aprikalim and Myocardial-Ischemia

Recently, much interest has been focused on the pharmacology of ATP-sensitive potassium channels (KATP) in myocardial ischemia. KATP are thought to be involved with the mechanism of myocardial preconditioning, therefore further increasing the level of interest in these channels. Pharmacologic KATP openers have been shown by numerous investigators to protect ischemic-reperfused myocardium. These agents reduce necrosis, improve postischemic functional recovery, and inhibit contracture formation. These protective effects are abolished by KATP blockers. The cardioprotective effects of KATP openers are independent of vasodilator and cardiodepressant effects, but seem to be mediated by energy conservation (reduced ATP hydrolysis). Action potential shortening is also not correlated with cardioprotection, suggesting a role for intracellular (mitochondrial) KATP. Agents have been developed that retain the glyburide-reversible cardioprotective effects of cromakalim but are devoid of vasodilator and action potential shortening activity. Currently, studies are underway to determine the mechanism of cardioprotection. The potential role of mitochondrial KATP in the pathogenesis of ischemia is discussed in this review article.

Topics: Animals; ATP-Binding Cassette Transporters; Benzopyrans; Cromakalim; Guanidines; Humans; Ischemic Preconditioning, Myocardial; KATP Channels; Mitochondria, Heart; Models, Cardiovascular; Myocardial Ischemia; Myocardial Reperfusion; Niacinamide; Nicorandil; Picolines; Pinacidil; Potassium Channels; Potassium Channels, Inwardly Rectifying; Pyrans; Pyrroles; Rats

Adenosine triphosphate (ATP)-sensitive potassium channels (KATP) exist in cardiac tissue and a potential role in the pathogenesis of myocardial ischemia was hypothesized early after their discovery. Studies in in vitro models of myocardial ischemia and reperfusion have indicated that KATP openers, as a class, exert protective effects. This has been assessed by determination of recovery of contractile function, inhibition of contracture, or inhibition of necrosis. This protective effect appears to be exerted directly on the myocardium and is not dependent on peripheral or coronary dilator activities. These protective effects are uniformly abolished by blockers of KATP. The protective effects of KATP openers are accompanied by a conservation of myocardial energy during ischemia, and this occurs despite a relative lack of cardiodepressant effects. In vivo studies have shown more variable results with some investigators showing efficacy and others not showing efficacy. The lack of efficacy for some investigators may be related to the potent vasodilator activity of the KATP openers used. Efficacy for KATP openers has been shown in canine models of infarction and stunned myocardium. KATP blockers also appear to abolish the protective effects of KATP openers in these models. Future work on KATP openers is focused on the determination of the molecular mechanism of action for the cardioprotective effects of these agents, development of tissue selectivity, and the importance of action potential shortening in mediating cardioprotection.

Topics: Action Potentials; Adenosine Triphosphate; Animals; Benzopyrans; Cromakalim; Dihydropyridines; Disease Models, Animal; Dogs; Guanidines; Guinea Pigs; Myocardial Contraction; Myocardial Infarction; Myocardial Ischemia; Picolines; Pinacidil; Potassium Channels; Pyrans; Pyrroles; Rats; Vasodilator Agents

We tested the hypothesis that blockade of the ATP-sensitive K+ channel (IK(ATP)) is an antiarrhythmic mechanism in acute myocardial ischaemia, using an opener of the channel (10 microM RP 49356, RP) and a blocker of the channel (10 microM glibenclamide, GL) and a combination of the two drugs (GL+RP, 10 microM each) in a randomised blinded study. Isolated rat hearts (n = 8 per group) were subjected to 30-min left regional ischaemia. GL and GL+RP widened QT interval after 10-min ischaemia (197 +/- 39 and 203 +/- 20 ms, respectively vs. 154 +/- 12 ms in controls), whereas RP significantly shortened QT interval (123 +/- 6 ms). GL and GL+RP decreased coronary flow (p < 0.05). RP caused slight increase in flow during ischaemia. These effects are all consistent with modulation of vascular and cardiac IK(ATP). RP alone had no effect on ischaemia-induced arrhythmias. Neither did GL have any effect on the incidence of ventricular fibrillation (VF: 88 vs. 100% in controls). However, GL reduced the incidence of sustained VF (VF lasting continuously for > 2 min) to 14% vs. 88% in controls (p < 0.05). Therefore, GL had defibrillatory activity. Surprisingly, in view of these findings, the GL+RP combination significantly reduced the incidence of VF to 25% (from 100% in control hearts, p < 0.05) i.e., had an antifibrillatory effect. So, two agents that produce pharmacological effects attributable to block and opening of IK(ATP) when administered singly had no effects on the incidence of ischaemia-induced VF.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Animals; Anti-Arrhythmia Agents; Coronary Circulation; Electrocardiography; Glyburide; Male; Myocardial Ischemia; Picolines; Potassium Channels; Pyrans; Rats; Rats, Wistar; Ventricular Fibrillation

The aim was to compare the effects of a potassium channel opener, aprikalim, and of hypoxic and ischaemic preconditioning on extracellular K+ concentration change, metabolism, and ventricular function in isolated globally ischaemic rat hearts.. Isovolumetric rat hearts (37 degrees C) were treated with 1 microM (apri 1) or 30 microM (apri 30) aprikalim, or preconditioned with either 10 min of hypoxia (N2PC) or 5 min of ischaemia followed by 5 min of perfusion (IPC5) or 10 min of ischaemia followed by 3 min of perfusion (IPC10). Control hearts received neither treatment nor preconditioning. All hearts received 30 min of sustained ischaemia followed by 25 min of reperfusion. Extracellular K+ concentration was measured with a potassium sensitive electrode inserted into the extracellular space of the left ventricular wall.. Recovery of left ventricular developed pressure after 25 min of reperfusion was only 19.20(SEM 5.09)% of the preischaemic level in the control group. No recovery was obtained for the apri 1 group. In contrast, a very good recovery was obtained for the apri 30 group [96.69(10.92)%], the N2PC group [104.92(17.40)%], and the IPC10 group [84.96(9.86)%]. The IPC5 group, however, did not have improved recovery of left ventricular pressure [14.15(5.61)%]; this is likely to be related to differences in the stimulation of anaerobic glycolysis. The protection was also markedly attenuated by pretreatment with 50 microM glibenclamide in the apri 30, N2PC, and IPC10 groups [22.76(9.00), 66.06(6.09), and 46.18(7.06)%, respectively]. Hearts treated with aprikalim before inducing ischaemia showed a concentration dependent increase in [K+]e. Hypoxic (N2PC) and ischaemic preconditioning (IPC5 and IPC10) were also associated with an increase in [K+]e over the 5-10 min period preceding the 30 min of sustained ischaemia. During sustained ischaemia all groups showed a nearly triphasic pattern of extracellular K+ changes with an early rising phase, with the exception of the N2PC group for which the early [K+]e rise was barely detectable.. An increase in [K+]e before sustained ischaemia is one of the mechanisms involved in the conditions affording protection. Although important, this is not sufficient, and further protection may be accomplished by decreased stimulation of anaerobic glycolysis during the sustained ischaemia.

Topics: Animals; Antihypertensive Agents; Basal Metabolism; Extracellular Space; Heart; Hypoxia; Lactates; Lactic Acid; Male; Myocardial Ischemia; Myocardial Reperfusion; Perfusion; Picolines; Potassium; Pyrans; Rats; Rats, Wistar

Topics: Animals; In Vitro Techniques; Lipid Metabolism; Myocardial Ischemia; Myocardial Reperfusion Injury; Myocardium; Niacinamide; Nicorandil; Picolines; Potassium Channels; Pyrans; Rats

There is clinical evidence that myocardial stunning is a frequent sequela of surgical global ischemia, despite our modern techniques of myocardial protection. The ubiquitous usage of hyperkalemic depolarizing solutions in all forms of cardioplegia may be partly responsible for this phenomenon because of the known ongoing metabolic requirements and damaging transmembrane ionic fluxes that occur at depolarized membrane potentials. Cardiac arrest at hyperpolarized potentials, the natural resting state of the heart, may avoid the shortcomings of depolarized arrest and provide an alternative means of myocardial protection. To test this hypothesis, a potassium channel opener, aprikalim, was used to induce hyperpolarized arrest in an isolated rabbit heart model. Aprikalim was able to produce sustained and reproducible electromechanical arrest that was reversible by reperfusion. When compared with depolarized hyperkalemic arrest, hyperpolarized arrest afforded better protection after short 20-minute periods of global ischemia and resulted in less myocardial stunning. Moreover, aprikalim was able to significantly prolong the time to ischemic contracture and improve functional recovery after the onset of ischemic contracture when compared with either traditional hyperkalemic cardioplegia or no cardioplegia at all. There was a dose dependence to the protective effect of aprikalim. Preliminary studies in the intact porcine cardiopulmonary bypass model also have revealed that hyperpolarized arrest can effectively protect the heart during surgical global ischemia.

Topics: Animals; Cardioplegic Solutions; Heart Arrest, Induced; Myocardial Ischemia; Myocardial Reperfusion; Myocardial Stunning; Picolines; Potassium Channels; Pyrans; Rabbits; Vasodilator Agents

Topics: Benzopyrans; Cromakalim; Dihydropyridines; Guanidines; Humans; Myocardial Ischemia; Myocardium; Niacinamide; Nicorandil; Picolines; Pinacidil; Potassium Channels; Pyrans; Pyrroles; Sodium-Potassium-Exchanging ATPase; Vasodilator Agents

Hyperkalemic depolarized cardiac arrest has been the cornerstone of myocardial protection during cardiac surgery for more than 30 years. Many of the advances in myocardial protection seek to minimize the cellular damage and to reduce the ongoing metabolic processes occurring as a direct consequence of the depolarized state. Ideally, cardiac arrest at hyperpolarized cellular membrane potentials--the natural resting state of the heart--will meet all the requirements of modern cardioplegia, namely, electromechanical asystole and cardiac relaxation, while preserving the vital integrity of the heart itself.. To determine whether activation of adenosine triphosphate-sensitive potassium channels by pharmacologic agents could produce hyperpolarized cardiac arrest, we tested the ability of aprikalim, a known adenosine triphosphate-sensitive potassium channel opener, to arrest the intact beating heart. In a normothermic (37 degrees C) isolated rabbit heart preparation, aprikalim was found to rapidly shorten the action potential duration and produce cardiac asystole that was maintained during 20 minutes of "no-flow" global ischemia without a rise in end-diastolic pressure. Cardiac rhythm and function were fully restored by reperfusion alone (developed pressure was 100.6% +/- 7.9% of prearrest value after 30 minutes of reperfusion). In contrast, 20 minutes of unprotected normothermic global ischemia resulted in a 2.7 +/- 0.55 mmHg rise in end-diastolic pressure and only 58.2% +/- 3.8% recovery of developed pressure after 30 minutes of reperfusion. By way of comparison, 20 minutes of standard hyperkalemic depolarized normothermic rest was accompanied by a 1.2 +/- 0.6 mmHg rise in end-diastolic pressure and only 80.8% +/- 2.6% recovery of developed pressure after 30 minutes of reperfusion. To directly compare hyperkalemic depolarized cardiac arrest to hyperpolarized cardiac arrest induced by potassium channel openers and to better define the characteristics of such hyperpolarized arrest, we studied a fixed (4 mmHg rise in end-diastolic pressure--contracture) ischemic injury model. The time to development of the contracture was prolonged by hyperkalemic arrest (35.8 +/- 1.7 minutes) and significantly more so by hyperpolarized arrest (47.0 +/- 3.3 minutes) when compared with that of unprotected hearts (24.0 +/- 1.2 minutes). Moreover, aprikalim resulted in significantly better postischemic recovery of function (developed pressure was 69.0% +/- 6.7% of prearrest value after 30 minutes of reperfusion) than after no cardioplegia (45.4% +/- 7.5%) or standard hyperkalemic cardioplegia (44.3% +/- 5.7%).. Pharmacologic activation of adenosine triphosphate-sensitive potassium channels can result in predictable and sustainable hyperpolarized cardiac arrest that is reversible by reperfusion. This method of myocardial protection was found to fully preserve cardiac electromechanical function after a 20-minute period of global normothermic ischemia. Furthermore, hyperpolarized arrest induced by potassium channel openers significantly prolonged the period to the development of contracture and afforded a significantly better postischemic recovery of function than obtained in either hearts protected with hyperkalemic depolarized arrest or those not protected by any form of cardioplegia.

Topics: Adenosine Triphosphate; Animals; Dose-Response Relationship, Drug; Female; Heart Arrest; In Vitro Techniques; Male; Models, Cardiovascular; Myocardial Ischemia; Picolines; Potassium Channels; Pyrans; Rabbits

The effect of three potassium channel openers, nicorandil, aprikalim, and bimakalim, on experimental myocardial ischaemia/reperfusion injury was examined in barbital-anaesthetized dogs. In a model of reversible injury, administration of nicorandil at a hypotensive dose and aprikalim at a non-hypotensive dose resulted in a reduction in contractile dysfunction during reperfusion ('stunning') following brief coronary artery occlusion (15 min) when the drugs were administered before occlusion. Administration of aprikalim only during reperfusion had no beneficial effect. Pre-treatment with the adenosine triphosphate (ATP)-dependent potassium (KATP) channel antagonist, glibenclamide, blocked completely the beneficial effects of nicorandil and aprikalim, although glibenclamide did not block the haemodynamic effects of nicorandil. In a model of irreversible ischaemia/reperfusion injury (120 min of ischaemia and 30 min of reperfusion) pre-treatment with equihypotensive doses of nicorandil and bimakalim produced marked reductions in myocardial infarct size. Similarly, aprikalim at a non-hypotensive dose reduced myocardial infarct size in dogs subjected to 90 min of ischaemia and 5 h of reperfusion, and the protective effects of aprikalim were antagonized completely by glibenclamide. These results indicate that nicorandil, aprikalim, and bimakalim are protective in two experimental models of ischaemia/reperfusion injury. The mechanism of action of these agents is not completely understood, but it appears to be a result of myocardial KATP channel activation.

Topics: Animals; Antihypertensive Agents; Benzopyrans; Coronary Circulation; Dihydropyridines; Dogs; Female; Male; Myocardial Infarction; Myocardial Ischemia; Myocardial Reperfusion Injury; Niacinamide; Nicorandil; Picolines; Potassium; Potassium Channels; Pyrans; Vasodilator Agents

The role of KATP channels in myocardial stunning produced by repetitive coronary occlusions was studied in barbital-anesthetized dogs. Regional percent segment function (%SS) was measured by sonomicrometry, and the monophasic action potential (MAP) in the ischemic region was measured by an epicardial probe. Under control conditions, six 5-min periods of coronary occlusion, interspersed with 10-min periods of reperfusion, and ultimately followed by 2 h of reperfusion produced regional segment dysfunction and a similar rate and amount of shortening of the MAP measured at 50% repolarization duration (MAPD50) during each successive ischemic period. Pretreatment with glibenclamide (0.3 mg/kg iv), a KATP channel antagonist, significantly prevented the reduction of MAPD50, particularly during the first occlusion period, and it worsened postischemic dysfunction. In contrast, pretreatment with aprikalim (10 micrograms/kg bolus +/- 0.1 microgram.kg-1.min-1 iv), a KATP channel opener, accelerated the rate and extent of shortening of MAPD50 during each occlusion and markedly improved %SS throughout reperfusion. Pretreatment with d-sotalol (2 mg/kg iv), an antagonist of voltage-dependent K+ channels, significantly prolonged MAPD50 of the ischemic region before coronary occlusion but did not alter the rate of shortening of MAPD50 during ischemia and did not affect the recovery of %SS. These results indicate that activation of KATP channels during ischemia with the resultant shortening of the MAPD50 is an endogenous adaptive mechanism that affords functional myocardial protection during repetitive, brief periods of coronary arterial occlusion.

Topics: Action Potentials; Adenosine Triphosphate; Animals; Coronary Circulation; Dogs; Female; Glyburide; Hemodynamics; Male; Myocardial Ischemia; Myocardial Reperfusion; Myocardium; Picolines; Potassium Channels; Pyrans; Reaction Time; Sotalol