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At least 199 records · Page 11Linked to original sources

PubMed1999

Protection of cardiomyocytes by pinacidil during metabolic inhibition and hyperkalemia.

The objective of this study is to understand the mechanism underlying the cardioprotective effects of pinacidil, an ATP-sensitive K+ channel (K(ATP)) opener. We examined the effects of 10 microM pinacidil in cultured chicken cardiomyocytes. Pinacidil caused a concentration-dependent delay in metabolic inhibition-induced increase in intracellular calcium concentration ([Ca2+]i) and creatine phosphokinase release, and this action was antagonized by glyburide, a K(ATP) blocker. Neither verapamil, an L-type Ca2+ channel blocker, nor bepridil, a Na+-Ca2+ exchange inhibitor, affected the time course of increase in [Ca2+]i induced by metabolic inhibition. Pinacidil did not have an effect on the amplitude of K+-induced increase in [Ca2+]i, but accelerated the rate of decline following peak stimulation. In contrast, glyburide reduced the amplitude of K+-induced increase in [Ca2+]i and prolonged the rate of decline. These results provide direct evidence that pinacidil protects cardiomyocytes from metabolic inhibition-induced injury by cyanide (CN) through a delay in the onset of increase in [Ca2+]i, rather than by inhibition of the L-type Ca2+-channels or by alteration of Na+-Ca2+ exchange.

Adenosine Triphosphate↗

PubMed2002

Cytochrome P450 3A4-mediated oxidative conversion of a cyano to an amide group in the metabolism of pinacidil.

The conversion of nitriles to amides is generally considered to be a hydrolytic process that does not involve redox chemistry. We demonstrate here that cytochrome P450 (CYP) is responsible for the conversion of the cyano group of pinacidil to the corresponding amide. The reaction in human liver microsomes was NADPH-dependent and was nearly completely inhibited by an anti-CYP3A4 antibody. Incubations of pinacidil with recombinant CYP enzymes confirm that CYP3A4 is the principal catalyst of this reaction. The kinetics of pinacidil amide formation by CYP3A4 yielded an apparent K(m) of 452 +/- 33 microM and k(cat) of 0.108 min(-1) (k(cat)/K(m) = 0.238 mM(-1).min(-1)). Incubation of pinacidil with CYP3A4 in the presence of (18)O(2) or H(2)(18)O showed that the amide carbonyl oxygen derived exclusively from molecular oxygen. The CYP3A4-mediated reaction also was supported by hydrogen peroxide when incubations were carried out in the absence of cytochrome P450 reductase and NADPH. The reaction can be explained by a nucleophilic attack of a deprotonated ferric peroxide intermediate (Fe(3+)-O-O(-)) on the carbon atom of the -C triple bond N triple bond to form an Enz-Fe(III)-O-O-C(=NH)R intermediate, followed by cleavage of the O-O bond to give pinacidil amide. This nucleophilic addition of an Fe(3+)-O-O(-) intermediate to a -C=N pi-bond in a P450 system resembles the analogous reaction catalyzed by the nitric oxide synthases.

Amides↗

PubMed1987

A double-blind, randomized, controlled trial comparing pinacidil to hydralazine in essential hypertension.

Pinacidil is a direct vasodilator with good absorption, a half-life of 2 to 4 hours, and side effects similar to those of other vasodilators. We hypothesized that controlled-release pinacidil would be comparable to or better than hydralazine for blood pressure control and side effects. A double-blind, randomized trial comparing pinacidil with hydralazine when combined with hydrochlorothiazide or propranolol to control side effects or the diastolic blood pressure was performed. Pinacidil decreased systolic and diastolic blood pressure from 156/100 mm Hg to 132/81 mm Hg. The increase in heart rate and weight with both drugs was controlled with the additional drugs. There was 1/17 successes on monotherapy with both drugs. When combined with other drugs there were 15/18 successes with hydralazine and 16/20 successes with pinacidil. Side effects were typical of vasodilators. Both drugs acutely increased plasma norepinephrine and epinephrine during chronic therapy.

Adult↗

PubMed1998

SUR2 subtype (A and B)-dependent differential activation of the cloned ATP-sensitive K+ channels by pinacidil and nicorandil.

1. The classical ATP sensitive K+ (K(ATP)) channels are composed of a sulphonylurea receptor (SUR) and an inward rectifying K+ channel subunit (BIR/Kir6.2). They are the targets of vasorelaxant agents called K+ channel openers, such as pinacidil and nicorandil. 2. In order to examine the tissue selectivity of pinacidil and nicorandil, in vitro, we compared the effects of these agents on cardiac type (SUR2A/Kir6.2) and vascular smooth muscle type (SUR2B/Kir6.2) of the K(ATP) channels heterologously expressed in HEK293T cells, a human embryonic kidney cell line, by using the patch-clamp method. 3. In the cell-attached recordings (145 mM K+ in the pipette), pinacidil and nicorandil activated a weakly inwardly-rectifying, glibenclamide-sensitive 80 pS K+ channel in both the transfected cells. 4. In the whole-cell configuration, pinacidil showed a similar potency in activating the SUR2B/Kir6.2 and SUR2A/Kir6.2 channels (EC50 of approximately 2 and approximately 10 microM, respectively). On the other hand, nicorandil activated the SUR2B/Kir6.2 channel > 100 times more potently than the SUR2A/Kir6.2 (EC50 of approximately 10 microM and > 500 microM, respectively). 5. Thus, nicorandil, but not pinacidil, preferentially activates the K(ATP) channels containing SUR2B. Because SUR2A and SUR2B are diverse only in 42 amino acids at their C-terminal ends, it is strongly suggested that this short part of SUR2B may play a critical role in the action of nicorandil on the vascular type classical K(ATP) channel.

ATP-Binding Cassette Transporters↗

PubMed2001

Vasorelaxing effect of the potassium (K+)-channel opener pinacidil in isolated porcine ciliary arteries.

PURPOSE: The aim of this study was to investigate the vasorelaxing properties of pinacidil (a potassium-channel-opener) in isolated porcine ciliary arteries. METHODS: Isometric contractions of isolated porcine ciliary arteries were measured with a myograph system. The vessels were first precontracted with the thromboxane A2 analog U 46619 (0.1 microM), and then exposed, in a cumulative manner, to increasing concentrations of pinacidil (1 nM-100 microM). Relaxations have been expressed in percent of the maximal contraction evoked by U 46619 (0.1 microM). RESULTS: Pinacidil showed a pronounced concentration-dependent relaxing effect in isolated porcine ciliary arteries. The difference between pinacidil and time-control experiments was significant (100 microM: 112 +/- 2% vs. 18 +/- 6%, P < 0.0001). The half-maximal concentration (pD50) value was 5.3 +/- 0.1 (-log M). CONCLUSIONS: The present study indicates that pinacidil has marked vasorelaxing properties in isolated porcine ciliary arteries.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1992

Inhibition by glibenclamide of negative chronotropic and inotropic responses to pinacidil, acetylcholine, and adenosine in the isolated dog heart.

The blocking effects of glibenclamide on the chronotropic and inotropic responses to K+ channel openers pinacidil (ATP-sensitive) and acetylcholine (ACh) or adenosine (receptor-operated) were investigated in the isolated, blood-perfused canine atrium or ventricle. Glibenclamide (0.1-3 mumol) induced no significant cardiac effects. Cumulative administration of pinacidil (0.03-3 mumol) dose-dependently decreased sinus rate much less than the contractile force of the atrial and ventricular muscles. Glibenclamide similarly inhibited the negative chronotropic and inotropic responses to pinacidil in a dose-related manner. A high dose of glibenclamide (3 mumol) slightly but significantly attenuated the negative chronotropic and inotropic responses to ACh and adenosine but not to verapamil. These results demonstrate that glibenclamide inhibits the negative chronotropic and inotropic responses to the ATP-sensitive K+ channel opener pinacidil and the receptor-operated K+ channel openers ACh and adenosine but more selectively antagonizes the responses to pinacidil in the dog heart and suggest that in contrast to ACh and adenosine, an ATP-sensitive K+ channel opener has a greater effect on the ventricle than on the sinoatrial node.

Acetylcholine↗

PubMed2002

Improved myocardial function with the addition of pinacidil to custadiol.

BACKGROUND: This study investigates the efficacy of pinacidil, an adenosine triphosphate-sensitive potassium (KATP) channel opening agent, added to custadiol solution on myocardial protection during deep hypothermia and prolonged global ischemia on isolated rat hearts. METHODS: After 20 minutes of stabilization, 24 rats were divided into two groups. In group I (n=12), hearts were arrested with cold (4 degrees C) custadiol solution containing 50 micromol/L of pinacidil and subsequently dipped into the same solution for 120 minutes at 4 degrees C. Group I hearts were perfused with low-flow pinacidil-custadiol (PC) solution during the ischemic period. Group II (n=12) hearts, after the stabilization period, were arrested with cold custadiol solution only, then subsequently dipped and perfused with the same solution for 120 minutes at 4 degrees C. All hearts were reperfused with Krebb's-Henseleit solution at 37 degrees C for 60 minutes. Hemodynamic parameters (peak systolic pressure, end diastolic pressure, maximum rate of increase of left ventricular pressure [+dP/dt], ischemic contracture, and coronary sinus flow) were recorded at the end of the stabilization period and at 10-minute intervals during the reperfusion period. Biochemical data (creatine kinase [CK-MB] washout and troponin I [cTnI] levels) were compared between the two groups. RESULTS: There was no significant difference in any hemodynamic or biochemical parameters between the two groups during the stabilization period. The peak systolic pressure, +dP/dt, ischemic contraction amplitude, and coronary flow values were significantly higher in group I ( P<0.05) compared with group II during reperfusion. End diastolic pressures as well as CK-MB and cTnI levels were lower in the pinacidil-treated group, which is consistent with improved functional recovery during the reperfusion period. CONCLUSION: The addition of pinacidil to the preservation solution, custadiol, improves myocardial recovery after deep hypothermia and prolongs ischemia.

Animals↗

PubMed1988

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.

Animals↗

PubMed1989

Effects of pinacidil on the sympatho-adrenal system in dogs.

1. The aim of the present work was to study the antihypertensive effect of pinacidil, a potassium channel opener, in sinoaortic denervated (SAD) conscious dogs and to investigate whether the involvement of the sympathetic nervous system induced by this vasodilator compound is only of baroceptor reflex origin. 2. Pinacidil (0.1, 0.2, 0.4 mg kg-1 i.v.) induced a dose-dependent decrease in blood pressure in normal as well as in SAD dogs. In contrast, the induced-tachycardia observed in normal dogs was not found in SAD animals. 3. Since pinacidil induced an increase in plasma catecholamines, free fatty acids, glucose, plasma renin activity and aldosterone in SAD dogs it is suggested that this sympathetic activation is independent of the baroreceptor reflex pathways. 4. The sympathetic activation is mainly of peripheral origin, since pinacidil (0.7 mg kg-1 i.v.) induced an increase in adrenaline release from the adrenal gland after section of the great splanchnic nerve in anaesthetized dogs. This increase is probably due to an effect that does not involve K+ channel opening. However, this effect of pinacidil was not observed during splanchnic nerve stimulation (in this case, the involvement of K+ channel opening is suggested).

Adrenal Glands↗

PubMed1993

Modulation of vasodilatation to levcromakalim by hypoxia and EDRF in the rabbit isolated ear: a comparison with pinacidil, sodium nitroprusside and verapamil.

1. We have used an isolated buffer-perfused preparation of the rabbit ear to investigate the effects of hypoxia and inhibition of endothelium-derived relaxing factor (EDRF) synthesis on the vasodilator responses to the potassium channel opener, levcromakalim (the active (-)-enantiomer of cromakalim). The results obtained with levcromakalim have been compared with those for pinacidil, sodium nitroprusside and verapamil. 2. Levcromakalim relaxed preconstricted preparations with an EC50 = 343 +/- 41 nM and Rmax = 80.3 +/- 6.4%. Under hypoxic conditions the concentration-response curve was significantly (P < 0.01) shifted to the left with an EC50 = 118 +/- 16 nM and Rmax = 89.9 +/- 2.7%. Hypoxia did not influence relaxation to either pinacidil, sodium nitroprusside or verapamil. 3. Inhibition of EDRF synthesis with 100 microM NG-nitro-L-arginine methyl ester (L-NAME) also significantly (P < 0.001) increased the vasodilator potency of levcromakalim (EC50 = 56 +/- 5 nM), and caused a similar shift in the concentration-response curve to sodium nitroprusside. It did not influence vasodilation to either verapamil or pinacidil. The potentiation of vasodilator responses to levcromakalim by L-NAME was reversed by an excess of L-arginine. 4. Impairment of oxidative phosphorylation with 400 nM carbonyl cyanide m-chlorophenylhydrazone significantly (P < 0.05) increased the potency of levcromakalim (EC50 = 120 +/- 20 nM) but did not influence vasodilation to pinacidil or endothelium-dependent relaxations to acetylcholine. 5. Vasodilatation to levcromakalim was augmented both by hypoxia and by inhibition of EDRF activity. Since impairment of oxidative phosphorylation increased the potency of levcromakalim but did not alter EDRF activity then the mechanism responsible for hypoxic facilitation of responses to levcromakalim is likely to be due to reduced ATP levels in hypoxic smooth muscle cells rather than a change in EDRF activity. These results suggest that levcromakalim may selectively dilate both hypoxic vessels and vessels with impaired EDRF activity. The results also point to important differences in the pharmacology of levcromakalim and pinacidil.

Acetylcholine↗

PubMed1995

Effects of pinacidil on arterial and venous resistances and mean circulatory filling pressure in rats.

1. The effects of the potassium channel opener, pinacidil, on mean arterial pressure (MAP), mean circulatory filling pressure (MCFP), total peripheral resistance (TPR), cardiac output (CO) and resistance to venous return (Rv) were studied in rats. 2. In pentobarbitone-anaesthetized rats given mecamylamine (ganglionic blocker, 3.7 micrograms kg-1) and noradrenaline (1.5 micrograms kg-1 min-1) to suppress autonomic reflexes, pinacidil (60 and 180 micrograms kg-1 min-1), relative to the vehicle, reduced MAP and TPR in a dose-dependent manner but did not significantly alter CO, MCFP or RV. 3. Pinacidil (10-300 micrograms kg-1 min-1) caused similar increases in MCFP, an inverse index of venous compliance, and similar dose-dependent reductions in mean arterial pressure (MAP) in conscious, intact rats and rats infused with the ganglionic blocker, hexamethonium (150 micrograms kg-1 min-1). In rats with vasomotor tone elevated by the infusion of noradrenaline (1.5 micrograms kg-1 min-1), pinacidil caused markedly greater depressor responses but did not significantly alter MCFP. 4. Our results show that pinacidil is an efficacious vasodilator of arterial resistance blood vessels but has little venodilator activity.

Anesthesia↗

PubMed1990

Lack of effect of pinacidil on theophylline pharmacokinetics and metabolism in man.

Pinacidil, a pyridyl cyanoguanidine derivative, is a new antihypertensive vasodilator drug. It shares structural similarities with the histamine H2-receptor blocker cimetidine, an imidazole cyanoguanidine derivative, which is a potent inhibitor of cytochrome P-450 and of theophylline metabolism. In the present study the pharmacokinetics and metabolism of theophylline were determined in six healthy volunteers before and on the last day of oral pinacidil administration for two weeks. The dosage of pinacidil was 12.5 mg twice a day in the first week and 25 mg in the second. There were no significant changes in theophylline plasma clearance, terminal half-life or volume of distribution during pinacidil administration. Also the renal and metabolic clearance of theophylline and the formation clearances of the major theophylline metabolites in the urine (DMU, 1MU, 3MX) did not change significantly during administration of therapeutic doses of pinacidil.

Administration, Oral↗

PubMed1990

Effect of pinacidil on the electrophysiological properties in guinea-pig papillary muscle and rabbit sino-atrial node.

The electrophysiological effect of the antihypertensive drug pinacidil has been examined in preparations of guinea-pig papillary muscle and rabbit sino-atrial node using a standard microelectrode method. In papillary muscle preparations, pinacidil (greater than 30 microM) shortened the action potential duration (APD), whereas it did not affect the maximum rate of rise (Vmax). Pinacidil (greater than 1 microM) also decreased APD of slow action potentials evoked by high K+ (27 mM) solution containing 0.2 mM Ba2+. At 30 microM, the drug reduced the Vmax of slow action potentials. In the spontaneously beating sino-atrial node, pinacidil (greater than 30 microM) shortened APD. At 100 microM, it also decreased the heart rate, Vmax, action potential amplitude and the rate of diastolic depolarization. It is concluded that pinacidil modifies the electrical activity of myocardial cells probably due to an increase in the potassium conductance although in high concentrations the compound might also reduce Ca2+ influx through the cell membrane, which would contribute to an obvious negative chronotropic action.

Action Potentials↗

PubMed1989

Activation of ATP-sensitive K channels in heart cells by pinacidil: dependence on ATP.

We have investigated the effects of pinacidil on channel activity recorded from inside-out patches of membrane excised from guinea pig ventricular cells. If the cytosolic ATP concentration is greater than 0 but less than 500 microM, pinacidil increases the activity of a channel identified as the ATP-sensitive K channel (IKATP) by its single-channel conductance, its inhibition by ATP, and its sensitivity to glybenclamide. When ATP is greater than 3.0 mM the effects of pinacidil are inhibited. Our experiments show that pinacidil enhances the activity of IKATP in heart cells, but that the action of the drug depends on the ATP concentration of the cytosolic solutions. The results suggest that pinacidil acts indirectly, perhaps at an ATP-binding site that regulates this channel.

Adenosine Triphosphate↗

PubMed1996

ATP-sensitive K+ channel opener pinacidil augments beta 1-adrenoceptor-induced coronary vasodilation in dogs.

The opening of ATP-sensitive K+ (K+ATP) channels contributes to the mechanism of metabolic coronary vasodilation. The aim of the present study was to determine whether K+ATP channel opener pinacidil augments coronary vasodilation induced by beta-adrenoceptor stimulation. In anesthetized dogs, coronary vasodilation in response to intracoronary infusion of a beta 1-adrenoceptor agonist denopamine, selective beta 2-adrenoceptor stimulation with isoproterenol after bisoprolol or nitroglycerin was studied before and during simultaneous intracoronary infusion of pinacidil at a dose of 1 microgram/min, which had no effect on basal hemodynamics. Pinacidil augmented the denopamine-induced increase in coronary blood flow (CBF) from 38 +/- 9 to 66 +/- 16% (P < 0.05) but did not affect the denopamine-induced by isoproterenol or nitroglycerin. Thus pinacidil selectively augmented beta 1-adrenoceptor-mediated coronary vasodilation. These observations suggest that the K+ATP channel opener pinacidil may increase myocardial perfusion during metabolic stress associated with beta 1-adrenoceptor stimulation.

Adenosine Triphosphate↗

PubMed1997

Unanticipated lessening of the rise in extracellular potassium during ischemia by pinacidil.

BACKGROUND: The efflux of potassium (K) through the ATP-sensitive K channel is considered an important cause of the rise in extracellular K ([K+]e) during no-flow ischemia. We postulated that agents that enhance K conductance in this channel would enhance the rise in [K+]e. METHODS AND RESULTS: We studied the effects of 10 and 25 mumol/L pinacidil, and ATP-sensitive K channel opener that provides metabolic protection to the ischemic myocardium, on the rise in [K+]e recorded by K-sensitive electrodes, the change in action potential duration (APD) recorded by microelectrodes, and the changes in activation during ischemia in in situ pig hearts and Tyrode-perfused rabbit interventricular septa. Pinacidil 25 mumol/L unexpectedly lessened the rise in [K+]e and the activation delay in both preparations. Pinacidil 10 mumol/L had no effect in the rabbit and only a slight effect in the pig. Both concentrations significantly exaggerated the APD shortening induced by ischemia. By varying stimulation frequency, we demonstrated that the rise in [K+]e during ischemia, both before and after pinacidil, correlated with the time that the action potential was at its plateau voltage. CONCLUSIONS: Our results indicate that the rise in [K+]e during ischemia is due to multiple factors, including K conductance across membrane channels, K driving force as reflected by the time that the action potential is at its plateau voltage, and the metabolic effects of ischemia. The unanticipated lessening of the rise in [K+]e by pinacidil reflects the balance of its effects on these several parameters.

Adenosine Triphosphate↗

PubMedDate not supplied

Systemic and coronary hemodynamic effects of pinacidil in awake normotensive and hypertensive dogs.

We studied the systemic and coronary hemodynamic effects of a new antihypertensive agent, pinacidil, in nine morphine-sedated chronically instrumented dogs with one-kidney renal hypertension and eight similarly treated sham-operated normotensive dogs. The renal hypertensive dogs exhibited higher mean aortic blood pressure, total peripheral vascular resistance, and plasma renin activity before pinacidil administration than the sham-operated animals. The renal hypertensive dogs also had a lower left ventricular norepinephrine content, but the two groups did not differ significantly in plasma norepinephrine levels, cardiac output, or heart rate. Pinacidil decreased mean aortic pressure and total peripheral vascular resistance and increased cardiac output and heart rate in both groups. The changes in aortic pressure, total peripheral vascular resistance, and cardiac output were similar between the two groups, but the increase in heart rate was attenuated in renal hypertension. The peak rate of rise of left ventricular pressure (dP/dt), the ratio of left ventricular dP/dt and the developed pressure during isovolumic contraction (dP/dt/P), myocardial oxygen consumption, and plasma norepinephrine levels increased after pinacidil administration in the sham-operated dogs, but did not change in the renal hypertension group. The two groups did not differ in their responses of left ventricular dP/dt to intravenous isoproterenol. Pinacidil also caused coronary vasodilation in both groups, as evidenced by an increase in coronary blood flow and decreases in coronary vascular resistance and myocardial oxygen extraction. The decrease in myocardial oxygen extraction was similar in the two groups, but the increase in coronary blood flow was significantly less (p less than 0.05), probably because of the absence of an increase in myocardial oxygen consumption in the renal hypertensive dogs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1991

Antiarrhythmic actions of the ATP-regulated K+ current activated by pinacidil.

We tested the hypothesis that a selective increase in membrane current, as contrasted with the decreases in currents caused by most antiarrhythmic agents, would be an effective antiarrhythmic intervention. We studied models of early afterdepolarizations (EADs), delayed afterdepolarizations (DADs), and abnormal automaticity in single canine ventricular myocytes using intracellular microelectrodes or patch electrodes. EADs were induced by injected current, Bay K 8644 (0.5-1 microM), or ketanserin (1.0 microM); DADs were induced by ouabain intoxication (2 x 10(-7) M); and abnormal automaticity was induced by exposure to barium (0.25 mM). To increase outward K+ current, we used pinacidil and the protein kinase C activator 4 beta-phorbol 12,13-dibutyrate (PDBu). Under control conditions, 10-100 microM pinacidil caused a concentration-dependent and reversible decrease in action potential duration and an increase in steady-state outward current; both effects were blocked by glibenclamide and thus presumably reflected changes in the ATP-regulated potassium current. Pinacidil increased the current required to induce EADs and abolished EADs caused by Bay K 8644 or ketanserin. After exposure of myocytes to ouabain, pinacidil caused a decrease in action potential duration and diminished or abolished DADs. Finally, pinacidil arrested abnormal automaticity caused by Ba2+. PDBu (30 nM) shortened action potential duration without altering plateau amplitude in some of the myocytes. In these cells the depolarizing current needed to produce an EAD was increased by over 70%; outward potassium current tails were also increased, an effect consistent with an increase of the repolarizing potassium current (IK). These findings show that each of the mechanisms for abnormal impulse generation can be effectively antagonized by an increase in outward current and suggest to us that selective augmentation of a repolarizing current, possibly IK, might be a reasonable antiarrhythmic intervention.

Action Potentials↗