aprikalim and Disease-Models--Animal

Mounting clinical and experimental evidence suggests that postoperative myocardial dysfunction is a frequent consequence of surgical global ischemia and reperfusion, despite our modern techniques of myocardial protection. The ubiquitous use of hyperkalemic depolarizing solutions in all forms of cardioplegia may be partly responsible for this phenomenon because of the known ongoing metabolic processes 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.. An adenosine triphosphate-sensitive potassium channel opener, aprikalim, was used to induce hyperpolarized arrest. Aprikalim was able to produce sustained and reproducible electromechanical arrest that was reversible by reperfusion.. In isolated heart models, when compared with depolarized hyperkalemic arrest, hyperpolarized arrest afforded better protection from global normothermic ischemia and resulted in better postischemic recovery of function upon reperfusion. Preliminary studies in a porcine cardiopulmonary bypass model also have revealed that hyperpolarized arrest can be achieved in a model more closely approximating the clinical setting, and can effectively protect the heart during normothermic surgical global ischemia.. Hyperpolarized cardiac arrest may offer an effective alternative to traditional potassium arrest.

Topics: Animals; Cardioplegic Solutions; Cardiopulmonary Bypass; Disease Models, Animal; Heart Arrest, Induced; Membrane Potentials; Myocardial Reperfusion; Picolines; Potassium; Potassium Channels; Pyrans; Swine

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

Potassium adenosine triphosphate (KATP) channel openers have been involved in the enhancement of ischemic tolerance in various tissues. The purpose of the present study is to evaluate the effects of aprikalim, a specific KATP channel opener, on spinal cord ischemic injury.. Fifty-four rabbits were randomly assigned to three groups: group 1 (n = 18, sham operation), group 2 (n = 18, 30 min of normothermic aortic cross-clamping) and group 3 (n = 18, aprikalim 100 μg/kg was administered 15 min before 30 min of normothermic aortic cross-clamping). Neurologic evaluation was performed according to the modified Tarlov scale. Six animals from each group were sacrificed at 24, 48 and 168 h postoperatively. The lumbar spinal cords were harvested and examined histologically. The motor neurons were counted and the histologic lesions were scored (0-3, 3: normal).. Group 3 (aprikalim group) had better Tarlov scores compared to group 2 at all-time points (P < 0.025). The histologic changes were proportional to the Tarlov scores and group 3 had better functional outcome as compared to group 2 at 168 h (number of neurons: 21.2 ± 4.9 vs. 8.0 ± 2.7, P < 0.001 and histologic score: 1.67 ± 1.03 vs. 0.50 ± 0.55, P = 0.03). Although aprikalim exhibited improved effect on clinical and histologic neurologic outcome when compared to normothermic spinal cord ischemia, animals in group 3 had worse Tarlov score, reduced number of motor neurons and worse histologic score when compared to group 1 (sham operation) at 168 h (P = 0.003, P = 0.001 and P = 0.019 respectively).. Aprikalim reduces the severity of spinal cord ischemic injury in a rabbit model of spinal cord ischemia.

Topics: Animals; Blood Pressure; Disease Models, Animal; Female; Heart Rate; Male; Motor Neurons; Musculoskeletal Physiological Phenomena; Neuroprotective Agents; Picolines; Potassium Channels; Pyrans; Rabbits; Severity of Illness Index; Spinal Cord; Spinal Cord Ischemia; Statistics, Nonparametric

Pharmacologic treatment using potassium-channel openers (PCOs) before cardioplegic arrest has been demonstrated to provide beneficial effects on left ventricular performance with subsequent reperfusion and rewarming. However, the PCO treatment interval necessary to provide protective effects during cardioplegic arrest remains to be defined. The present study was designed to determine the optimum period of PCO treatment that would impart beneficial effects on left ventricular myocyte contractility after simulated cardioplegic arrest.. Left ventricular porcine myocytes were assigned randomly to three groups: (1) normothermic control = 37 degrees C for 2 hours; (2) cardioplegia = K+ (24 mEq/L) at 4 degrees C for 2 hours followed by reperfusion and rewarming; and (3) PCO and cardioplegia = 1 to 15 minutes of treatment with the PCO aprikalim (100 micromol/L) at 37 degrees C followed by hypothermic (4 degrees C) cardioplegic arrest and subsequent rewarming. Myocyte contractility was measured after rewarming by videomicroscopy. A minimum of 50 myocytes were examined at each treatment and time point.. Myocyte velocity of shortening was reduced after cardioplegic arrest and rewarming compared with normothermic controls (63+/-3 microm/s versus 32+/-2 microm/s, respectively; p < 0.05). With 3 minutes of PCO treatment, myocyte velocity of shortening was improved after cardioplegic arrest to values similar to those of normothermic controls (56+/-3 microm/s). Potassium channel opener treatment for less than 3 minutes did not impart a protective effect, and the protective effect was not improved further with more prolonged periods of PCO treatment.. A brief interval of PCO treatment produced beneficial effects on left ventricular myocyte contractile function in a simulated model of cardioplegic arrest and rewarming. These results suggest that a brief period of PCO treatment may provide a strategy for myocardial protection during prolonged cardioplegic arrest in the setting of cardiac operation.

Topics: Adenosine Triphosphate; Adrenergic beta-Agonists; Animals; Cardioplegic Solutions; Cardiotonic Agents; Cells, Cultured; Disease Models, Animal; Glyburide; Heart Arrest, Induced; Hypothermia, Induced; Image Processing, Computer-Assisted; Isoproterenol; Isotonic Solutions; Microscopy, Video; Myocardial Contraction; Myocardial Reperfusion; Myocardium; Picolines; Potassium; Potassium Channel Blockers; Potassium Channels; Pyrans; Random Allocation; Rewarming; Ringer's Solution; Swine; Time Factors; Ventricular Function, Left

The potential cardioprotective effect of two pure potassium channel openers, bimakalim (EMD 52692) and aprikalim (RP 52891), on myocardial ischaemia/reperfusion injury was investigated in barbital-anaesthetized dogs. In a model of reversible ischaemia/reperfusion injury, administration of bimakalim as an intravenous bolus prior to ischaemia or administration of a non-hypotensive dose of aprikalim as a constant intravenous infusion resulted in a reduction in reperfusion contractile dysfunction (myocardial 'stunning') produced by a single 15-min coronary artery occlusion. Administration of aprikalim only during the reperfusion period had no beneficial effect. Similarly, in a model of irreversible ischaemia/reperfusion injury (90 min of coronary artery occlusion followed by 5 h of reperfusion), intravenous infusion of bimakalim at a dose which reduced aortic blood pressure approximately 15-20 mmHg or infusion of aprikalim at a non-hypotensive dose throughout the entire experiment produced a significant reduction in myocardial infarct size. A protective effect of bimakalim was not observed when it was administered during the reperfusion period only. In both the stunned myocardium model as well as the infarcted myocardium model, the beneficial effects of the potassium channel openers could not be attributed to differences in the traditional determinants of the extent of ischaemia/reperfusion injury; area at risk size, oxygen consumption, or collateral blood flow. Furthermore, the anti-ischaemic actions of the potassium channel openers were blocked by pre-treatment with the ATP-dependent potassium (KATP) channel antagonist, glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Benzopyrans; Dihydropyridines; Disease Models, Animal; Dogs; Female; Glyburide; Male; Myocardial Infarction; Myocardial Stunning; Picolines; Potassium Channel Blockers; Potassium Channels; Pyrans; Vasodilator Agents