SEARCH · PubMed Health

Results for “Pinacidil”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 37 records · Page 2Linked to original sources

PubMed1994

Glibenclamide enhances but pinacidil reduces attenuation in sympathetic responsiveness after acute coronary artery occlusion.

To investigate the role of ATP-sensitive K+ channels in modulating the efferent autonomic response following acute myocardial ischemia/infarction, we examined the effects of a blocker (glibenclamide) and an opener (pinacidil) of ATP-sensitive K+ channels on the time course and extent of the attenuation in efferent cardiac sympathetic responsiveness in anesthetized dogs. We measured the effective refractory periods (ERPs) at nonischemic sites basal and apical to the area of myocardial ischemia/infarction in the baseline state and during bilateral stimulation of the ansae subclaviae before and after each drug administration and 5, 30, 60, 120, and 180 minutes after latex injection of a diagonal branch of the left anterior descending coronary artery. Animals received either vehicle (n = 12), glibenclamide (0.3 mg.kg-1, n = 10), pinacidil (0.15 mg.kg-1 + 0.2 mg.kg-1 infusion, n = 10), or a combination of these two drugs (n = 9) intravenously. In another group of dogs receiving just pinacidil (n = 10), an intra-aortic balloon was inflated distal to the renal arteries to prevent pinacidil-induced hypotension. Another group of dogs received either high-dose glibenclamide (0.3 mg.kg-1 + 0.15 mg.kg-1, n = 4), low-dose glibenclamide (0.06 mg.kg-1, n = 4), medium-dose pinacidil (0.03 mg.kg-1 + 0.04 mg.kg-1 infusion, n = 4), or low-dose pinacidil (0.0075 mg.kg-1 + 0.01 mg.kg-1 infusion, n = 4). In all dogs, basal sites exhibited no attenuation of sympathetically induced shortening of the ERP throughout the period of acute myocardial ischemia/infarction. Cumulative attenuation in sympathetic responsiveness (shortening of ERP < or = 2 milliseconds induced by bilateral stimulation of the ansae subclaviae) at nonischemic test sites apical to the area of ischemia/infarction during a 3-hour period was greater in the glibenclamide group (26 of 44 sites, P = .008) and less in the pinacidil (2 of 44 sites, P = .002) and pinacidil-balloon (1 of 48 sites, P < .001) groups compared with the vehicle group (14 of 46 sites). Glibenclamide abolished the protective effect of pinacidil so that 10 of 45 sites had < 2-millisecond shortening during a 3-hour period in the glibenclamide + pinacidil group (P = .018 versus pinacidil group, P = .286 versus vehicle group). Such effects of glibenclamide and pinacidil on sympathetic attenuation were dose dependent. Maintaining the blood glucose level during glibenclamide administration did not affect the sympathetic attenuation after acute coronary artery occlusion.(ABSTRACT TRUNCATED AT 400 WORDS)

Acute Disease↗

PubMed1988

In vitro studies on the mode of action of pinacidil.

(+/-) Pinacidil inhibited noradrenaline-induced contractions in rat aorta and portal vein. The spontaneous tone of guinea-pig bronchial and taenia caeci muscles was relaxed and the spontaneous mechanical activity of rat portal vein was abolished. (+/-) Pinacidil abolished contractions produced by low concentrations of KCl in rat aorta and portal vein, but had relatively little effect on responses to high KCl concentrations. The mechano-inhibitory effects of (+/-) pinacidil were antagonised by tetraethylammonium or procaine. In studies with the purified enantiomers of pinacidil, (-) pinacidil was approximately 20 times more potent that (+) pinacidil. Measurements of electrical activity showed that low concentrations of (+/-) pinacidil selectively inhibited spontaneous electrical discharges in rat portal vein. The duration of multispike electrical complexes was shortened, but spike frequency within a complex and the rate of spike rise and fall were unaffected. At higher concentrations, a dose-dependent hyperpolarisation was observed in both rat aorta and portal vein and the membrane potential approached EK. Using both 86Rb and 42K, (+/-) pinacidil produced a concentration-dependent increase in isotope exchange which correlated with those concentrations at which electrical and mechanical inhibitory effects were observed. Using radioimmunoassay, no pinacidil-induced changes in cyclic AMP or cyclic GMP concentrations were detected in rat aorta. These electrical, ion flux and biochemical measurements suggest that the in vitro mechano-inhibitory effects of pinacidil are associated with the opening of 86Rb-permeable K+ channels in smooth muscle. These effects were observed at concentrations of pinacidil similar to those found in vivo in the plasma of experimental animals and man. It is thus concluded that the hypotensive and antihypertensive effects of pinacidil are the consequence of the cessation of ongoing electrical activity and hyperpolarisation which follows the opening of K+ channels in vascular smooth muscle.

Animals↗

PubMed1996

No deterioration of insulin secretion by the potassium channel opener pinacidil in essential hypertension.

Hypertension has been associated with hyperinsulinemia and insulin resistance. The elevations in plasma insulin are the apparent adaptation of the pancreatic beta cell to the resistance to insulin. Maintenance of normal insulin release is therefore of great importance for subjects with hypertension. The potassium channel opener pinacidil has antihypertensive properties. Pinacidil has been shown to inhibit Insulin release in vitro in isolated pancreatic beta cells. We therefore studied the acute effect of pinacidil on insulin secretion and insulin sensitivity in hypertensive and control subjects. The acute effect of pinacidil (25 mg, orally) on plasma insulin was studied during a hyperglycemic clamp (180 min, blood glucose 10 mmol/L) in 10 healthy volunteers and in 10 non-obese hypertensive patients in a randomised, placebo controlled double blind study. Fasting plasma insulin levels were 54.8 +/- 10.9 and 51.1 +/- 8.8 pmol/L in the control group and statistically significantly higher in the hypertensive group: 90.5 +/- 16.6 and 100.0 +/- 16.2 pmol/L (with and without pinacidil, respectively, both P < 0.02 vs control group). Plasma insulin levels rose to maximum levels of 246.7 +/- 44.6 and 267.2 +/- 56.2 pmol/L after 5 min in the control group (with and without pinacidil, respectively, NS) and to maximum levels of 248.9 +/- 37.3 and 238.0 +/- 39.1 pmol/L after 5 min in the hypertensive group (with and without pinacidil, respectively, NS). Areas under the insulin curve (AUCinsulin) of the first and second phase did not differ between the control and hypertensive group, with or without pinacidil. In the control and the hypertensive group separately no statistically significant effect of pinacidil on the mean glucose infusion rate/mean insulin level (M/I) ratio, a measure for insulin sensitivity, was shown. When both groups were taken together, an increase in the M/I ratio under the influence of pinacidil was found for the third hour of the clamp (P < 0.02). In conclusion, fasting insulin levels in the hypertensive subjects were significantly higher than in the control subjects. The potassium channel opener pinacidil did not influence insulin secretion in hypertensive patients and healthy controls. Pinacidil may have an enhancing effect on insulin sensitivity.

Adult↗

PubMed1990

Inhibition by the putative potassium channel opener pinacidil of the electrically-evoked release of endogenous dopamine and noradrenaline in the rat vas deferens.

The effect of pinacidil on the release of endogenous noradrenaline and dopamine from the sympathetic innervation of the rat vas deferens was examined. Amine release was evoked by electrical stimulation (1, 2, 5 and 10 Hz) or by depolarization with high potassium (75 mmol/l) in the medium. Dopamine and noradrenaline were measured by means of high pressure liquid chromatography with electrochemical detection. Pinacidil (1, 5, 10 and 50 mumol/l) produced a concentration-dependent inhibition of the electrically stimulated (2 Hz) overflow of noradrenaline and dopamine. Only pinacidil 50 mumol/l increased the spontaneous loss of dopamine and noradrenaline. The inhibitory effects of pinacidil (5 mumol/l) on amine overflow were also observed at other frequencies of stimulation (1, 5 and 10 Hz). The magnitude of the inhibitory effect on noradrenaline release was approximately the same at all frequencies (63% to 56% reduction); for dopamine, the higher the frequency of stimulation, the greater the inhibitory effect of pinacidil (up to 73% reduction). When the preparations were continuously stimulated for 70 min at 2 Hz, pinacidil (5 mumol/l) reduced the overflow of dopamine and noradrenaline during the first 40 or 30 min of stimulation only. The addition of phentolamine (1 mumol/l) to the perifusion medium slightly reduced the inhibitory effect of pinacidil on amine overflow, but the inhibition by pinacidil remained statistically significant. Tetraethylammonium (10 mmol/l) completely abolished the inhibitory effect of pinacidil (10 mumol/l). Pinacidil (5 mumol/l) did not reduce the potassium-evoked release of the amines. The results demonstrate that pinacidil impairs transmitter release from the sympathetic innervation of the rat vas deferens, probably as a consequence of the opening of potassium channels.

Animals↗

PubMed1991

Analysis of cromakalim-, pinacidil-, and nicorandil-induced relaxation of the 5-hydroxytryptamine precontracted rat isolated basilar artery.

The effects of the K+ channel activators cromakalim, pinacidil, and nicorandil were investigated in endothelium intact, 5-hydroxytryptamine (5-HT) precontracted rat isolated basilar artery. Cromakalim, pinacidil, and nicorandil produced concentration-dependent relaxation of rat isolated basilar artery precontracted with 5-HT with a rank order of potency of cromakalim greater than pinacidil greater than nicorandil. All compounds produced full or nearly full relaxation. The calculated Hill coefficients for cromakalim-, pinacidil-, and nicorandil-induced relaxation of 5-HT-precontracted rat isolated basilar artery were 2.20 +/- 0.36, 1.30 +/- 0.07, and 1.00 +/- 0.01, respectively. Under conditions of increased tone produced by 50 mmol/l KCl (which inhibits cromakalim-induced relaxation) pinacidil and nicorandil produced marked reversal of spasm, with pinacidil being more potent than nicorandil. In arteries precontracted with 5-HT, preincubation with glibenclamide (0.1-1 mumol/l) produced concentration-related inhibition of relaxation with calculated mean pA2 values (and slopes of Schild regression) +/- SEM of 6.84 +/- 0.20 (1.1 +/- 0.20) against cromakalim. 6.60 +/- 0.14 (0.95 +/- 0.23) against nicorandil, and 6.57 +/- 0.26 (1.04 +/- 0.18) against pinacidil. For cromakalim, pinacidil, and nicorandil the slopes of Schild regression were not significantly different from unity. Tolbutamide 10 mumol/l was without effect against the cromakalim-, pinacidil-, or nicorandil-induced relaxation. Tetraethylammonium (TEA; 1-10 mmol/l) produced noncompetitive inhibition of the cromakalim-induced relaxation, but appeared to produce competitive inhibition of the pinacidil- and nicorandil-induced relaxations. We conclude that cromakalim, pinacidil, and nicorandil produce relaxation of the 5-HT precontracted rat basilar artery by similar mechanisms to those identified in other peripheral vascular and visceral smooth muscle.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2004

Donor heart preservation with pinacidil: the role of the mitochondrial K ATP channel.

BACKGROUND: Pinacidil solutions have been shown to have significant cardioprotective effects. Pinacidil activates both sarcolemmal and mitochondrial potassium-adenosine triphosphate (K(ATP)) channels. This study was undertaken to compare pinacidil solution with University of Wisconsin (UW) solution and to determine if the protective effect of pinacidil involved mitochondrial or sarcolemmal K(ATP) channels. METHODS: Thirty-two rabbit hearts received one of four preservation solutions in a Langendorff apparatus: (1) UW; (2) a solution containing 0.5 mmol/L pinacidil; (3) pinacidil with Hoechst-Marion-Roussel 1098 (HMR-1098), a sarcolemmal channel blocker; and (4) pinacidil with 5-hydroxydecanote, a mitochondrial channel blocker. Left ventricular pressure-volume curves were generated by an intraventricular balloon. All hearts were placed in cold storage for 8 hours, followed by 60 minutes of reperfusion. RESULTS: Postischemic developed pressure was better preserved by pinacidil than by UW. This cardioprotective effect was eliminated by 5-hydroxydecanote and diminished by HMR-1098. Diastolic compliance was better preserved by pinacidil when compared with UW. This protection was abolished by the addition of 5-hydroxydecanote and moderately decreased by HMR-1098. CONCLUSIONS: Our results support the superiority of pinacidil over UW after 8 hours of storage. The cardioprotective role of pinacidil is mediated primarily by the mitochondrial K(ATP) channel.

Adenosine↗

PubMed1988

The relation between vascular relaxant and cardiac electrophysiological effects of pinacidil.

Pinacidil may represent an example of a new class of vasodilators that act by increasing membrane permeability to potassium ions. In the present study, the cardiac electrophysiological and venorelaxant effects of a series of pinacidil analogs in canine tissues in vitro were examined. Piacidil (3 x 10(-5) M) markedly reduced action potential duration in Purkinje fibers (82 +/- 3% decrease) and ventricular muscle (54 +/- 2% decrease) without significantly affecting maximal upstroke velocity of the action potential or conduction time. The EC50 for the reduction in Purkinje fiber action potential duration was 2.6 +/- 0.5 microM. Pinacidil also decreased barium-induced automaticity in Purkinje fibers; the concentration that decreased the rate of firing by 50% was identical to the EC50 for decreasing action potential duration. In some preparations, high concentrations of pinacidil (greater than or equal to 3 x 10(-5) M) were associated with the appearance of spontaneous action potentials that were closely coupled to the preceding driven action potential. The EC50 for pinacidil in relaxing phenylephrine-contracted cephalic veins was 0.43 +/- 0.09 microM, and in isolated cat papillary muscle, pinacidil had a direct negative inotropic effect with an EC50 of 4.1 +/- 0.7 microM. Thus, pinacidil was 6 and 10 times more potent in relaxing phenylephrine-contracted veins than in shortening action potential or decreasing cardiac contractility. There was an excellent correlation (r = 0.933, p = 0.002) between decreases in action potential duration and venorelaxation for all pinacidil analogs, as well as for BRL 34915 and nicorandil, two purported potassium channel openers. Significant correlations were also obtained between negative inotropic effects and reductions in action potential duration for the pinacidil series. Pinacidil (10(-5) M) also inhibited the venoconstrictor responses to the selective alpha 2 agonist, B-HT 920, to a greater extent than the alpha 1 agonist, methoxamine. Since a good correlation exists in vitro among all the compounds studied in reducing action potential duration, relaxing vascular tissue, and decreasing cardiac contractility, it is concluded that pinacidil as well as nicorandil and BRL 34915 affect vascular and cardiac tissues by similar mechanisms, possibly by increases in potassium ion permeability, although other mechanisms may also play a role.

Action Potentials↗

PubMed1990

Pinacidil inhibits neuromuscular transmission indirectly in the guinea-pig and rabbit mesenteric arteries.

1. Effects of pinacidil were investigated on neuromuscular transmission in smooth muscle tissues of the rabbit and guinea-pig mesenteric arteries by both electrophysiological procedures and a bioassay of noradrenaline (NA) outflows. 2. Pinacidil (over 1 microM) hyperpolarized smooth muscle cell membranes in both tissues, in a concentration dependent manner. Pinacidil hyperpolarized and increased the ionic conductance of smooth muscle membrane more markedly in the rabbit mesenteric artery than in the guinea-pig. The hyperpolarization induced by pinacidil occurred in the presence or absence of endothelial cells and was blocked by glibenclamide. 3. Perivascular adrenergic nerve stimulation produced excitatory junction potentials (e.j.ps) and repetitive stimulation produced a facilitation of e.j.ps in both tissues. Pinacidil (over 1 microM) reduced the amplitude and the decay time of e.j.ps to a consistently greater extent in the rabbit mesenteric artery than in the guinea-pig. However, the facilitation process of e.j.ps was not modified following application of pinacidil (1 microM). The pinacidil-induced inhibition of e.j.ps was prevented by pretreatment with glibenclamide. 4. Pinacidil (30 microM) marginally increased the overflows of NA and its metabolite, 3,4-dihydroxyphenylglycol (DOPEG) released following repetitive perivascular nerve stimulations. 5. Pinacidil (10 microM) partly inhibited the voltage-dependent Ca channel, as estimated from the recovery process following removal of pinacidil, of action potentials evoked on e.j.ps. 6. It is concluded that pinacidil increases ionic conductance and hyperpolarizes smooth muscle cell membranes of the guinea-pig and rabbit mesenteric arteries and as a consequence, inhibits the neuromuscular transmission process occurring on adrenergic nerve stimulation with no reduction in the amount of released transmitter.

Animals↗

PubMed1994

Selective in vivo antagonism of pinacidil-induced hypotension by the guanidine U37883A in anesthetized rats.

The pyridylcyanoguanidine pinacidil exerts its hypotensive effect by opening ATP-sensitive potassium channels (K+ATP) in vascular smooth muscle. Direct glyburide-like antagonism of pinacidil-induced vasorelaxation by the guanidine U37883A (4-morpholinecarboximidine-N-1-adamantyl-N'- cyclohexylhydrochloride) has recently been demonstrated in isolated rabbit mesenteric artery. We herein report the first detailed in vivo cardiovascular interaction between U37883A and pinacidil in an anesthetized rat model. U37883A, administered from 0.1 to 3.0 mg/kg i.v. 10 min subsequent to pinacidil, immediately and dose-dependently reversed pinacidil's steady-state hypotensive effects by 29-100% (ED50 = 0.4 mg/kg), while reversal of pinacidil's tachycardiac effects from 10 to 79% was evident with 0.1-1.0 mg/kg i.v. U37883A (ED50 = 0.5 mg/kg). In contrast to these effects, pretreatment with 0.3-3.0 mg/kg i.v. U37883A only moderately inhibited the acute pinacidil-induced hypotension by 6-58%. Because U37883A's separate bradycardiac effects lowered basal heart rate, U37883A pretreatment precipitated a paradoxical 15-51% augmentation of sustained pinacidil-induced tachycardia, although absolute heart rates were below those seen with pinacidil alone. Qualitatively similar K+ATP blocking effects by U37883A were also observed in rats treated with the K+ATP openers (PCOs) cromakalim (BRL 34915), RPS 49365 and minoxidil. However, U37883A-treated rats remained responsive to the hypotensive action of both i.v. sodium nitroprusside and isoproterenol and buccal nifedipine. This study corroborates prior in vitro and in vivo findings and establishes that the guanidine U37883A is an effective and relatively selective blocker of PCO-induced vasodilation in the anesthetized rat. U37883A also appears more effective at closing basally and pinacidil-opened K+ATP than preventing K+ATP opening by pinacidil in vivo.

Adamantane↗

PubMed1990

Pinacidil. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic potential in the treatment of hypertension.

Pinacidil is an orally administered antihypertensive drug that acts via direct relaxation of vascular smooth muscle to produce peripheral vasodilatation and a reduction in blood pressure without significant direct effects on cardiac electrophysiology. Pinacidil is unrelated to other antihypertensive drugs in clinical use, either in structure or mechanism of action. It belongs to a new class of agents called 'potassium channel openers' which act via potassium efflux to hyperpolarize cell membranes, indirectly causing a net reduction in intracellular calcium that leads to relaxation of vascular smooth muscle. Pinacidil is indicated in the management of essential hypertension. In clinical trials of up to 1 year duration, pinacidil administered twice daily in a controlled release capsule formulation has been shown to achieve adequate blood pressure control both in previously untreated patients and in those with blood pressure inadequately controlled by beta-adrenoceptor blocking drugs or thiazide diuretics. In long term (up to 1 year) comparative studies pinacidil was at least as effective as hydralazine, prazosin or nifedipine in maintaining blood pressure control. Pinacidil may also have a potential use in the treatment of patients with secondary renal hypertension. Clinical trials to date have usually allowed the addition of a thiazide diuretic and/or beta-adrenoceptor blocking drug to enhance the efficacy of pinacidil and/or to reduce the incidence of adverse effects. The main adverse effects of pinacidil treatment, which result from its peripheral vasodilator activity, are headache, oedema, palpitations and tachycardia. Although the overall incidence of adverse effects is quite high, they are usually mild, transient in nature and respond to a reduction in dose. Nevertheless, these effects may occasionally be severe, necessitating withdrawal from therapy. Thus, pinacidil is an effective antihypertensive drug for the treatment of mild to moderate essential hypertension. Despite its novel mechanism of action pinacidil causes adverse effects typical of peripheral vasodilators; during long term use with twice daily administration of the controlled release capsule formulation, the addition of a diuretic is often necessary to attenuate peripheral oedema and maintain adequate control of blood pressure. Further long term controlled trials are needed to determine the precise role of pinacidil relative to that of the angiotensin converting enzyme (ACE) inhibitors and calcium channel blocking drugs.

Animals↗

PubMed1992

Effect of pinacidil on the membrane electrical activity of guinea pig detrusor muscle.

The effects of pinacidil on the guinea pig detrusor smooth muscle membrane were studied to investigate the electrophysiological mechanisms by which this drug relaxes smooth muscle tissue and, thus, might be of value in the treatment of detrusor instability. Pinacidil (> or = 3 x 10(-7) M) hyperpolarized the membrane in a concentration-dependent manner, with a reduction in spontaneous spike discharges. The membrane hyperpolarization induced by pinacidil was consistently associated with an increase in membrane ionic conductance. Glybenclamide (10(-6) M) completely inhibited the membrane hyperpolarization induced by pinacidil (up to 10(-5) M). Membrane hyperpolarization with pinacidil was consistently greater in a low-K+ solution, and it decreased in the presence of a high-K+ solution, compared with that measured in normal Krebs solution. Pinacidil consistently suppressed carbachol-induced depolarization of the membrane, with a reduction in the frequency of spontaneous action potentials. Glybenclamide (10(-6) M) did not inhibit the effect of pinacidil on increased action potential frequency induced by carbachol but blocked the membrane hyperpolarization induced by pinacidil (10(-5) M). In addition, the amplitude and maximum velocity of depolarization of carbachol- and current-induced action potentials were significantly decreased by pinacidil in the presence of glybenclamide. These results suggest that pinacidil blocks action potential generation in detrusor smooth muscle by inducing membrane hyperpolarization secondary to an increase in K+ permeability. Pinacidil, at high concentrations (> or = 10(-5) M), might block action potentials by inhibiting the voltage-sensitive Ca++ influx independently of hyperpolarization of the membrane. These mechanisms might be of benefit therapeutically in relaxation of unstable detrusor contractions.

Animals↗

PubMed1988

Disposition of [14C]pinacidil in humans.

Pinacidil [(+/-)-2-cyano-1-(4-pyridyl)-3-(1,2,2-trimethylpropyl)guanidine monohydrate] is a novel, direct-acting vasodilator antihypertensive agent. The cyano 14C-labeled drug is rapidly and completely absorbed after an oral 12.5-mg dose in solution. The blood:plasma concentration ratios (0.8-0.9) indicate transient penetration of radioactivity into blood cells. Blood and plasma tmax (0.5 h) and t 1/2 (4 h) of [14C]pinacidil equivalents are similar. Pinacidil (51%), pinacidil N-oxide (28%), and unidentified polar metabolites (21%) comprise the plasma radioactivity. The plasma t 1/2 of pinacidil is 2-3 h, and that of pinacidil N-oxide is 4-5 h. Renal excretion of radioactivity is the major route (80-90% dose) of drug elimination; fecal elimination accounted for 4% of the dose. Renal clearance of the N-oxide is 10 times the renal clearance of the parent drug and exceeds the creatinine clearance. Biotransformation products in 0-24-h urine samples include pinacidil (10%), pinacidil N-oxide (60%), and free and conjugated analogues of pinacidil and metabolites (30%). Stereoselective metabolism is not a major biotransformation pathway of pinacidil or the N-oxide metabolite.

Adult↗

PubMed1994

Diverse effects of pinacidil on KATP channels in mouse skeletal muscle in the presence of different nucleotides.

OBJECTIVE: The potassium channel opener pinacidil relaxes smooth muscle and exerts cardioprotective effects. The aim of the study was to investigate the actions of pinacidil on ATP sensitive potassium channels (KATP channels) in mammalian skeletal muscle and to explore the interrelations of this drug with various nucleotides. METHODS: Single skeletal muscle fibres were prepared enzymatically from flexor digitorum brevis muscles of adult mice. Membrane patches of the inside-out configuration were excised in a Ca(2+)-free solution, and currents through single KATP channels were recorded at -40 mV. The cytoplasmic face of the patch was exposed to a K(+)-rich solution with MgCl2 (1 mM), and pinacidil (0.1 or 0.4 mM) and the nucleotides (0.1 mM) were added to this internal solution. RESULTS: KATP channels were not activated by pinacidil in the presence of the nonhydrolysable ATP analogue AMP-PNP, in contrast to the reported channel activation by pinacidil and ATP. KATP channels had a high activity in the control and were blocked by ADP; the subsequent addition of pinacidil did not enhance the open probability of KATP channels. Pinacidil in the presence of a mixture of AMP-PNP and ADP activated KATP channels. CONCLUSIONS: The diverse effects of pinacidil are interpreted with a model of the KATP channel containing a binding site for pinacidil and two sites for nucleotides, one activatory (A) site and one inhibitory (I) site. Occupation of the A site by ATP or ADP activates the channel, while occupation of the I site by ATP, AMP-PNP, ADP closes the channel. Pinacidil activates the channel and displaces blockers from the I site only if the A site is occupied.

Action Potentials↗

PubMed1990

Effect of pinacidil on myocardial blood flow in the presence of a coronary artery stenosis.

This study examined the effect of pinacidil on transmural distribution of myocardial blood flow during normal conditions and in the presence of a coronary artery stenosis. Studies were performed in 11 awake dogs; blood flow was measured with radioactive microspheres. Two doses of pinacidil were administered to decrease mean arterial pressure (MAP) by approximately 10 mm Hg (low dose, 0.18 +/- 0.02 mg/kg) and 20 mm Hg (high dose, 0.32 +/- 0.03 mg/kg). Measurements were performed during unimpeded arterial inflow and with two levels of coronary stenosis that limited blood flow to approximately 60% above (moderate stenosis) and approximately 30% above basal flow (severe stenosis). With no stenosis, coronary flow increased 227 +/- 17% after low-dose and 321 +/- 31% after high-dose pinacidil (each p less than 0.01). During control conditions, subendocardial (endo) flow exceeded subepicardial (epi) flow (endo/epi ratio = 1.33). This ratio was not changed by low-dose pinacidil but decreased to 0.93 after high-dose pinacidil (p less than 0.05). During high-dose pinacidil, a coronary stenosis caused uniform reduction of blood flow across the left ventricular wall, with no further significant change in the ratio of endo/epi flow. With low-dose pinacidil, both moderate and severe degrees of stenosis caused redistribution of flow away from the subendocardium similar to that observed with high-dose pinacidil. Although a stenosis that limited the increase in mean coronary flow after pinacidil administration to 162% of the predrug control value had a 95% probability of not causing a decrease in absolute subendocardial flow, the data suggest that pinacidil could have potential for aggravating subendocardial ischemia in severe occlusive coronary artery disease.

Animals↗

PubMed1991

Arterial vasodilating profile and biological effects of pinacidil in healthy volunteers.

1. The effects of pinacidil (25 mg, sustained release formulation) a) on systemic (arterial pressure, cardiac output) and regional (brachial and carotid arteries' diameters and flows) haemodynamics (pulsed Doppler techniques), b) on sympathetic (plasma noradrenaline) and renin-angiotensin (plasma renin activity) systems, and c) on atrial natriuretic factor have been investigated and compared with those of a placebo during the 12 h period following oral administration in a randomized, double-blind and cross-over study performed in six healthy volunteers. Simultaneously, the plasma levels of pinacidil and of its active metabolite, pinacidil N-oxide, were determined. 2. As compared with placebo, pinacidil decreased systemic vascular resistance and arterial blood pressure but cardiac output was not modified. 3. Pinacidil significantly increased brachial and carotid arteries' diameters (by 7 and 8% respectively) and flows (by 60 and 17% respectively) and decreased forearm vascular resistance (by 43%). Thus, pinacidil dilates both large and small arteries, increases large vessels' compliance and redistributes blood flow towards the muscular vascular bed. These effects peaked at 4 h and their duration at the brachial level was 8 h. 4. Pinacidil administration resulted in a stimulation of both sympathetic (increases in heart rate and plasma noradrenaline) and renin-angiotensin systems, and induced a transient increase in atrial natriuretic factor. 5. The duration of pinacidil haemodynamic effects at the brachial level is consistent with the pharmacokinetic data which show that pinacidil and pinacidil N-oxide plasma levels almost plateaued between 3 and 8, and 2 and 8 h respectively after oral administration of the sustained release formulation used.

Adult↗

PubMed1997

The effects of levcromakalim and pinacidil on the human internal mammary artery.

The present study was undertaken to examine the effects of pinacidil and levcromakalim, two potassium, channel openers, on human internal mammary artery (HIMA) obtained from patients undergoing coronary artery bypass surgery, and to clarify the contribution of different K+ channel subtypes in pinacidil and levcromakalim action in this blood vessel. Pinacidil and levcromakalim induced a concentration-dependent relaxation of the precontracted arterial segments (pEC50 = 5.77 +/- 0.05 and 6.89 +/- 0.03, respectively), 4-Aminopyridine (3 mM), a non-selective blocker of K+ channels, induced significant shifts to the right of the concentration-response curves for pinacidil and levcromakalim. Tetraethylammonium (6 mM), charybdotoxin (0.4 microM) and apamin (0.1 microM), blockers of Ca(2+)-sensitive K+ channels, had no effect on the pinacidil- and levcromakalim-evoked relaxation. Glibenclamide (0.1-10 microM), a selective blocker of adenosine triphosphate (ATP)-sensitive K+ channels, competitively antagonized the response to levcromakalim (pKB = 7.92 +/- 0.07). In contrast, glibenclamide, in significantly higher concentrations (3-30 microM), non-competitively antagonized the response to pinacidil. High concentrations of pinacidil (> 10 microM) relaxed arterial rings bathed by a medium containing 100 mM K+ with maximum response 83 +/- 6%. Under the same conditions, the maximum levcromakalim-induced relaxation on HIMA was almost abolished (15 +/- 2%). It is concluded that pinacidil and levcromakalim do not relax the HIMA through the same subtype of K+ channel. ATP-sensitive K+ channels are probably involved in levcromakalim- but not in a pinacidil-induced relaxation in the HIMA. In addition, in pinacidil-induced relaxation of the HIMA, K+ channel-independent mechanisms seem to be involved.

4-Aminopyridine↗

PubMed1991

Inhibition of aldosterone production by pinacidil in vitro.

Pinacidil, an antihypertensive agent that opens potassium channels, lowers plasma aldosterone levels in hypertensive patients by an unknown mechanism. In the present study, pinacidil's direct effects on production of aldosterone were assessed using isolated cells from bovine adrenal glomerulosa. Pinacidil was found to inhibit aldosterone production, both basally and during stimulation with either potassium, angiotensin II (Ang II), or adrenocorticotropic hormone (p less than 0.001), with half maximal inhibition occurring at 10(-5) M. As assessed by the exclusion of trypan blue from cells, pinacidil did not inhibit secretion through injurious effects on glomerulosa cells. Also, washing of cells previously exposed to pinacidil restored secretory responsiveness. Pinacidil did not alter cytosolic calcium (Ca2+) concentrations when aequorin was used as a photoluminescent indicator of Ca2+ levels, suggesting that pinacidil acted by a non-Ca(2+)-mediated mechanism. Consistent with direct inhibition of the late pathway in steroidogenesis was that pinacidil decreased conversion of pregnenolone and corticosterone to aldosterone. Pinacidil did not block binding of Ang II to its receptor, nor did it appear to affect adrenocorticotropic hormone-receptor binding, since stimulation by cyclic AMP, the post-receptor second messenger of adrenocorticotropic hormone, was also inhibited. In summary, pinacidil inhibited directly the adrenal's production of aldosterone. The mechanism whereby the inhibition occurred was unclear.

Adrenocorticotropic Hormone↗

PubMed1990

Interrelation between pinacidil and intracellular ATP concentrations on activation of the ATP-sensitive K+ current in guinea pig ventricular myocytes.

The patch-clamp technique was used to study the relation between pinacidil and intracellular ATP concentration [( ATP]i) on the activation of the outward K+ current in guinea pig ventricular myocytes. Pinacidil shortened the action potential duration, exhibiting stronger effect at 2 mM [ATP]i than at 5 mM [ATP]i. Pinacidil at 5 microM or higher concentrations activated the time-independent outward current at potentials positive to -80 mV, and the pinacidil-activated current was suppressed by increasing [ATP]i from 2 to 5 mM. The dose-response curve of pinacidil at different [ATP]i showed a shift to the right and a depression of the maximum response at increased [ATP]i. The pinacidil-induced shortening of the action potential duration and outward current were inhibited by application of 0.3-1.0 microM glibenclamide. In single-channel current recordings, pinacidil activated the intracellular ATP-sensitive K+ channel current without changing the unitary amplitude, and increased open probability of the channel, an effect dependent on [ATP]i. The pinacidil-activated single-channel current was blocked by glibenclamide. These results prove the notion that pinacidil activates the ATP-sensitive K+ channel current, which explains the action potential shortening in cardiac cells after application of pinacidil.

Action Potentials↗