Hemodynamic and cardiac effects of BMS-180448, a novel K+ATP opener, in anesthetized dogs and isolated rat hearts.

Hemodynamic and cardiac effects of BMS-180448 (0.3-10 mg/kg i.v.) or cromakalim (0.01-0.3 mg/kg i.v.) were evaluated in anesthetized open-chest dogs and isolated perfused rat hearts. In the canine studies, heart rate (HR), mean arterial pressure and left ventricular pressure were measured as well as electromagnetic blood flows recorded from the aortic, renal, coronary and femoral vascular beds. BMS-180448 was 187-fold less potent than cromakalim in lowering blood pressure (ED-20 values of 7.84, and 0.042 mg/kg for BMS-180448 and cromakalim, respectively). Both compounds increased HR. Effects of BMS-180448 occurred at doses higher than those of cromakalim, but at doses slightly lower than those needed to cause hypotension (ED(HR)/ED(MABP) ratio of 0.18 for BMS-180448). BMS-180448 had no effect on myocardial contractility or relaxation over the doses studied, whereas cromakalim significantly increased +dP/dt and lowered -dP/dt. Effects on +dP/dt were associated with a decrease in blood pressure. Although BMS-180448 reduced total peripheral resistance (ED-25 = 5.75 mg/kg), it had little effect on specific vascular beds, with the exception of the coronary bed. BMS-180448, unlike cromakalim which caused more general vasodilating effects, appeared to be relatively selective in dilating the coronary vascular bed. In isolated perfused rat hearts, BMS-180448, 10-fold more potent as a cardioprotectant (EC25 = 2.7 microM) than as a cardiodepressant (ED-25 = 27.8 microM), had no effect on HR, suggesting a lack of effect of BMS-180448 on myocardial conduction. In conclusion, BMS-180448, a recently developed K+ATP opener, exerted less hypotensive and more selective vascular effects than did cromakalim. These results suggest that BMS-180448, at doses previously reported to give cardioprotection, should have a safe hemodynamic profile.

A comparison between the effects of BMS-180448, a novel K+ channel opener, and cromakalim in rat and dog.

BMS-180448 [(3S-trans)-N-(4-chlorophenyl)-N'-cyano-N"-(6-cyano-3, 4-dihydro-3-hydroxy-2,2-dimethyl-2H-1-benzopyran-4-yl) guanidine] is a structural analog of cromakalim, which was found to similarly decrease ischemic injury, but was 18- to 100-fold less potent as a vasodilator. In the present study, the vascular and cardiac effects of cromakalim and BMS-180448 were evaluated in both in vitro and in vivo preparations. Cromakalim evoked a concentration-dependent relaxation to a K(+)-induced contracture in rat aorta. BMS-180448 behaved in a similar fashion but was 18-fold less potent than cromakalim. Measurements of ischemic damage made in isolated perfused rat hearts demonstrated that cromakalim and BMS-180448 were equipotent as cardioprotective agents; time to contracture was increased with an EC25 value of 4.8 and 4.7 microM, respectively, and lactate dehydrogenase levels were significantly reduced compared to those in the presence of vehicle. In vivo electrophysiologic studies in anesthetized dogs were conducted at basic cycle lengths of 400, 333, and 286 ms, and showed that BMS-180448 caused no significant effect on electrophysiologic parameters with the exception of decreasing atrial effective refractory periods by 12 +/- 3% and 17 +/- 4% at 3 and 10 mg/kg, respectively. There was also a significant drop in mean blood pressure of 18 +/- 5% and 33 +/- 4% at these doses. In contrast, cromakalim was shown to produce shortening of atrial to His conduction time (20 +/- 7%; basic cycle length = 286 ms), atrial effective refractory period (34 +/- 3%; basic cycle length = 400 ms), ventricular effective refractory period (14 +/- 2%; basic cycle length = 400 ms), wavelength (13 +/- 3%; basic cycle length = 400 ms), PR-interval (14 +/- 3%; basic cycle length = 333 ms) and mean blood pressure (65 +/- 3%; basic cycle length = 400 ms) at a dose of 0.3 mg/kg. No supraventricular or ventricular arrhythmias were observed for either compound tested. Based on the reduced cardiac electrophysiologic and vascular effects of BMS-180448, we suggest that BMS-180448 should provide cardioprotective efficacy similar to cromakalim with reduced risk of hypotension or arrhythmias.

Effects of dofetilide on electrical dispersion and arrhythmias in post-infarcted anesthetized dogs.

An increase in dispersion of myocardial refractoriness has been shown to coincide with a greater risk of inducible ventricular arrhythmias. We compared the dispersion of electrophysiologic parameters and antiarrhythmic effects of dofetilide (0.03, 0.1, 0.3 and 1 mg/kg i.v.) in post-infarcted anesthetized dogs. Animals were tested for inducibility of arrhythmias using a programmed electrical stimulation (PES) protocol, and divided into inducible (I) and non-inducible (NI) groups. In addition, myocardial vulnerability was measured using ventricular fibrillation thresholds (VFT), as well as susceptibility to sudden cardiac death (SCD). Dofetilide significantly increased ventricular effective refractory periods (ERP) and monophasic action potential durations (APD) in a dose-dependent manner. The standard deviation of ERP, which was used as an index of dispersion of refractoriness, increased from sham (control value of 5.4 +/- sd 2.5 ms), non-inducible (control value of 11.0 +/- 5.5 and 8.0 +/- 3.7 ms for vehicle and dofetilide groups, respectively) and inducible states (control value of 17.3 +/- 6.2 and 21.6 +/- 7.1 ms for vehicle and dofetilide groups, respectively). However, dofetilide treatment did not alter dispersion of refractoriness over the dose range studied. Dofetilide did not significantly increase inducibility in the NI group (2 out of 8 [25%] compared to 0 out of 9 [0%] in vehicle treated animals). In the I group, dofetilide (0.3 mg/kg) treated animals converted 2 out of 7 (29%) to NI, and 5 out of 7 (71%; significant at p < 0.05) to a NI or non sustained ventricular tachycardia. There were no significant changes in VFT following the last dose of dofetilide given. Dofetilide did not significantly affect SCD survival (88% and 29% in the NI and I group, respectively) relative to vehicle (66% and 50% in the NI and I group, respectively). Although infarct sizes were significantly greater in the I groups, there was no difference between vehicle and dofetilide animals within these groups. In conclusion, dofetilide increased ERP and APD values, but did not affect dispersion of refractoriness. Thus, changes in dispersion of refractoriness may be used as a marker for inducibility in untreated animals, but it did not predict the antiarrhythmic effects observed with dofetilide.

Effects of cromakalim or glibenclamide on arrhythmias and dispersion of refractoriness in chronically infarcted in anesthetized dogs.

The proarrhythmic effects of the ATP-sensitive potassium channel modulators cromakalim (n = 10; 0.01 to 0.3 mg/kg i.v.), glibenclamide (n = 10; 0.3 to 10 mg/kg i.v.) or volume equivalents of vehicle (n = 10) were evaluated in post-infarcted anaesthetised dogs. Dogs were anaesthetised, subjected to an anterior-apical myocardial infarction, and allowed to recover. At 7.4 +/- 0.7 days post infarction, animals were anaesthetised again, electrophysiologic measurements (effective refractory periods, QT-intervals and ventricular fibrillation thresholds) were taken, and animals were tested for arrhythmias using a programmed electrical stimulation protocol. Only animals that did not have programmed electrical stimulation-inducible arrhythmias were used. Ventricular fibrillation thresholds were determined twice, once before the first dose then after the last dose of drug. At the end of the experiment, animals were subjected to ligation of the left circumflex coronary artery and survival was measured over the next two hours. Cromakalim significantly increased heart rate and decreased blood pressure. Although cromakalim significantly reduced effective refractory periods, it neither increased electrical dispersion, as determined by the standard deviation or coefficient of variance of the effective refractory period, nor did it enhance inducibility (0 out of 10 in both vehicle and cromakalim treated animals), change ventricular fibrillation thresholds, or reduce sudden death survival relative to vehicle. Glibenclamide did not increase electrical dispersion, but slightly increased the incidence of programmed electrical stimulation-induced arrhythmias (3 out of 10), and lowered ventricular fibrillation thresholds values. However, these changes were not statistically significant. Glibenclamide did not significantly affect survival relative to vehicle.(ABSTRACT TRUNCATED AT 250 WORDS)

In vitro effects of capsaicin: antiarrhythmic and antiischemic activity.

The antiarrhythmic effects of vehicle (0.1% dimethyl sulfoxide: DMSO) or capsaicin were evaluated in isolated perfused rat and guinea pig heart preparations. In the rat, capsaicin reduced ischemic ventricular tachycardia from 100% in control to 0%, and ischemic ventricular fibrillation from 60% in control to 0% at 30 microM, and diltiazem reduced the incidence of ischemic ventricular tachycardia and ventricular fibrillation to 55% and 0%, respectively. Reperfusion ventricular fibrillation was reduced from 90% to 20% and 33% for capsaicin and diltiazem, respectively, at these concentrations. In isolated perfused globally ischemic rat hearts, antiischemic efficacy was assessed as a significant extension (36% and 50%) in time to contracture with 30 microM capsaicin and 1 microM diltiazem, respectively. Capsaicin reduced left ventricular developed pressure by 35% in non-ischemic rat hearts, and increased coronary flow by 40%. The increased time to contracture for either compound was not blocked by glyburide (0.1 microM) suggesting a lack of any involvement of ATP-sensitive K+ channels. In isolated guinea pig hearts subjected to global ischemia, capsaicin and diltiazem reduced reperfusion ventricular fibrillation from 100% to 10% and 0% at 30 and 3 microM, respectively. Electrophysiologic evaluation in guinea pig papillary muscles using standard microelectrode techniques demonstrated significant (P < 0.05) action potential durations at 90% repolarization shortening at 1 Hz by 9%, 28% and 39%, and 23%, 37% and 51% at 10, 30, and 100 microM of capsaicin or diltiazem, respectively. Unlike diltiazem, no changes in action potential duration were observed with capsaicin (up to 100 microM) at faster stimulation rates (5 Hz). In conclusion, capsaicin displays both antiarrhythmic and antiischemic efficacy. These data suggest that the effects of capsaicin are mediated primarily through block of Ca2+ channels in these preparations.

Effect of potassium on the action of the KATP modulators cromakalim, pinacidil, or glibenclamide on arrhythmias in isolated perfused rat heart subjected to regional ischaemia.

OBJECTIVE: The ATP sensitive potassium channel openers cromakalim (n = 10) and pinacidil (n = 10), and a blocker of this channel, glibenclamide (n = 10), were studied in isolated perfused rat hearts subjected to regional ischaemia at varying concentrations (2 to 8 mM) of external potassium ([K+]o). METHODS: Hearts were isolated and perfused on a Langendorff apparatus. Vehicle (0.1% DMSO), cromakalim (10 microM), pinacidil (10 microM), or glibenclamide (10 microM) were given 10 min before ischaemia. The left coronary artery was then occluded for 15 min and reperfused for 5 min. RESULTS: No agent caused more than a 10% change in heart rate. Both cromakalim and pinacidil increased (30%), and glibenclamide decreased (30%) coronary flow at 4 and 6 mM [K+]o. In the vehicle group, increases in [K+]o produced concentration dependent reductions in arrhythmia scores by decreasing ventricular fibrillation. No concentration dependent effects of [K+]o on ischaemic ventricular tachycardia was observed. Under ischaemic conditions, potassium channel openers and glibenclamide more markedly reduced ischaemic ventricular tachycardia and fibrillation relative to the effects of increased [K+]o. CONCLUSIONS: Ischaemic ventricular fibrillation was inversely related to changes in [K+]o, whereas effects on ventricular tachycardia were all-or-none. Neither potassium channel openers nor glibenclamide elicited significant proarrhythmic activity despite variations in [K+]o. These data suggest that both potassium channel openers and glibenclamide display potential antiarrhythmic activity through their ability to abolish two distinct arrhythmogenic mechanisms during ischaemia. It is also suggested that the underlying mechanisms of ventricular tachycardia and fibrillation are coupled during ischaemia in the rat.

Effects of cromakalim or pinacidil on pacing- and ischemia-induced ventricular fibrillation in the anesthetized pig.

The effects of the potassium channel openers (KCO), cromakalim or pinacidil, were evaluated in an anesthetized porcine model of pacing- and ischemia-induced ventricular fibrillation (VF). Hearts were paced at 180 bpm and the left anterior descending coronary artery was occluded until VF was induced. Reproducible times to VF (in seconds) were obtained allowing at least 20 min recovery following defibrillation. Cromakalim (0.3 mg/kg) or pinacidil (3 mg/kg) produced equivalent drops in mean arterial blood pressure. At these doses, cromakalim reduced monophasic action potential duration measured at 90% repolarization (APD90). Although time to VF in the cromakalim group was significantly greater than the vehicle treated group, it was not significantly different from its predrug value. In contrast, pinacidil reduced APD90, and significantly increased time to VF from 134 +/- 5 to 322 +/- 62 s (p < 0.05). Neither cromakalim nor pinacidil affected whole-cell calcium currents recorded in guinea pig myocytes. During ischemia, cromakalim or pinacidil further reduced APD90; however, pinacidil had a two-fold greater effect than did cromakalim. The Class III antiarrhythmic agent, dofetilide, prolonged APD90, but did not increase time to VF. In conclusion, the increased time to VF observed with pinacidil coincides with its ability to shorten APD, and is consistent with activation of ATP-sensitive K+ channels (K+ ATP). It is suggested that indirect reduction of calcium influx through K+ ATP activation and APD shortening is sufficient to increase time to VF in this model. However, the inability of dofetilide to be effective suggests that this model would not be useful to test for Class III antiarrhythmic agents.

Effects of intracoronary glyburide on cesium-induced arrhythmias in anesthetized dogs.

Intracellular calcium plays an essential role in regulation of many cellular processes, but increases in internal calcium levels can also exacerbate pathophysiologic or pharmacologic responses, in particular myocardial arrhythmias. Pharmacologic increases in intracellular calcium may be obtained by opening calcium channels, either directly or indirectly, or by increasing calcium release from intracellular stores. In this study, cesium chloride administered intracoronarily (i.c.) through the left anterior descending coronary artery (LAD) dose-dependently elicited ventricular arrhythmias. Glyburide (3 micrograms/kg/min i.c.), clofilium (1 micrograms/kg/min i.c.) or ryanodine (0.03 micrograms/kg/min i.c.) exacerbated arrhythmias. Specifically, the ED50 values for cesium were shifted from 0.56 mM in the vehicle group to 0.17, 0.27, and 0.20 mM in the glyburide, clofilium, and ryanodine groups, respectively. Coronary blood flow (CBF) and blood pressure (BP) did not change significantly in any treatment group. Effects of glyburide were not mediated by either insulin or decreased glucose levels, since infusions of insulin (decreasing blood glucose to 20 mg/dl) did not exacerbate arrhythmias. In vitro electrophysiologic studies showed that glyburide (1 microM) and ryanodine (1 microM) did not significantly affect action potential durations (APD). In contrast, clofilium (1 microM) significantly prolonged APD. These results demonstrate that glyburide, clofilium, and ryanodine tend to exacerbate cesium-induced arrhythmias. We suggest that glyburide and ryanodine may exacerbate arrhythmias by increasing internal calcium from intracellular stores, whereas clofilium may increase internal calcium by increasing influx of calcium across the sarcolemma.

Effects of intracoronary cromakalim, pinacidil, or diltiazem on cesium chloride-induced arrhythmias in anesthetized dogs under conditions of controlled coronary blood flow.

The effects of intracoronary (i.c.) cromakalim (1 microgram/kg/min) or pinacidil (3 micrograms/kg/min) were evaluated to assess the effects of blood flow on arrhythmogenesis in a canine model of CsCl-induced triggered activity. CsCl (1 M) was administered i.c. through the left anterior descending coronary artery (LAD) at volumes of 0.1, 0.2, 0.5, 0.75, 1.0, and 2.0 ml. In the vehicle group, CsCl produced significant increases in percentage of ectopy from control (ED50 = 0.56 mM). Under conditions of uncontrolled LAD flow, pretreatment with either cromakalim or pinacidil significantly reduced ectopy as compared with vehicle (ED50 = 1.12 and 1.55 mM, respectively). Both cromakalim and pinacidil produced a three-fold increase in blood flow. Under conditions of controlled flow, cromakalim and pinacidil failed to reduce ectopy (ED50 = 0.54 and 0.66 mM, respectively). Doses of cromakalim that elicited a modest (10%) increase in coronary flow also failed to suppress ectopy (ED50 = 0.56 mM). Ectopy was reduced when flow was increased threefold from control using a carotid-LAD shunt without drug. In contrast, diltiazem (3 micrograms/kg/min), a calcium channel antagonist, reduced ectopy even though flow was held constant (ED50 > 2 mM). Cromakalim, pinacidil, and diltiazem significantly decreased mean blood pressure (BP) 20, 19, and 10%, respectively. These studies suggest that the antiarrhythmic activity of both cromakalim and pinacidil in this model is not directly mediated, but instead is indirectly mediated through an increase in coronary blood flow. In contrast, diltiazem was shown to have direct antiarrhythmic effects.