these substances are more resistant to oxidative stress. Heat-shocked isolated rat hearts subjected to 30 minutes of low-flow ischemia possessed elevated catalase activity which, upon reperfusion, exhibited enhanced recovery of function relative to control hearts (42). Endotoxin pretreatment also resulted in elevated catalase activity in rat myocardiumwhich was accompanied by an increase in myocardial function after ischemia and reperfusion (43). These observations suggest that endogenous catalase levels may influence susceptibility to ischemia-induced myocardial injury. Endogenous myocardial glutathione (GSH) may also play an important protective role in the heart. Enhanced myocardial GSH content by continuous intravenous GSH infusion was associated with a reduction in infarct size in pigs subjected to 45 minutes of coronary artery occlusion and 2 hours of reperfusion (44). Treatment with N-acetylcysteine,on the other hand, did not reduce infarct size in dogs subjected to 90 minutes of coronary artery occlusion and 24 hours of reperfusion (45), although an improvement in ventricular function was observed which may have been due to direct free radical scavenging by this agent (46). A 65% depletion of GSH with diethylmaleate impaired functional recovery of buffer-perfusedisolated rat hearts subjected to ischemia and reperfusion (47). However, a 70% GSH depletion with L-buthionine-h,.Bsulphoximine had no apparent adverse effect on cardiac energy metabolism during total global ischemia followed by reperfusion (48). NeutroDhilS - Reviews on the role of infiltrating leukocytes and the inflammatory response (24,49,50), as well as the relationship between neutrophils and platelets (51) in postischemic myocardial injury have appeared. Activated neutrophils release a variety of mediators that may contribute to ischemia-induced myocardial damage (52,53). Leukocytes may also exacerbate ischemic injury through capillary plugging in the coronary microcirculation (no-reflow phenomenon). Although neutrophil depletion by extracorporeal filtration initiated at the time of reperfusion reduced canine infarct size (54), the role of the neutrophil in myocardial stunning is presently unclear (55-58). A recent clinical study examined several aspects of neutrophil function in patients with stable angina, unstable angina and acute myocardialinfarction (59).

s

L

Adenosine has been proposed to regulate the ischemia-induced inflammatory reaction in the microcirculation by linking ATP catabolism with inhibition of granulocyte activation and adherence (60). lntracoronary adenosine administration reduced infarct size (61) and attenuated microvasculature abnormalities in canine models of regional myocardial ischemia and reperfusion (62). In addition, augmenting the local concentration of adenosine with 5-amino-4-imidazole carboxamide (AICA) riboside pretreatment decreased granulocyte accumulation and increased collateral flow in the myocardium of dogs subjected to 60 minutes of coronary artery occlusion (60). Enhanced adenosine release by a1 -adrenoceptor stimulation also attenuated myocardial stunning in dogs (63). Several agents which inhibit functional responses of neutrophils have recently been reported to reduce infarct size in canine models of ischemia-induced myocardial damage. These include azapropazone Fluosol-DA and Cl-922 (64-66). The protective effect of Cl-922 (8)was attributed to suppressed neutrophil release of various mediators including activated oxygen species, lysosomal enzymes and leukotrienes.

(z),

Lidocaine has been shown to inhibit neutrophil function in vitro (67,68) and more recently, to decrease mitochondria1 dysfunction and leakage of lysosomal enzymes in a canine model of permanent coronary artery occlusion (69). However, lidocaine pretreatment (beginning 30 minutes before coronary occlusion) in dogs subjected to 2 hours of regional myocardial ischemia and 6 hours of reperfusion, failed to reduce neutrophil accumulation or infarct size (70). In

74

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Robertson, Ed

contrast, lidocaine pretreatment (beginning 90 minutes before coronary occlusion) in dogs subjected to a shorter period (90 minutes) of regional myocardial ischemia and 5 hours of reperfusion, limited infarct size without reducing neutrophil accumulation in the area at risk (71). Since lidocaine reduced coronary sinus levels of conjugated dienes, a potential marker of lipid peroxidation,the protective effect by this drug was attributed to cell membrane stabilization. The monoclonal antibody 904 which binds to and interferes with the function of the alpha subunit of the leukocyte adhesion-promoting glycoprotein CD11b/CD18, reduced myocardial infarct size when administered to dogs subjected to 90 minutes of coronary artery occlusion followed by 6 hours of reperfusion (72). Circulating neutrophil count was not different from controls, but neutrophil accumulation within the myocardium was significantly attenuated when assessed histologically. In a subsequent study, myocardial infarct size was reduced in dogs treated with the F(ab)2 fragment of 904 after 90 minutes of coronary occlusion and 72 hours of reperfusion (73). The F(ab')2 fragment was ineffective for reducing the prolonged ventricular dysfunction associated with a short period of regional ischemia in a canine model of myocardial stunning (55). The role of arachidonic acid metabolites in myocardial ischemia and reperfusion injury has been reviewed (74,75). The nonsteroidal antiinflammatory drugs indomethacin and aspirin were recently shown to have detrimental effects manifested by a further decrease in contractility and increase in coronary perfusion pressure in isolated buffer-perfused rabbit hearts subjected to lowflow ischemia and reperfusion (76). Stimulation of prostaglandin synthesis by defibrotide had a beneficial effect, suggestinga protective role for PG12 and PGE2. In a canine model of myocardial stunning, iloprost improved postischemic contractile function (77). PG12 (78), iloprost (79,25), PGEl (80) and defibrotide (81) have also been shown to reduce infarct size in animal models of ischemia-induced myocardial damage, effects which may be related to reduced neutrophil activation. Extended inhibition of neutrophil activation and accumulation (between 2 and 48 hours of continuous iloprost infusion), however, was necessary for a reduction in ultimate infarct size quantitated 72 hours post-reperfusion (25). Thromboxam - A number of thromboxane receptor antagonists and thromboxane synthetase inhibitors have been recently reported to exhibit beneficial effects in experimental models of myocardial ischemia (see Chapter 11). These include the thromboxane receptor antagonists BM13,505 (82-85), SO-30,741 (86) and AH-23,848 (87) as well as the thromboxane synthetase inhibitors OKY-046 (88), HOE-944 (89), CV-4151 (90) and RS-5186 (91). In particular, CGS13080 (a thromboxane synthetase inhibitor) in combination with streptokinase enhanced reperfusion and prevented reocclusion in a canine model of coronary artery thrombolysis (92). Moreover, CGS-13080 in combination with 1-PA synergistically attenuated creatine kinase release and reduced infarct size in cats subjected to 2 hours of coronary artery occlusion followed by 4 hours of reperfusion, whereas neither tPA nor CGS-13080 alone was effective for reducing tissue damage (93). Dazmegrel (a thromboxane synthetase inhibitor) but not EM-13,505 (a thromboxane receptor antagonist) enhanced postischemic recovery of canine myocardial function (94). Thus, PG12 elevation through metabolic precursor shunting (endoperoxide shunting) rather than thromboxane reduction w s may underly the beneficial effects of thromboxane synthetase inhibitors in this model of myocardial stunning (95). In addition, thromboxane synthetase inhibitors may reduce infarct size through a platelet-dependent, aspirinsensitive mechanism (96). Thromboxane receptor antagonists and thromboxane synthetase inhibitors are reviewed in greater detail in Chapter 11 of this volume. Leukotrienes - The peptidoleukotnene receptor antagonist SK&F-l04,353 did not protect against ischemia-inducedmyocardial damage or reduce infarct size in rat models of coronary artery occlusion-reperfusion (97,98). However, in dogs subjected to 2 hours of coronary artery occlusion and 5 hours of reperfusion, the peptidoleukotriene receptor antagonist ONO-1078 and the lipoxygenase inhibitor AA-861 reduced myocardial infarct size (99).

Calcium - The role of calcium (100,101) and calcium antagonists as potential adjunctive agents

during reperfusion of ischemic myocardium have been reviewed (102). A discussion on the therapeutic potential of cytoprotective calcium antagonists with little or no primary hemodynamic effects has also appeared (103). Studies with buffer-perfused isolated rat hearts suggest the presence of contraction dependent and contraction independent routes of reperfusion-induced calcium entry (104), and that interventions introduced at the time of reperfusion might only delay rather than abolish reperfusion-induced calcium gain (105). Low concentration calcium

Chap. 8

Yu, Simpson

Acute Myocardial Ischemia

7s

reperfusion has been investigated but with variable results (106). Pretreatment with diltiazem reduced infarct size in a canine model of myocardial occlusion and reperfusion (107). More recently, intracoronary administrationof diliazern, but not verapamil or nifedipine, at the moment of reperfusion reduced infarct size in pigs subjected to 45 minutes of occlusion followed by 3 days of reperfusion (108). The salutary effects of diltiazem may be related to reduced myocardial lipid peroxidation (109). Verapamil administered either before coronary artery occlusion, at the moment of reperfusionor 30 minutes after reperfusion reduced myocardial stunning in dogs (1 10). Low-dose intracoronary nifedipine administered after reperfusion also enhanced postischemic contractile function in the absence of systemic hernodynamic effects (111). When infused 30 minutes after occlusion, nisoldipine reduced myocardial infarct size independent of myocardial oxygen demand in cats subjected to 2 hours of coronary artery occlusion and 4 hours of reperfusion (112). If administered 90 minutes after occlusion, no protection was observed. Pretreatment with the intracellular calcium antagonist KT-362 (9) reduced infarct size and myocardial stunning in canine models of ischemia-reperfusion(113,114). The relevant beneficial effects of this agent were attributed to a reduction in myocardial energy and oxygen demand.

9

LQ

Platelets -

Reviews on platelet-endothelium interactions in the pathophysiology of myocardial ischemia (115) and the relationship between platelets and thrornbolysis (116) have appeared. Recent studies suggest that PAF is released during reperfusionof isolated ischemic rabbit hearts (117), and may contribute to ischemia and reperfusion-inducedarrythmias in anesthetized dogs (118). In a preliminary report, the PAF antagonists BN-52021 and CV-3988 reduced infarct size in dogs subjected to 90 minutes of coronary artery occlusion followed by 3 hours of reperfusion (1 19).

-

Qther Aaents In a canine model of permanent coronary artery occlusion, the sodium channel blocker SUN-1165 (Lp) reduced ischemia-induced myocardial damage assessed by mitochondria1 dysfunction and lysosomal enzyme leakage (120), while the PLA2 inhibitor, 11, limited canine infarct size when assessed 6 hours post-occlusion (121). The hemorrheological agent pentoxifylline however, was ineffective in reducing infarct size or enhancing collateral blood flow in dogs following 6 hours of coronary artery occlusion (122). Nicorandil (13) exhibited beneficial effects on metabolic and functional recovery of stunned canine myocardium (123) without increasing PG12 levels (124), and reduced infarct size in dogs subjected to 6 hours of two agents that activate ATPcoronary artery occlusion (125). Pinacidil u4) and cromakalim dependent potassium channels, reduced myocardial infarct size when administered to dogs via the intracoronary route before the induction of 90 minutes of regional ischemia and 5 hours of reperfusion (126). The protective effects were not due to increasing collateral blood flow to the ischemic myocardium.

a),

m,

Robertson. Ed

Section 11-Caraovascular and Pulmonary Agents

76

14

l-3

15

-

C o n c l w Many of the biochemical and functional abnormalities associated with myocardial ischemia and reperfusion are actively being studied experimentally. A number of agents appear to improve postischemic contractile function andlor reduce infarct size in experimental models. These encouraging results suggest that ischemia-induced myocardial injury may b e further attenuated by appropriate pharmacological intervention in conjunction with early reperfusion. The role of oxygen-derived free radicals and the efficacy of SOD in myocardial ischemia with evolving infarction in humans may b e clarified as clinical trials progress. Newer pharmacological interventions aimed at inhibiting neutrophil functional responses during the process of myocardial infarction may offer the most promise for the future pharmacotherapy of this disease.

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