Specificity of action of the novel antihypertensive agent, BRL 34915, as a potassium channel activator. Comparison with nicorandil

Experiments have been performed to investigate the specificity of the mechanism of action of the novel antihypertensive agent, BRL 34915. BRL 34915 (0.5-100 microM) and nicorandil (10-500 microM) stimulated the efflux of rubidium from preloaded rabbit isolated mesenteric arteries. BRL 34915 also caused an increase in the rubidium efflux rate constant in other vascular smooth muscles. Tetraethylammonium (0.1-30 mM) inhibited BRL 34915 (10 microM), nicorandil (100 microM) and potassium (30 mM) induced stimulations of rubidium efflux, but had no effect on noradrenaline (30 microM) induced efflux. Only noradrenaline induced efflux was inhibited by apamin (3-100 nM). Examination of other second messenger systems demonstrated that BRL 34915 (at concentrations up to 100 microM) did not have any appreciable effect on cGMP accumulation in rabbit mesenteric artery, cAMP or cGMP phosphodiesterase in rat heart, or cAMP and inositol phosphate accumulation in rat brain slices. Nicorandil (100 microM) caused a small increase in cGMP accumulation in rabbit mesenteric artery. Radioligand binding studies showed that BRL 34915 did not interact with dihydropyridine, 5-hydroxytryptamine, dopamine, alpha 1, alpha 2 or beta adrenoceptor binding sites. [3H]-BRL 34915 did not bind specifically to any site in any tissue studied, either in vitro or ex vivo. Thus we have been unable to demonstrate an effect of BRL 34915 other than of increasing potassium efflux in rabbit vascular smooth muscle. This lends support to other evidence suggesting that BRL 34915 relaxes vascular smooth muscle (and hence lowers blood pressure) by a novel, and specific, mechanism involving hyperpolarisation of the smooth muscle cell membrane.     

Clinical pharmacokinetics of pinacidil, a potassium channel opener, in hypertension

Pinacidil is a potassium channel opener that decreases blood pressure by reducing peripheral arterial resistance. In two multicenter trials, we studied the concentrations and apparent clearance of pinacidil (406 patients) and concentrations of its pyridyl-N-oxide metabolite (147 patients). Responding patients had plasma samples collected hourly for 12 hours on 2 occasions after weeks to months of treatment. Pinacidil dose was titrated from 12.5 to 75 mg b.i.d. The peak concentration of pinacidil and N-oxide and the area under the concentration-time curve (AUC) were proportional to the dose of pinacidil, with an average pinacidil concentration of 268 micrograms/L (1.02 microM) and N-oxide concentration of 172 micrograms/L (0.65 microM) for every 1 mg/kg pinacidil administered. Clearance of pinacidil (Clp = Dose/AUC) was 31 L/hr in patients younger than 45 years and 27 L/hr in those older than 60. Clp was significantly smaller in white patients compared with other races (Clp = 28 vs. 34 L/hr). Clp was significantly less in patients taking hydrochlorothiazide (27 vs. 31 L/hr) and greater in smokers (33 vs. 29 L/hr). Concomitant propranolol use did not influence Clp.     

Effects of pinacidil, RP 49356 and nicorandil on ATP-sensitive potassium channels in insulin-secreting cells.

1. The whole-cell patch-clamp technique has been used to investigate the effects of pinacidil, RP 49356 and nicorandil on membrane potential and adenosine 5'-triphosphate (ATP)-sensitive K+ channel currents in the insulin-secreting cell line RINm5F. Interactions between pinacidil, RP 49356, nicorandil, diazoxide and ATP have been studied in excised outside-out membrane patches and open-cells. 2. In RINm5F whole-cells (current-clamp mode) continually exposed to glucose, pinacidil, RP 49356 and nicorandil, at concentrations greater than 100 microM, consistently reversed the effects of the sugar by repolarizing the membrane and terminating voltage-gated Ca2+ spike-potentials. 3. The actions of pinacidil, RP 49356 and nicorandil on membrane potential may be explained by their effects on the opening of ATP-sensitive K+ channels, since all three compounds activated channels in whole-cells (voltage-clamp mode), excised outside-out membrane patches and open-cells, at concentrations greater than 100 microM. Below 100 microM the actions of pinacidil, RP 49356 and nicorandil were weak and inconsistent. 4. The mechanism of channel activation appears to depend on the presence of cytosolic ATP, since in its absence, pinacidil, RP 49356 and nicorandil (greater than 100 microM) had either no effects or inhibited K+ channels. 5. Pinacidil, nicorandil and RP 49356 (200-500 microM) also appeared to open K+ channels inhibited by quasi-physiological concentrations of ATP (4 mM) and ADP (1 mM). However, in comparison to diazoxide their effects were weak.(ABSTRACT TRUNCATED AT 250 WORDS)     

两种不同结构类型的钾通道开放剂埃他卡林和吡那地尔联合用药降压作用的特征

目的 :观察两种不同种类的钾通道开放剂(potassiumchannelopeners ,KCOs)埃他卡林 (iptakal im ,Ipt)和吡那地尔 (pinacidil ,Pin)联用降压作用的特征。方法 :用无创性套尾法观察药物对清醒大鼠血压和心率的影响。结果 :Pin在 2 .0和 4 .0mg·kg-1剂量下 ,可剂量依赖性降低清醒大鼠的血压 ,加快其心率。Ipt在 2 .0 ,4 .0和 8.0mg·kg-1剂量下 ,可剂量依赖性降低血压 ,但不影响心率。Ipt(2 .0～8.0mg·kg-1)与Pin(4 .0mg·kg-1)合用时 ,其降压作用产生协同效应 ,但加快心率的作用与Pin相同。结论 :Ipt和Pin降压特点不同 ,二者联用的降压作用增强。     

Comparative effects of K+ channel blockade on the vasorelaxant activity of cromakalim, pinacidil and nicorandil

Three agents with K+ channel blocking activity, procaine, 4-aminopyridine (4-AP) and tetraethylammonium (TEA), were tested for inhibition of vasorelaxation and 86Rb+ efflux induced by cromakalim (BRL 34915), pinacidil and nicorandil in rabbit isolated mesenteric artery. The potency order for inhibition of vasorelaxation was procaine greater than 4-AP greater than TEA and for inhibition of efflux was procaine = 4-AP greater than TEA. The K+ channel blockers did not discriminate between cromakalim, pinacidil or nicorandil on efflux but demonstrated preferential inhibition of vasorelaxation to cromakalim greater than pinacidil greater than nicorandil. In addition, the maximum response to cromakalim was depressed but that to pinacidil and nicorandil was not. The results confirm the role of K+ channel activation in vasorelaxation to cromakalim, pinacidil and nicorandil, but suggest that additional mechanisms may be involved for pinacidil and, in particular, for nicorandil.     

SC-36602, a new antiarrhythmic agent: comparison of its cardiovascular profile with that of other antiarrhythmic drugs

The cardiovascular profile of SC-36602, a new class 1A/1B antiarrhythmic agent, was compared to those of disopyramide, lidocaine, mexiletine, flecainide, encainide, lorcainide, and quinidine. These drugs were compared at their respective canine antiarrhythmic doses in a hemodynamic evaluation using anesthetized dogs. In another test using anesthetized dogs, the cardiovascular effects of cumulative doses of SC-36602 were assessed. The direct negative inotropic potential of each drug was also determined using isolated cat papillary muscles. In the hemodynamic study, SC-36602 and quinidine did not cause significant myocardial depression, measured as a decrease in the maximal first derivative of the left ventricular pressure. (Heart rate and diastolic filling pressure were not controlled in order to mimic clinical conditions). SC-36602, mexiletine, flecainide, and quinidine increased heart rate. SC-36602 and mexiletine caused a small increase in mean arterial pressure, whereas disopyramide and quinidine decreased it. Disopyramide was the only drug studied that increased left ventricular end-diastolic pressure. SC-36602, quinidine, and mexiletine increased index of cardiac effort. Disopyramide caused a decrease in the latter. Disopyramide, flecainide, encainide, and lorcainide lengthened the ECG intervals. Cumulative intravenous doses of SC-36602 up to 50 mg/kg produced significant decreases in mean arterial pressure, increases in heart rate, and increases in P-R and QRS intervals of the ECG relative to placebo-matched controls. SC-36602 had the least direct negative inotropic action of the drugs studied, as measured in isolated papillary muscles. These data suggest SC-36602, when compared to the other antiarrhythmic drugs studied, has the least amount of hemodynamic side-effects at its antiarrhythmic dose.     

Effect of three novel K+ channel openers, cromakalim, pinacidil and nicorandil on allergic reaction and experimental asthma.

The anti-allergic and anti-asthmatic activities of three potassium (K+) channel openers, cromakalim, pinacidil, and nicorandil, were investigated. 1) Forty-eight-hour homologous passive cutaneous anaphylaxis (PCA) in mice was not affected by cromakalim, pinacidil, or nicorandil. Ketotifen significantly inhibited the reaction. 2) Antigen-induced histamine release from sensitized guinea pig lung tissue was not affected by cromakalim, pinacidil or nicorandil (except for 10(-4) M nicorandil). Salbutamol inhibited the release of histamine. 3) Histamine, serotonin and LTC4-induced vasculitis in rat back skin was not affected by any of these three K+ channel openers. 4) Antigen-induced constriction of isolated sensitized guinea pig tracheal muscle was relaxed by each of the K+ channel openers. 5) Constrictions of isolated guinea pig tracheal muscle caused by high potassium, histamine, LTC4, or U-46619 were clearly relaxed by each of the three K+ channel openers. 6) Increases of airway resistance caused by histamine, LTD4, or U-46619 in guinea pigs in vivo were inhibited by administration of each of the three K+ channel openers. 7) Experimental asthma caused by the IgE antibody and antigen system in guinea pigs was inhibited by each of the three K+ channel openers.     

The negative inotropic effect of nicorandil is independent of cyclic GMP changes: a comparison with pinacidil and cromakalim in canine atrial muscle.

1. The negative inotropic effects of nicorandil, a nitrate with K-channel opening properties, have been compared with those of pinacidil, cromakalim and nifedipine, in canine right atrial muscle. 2. Cromakalim, pinacidil and nicorandil all produced a negative inotropic effect. However, even at their maximally effective concentrations, the force of contraction remained at about 10% of control levels, whereas contraction was abolished by nifedipine. 3. The pD2 values for the negative inotropic effects of cromakalim, pinacidil and nicorandil were 5.93, 5.37, and 4.35, respectively. 4. The negative inotropic effects of cromakalim (3 x 10(-5)M), pinacidil (3 x 10(-5) M and 3 x 10(-4) M) and nicorandil (3 x 10(-5) M) were not accompanied by changes in cyclic AMP and cyclic GMP levels, whereas that of 3 x 10(-4) M nicorandil was accompanied by an increase in cyclic GMP but not cyclic AMP concentrations. 5. The negative inotropic effect produced by 3 x 10(-4) M nicorandil was greatly reduced by 10(-2) M tetraethylammonium, whereas the increase in cyclic GMP produced by this concentration of nicorandil was not significantly changed. Sodium nitroprusside (10(-3) M) produced a large increase in cyclic GMP concentrations but had no significant negative inotropic effect. 6. It is concluded that the negative inotropic effects of nicorandil like those of cromakalim and pinacidil do not result from an increase in cyclic GMP concentrations. Instead these effects may be due to their action as K-channel openers.     

Evaluation of the potassium channel activator cromakalim (BRL 34915) as a bronchodilator in the guinea-pig: comparison with nifedipine.

1. The potential of the potassium channel activator, cromakalim (BRL 34915), as a bronchodilator has been evaluated in guinea-pig models in comparison with nifedipine. Some effects of the compounds on guinea-pig tracheal spirals have been studied in an attempt to elucidate their different efficacies in vivo. 2. When given by the intraduodenal route to anaesthetized guinea-pigs, cromakalim (3 and 10 mg kg-1) inhibited 5-hydroxytryptamine (5-HT)-induced bronchospasm for at least 60 min. When given by the i.v. route, the dose of cromakalim producing 50% inhibition of the 5-HT response was 84 micrograms kg-1. Nifedipine failed to show any protective effect up to 100 micrograms kg-1, i.v. and was lethal at higher dose levels. 3. Cromakalim protected conscious guinea-pigs from asphyxic collapse in response to histamine aerosol. The maximal effect occurred 60 min following oral dosing, with 2.5 mg kg-1 providing complete protection for almost half of the animals. Nifedipine had only a weak protective effect even at a high dose level of 50 mg kg-1, p.o. 4. Cromakalim prolonged the time before convulsive cough in response to an antigen challenge in actively sensitized guinea-pigs. Its minimum protective dose was 1 mg kg-1, p.o. Nifedipine (50 mg kg-1, p.o.) was ineffective. 5. Cromakalim inhibited both spontaneous and prostaglandin E2-induced tone in guinea-pig isolated tracheal spirals with IC50 values, relative to the maximum inhibition achieved by isoprenaline (10(-3)M), of 1.1 x 10(-6)M and 8.9 x 10(-7)M, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Anti-ulcer activity of SKP-450, a novel potassium channel activator, in rats.

The anti-ulcer effects of SKP-450, a new potassium channel activator, were evaluated on basal and histamine-induced gastric acid secretion, and against experimentally-induced ulcers such as ethanol-induced and NaOH-induced gastric ulcers. In the pylorus-ligated rat, SKP-450 (0.1-0.5 mg kg(-1)) significantly decreased volume and concentration of gastric juice, and total acid output (ED(50): 0.12 mg kg(-1)). SKP-450 (0.3-3.0 mg kg(-1)) also inhibited histamine-induced gastric acid secretion, maximal effects being achieved at 1.0 mg kg(-1)(37.9% inhibition). In the 95% ethanol-treated rats, SKP-450 significantly reduced the mucosal lesions (46.9 and 31.4% inhibition at 0.1 and 0.2 mg kg(-1), respectively). A significant reduction in the ulcer index by SKP-450 was also observed in 0.3 n NaOH-treated rats (31.5 and 64.3% inhibition at 0.5 and 1.0 mg kg(-1), respectively). The effects of SKP-450 on histamine-induced acid secretion and on NaOH-induced ulcers were inhibited by glibenclamide (20 mg kg(-1), i.v.), a selective blocker of ATP-sensitive potassium channel. These results indicate that SKP-450 possesses anti-ulcer effects and its effects may be mediated by activation of ATP-sensitive potassium channels.     

The potassium channel opening action of pinacidil; studies using biochemical,ion flux and microelectrode techniques

Summary In rat aorta and rat portal vein, (–)- and (+)-pinacidil each produced a concentration-dependent inhibition of tension development. Although the (–) isomer was the more potent, concentration effect curves for each isomer were steep with similar slopes. In rat portal vein, tetraethylammonium and procaine antagonised the relaxant effect of (±)-pinacidil, whereas 3,4-diamino-pyridine was without effect. Intracellular microelectrode recording in rat portal vein showed that low concentrations of (±)-pinacidil reduced the duration of multispike electrical complexes. In both rat aorta and rat portal vein, higher concentrations of (±)-pinacidil hyperpolarised the membrane towards the potassium equilibrium potential. (±)-Pinacidil increased ⁸⁶Rb efflux from rat aorta and rat portal vein in a concentration dependent manner. In a separate study, (±)-pinacidil increased ⁴²K efflux from rat portal vein. (±)-Pinacidil had no effect on cyclic GMP or cyclic AMP levels in rat aorta. It is concluded that pinacidil opens ⁸⁶Rb-permeable potassium channels in rat aorta and rat portal vein. This mechanism is independent of cyclic nucleotide changes and may be responsible for the antihypertensive effect of pinacidil. Send offprint requests to: A. H. Weston at the above address     

Electrocardiographic interactions between pinacidil,a potassium channel opener and class I antiarrhythmic agents in guinea-pig isolated perfused heart.

1. Drugs that shorten action potential duration could decrease the Na-channel blocking effect of class I antiarrhythmic agents by reducing the availability of Na channel in the inactivated state. 2. This hypothesis was tested in guinea-pig perfused heart, measuring the surface ECG effects of three class I drugs endowed with different binding kinetics (15 microM mexiletine, 10 microM quinidine and 3 microM flecainide) in the presence of increasing concentrations of pinacidil (10 microM, 30 microM, 50 microM), a potassium channel opener that shortens action potential duration. 3. The ECG parameters measured were: the QRS interval, i.e. the intraventricular conduction time; the JT interval, which reflects the duration of ventricular repolarization; the ratio between JT peak (the time from the end of QRS and the peak of T wave) and JT interval, which quantifies changes in the morphology of the T wave. 4. At the concentrations tested all the antiarrhythmic drugs widened the QRS complex by 55-60%. Flecainide did not significantly change JT interval, but quinidine prolonged and mexiletine shortened it. Mexiletine also decreased the JTpeak/JT ratio. Pinacidil by itself decreased the JT interval and the JT peak/JT ratio in a dose-dependent way, but did not affect QRS duration. 5. In the presence of fixed antiarrhythmic drug concentrations, however, pinacidil decreased the QRS prolongation induced by mexiletine (-17%) and quinidine (-8%), but not that induced by flecainide: this effect was already maximal at the lower concentration tested (10 microM) and there was no relationship between pinacidil-induced JT shortening and QRS changes.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cardiovascular profile of Bay k 8644, a presumed calcium channel activator,in the dog

Summary The action of substance P (SP) on mucosal ion transport has been investigated in the guinea-pig small intestine. Segments of intestine were dissected free of external muscle and myenteric plexus and mounted in Ussing chambers. Short-circuit current (I _sc) was measured as an indication of net ion transport across the tissue.SP (>10^–10 M) added to the submucosal side of the tissue caused a transient increase in I _sc. Tetrodotoxin (TTX, 10^–7 M) decreased the maximum SP response to 11% of the control value. TTX completely inhibited the response to electrical field stimulation but had no effect on I _sc increases due to carbachol or theophylline. In the presence of hyoscine (10^–7 M) the SP response was reduced to 42% of the control value, but hyoscine had no effect on the TTX-resistant SP response. Mepyramine (10^–6 M) had no significant effect on the SP response. These results suggest that SP alters mucosal ion transport by stimulation of cholinergic and non-cholinergic nerves in the mucosa-submucosa. A small part of the SP response appears to be due to a direct action on epithelial cells.The SP antagonist (d-Arg¹, d-Pro², d-Trp^7.9, Leu¹¹)-SP decreased the magnitude of the TTX-resistant SP response, and caused a decrease of similar magnitude in the total SP response. These results imply that the major component of the SP response, which is due to an action on neurons, is unaffected by this antagonist. It is concluded that the SP receptors on epithelial cells are blocked by the antagonist and are different to the SP receptors on submucous neurons, which are not blocked by the antagonist.     

BRL 34915, a novel antihypertensive agent: comparison of effects on blood pressure and other haemodynamic parameters with those of nifedipine in animal models

The effects of BRL 34915, (+/-) 6-cyano-3,4-dihydro-2,2-dimethyl-trans-4-(2-oxo-1-pyrrolidyl)-2H-b enzo [b]-pyran-3-ol, on blood pressure and other haemodynamic parameters in animals have been investigated in comparison with those of nifedipine. In conscious spontaneously hypertensive rats and renal hypertensive cats and dogs the oral doses of BRL 34915 lowering blood pressure are 10 to 30 times lower than those of nifedipine. Tachycardia evoked by BRL 34915 tends to be less than that produced by nifedipine in the cat and of similar magnitude in the dog. The antihypertensive response to BRL 34915 in these models is reproducible on repeat once daily dosing without rebound hypertension on cessation of dosing. In studies using electromagnetic flow probes to measure regional blood flow in anaesthetised cats the intravenous administration of BRL 34915, unlike that of nifedipine, markedly increases renal blood flow yet BRL 34915 lacks the marked effect of nifedipine on femoral blood flow. BRL 34915, a compound structurally unrelated to existing cardiovascular drugs, is a potent new antihypertensive agent having an interesting profile of activity that renders this compound of clinical interest.     

埃他卡林等三种结构类型的钾通道开放剂对非血管平滑肌舒张作用的选择性

目的:研究新结构类型的ATP-敏感性钾通道 (KATP) 开放剂 (KCO)、抗高血压新药埃他卡林 (iptakalim,Ipt) 对胃、回肠和膀胱等非血管平滑肌舒张作用的影响,并比较Ipt与其结构完全不同的KCO、氰胍类的吡那地尔 (pinacidil,Pin) 和苯并噻二嗪类的二氮嗪 (diazoxide,Dia)舒张作用的差异,为进一步明确Ipt舒张作用的选择性特征提供一定的依据.方法:采用大鼠离体胃底、回肠和膀胱肌条3种组织,以10-5 mol·L-1 乙酰胆碱预收缩,观察不同浓度的药物对它们的舒张作用.结果:Ipt 在10-8～10-4 mol·L-1范围内对3种组织均无显著的舒张作用;Pin在10-8～10-4 mol·L-1范围内对胃底条和膀胱平滑肌等均无显著的舒张作用,但在10-5和10-4 mol·L-1时对回肠的舒张率分为 28.8%和 51.9%,诱发显著的舒张作用;Dia对3种组织的作用与Ipt相似,均不引起明显的舒张作用.结论:Ipt不影响胃、回肠和膀胱的舒张作用,选择性优于Pin,与Dia相似;化学结构类型不同的KCO对回肠、胃和膀胱的作用既相似也有不同.     

Cardiovascular profile of FPL 62129, a novel dihydropyridine calcium channel blocker, in anaesthetised dogs: a comparison with nifedipine

The cardiovascular effects of FPL 62129, a novel dihydropyridine calcium channel blocker, were studied in chloralose-anaesthetised dogs in comparison with those of nifedipine. FPL 62129 and nifedipine produced dose-related falls in blood pressure and total peripheral resistance and were of similar potency in these respects. While the vasodilator effects of nifedipine were accompanied by reflex tachycardia, FPL 62129 reduced blood pressure without altering heart rate. Both compounds increased cardiac contractility and cardiac output. Nifedipine reduced PR interval duration of the ECG, whereas FPL 62129 produced no change. These differences between FPL 62129 and nifedipine are reflections of their respective cardiac profiles. In studies performed after cardiac autonomic block (to eliminate the contribution from reflexes), FPL 62129 showed marked activity at the sinus node and to a lesser extent at the atrioventricular node. Unlike nifedipine, FPL 62129 demonstrates vasodilator and direct decelerator properties over the same dose range, which accounts for its ability to lower blood pressure without causing reflex tachycardia in this model. The observed profile of FPL 62129 questions attempts to classify calcium channel blockers of the dihydropyridine type as selective vasodilators.     

Effect of amiodarone on Kv1.4 channel C-type inactivation: comparison of its effects with those induced by propafenone and verapamil

As the major component of I(to) (slow), Kv1.4 channel plays an important role in repolarization of cardiac myocytes. C-type inactivation is one of Kv1.4 inactivation and can be affected by open channel blockers. We used the two-electrode voltage clamp technique to observe the effect of amiodarone on Kv1.4 C-type inactivation and compare amiodarone's effects on Kv1.4 with propafenone and verapamil. Our data show that those three antiarrhythmic drugs blocked fKv1.4 delta N (N-terminal deleted Kv1.4 channel from ferret heart) in voltage- and frequent-dependent manners. The amiodarone's IC50 was 489.23 +/- 4.72 microM, higher than that of propafenone (98.97 +/- 1.13 microM) and verapamil (263.26 +/- 6.89 microM) for fKv1.4 delta N channel (+50 mV). After application of amiodarone, propafenone and verapamil, fKv1.4 delta N inactivation becomes bi-exponential: the faster portion of inactivation (drug-induced inactivation) and the slower portion of inactivation (C-type inactivation). Amiodarone and verapamil fastened C-type inactivation in fKv1.4 delta N, but propafenone did not. Unlike propafenone that had no effect on fKv1.4 delta N recovery, amiodarone and verapamil slowed recovery in fKv1.4 delta N.     

Differential action of KR‐31378, a novel potassium channel activator,on cardioprotective and hemodynamic effects

The cardioprotective and hemodynamic effects of KR‐31378, a highly cardioselective ATP‐sensitive potassium channel activator with minimal hypotensive effect, were evaluated in rats and dogs, and compared with those of BMS‐191095 and lemakalim. KR‐31378 did not show any significant effect on methoxamine‐induced aortic constriction up to doses of 300 μM, whereas BMS 191095 produced a moderately potent relaxant effect (IC₅₀: 9.0 μM). In conscious rats, KR‐31378 slightly increased blood pressure only at high dose (100 mg/kg, iv), unlike BMS‐191095 that dose‐dependently decreased blood pressure (ED₂₀: 2.03 mg/kg). In anesthetized beagle dogs, KR‐31378 was approximately 100‐fold less potent than BMS‐191095 for most hemodynamic parameters (iv ED₂₀ for blood pressure lowering: 33.7 and 0.37 mg/kg, respectively). In anesthetized rats subjected to 45‐min coronary occlusion and 90‐min reperfusion, KR‐31378 (iv) dose‐dependently reduced the infarct zone from 58.6% to 42.1%, 36.6%, and 34.3% for 0.1, 0.3, and 1.0 mg/kg, respectively (P < 0.05), the effects being comparable to those of BMS 191095. In anesthetized beagle dogs that underwent 2‐h occlusion followed by 4.5‐h reperfusion, KR‐31378 (2 mg/kg, iv infusion) markedly reduced the infarct zone from 48.7% in controls to 19.1% at a dose of 2 mg/kg (P < 0.05). The reduction in infarct zone afforded by KR‐31378 in rats was inhibited by pretreatment with selective ATP‐sensitive potassium channel blockers, sodium 5‐hydroxydecanoate and glibenclamide. These results indicate that KR‐31378 is a potent cardioprotective agent with potentially minimal hypotensive effects. Thus, it could be potentially useful in the prevention and treatment of acute myocardial infarction. Drug Dev. Res. 54:182–190, 2001. © 2002 Wiley‐Liss, Inc.