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PubMed1997

Pinacidil's Effects on Defibrillation Outcomes: Role of Increased Potassium Conductance Via the K(ATP) Channel.

BACKGROUND: It has been shown that the inhibition of potassium ion conductance decreases defibrillation threshold. We postulated that if potassium conductance is a primary mechanism affecting defibrillation threshold values, then increasing potassium ion conductance will increase defibrillation values. The primary objective of this study was to determine if the ATP-dependent potassium (K(ATP)) channel opener pinacidil would increase defibrillation threshold values. The second objective was to prove that the observed changes were due to potassium conductance by using the K(ATP) inhibitor, glyburide, to reverse the electrophysiologic actions of pinacidil. The third objective was to determine if the electrophysiology action sof pinacidil correlate with changes in defibrillation threshold value. METHODS AND RESULTS: Domestic farm swine (n = 14) were anesthetized and intubated. Subsequently, they were instrumented with monophasic action potential catheters and epicardial defibrillation patches. Defibrillation threshold values, action potential duration, effective refractory period, and ventricular fibrillation cycle length were determined at baseline and during treatment phase 1 and treatment phase 2. Pigs were randomized into 2 groups: group 1 (n = 6) received D(5)W in treatment phase one followed by D(5)W in treatment phase 2 and group 2 (n = 8) received pinacidil in treatment phase one followed by the addition of glyburide in treatment phase two. DFT(ED50) did not change at baseline, treatment phase one or treatment phase two for group 1 (10.5 +/- 2, 11.1 +/- 1.7, 10.5 +/- 1.0 J) or for group 2 (10.1 +/- 2.2, 11.4 +/- 4.2, 11.4 +/- 3.0 J). Electrophysiologic parameters )QRS, effective refractory period, action potential duration(90), and ventricular fibrillation cycle length) were not significantly changed from baseline in group 1. In contrast, effective refractory period, action potential duration(90), and ventricular fibrillation cycle length significantly decreased at all recorded sites after the administration of pinacidil in group 2 (range of 7-13%, 6-9%, and 12-17%, respectively). However, pinacidil did not change the basal level of dispersion in effective refractory period, action potential duration, and ventricular fibrillation cycle length during paced rhythm or ventricular fibrillation. Glyburide reversed pinacidil's electrophysiologic actions. CONCLUSIONS: Pinacidil does not alter defibrillation threshold, but it reduces effective refractory period, action potential duration, and ventricular fibrillation cycle length and does not increase electrical heterogeneity. Therefore, changes in potassium channel conductance as well as shortening repolarization are unlikely primary mechanisms for elevating defibrillation threshold.

Journal Article↗

PubMed1990

Pinacidil activates the ATP-sensitive K+ channel in inside-out and cell-attached patch membranes of guinea-pig ventricular myocytes.

Patch-clamp techniques were used to study the effects of pinacidil on the adenosine-5'-triphosphate (ATP)-sensitive K+ channel current in guinea-pig ventricular myocytes. In inside-out patches, the ATP-sensitive K+ channel current could be recorded at an internal ATP concentration of 0.5 mM or less and almost complete inhibition was achieved by raising the concentration to 2 mM. Application of pinacidil (10-30 microM) in the presence of 2 mM ATP restored the current, whereas 5 mM ATP antagonized the effect of pinacidil. The conductance of the channel at symmetrical K+ concentrations of 140 mM was 75 pS with a slight inward rectification at voltages positive to + 40 mV. There was no significant change in the conductance after application of pinacidil. In 0.5 mM ATP, at -80 mV, both the distributions of the open time and the life-time of bursts could be fitted by a single exponential. An increase in ATP concentration decreased the mean life-time of bursts, whereas pinacidil increased it with little increase in the mean open time. Closed time distributions of the channel were fitted by at least two exponentials, with a fast and a slow time constant. An increase in ATP concentration markedly increased the slow time constant associated with a decrease in the number of bursts, whereas the effect of pinacidil was opposite to that of increased ATP. These results indicate that pinacidil increases the open-state probability of the ATP-sensitive K+ channel.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗

PubMed1984

Pharmacokinetics and hypotensive effect in healthy volunteers of pinacidil, a new potent vasodilator.

Preliminary investigation in 3 healthy volunteers suggested that intravenous pinacidil in a dose of 0.2 mg/kg had a potent but well-tolerated hypotensive action in the supine position. Facial flushing, uncomfortable chest sensation and distressing postural hypotension occurred at serum concentrations above 300 ng/ml. Pinacidil, 0.2 mg/kg, was given intravenously over 4 min to 15 healthy volunteers in the supine position. Maximum fall in mean arterial pressure (MAP) was 15.7 +/- 6.0 mmHg. Maximum rise in heart rate was 23.8 +/- 6.6 beats/min. Pinacidil serum distribution half-life (T1/2 alpha) was 13.4 +/- 8.5 min and elimination half-life (T1/2 beta) was 2.13 +/- 0.49 h. The apparent volume of distribution (Vd beta) was 90.3 +/- 13.21 and total body clearance was 31.1 +/- 9.61/h. Pinacidil was approximately 40% bound to plasma protein over the concentration range 40-400 ng/ml. Urinary excretion of unchanged pinacidil accounted for 5.7 +/- 1.3% of the administered dose over 24 hours and urinary excretion of the major metabolite, pinacidil pyridine-N-oxide, was 31.6 +/- 9.2% of the administered dose. It was concluded that intravenous pinacidil is a potent vasodilator hypotensive compound, with a duration of action between 1.5 and 2 h.

Adult↗

PubMed1985

Treatment of essential hypertension and hypertension associated with renal impairment with pinacidil: a new vasodilator.

Twenty patients with uncontrolled hypertension were treated with pinacidil for a mean period of 43 weeks (range 10-63 weeks). All patients achieved and maintained significant reductions in blood pressure. The supine blood pressure at baseline was 184/116 mmHg; after one week it was 161/95 mmHg and at 43 weeks it was 138/79 mmHg. The mean dose of pinacidil was 30 mg/day. There was no significant difference between the two groups with respect to the dose of pinacidil or the blood pressure response. Pulse rate and weight remained stable for the group as a whole. Five patients were not taking beta-blockers. The mean baseline pulse rate for this group was 78 beats/min and when maintained on pinacidil it was 82 beat/min (NS). Six patients were not taking diuretics. The mean baseline weight for this group was 78.5 kg and while maintained on pinacidil it was 79.2 kg (NS). There was no occurrence of oedema, hirsutism or first dose phenomenon. The mean glomerular filtration rate and renal plasma flow for the renal plasma flow for the renal group was 35.4 ml/min and 192.3 ml/min before pinacidil and after six months they were 32.7 ml/min and 183.2 ml/min (NS) respectively. Six patients experienced minor side-effects. We conclude that pinacidil is a potent, well tolerated antihypertensive agent which merits further study.

Adult↗

PubMedDate not supplied

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.

Animals↗

PubMed2005

Effects of pinacidil on reentrant arrhythmias generated during acute regional ischemia: a simulation study.

Many experimental studies have pointed out the controversy involving the arrhythmogenic effects of potassium channel openers (KCOs) in ischemia. KCOs activate the ATP-sensitive potassium current [IK(ATP)], resulting in action potential duration (APD) shortening, especially under pathological conditions such as ischemia. Acute myocardial ischemia leads to electrophysiological inhomogeneities in APD, conduction velocity, and refractoriness, which provide the substrate for reentry initiation and maintenance and may lead to malignant arrhythmias. The aim of this work is to analyze the effect of the KCO pinacidil on vulnerability to reentry during acute regional ischemia using computer simulations. We use a two-dimensional virtual heart tissue with implementation of acute regional ischemia conditions. Membrane kinetics are represented by a modified version of Luo-Rudy (phase II) action potential model that incorporates the effect of pinacidil on IK(ATP). The vulnerable window (VW) for reentry is quantified for different doses of pinacidil. Our results show that for doses below 3 micromol/l the VW widens with increasing pinacidil concentration, whereas for higher doses of pinacidil the VW decreases, becoming zero for concentrations above 10 micromol/l. The ionic mechanisms involved in this behavior are explored. This study demonstrates that the effect of pinacidil on arrhythmogenesis is strongly dose-dependent, and that high doses of pinacidil exert a strong antiarrhythmic effect.

Action Potentials↗

PubMed1998

Activation of large-conductance potassium channels in pregnant human myometrium by pinacidil.

OBJECTIVE: The aim was to investigate the effects of the potassium-channel opener pinacidil on single uterine potassium channels and the contribution of the latter to pinacidil-induced myometrial relaxation. STUDY DESIGN: Myometrial strips and freshly dispersed uterine myocytes were prepared from the myometrial biopsy samples of women undergoing elective, nonlabor caesarean section at term gestation. RESULTS: In isometric tension experiments pinacidil potently relaxed pregnant nonlabor human myometrial strips, with an agonist concentration yielding the half maximal response of 0.4 +/- 0.1 micromol/L. This effect was antagonized by 500 nmol/L charybdotoxin. Application of 10 micromol/L glibenclamide also inhibited the pinacidil-induced relaxation. Coapplication of charybdotoxin (500 nmol/L) and glibenclamide (10 micromol/L) produced a biphasic curve, which was fitted to a two-site model with values for agonist concentration yielding the half maximal response of 0.6 +/- 0.2 micromol/L and 189.7 +/- 0.8 micromol/L. Large-conductance calcium-dependent potassium channel activity was dramatically increased after application of pinacidil (between 10 and 100 micromol/L) to both inside-out and outside-out patches. The activation required the presence of calcium ions at the intracellular aspect of the membrane. Charybdotoxin but not glibenclamide blocked pinacidil-induced unitary large-conductance calcium-dependent potassium channel activity. CONCLUSION: Pinacidil-mediated relaxation of human pregnant myometrial strips may be partially attributable to the opening of uterine large-conductance calcium-dependent potassium channels in addition to adenosine triphosphate potassium channel activation. Drugs with specific potassium channel-activating properties may have important clinical application as novel tocolytics in the treatment of preterm labor.

Calcium↗

PubMed1998

Basal nitric oxide release differentially modulates vasodilations by pinacidil and levcromakalim in goat coronary artery.

In the current investigation, the role of basal nitric oxide (NO) in modulating the vasorelaxant responses to pinacidil and levcromakalim was examined in goat isolated coronary artery. Pinacidil (10(-8) 10(-4) M) elicited concentration-dependent relaxations of the coronary artery ring segments (with intact endothelium) constricted with 30 mM K+ saline solution. The EC50 of the vasodilator was 2.57 x 10(-6) M (95% CL, 1.9-3.46 x 10(-6) M). The removal of endothelium by mechanical rubbing caused a rightward shift in the concentration-response curve of pinacidil with a corresponding increase in EC50 value (1.90 x 10(-5) M; 95% CL, 1.12-3.23 x 10(-5) M). Similar to endothelium removal, treatment of endothelium-intact rings either with the NO synthesis inhibitor L-NAME (NG-nitro-L-arginine methyl ester; 3 x 10(-5) M) or the guanylate cyclase inhibitor, methylene blue (3 x 10(-6) M) resulted in a marked inhibition in the relaxant responses to pinacidil. Hence, the EC50 values of the potassium channel opener were significantly higher in tissues treated either with L-NAME (7.41 x 10(-6) M; 95% CL, 6.02-9.12 x 10(-6) M) or methylene blue (2.29 x 10(-5) M; 95% CL, 1.58-3.31 x 109-5) M) as compared to untreated controls. The ATP-sensitive potassium (KATP) channel blocker glibenclamide, which caused a significant rightward shift in the concentration-relaxation curve of pinacidil in control tissues, was found to be less potent in antagonising the relaxant responses of the KATP channel opener in endothelium-denuded rings and in rings with intact endothelium but treated with either L-NAME or methylene blue. In contrast to the observations made with pinacidil, the vasodilator responses to another KATP channel opener, levcromakalim, were potentiated in the absence of basal NO. Thus, the EC50 of levcromakalim was 1.33 x 10(-8) M (95% CL, 0.8-2.21 x 10(-8) M) in control tissues with intact endothelium, which was significantly higher than those obtained in endothelium-deprived rings (4.81 x 10(-9) M; 95% CL, 4.04-5.73 x 10(-9) M) or endothelium intact rings treated either with L-NAME (2.63 x 10(-9) M; 95% CL, 1.58-4.36 x 10(-9) M) or methylene blue (2.82 x 10(-9) M; 95% CL, 1.7-4.68 x 10(-9) M). The selective modulation by basal NO of the arterial relaxations elicited with the KATP channel openers was evident from the findings that papaverine-induced relaxations were not affected in the absence of basal NO. Taken together, the results of the present study suggest that basal NO differentially modulates the interaction of pinacidil and levcromakalim with the KATP channels in goat coronary artery through a cGMP-dependent pathway.

Animals↗

PubMed2000

Donor heart preservation with the potassium channel opener pinacidil: comparison with University of Wisconsin and St. Thomas' solution.

BACKGROUND: Hyperpolarized arrest with the potassium channel opener pinacidil has been shown to provide effective myocardial protection during short-term global ischemia. This study tested the hypothesis that pinacidil may provide effective long-term protection for heart transplant preservation. METHODS: Four concentrations of pinacidil (50 microM, 100 microM, 0.5 mM, 1.0 mM) mixed in Krebs-Henseleit solution were compared with University of Wisconsin and St. Thomas' Hospital solutions in a Krebs-Henseleit perfused rabbit Langendorff model (n = 6 for each group). Hearts underwent 4 hours of hypothermic (4 degrees C) storage. Over a wide range of volumes, left ventricular systolic function, diastolic compliance, and coronary flow were measured prior to and following storage. Time to mechanical and electrical arrest, and post-ischemic percent tissue water were also measured. RESULTS: Pinacidil 0.5 mM provided the best preservation of post-ischemic systolic function and coronary flow compared with the other pinacidil concentrations and was statistically equivalent to St. Thomas' solution in terms of post-ischemic systolic, diastolic, and flow properties. However, hearts protected with University of Wisconsin solution had significantly better preservation of systolic function and coronary flow. CONCLUSIONS: This investigation demonstrated that pinacidil in Krebs-Henseleit solution possesses efficacy in long-term donor heart preservation. Pinacidil was equivalent to St. Thomas' solution but inferior to University of Wisconsin solution. Hyperpolarized arrest with potassium channel openers may be a novel strategy to improve donor heart preservation.

Adenosine↗

PubMed1985

Acute hemodynamic effects of pinacidil and hydralazine in essential hypertension.

In a double-blind, randomized, crossover study, the effects of intravenous pinacidil, 0.2 mg/kg, were compared with those of hydralazine, 0.3 mg/kg, before and after beta-adrenoceptor blockade in six subjects with hypertension. Both drugs equally reduced total peripheral resistance by about 40%. Pinacidil reduced mean blood pressure by an average of 30 mm Hg, while the reduction after hydralazine was 10 mm Hg. The difference in antihypertensive effect resulted from greater increases in heart rate, cardiac contractility (systolic time intervals), and cardiac index (thermodilution) after hydralazine. These effects after hydralazine could not be fully abolished by beta-blockade, as could the effects after pinacidil. Pinacidil decreased pulmonary blood pressure, whereas there was a slight rise in pulmonary blood pressure after hydralazine. Forearm blood flow (venous occlusion strain gauge plethysmography) increased equally after both drugs; thus pinacidil decreased forearm vascular resistance more than hydralazine did. Serum concentrations of both drugs were within the therapeutic range and correlated with the fall in mean blood pressure. Five subjects complained of side effects after hydralazine, but none were reported after pinacidil. Hydralazine increased myocardial oxygen consumption (as estimated from the rate-pressure product) by 35%; there was no change after pinacidil. It is suggested that hydralazine has direct cardiostimulatory effects that limit its antihypertensive effectiveness. These effects increase myocardial oxygen consumption and may be responsible for the common and sometimes severe cardiovascular side effects of hydralazine.

Adrenergic beta-Antagonists↗

PubMed1986

Effect of cirrhosis and debrisoquin phenotype on the disposition and effects of pinacidil.

Pinacidil is an investigational vasodilator currently undergoing clinical trials as an antihypertensive agent. It is metabolized in humans to pinacidil N-oxide. To determine whether pinacidil's metabolism or effects were influenced by either liver disease or the subject's debrisoquin phenotype, eight patients with chronic stable cirrhosis and 13 healthy subjects were studied. Seven of the healthy volunteers were extensive metabolizers of debrisoquin, whereas six were of the poor metabolizer phenotype. Neither the clearance of pinacidil nor the production of the N-oxide was altered by the subjects' debrisoquin phenotype. Cirrhosis produced a 50% reduction in pinacidil's clearance (20.7 +/- 1.4 vs. 42.1 +/- 5.1 L/hr; P less than 0.0005) and a prolongation in the elimination t1/2 from 3.9 +/- 0.3 to 6.1 +/- 0.6 hours (P less than 0.01). Less pinacidil was metabolized to the N-oxide metabolite in the patients with cirrhosis than in the normal individuals. Thus pinacidil's metabolism and clearance are reduced in patients with cirrhosis but are independent of debrisoquin phenotype.

Adult↗

PubMed1989

Dose-effect and concentration-effect relationships of pinacidil and hydrochlorothiazide in hypertension.

To determine dose-effect and concentration-effect relationships in hypertension for pinacidil and hydrochlorothiazide when given alone and together, we conducted a randomized, double-blind, 4 X 3 factorial, modified fixed-dose multicenter trial. Three hundred and eighty-four patients with essential hypertension (supine diastolic blood pressure, 95 to 110 mm Hg) were assigned to one of 12 groups that received all combinations of four doses of pinacidil (0, 12.5, 25, and 37.5 mg, b.i.d.) with three doses of hydrochlorothiazide (0, 12.5, and 25 mg, b.i.d.). Significant dose- and concentration-effect relationships were seen for pinacidil and hydrochlorothiazide on diastolic blood pressure. For pinacidil, dose- and concentration-effect relationships were steeper after the dose than before the dose. A significant interaction with hydrochlorothiazide was noted such that, when combined with 12.5 mg hydrochlorothiazide, 12.5 mg pinacidil had near-maximal effects on blood pressure at both peak and trough. Edema occurred in 47% of those who received 37.5 mg pinacidil monotherapy (19% discontinued). The administration of 12.5 mg pinacidil with 12.5 mg hydrochlorothiazide appears to be optimal for efficacy and safety.

Adult↗

PubMed1988

The mode of action of pinacidil and its analogs P1060 and P1368: results of studies in rat blood vessels.

In rat portal vein and aorta, pinacidil (0.3-100 microM) inhibited spontaneous mechanical activity (portal vein) and responses to norepinephrine (0.001-100 microM) and to KCl (5-80 mM). Pinacidil and its analogs P1060 and P1368 inhibited established contractions to 20 mM KCl but had little effect on responses to 80 mM KCl. The order of spasmolytic potency was P1060 greater than pinacdil greater than P1368. Intracellular electrical recording showed that in a portal vein, pinacidil (0.3-10 microM) abolished spontaneous electrical activity and hyperpolarised the cells to the region of the calculated EK. Pinacidil (3-10 microM) produced a similar hyperpolarisation in rat aorta, and in both tissues the hyperpolarisation was maintained in the continuing presence of pinacidil. Using 86Rb as a K+ marker, pinacidil increased 86Rb exchange in both the rat portal vein and aorta. The analog P1060 also increased 86Rb efflux in the rat portal vein; P1368 had no significant effect. It is concluded that the inhibitory effects of pinacidil in rat blood vessels are associated with the opening of 86Rb-permeable K+ channels. This mechanism produces a low-resistance pathway in the membrane and this inhibits the ability of pressor agents to produce smooth muscle contraction.

Animals↗

PubMed1988

Clinical pharmacology of pinacidil, a prototype for drugs that affect potassium channels.

The clinical pharmacology of potassium channel openers has been reviewed using pinacidil as a prototype drug. When administered acutely or chronically, the hemodynamic and neuroendocrine profile is that of a peripheral arterial vasodilator. The drug produces decreases in peripheral vascular resistance, and subsequent blood pressure decreases are associated with reflex increments in heart rate. When studied, plasma catecholamines increased about twofold during chronic therapy. Plasma renin activity, however, was not increased during chronic therapy with pinacidil monotherapy. When patients were treated with pinacidil doses ranging from 12.5 to 75 mg b.i.d., 66.9% of patients had a decrease in supine diastolic blood pressure to below 91 mm Hg and 10 mm Hg less than baseline, whereas only 23.9% of patients had similar falls during placebo treatment. During maintenance therapy with pinacidil, the average blood pressure during the daytime dosing interval was 137.8 +/- 1.2/83.4 +/- 0.7 mm Hg (mean +/- SEM). Titration of pinacidil as monotherapy resulted in a characteristic adverse event profile dominated by the presence of dose-related edema. Other characteristic events included tachycardia, palpitations and headache. When pinacidil was given to patients unresponsive to hydrochlorothiazide (25 mg b.i.d.), similar efficacy relative to placebo was noted with a change of post-dose supine diastolic blood pressure in the pinacidil group of 13.5 +/- 0.8 mm Hg and 7.3 +/- 0.9 mm Hg in the placebo group.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive Agents↗

PubMed1993

Electrophysiologic effects of a potassium channel activator (pinacidil) on repolarization parameters in healthy volunteers: a surface ECG study.

About a quarter to a third of patients receiving pinacidil, a new cyanoguanidine vasodilator, show ECG changes, in particular T-wave modifications that sometimes mimic myocardial ischemia. To investigate these changes, we performed a randomized placebo-controlled trial in 10 carefully selected, healthy subjects who received single oral doses of either pinacidil (25 mg), quinidine (330 mg), and placebo. Quinidine, which induces specific modifications to the surface ECG signal, was used as an internal control. The complete experimental design involved five consecutive administrations of the drugs in random order: pinacidil (twice), quinidine (twice), and placebo (once), separated by a week-long washout period. Electrophysiologic data acquisition and signal analysis were performed with the Lyon vectocardiographic processing system. Pinacidil decreased T-wave amplitude (-0.26 +/- 0.1 mV) significantly as compared with placebo (-0.14 +/- 0.06 mV), but did not change the duration of the T-wave. Although the cardiac rate increased with pinacidil, the QTc interval remained constant. Conversely, quinidine did not modify the RR interval but significantly increased duration of the T-wave (+67 +/- 20 ms) and QTc interval (+53 +/- 13 ms) as compared with placebo (+17 +/- 13 and +18 +/- 11 ms). In addition, no specific ischemic changes to the T-loop were observed with pinacidil. The modifications to the surface ECG signal caused by pinacidil appear to be drug-specific and related to its electrophysiologic properties rather than involving any ischemic mechanism. Such an approach may be useful for describing morphologic ECG changes caused by new drugs and identifying possible underlying electrophysiologic mechanism(s), which should then be confirmed in further studies.

Administration, Oral↗

PubMed1998

Intracellular nucleotide-mediated gating of SUR/Kir6.0 complex potassium channels expressed in a mammalian cell line and its modification by pinacidil.

1. We have examined the properties of intracellular nucleotide-mediated gating of K+ channel constructs composed of the sulphonylurea receptor 2B and the inwardly rectifying K+ channel subunits Kir6.1 and Kir6.2 (SUR2B/Kir6.1 and SUR2B/Kir6.2 complex K+ channels) heterologously expressed in human embryonic kidney (HEK) 293T cells. In the cell-attached form, both types of K+ channel were activated by pinacidil. 2. In inside-out (IO) patches, the SUR2B/Kir6.2 channels opened spontaneously and were inhibited by intracellular ATP (ATPi). Pinacidil attenuated the ATPi-mediated channel inhibition in a concentration-dependent manner. In contrast, the SUR2B/Kir6.1 channels required intracellular nucleoside di- or tri-, but not mono-, phosphates for opening. The potency of adenine, guanine or uracil nucleotides to activate SUR2B/Kir6.1 channels was enhanced by pinacidil. 3. In the presence of pinacidil, adenine and guanine, but not uracil, nucleotides exhibited bell-shaped concentration-dependent activating effects on SUR2B/Kir6.1 channels. This was due to channel inhibition caused by adenine and guanine nucleotides, which was unaffected by pinacidil. 4. From power density spectrum analysis of SUR2B/Kir6.1 currents, channel activation could be described by the product of two gates, a nucleotide-independent fast channel gate and a nucleotide-dependent slow gate, which controlled the number of functional channels. Pinacidil specifically increased the potency of nucleotide action on the slow gate. 5. We conclude that Kir6.0 subunits play a crucial role in the nucleotide-mediated gating of SUR/Kir6.0 complex K+ channels and may determine the molecular mode of pinacidil action.

Adenosine Diphosphate↗

PubMed1988

Pinacidil opens K+-selective channels causing hyperpolarization and relaxation of noradrenaline contractions in rat mesenteric resistance vessels.

1. The effects of pinacidil on noradrenaline-induced tone, smooth muscle membrane potential and 42K- and 86Rb-efflux from isolated mesenteric resistance vessels (internal diameter 200 microns) of the rat have been studied. 2. Pinacidil (0.3-10 microM) produced concentration-dependent suppression of noradrenaline-induced tone. 3. Pinacidil (0.3-10 microM) caused concentration-dependent hyperpolarization of the smooth muscle. 4. In rat resistance vessels loaded with 42K, pinacidil (1-10 microM) significantly increased the 42K-efflux rate constant. 5. With the use of 86Rb as a marker for K+, 1 microM pinacidil did not affect the 86Rb-efflux rate constant, while 10 microM pinacidil transiently increased the 86Rb rate constant. 6. The results indicate that the relaxant action of pinacidil in these vessels is due to the opening of K+-channels and consequent hyperpolarization. The K+-channels opened are selective for 42K over 86Rb.

Animals↗

PubMed1992

Effects of pinacidil on guinea-pig isolated perfused heart with particular reference to the proarrhythmic effect.

1. The effects of pinacidil (10, 30, 50 microM) on contractility (+dP/dtmax), coronary perfusion pressure (cP), and ECG intervals (PR, QRS, QT) have been studied on constant-flow perfused guinea-pig hearts, driven at four frequencies (2.5, 3, 3.5, 4 Hz). 2. Pinacidil decreased +dP/dtmax, cP and the QT interval in a dose-dependent manner, whereas the PR interval was increased. QRS duration was not modified. All these effects were independent of driving frequency. Pinacidil decreased the interval from Q-wave to T-wave peak (QTpeak) to a greater extent than the QT interval, thus decreasing the QTpeak/QT ratio. This effect, unlike that on QT interval, was more evident at the highest frequency of stimulation. 3. In 4 out of 20 hearts treated with pinacidil sustained ventricular fibrillation (VF) occurred following a short run of premature ventricular beats (R on T phenomenon). 4. In separate experiments, an attempt to induce VF electrically was made at drug concentrations ranging from 10 microM to 100 microM (8 experiments for each concentration). In control conditions and at the lowest concentrations of pinacidil tested (10 microM) VF could never be induced; in the presence of 30 microM pinacidil VF was induced in 5 out of 8 experiments. Drug concentrations higher than 50 microM permitted the induction of VF in every case. 5. Although the concentrations of pinacidil producing ventricular fibrillation are 30-40 times higher than those found in patients under long term treatment with this agent, it is suggested that caution should be used in prescribing this drug, at least in patients suffering from myocardial ischaemia.

Animals↗