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PubMed1988

Effect of pinacidil on norepinephrine- and potassium-induced contractions and membrane potential in rat and human resistance vessels and in rat aorta.

The effect of pinacidil on contractile responses to norepinephrine, potassium, and membrane potential was examined in rat and human resistance vessels. In some experiments rat aorta was also used. Pinacidil (0.1-30 microM) caused a concentration-dependent relaxation of norepinephrine-induced contractions in all vessels studied. In the same concentration range, pinacidil had only little effect on potassium (125 mM) activated rat mesenteric and femoral resistance vessels. In denervated rat mesenteric resistance vessels, a depolarization with potassium (125 mM) before superimposing a norepinephrine tone markedly diminished the effect of pinacidil. In resting rat mesenteric resistance vessels, pinacidil (1-10 microM) caused a hyperpolarization of 10-15 mV. In rat aorta, pinacidil (10 microM) caused a significant (p less than 0.001) increase in 86Rb+ efflux rate constant whereas 1 microM had no effect. The results of these experiments indicate that the vasodilating effect may be caused by a hyperpolarization of the vascular smooth muscle cell membrane.

Aged↗

PubMed1993

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.

Animals↗

PubMed1990

Effects of pinacidil upon penile erectile tissue, in vitro and in vivo.

The effect of pinacidil, a new antihypertensive vasodilator, was studied in vitro upon human and porcine Corpus cavernosum and in vivo upon simian Corpus cavernosum. In vitro, pinacidil incubation (10(-5)-10(-3) M) was found to induce a concentration-dependent inhibition of the tissue response to norepinephrine (NE) and high potassium (K+). Likewise a concentration-related relaxation of the tissue, precontracted with either NE or K+, was seen using pinacidil 10(-5)-10(-3) M. Depending on the concentration applied, spontaneous activity as well as tone and amplitude of the contractions were reduced until total relaxation of the tissue was obtained with a pinacidil incubation of 10(-3) M. In vivo, 5 mg pinacidil in 0.3 ml solution was injected intracavernosally in 17 monkeys. Sixteen monkeys developed tumescence and 10, rigidity of the penis as well. Only one of 5 showed a decrease in the systemic blood pressure. Pinacidil might be of clinical interest as an agent facilitating erection when given intravernosally.

Animals↗

PubMed1993

Modulation of rabbit aortic Ca(2+)-activated K+ channels by pinacidil, cromakalim, and glibenclamide.

Rabbit aortic smooth muscle microsomes were isolated and large-conductance Ca(2+)-activated K+ (BK) channels incorporated into planar lipid bilayers. The selectivity sequence and relative permeability ratios for monovalent cations was K+ (1.0) > Rb+ (0.68) > NH4+ (0.14) >> Na+, Cs+ (< 0.05). Application of pinacidil or cromakalim (0.05-10 microM) shifted the probability of opening (Po)-voltage relationship in the hyperpolarizing direction. The concentrations of pinacidil and cromakalim required to increase Po 50% of the maximum value at -40 mV were 0.96 +/- 0.04 and 0.52 +/- 0.03 microM, respectively. Neither pinacidil nor cromakalim altered the voltage sensitivity of the channel (11-13 mV/e-fold change in Po). Kinetic analysis of data at -40 mV demonstrated that pinacidil (1 microM) decreased the length of time the channel dwelled in its long-closed state by 50% from 173 +/- 50 to 86 +/- 19 ms. No significant change was observed for the open time constant (20 ms). Glibenclamide (10 microM) had no effect on Po of BK channels. However, glibenclamide reversed the pinacidil- or cromakalim-stimulated increase in Po of BK channels. These data suggest that both cromakalim and pinacidil increased the probability of opening of single rabbit aortic large-conductance Ca(2+)-activated K+ channels and that this channel modulation may contribute to the vasorelaxant properties of these drugs.

Animals↗

PubMed1997

Effects of pinacidil on K+ channels in human coronary artery vascular smooth muscle cells.

We investigated pinacidil-activated K+ currents in vascular smooth muscle cells (VSMC) from human coronary arteries with the patch-clamp method. In 19 of 54 VSMC, pinacidil (1 and 20 microM) induced a large, nonrectifying, outward current [IK(ATP)] and increased voltage-dependent outward K+ currents [IK(Ca)] positive to voltages of -25 mV. The pinacidil-induced (1 microM) IK(ATP) was blocked by glibenclamide (3 microM) but was not affected by iberiotoxin (100-300 nM). Pinacidil activated up to 150 functionally active ATP-dependent K+ channels (KATP channels) per cell with a single-channel conductance of approximately 17 pS at physiological membrane potentials (between -80 and -30 mV) and K+ gradients (6 mM/130 mM). In 26 of 54 VSMC, on the other hand, pinacidil (1-20 microM) failed to induce IK(ATP) but increased IK(Ca). This current was completely blocked by iberiotoxin (100-300 nM) and tetraethylammonium (1 mM) but not by glibenclamide (3 microM). The single-channel conductance of the channel underlying IK(Ca) was approximately 150 +/- 16 pS between -10 and +30 mV, consistent with large-conductance, maxi Ca(2+)-activated, K+ channels (BKCa channels). We conclude that pinacidil is a nonselective K+ channel opener targeting KATP and BKCa channels. Furthermore, the conductance of KATP channels in human coronary arteries is likely to be small under physiological conditions.

Animals↗

PubMed1990

Effect of pinacidil on ion permeability in resting and contracted resistance vessels.

Pinacidil is thought to cause vasodilatation by opening K+ channels and consequent hyperpolarization. This proposed mechanism of action is based mainly on membrane potential measurements and 42K or 86Rb efflux experiments under resting conditions. We have measured the simultaneous effect of pinacidil on force and membrane potential in resting and norepinephrine-contracted rat mesenteric resistance vessels. Also the effect of pinacidil on 42K and 36Cl efflux and 22Na uptake in the absence and presence of norepinephrine was examined. From the membrane potential and ion flux measurements the ion permeabilities were calculated. In both resting and norepinephrine-contracted vessels, pinacidil caused a large hyperpolarization, the latter situation being associated with an almost complete relaxation. In both resting and norepinephrine-stimulated vessels, pinacidil caused a large increase in K+ permeability and a decrease in Cl-permeability, whereas no significant change of Na+ permeability was found. Our results suggest that pinacidil causes vasodilation due to hyperpolarization. The major cause for the hyperpolarization is an increase in K+ permeability.

Animals↗

PubMed1992

Effects of potassium channel blockers on the negative inotropic responses induced by cromakalim and pinacidil in guinea pig atrium.

The K+ channel openers cromakalim and pinacidil induced a concentration-dependent reduction in atrial contraction force with EC50 values of 25 +/- 2 and 37 +/- 2 mumol/l, respectively. This depressant effect was antagonised by 50 mumol/l tacrine which displaced the concentration-response curves of cromakalim and pinacidil to the right. The respective DR50 values were 3.8 and 2.3. Increasing the tacrine concentration (100 and 500 mumol/l) produced no additional effect on the concentration-response relationships. Addition of 1 mumol/l atropine enhanced the antagonism due to tacrine by increasing the DR50 value from 3.8 to 6.5 for cromakalim and from 2.3 to 5.2 for pinacidil. Glibenclamide, an ATP-sensitive K+ channel blocker, competitively inhibited the negative inotropic effects of cromakalim and pinacidil. The respective dissociation constants for glibenclamide against cromakalim and pinacidil were 0.57 and 0.35 mumol/l. Neither apamin nor variation in external Ca2+ concentration affected the negative inotropic effects of the K+ channel openers. It was suggested that the mechanical effects of cromakalim and pinacidil are mediated through the ATP-sensitive K+ channels in the heart.

Adenosine Triphosphate↗

PubMed1994

Comparative effects of the potassium channel openers cromakalim and pinacidil and the cromakalim analog U-89232 on isolated vascular and cardiac tissue.

ATP-sensitive potassium (K+ATP) channel openers such as cromakalim and pinacidil exhibit both potent vasodilatory and anti-ischemic properties. U-89232, a cyanoguanidine analog of cromakalim, has recently been found to exhibit myocardial protection during ischemia without altering in vivo hemodynamics. We examined the effects of U-89232, cromakalim and pinacidil in isolated vascular and cardiac tissue and tested whether glyburide, a KATP channel blocker, could antagonize their effects. All three compounds produced concentration-dependent relaxation in isolated vascular segments, with cromakalim being approximately 100-fold more potent than either pinacidil or U-89232. Glyburide completely antagonized the effects of pinacidil but merely blunted the effects of cromakalim and U-89232. In an isolated rabbit cardiac tissue preparation, U-89232 had little effect on maximum tension in cardiac muscle, whereas cromakalim and pinacidil significantly decreased maximum developed tension in a concentration-dependent manner. Glyburide effectively antagonized the effects of cromakalim and pinacidil in cardiac tissue. These data suggest that U-89232, although chemically related to cromakalim, possesses activity which is not common to known potassium channel openers.

Animals↗

PubMed1994

Effect of cromakalim and pinacidil on 86Rb efflux from guinea pig urinary bladder smooth muscle.

86Rb efflux assay was used to investigate the effect of cromakalim, pinacidil and P1075 in guinea pig urinary bladder strips. The type of K channel opened by cromakalim and pinacidil was determined using specific K channel blockers through 86Rb efflux assay in detrusor strips. Cromakalim, pinacidil and P1075 all three potassium channel openers (PCOs) evoked a concentration-dependent increase in 86Rb efflux in bladder strips. This increase in isotope release was inhibited by pretreatment of bladder with 10 and 30 microM glibenclamide suggesting that both cromakalim and pinacidil interact with ATP-sensitive K channels (KATP). Further, an increase in basal 86Rb efflux was observed when 2-deoxy-D-glucose was substituted for glucose together with 0.24 micrograms/ml of oligomycin (known to lower intracellular ATP) indicating the presence of KATP channels in bladder smooth muscle. Charybdotoxin and apamin, blockers of large and small conductance Ca(2+)-dependent K channels, were found not to be involved in the action of these PCOs in bladder strips. alpha-Dendrotoxin, known to block voltage-dependent K channels, slightly reduced pinacidil-induced 86Rb release without affecting cromakalim-induced 86Rb efflux. The present studies show that ATP-sensitive K channels are present in guinea pig urinary bladder and that cromakalim and pinacidil act by opening these ATP-sensitive K channels in detrusor strips.

Adenosine Triphosphate↗

PubMed1988

Comparative effects of nitroprusside and pinacidil on myocardial blood flow and infarct size in awake dogs with acute myocardial infarction.

The effect of nitroprusside in limiting myocardial infarct was compared with that of pinacidil, a new antihypertensive agent with potent coronary vasodilator properties, in instrumented awake dogs subjected to 4 hr of left anterior descending coronary artery occlusion and 20 hr of reperfusion. Dogs were randomly assigned to receive intravenous normal saline, nitroprusside, or pinacidil beginning 40 min after the onset of coronary artery occlusion and continuing throughout the occlusion and the first hour of reperfusion. Nitroprusside and pinacidil were titrated to decrease mean aortic pressure by 25 mm Hg; normal saline had no effect on mean aortic pressure. Other systemic hemodynamic variables were not significantly altered by normal saline or nitroprusside, and myocardial blood flow did not change during normal saline infusion in normal and ischemic myocardium. In contrast, nitroprusside increased the blood flow and the endocardial/epicardial flow ratio in ischemic myocardium. This increase in ischemic myocardial blood flow was accompanied by a significant reduction in infarct size (40 +/- 3% of region at risk vs 58 +/- 4% in the normal saline group; p less than .05). Pinacidil increased heart rate, cardiac output, and the peak rate of rise of left ventricular pressure. Furthermore, despite causing a threefold to fourfold increase in normal myocardial blood flow, pinacidil had no effect on either blood flow to ischemic myocardium or infarct size (57 +/- 5%). The data indicate that the marked coronary vasodilator effect of pinacidil does not cause an increase in ischemic blood flow or a reduction in infarct size.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1988

Effects of an antihypertensive vasodilator, pinacidil, on regional blood flow in conscious spontaneously hypertensive rats.

Using a radioactive microsphere method, the effects of hydralazine and a new antihypertensive vasodilator, pinacidil, on systemic and regional hemodynamics were examined and compared in conscious Wistar Kyoto rats (WKY) and spontaneously hypertensive rats (SHR). A single intravenous administration of pinacidil decreased mean blood pressure in a dose dependent fashion (0.03-0.3 mg/kg), and the peak effect was observed within a few minutes after administration. The onset of the hypotensive action of hydralazine was relatively slow compared to that of pinacidil, and its peak effect appeared 5-10 min after administration. There was no difference between WKY and SHR in the time course of blood pressure change, but the pressure reduction in WKY was less than that in SHR. We observed regional hemodynamic differences between the normotensive rats and the hypertensive rats. The flow rates in the kidney, spleen, gastrointestinal tract and skin of SHR were significantly lower than those of WKY. The intravenous infusion of pinacidil at a rate of 0.06 mg/kg/min increased cardiac output and heart rate, and selectively increased flow rates in organs with low flow rates compared to normotensive controls except for the spleen. Thus, pinacidil reduced total peripheral resistance of SHR to levels of WKY and normalized hemodynamic abnormalities in SHR. The regional hemodynamic action of pinacidil in SHR was not qualitatively different from that of hydralazine except in a few organs.

Animals↗

PubMed1989

A study on the hypotensive mechanism of pinacidil: relationship between its vasodilating effect and intracellular Ca2+ levels.

The direct effect of pinacidil on contractile protein systems and the relationship between its vasodilating effects and intracellular Ca2+ concentration were studied in isolated smooth muscle of guinea pigs. Pinacidil, nifedipine and hydralazine did not inhibit Ca2+-induced contracture in saponin-treated taenia caecum of guinea pig, while trifluoperazine and W-7 markedly suppressed it. Simultaneous determination of the intracellular Ca2+ concentration (fura 2 method) and tension development of the isolated femoral artery of guinea pigs showed that the intracellular Ca2+ level always decreased before vasorelaxation after pinacidil or nifedipine administration. Pinacidil showed no effect on cyclic AMP or cyclic GMP contents in rabbit aortic strips. These results indicate that pinacidil, like nifedipine and hydralazine, do not seem to directly act on the process from the formation of Ca2+-calmodulin to the actinmyosin interaction in the contracting mechanism of vascular smooth muscle, and that pinacidil relaxes the vascular smooth muscle by decreasing intracellular Ca2+-levels without elevating cyclic nucleotides.

Animals↗

PubMed2002

Inhaled pinacidil, an ATP-sensitive K+ channel opener, and moguisteine have potent antitussive effects in guinea pigs.

We investigated whether inhaled pinacidil and moguisteine inhibit capsaicin-induced coughs in guinea pigs. Inhaled pinacidil (15 - 60 microg/ml), an ATP-sensitive K+ channel opener, and moguisteine (15 - 60 microg/ml) each dose-dependently inhibited the number of capsaicin-induced coughs. The antitussive effects of pinacidil and moguisteine were significantly antagonized by pretreatment with glibenclamide (10 mg/kg, i.p.), an ATP-sensitive K+ channel blocker. However, pretreatment with naloxone methiodide (10 mg/kg, s.c.) had no significant effect on the antitussive effects of either pinacidil or moguisteine. On the other hand, inhaled dihydrocodeine (15 - 60 microg/ml) also dose-dependently suppressed the number of capsaicin-induced coughs. The antitussive effect of inhaled dihydrocodeine was significantly antagonized by pretreatment with naloxone methiodide (10 mg/kg, s.c.), but not by glibenclamide (10 mg/kg, i.p.). These results indicate that inhaled pinacidil and moguisteine both attenuate capsaicin-induced coughs. Pinacidil and moguisteine may exert their antitussive effects through the activation of ATP-sensitive K+ channels in the tracheobronchial tract. Furthermore, it is possible that ATP-sensitive K+ channels may be involved in the antitussive effects of peripherally acting non-narcotic antitussive drugs.

Adenosine Triphosphate↗

PubMed1999

[Pre- and postsynaptic action of the ATP-dependent K+-channel-(K+ATP)-opener pinacidil in rabbit pulmonary artery].

Low frequency (2 Hz) of electrical depolarisation induced [3H]noradrenaline ([3H]NA) release has been measured from the isolated main pulmonary artery of the rabbit in the presence of uptake blockers (cocaine, 3x10(-5)M and corticosterone, 5x10(-5)M), with parallel measurements of post-junctional contractile responses. The K+ATP-channel opener pinacidil (10(-6)-10(-4)M), slightly potentiated the nerve-evoked release of [3H]NA which failed to show close concentration-dependency. Large concentration of pinacidil (10(-4)M) increased the ratio of [3H]NA release from 0.99 +/- 0.02 to 1.28 +/- 0.05 (P < 0.0005). On the other hand, pinacidil inhibited the nerve-evoked contractions in a concentration-dependent manner. 10(-4)M caused nearly 70% inhibition of contractile response. The pre- and post-junctional effects of pinacidil were studied under the following experimental conditions: 1) exogenously applied 1-NA; 2) excess K+; 3) 'L-type' Ca(2+)-channel activation (BAY K 8644); K(+)-channel inhibition (4-AP); and 5) Na(+)-pump inhibition/reactivation. Pinacidil (10(-4)M) retained its marginal NA-release stimulatory effect in all cases. However, pinacidil inhibited the contraction of smooth muscle, although to a different extent, in all of the experimental conditions used in our study.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMedDate not supplied

Gender differences in effects of pinacidil but not diazoxide on heart automatism in the isolated guinea pig right atria.

UNLABELLED: The aim of this paper was to investigate the effects of pinacidil and diazoxide, the activators of sarcolemmal and mitochondrial ATP-sensitive K(+) channels (K(ATP)), respectively, on heart rate and force of contraction in female and male guinea pigs. Experiments were performed on the isolated, spontaneously beating, right atria obtained from guinea pigs of both genders. First series of experiments were performed in the spring and repeated in the fall. It was found that diazoxide induced similar negative chronotropic effects in females (-logIC(50) = 4.34 +/- 0.05, E(max) = -90 +/- 6 beats min(-1)) and males (-logIC(50) = 4.42 +/- 0.1, E(max) = -91 +/- 6 beats min(-1)). Additionally, significant positive inotropic effect sensitive to 5-hydroxydecanoate was noted only in males (about 30% above control level at 300 microM). No differences in effects of diazoxide in the spring and in the fall were noted. On the other hand, pinacidil induced significant decrease in heart rate in female guinea pigs only in the fall (-logIC(50) = 4.79 +/- 0.15, E(max) = -77 +/- 9 beats min(-1)), but in males similar negative chronotropic action in the spring (-logIC(50) = 4.53 +/- 0.12, E(50) = -63 +/- 5 beats min(-1)) and in the fall (-logIC(50) = 4.75 +/- 0.2, E(max) = -59 +/- 8 beats min(-1)) was observed. Glibenclamide (10 microM), but not 5-hydroxydecanoate (300 microM) reversed negative chronotropic action of both, pinacidil and diazoxide. No significant inotropic action of pinacidil was observed. CONCLUSIONS: Although negative chronotropic effects of pinacidil and diazoxide are related to activation of sarcolemmal K(ATP) channels, only pinacidil affects heart rate of female and male guinea pigs in a different way. This difference is probably hormone-dependent as it appeared only in the spring.

Adenosine Triphosphate↗

PubMed2005

Effects of calcium channel blocker, mibefradil, and potassium channel opener, pinacidil, on the contractile response of mid-pregnant goat myometrium.

The present study was undertaken to investigate the in vitro influence of mibefradil, a calcium channel blocker, and pinacidil, a potassium channel opener, on pregnant goat myometrial spontaneous rhythmic contractility and contractions induced with the agonist, oxytocin. Longitudinal strips from the distal region of uterus, collected from goats at midgestation, were mounted in an organ bath for recording isometric contractions. Mibefradil (10(-8)-10(-4) M) or pinacidil (10(-10)-10(-4) M), added cumulatively to the bath at an increment of 1 log unit, caused concentration-dependent inhibition of the spontaneous rhythmic contractions of isolated uterine strips. The rhythmic contraction was, respectively, abolished at 100 and 10 microM concentrations of mibefradil and pinacidil. In a concentration-dependent manner, mibefradil (1 and 10 microM) antagonized the contractions elicited with oxytocin (10(-5)-10(-2) IU). Pretreatment of uterine strips with glibenclamide (10 microM), a selective KATP channel blocker, caused a rightward shift of the concentration-response curve of pinacidil with a concomitant decrease in its pD2 value. Pinacidil (0.3, 1 and 3 microM), in a concentration-related manner, antagonized the oxytocin (10(-5)-10(-2) IU)-induced contractile response. The inhibition of spontaneous rhythmic contractions and antagonism of oxytocin-induced contraction by mibefradil in the pregnant goat myometrium may be related to the antagonism of voltage-dependent Ca2+ channels, while by pinacidil suggests that KATP channel could be a therapeutic target for tocolysis.

Adenosine Triphosphate↗

PubMed1988

Pinacidil: history, basic pharmacology, and therapeutic implications.

Peripheral vasodilation has proved to be a successful method to control hypertension in recent years, as illustrated by the increasing number of marketed vasodilators like calcium antagonists, alpha-adrenergic antagonists, and angiotensin-converting enzyme inhibitors. A novel group of vasodilators showing excellent antihypertensive activity in spontaneously hypertensive rats and renal hypertensive dogs has been discovered. The first compounds of the group were pyridylthioureas. Chemical modification based on structure-activity studies involving a substitution of N-cyanoguanidine for the less active thiourea function has led to the synthesis of pinacidil, N'-cyano-N-(4-pyridyl)-N"-(1,2,2-trimethylpropyl) guanidine, recently introduced as the new antihypertensive drug, Pindac. Preclinical studies showed that pinacidil does not relax vascular smooth muscle by any known mechanism, but recent investigations indicate that the compound opens potassium channels in the cell membranes. The hyperpolarization that follows is responsible for the relaxation. Pinacidil is rapidly and almost completely absorbed after oral administration and produces a dose-dependent blood pressure fall in hypertensive animals and humans. The therapeutic plasma concentrations are in the range of those producing relaxation of isolated, noradrenalin-contracted human blood vessels in vitro. In dogs, pinacidil decreases vascular resistance in most tissues proportionally to the blood pressure fall, but elicits a specific increase in coronary blood flow at antihypertensive doses. The compound shows a selectivity for precapillary vessels. It is mainly eliminated by hepatic metabolism to pinacidil-N-oxide followed by renal excretion, and the N-oxidation is partly reversible. Pinacidil is relatively free of toxicity, and action-related side effects such as fluid retention and tachycardia are readily controlled with diuretics and beta-blockers.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1989

Similarities between the effects of pinacidil and diazoxide on ionic and secretory events in rat pancreatic islets.

The present study aimed at comparing the effects of pinacidil, a putative K+ channel opener, and diazoxide on ionic and secretory events in rat pancreatic islets. Pinacidil and diazoxide provoked a dose-dependent increase in 86Rb outflow from pancreatic islets perifused in the presence of glucose. Both drugs inhibited the glucose- and tolbutamide-induced increase in 45Ca outflow and insulin release whereas failing to affect the ionic and secretory responses to K+ depolarization. Pinacidil and diazoxide, in contrast to quinine, failed to affect 86Rb outflow from pancreatic islets stimulated by the Ca++-ionophore A23187. Pinacidil as well as diazoxide abolished the glucose-induced increase in [Ca++]i but did not modify the rise in [Ca++]i provoked by KCl. Lastly, both drugs were shown to stimulate an ouabain-resistant modality of 86Rb inflow into the islet cells. The close similarities between the ionic and secretory events mediated by pinacidil and diazoxide suggest that pinacidil could interfere with the same target site as diazoxide; namely the beta-cell ATP-sensitive K+ channel.

Animals↗