Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Pinacidil”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 433 records · Page 24Linked to original sources
PubMed2006

[Effects of ATP-regulated potassium channels modulators, N-(2-pyridyl)-N'-(4-toluol) sulfonylcarbamides, on electromechanical activity in guinea pig myocardium].

The aim of the study was to investigate the effects of 2-aminopyridine (2-AP) and its new sulfonylcarbamide derivatives AP21, AP22, AP26, and AP27 (10(-(5))-10(-(3)) M) on pinacidil (5x10(-(5)) M), an activator of K(ATP) channels, induced shortening of action potential duration and reduction of contraction force in guinea pig papillary muscles. Experiments were carried out using a standard method of myocardium electromechanical activity registration. Under control conditions (perfusion of papillary muscles with Tyrode solution), an average of action potential duration (APD), measured at 90% (APD(90)) and 50% (APD(50)) of repolarization, were 211.78+/-8.6 ms and 173.22+/-8.3 ms (n=18), respectively, and contraction force was 1.77+/-0.36 mN (n=18). Pinacidil markedly decreased APD(90) to 58.16+/-4.4%, APD(50) - to 52.51+/-4.85% (n=18), and contraction force - to 30.45+/-4.06% (n=18), (p<0.001) vs. control. 2-aminopyridine and its sulfonylcarbamide derivative AP22 (with 4-toluolsulfonylcarbamide fragment and methyl iodide-quaternized nitrogen of the pyridine ring) had no effect on the pinacidil-induced shortening of action potential and reduction of contraction force. 2-aminopyridine derivatives, AP21 (with 4-toluolsulfonylcarbamide fragment) and AP26 (with allyl bromide-quaternized nitrogen of the pyridine ring), showed a weak effect on pinacidil-induced shortening of action potential duration. The 2-aminopyridine derivative AP27 (with the 4-toluolsulfonylcarbamide fragment where nitrogen of the pyridine ring was quaternized by 4-nitrobenzyl bromide) had the most potent stimulatory effect on action potential duration and contraction force, which were reduced by pinacidil.

Action Potentials↗
PubMed1995

ATP-sensitive K+ currents in cerebral arterial smooth muscle: pharmacological and hormonal modulation.

Calcitonin gene-related peptide (CGRP), hypoxia, and synthetic activators of ATP-sensitive potassium (KATP) channels (e.g., pinacidil and levcromakalim) cause dilation of cerebral arteries that are attenuated by the KATP channel inhibitor glibenclamide. We have identified and characterized KATP currents in smooth muscle cells isolated from rabbit cerebral arteries, using the whole cell configuration of the patch-clamp technique. Pinacidil (10 microM) and levcromakalim (10 microM) increased glibenclamide-sensitive currents about sixfold in cells dialyzed with 0.1 mM ATP. Glibenclamide-sensitive currents in the presence of pinacidil were potassium selective, voltage independent, and reduced about threefold by elevating intracellular ATP from 0.1 to 3.0 mM. External tetraethylammonium and 4-aminopyridine at millimolar concentrations reduced pinacidil-induced currents, whereas iberiotoxin, a blocker of calcium-activated potassium channels, had no effect. The vasoconstrictors serotonin and histamine also inhibited pinacidil-induced currents. The vasodilators CGRP and adenosine, in contrast, increased glibenclamide-sensitive potassium currents. We conclude that cerebral artery smooth muscle cells have KATP channels that are regulated by endogenous vasoconstrictors and vasodilators. We propose that these channels are involved in the dilation of cerebral arteries to CGRP and synthetic vasodilators.

4-Aminopyridine↗
PubMed1996

Protective Effects of Ranolazine on Ventricular Fibrillation Induced by Activation of the ATP-Dependent Potassium Channel in the Rabbit Heart.

BACKGROUND: The authors studied the antifibrillatory effects of the adenosine-triphosphate (ATP)-sparing metabolic modulator ranolazine in a rabbit isolated heart model in which ventricular fibrillation occurs under conditions of hypoxia/reoxygenation in the presence of the ATP-dependent potassium channel opener pinacidil. METHODS AND RESULTS: Ten minutes after ranolazine or vehicle administration, addition of pinacidil (1.25 µM) to the buffer was followed by a 12-minute hypoxic period and 40 minutes of reoxygenation. At a reduced concentration of ranolazine (10 µM), ventricular fibrillation occurred in 60% of the hearts, compared to 89% in the control group (P = NS). In contrast, only three of nine hearts (33%) treated with 20 µM ranolazine developed ventricular fibrillation (P <.05 vs vehicle). Hemodynamic parameters including coronary perfusion pressure, left ventricular developed pressure, and +/-dP/dt were not affected by the presence of ranolazine in the perfusion medium. Ranolazine did not prevent or modify the negative inotropic or coronary vasodilator actions of pinacidil, suggesting a mechanism of action independent of potassium channel antagonism. CONCLUSIONS: Ranolazine significantly reduced the incidence of ventricular fibrillation in the hypoxic/reoxygenated heart exposed to the ATP-dependent potassium channel opener, pinacidil. The reported ability of ranolazine to prevent the decrease in cellular ATP during periods of a reduced oxygen supply may account for its observed antifibrillatory action. By maintaining intracellular ATP, ranolazine may modulate or prevent further opening of the ATP-dependent potassium channel in response to hypoxia and/or pinacidil.

Journal Article↗
PubMed2000

Opening of potassium channels protects mitochondrial function from calcium overload.

Ischemic preconditioning (IPC) protects myocardium from ischemia reperfusion injury by activating mitochondrial K(ATP) channels. However, the mechanism underlying the protective effect of K(ATP) channel activation has not been elucidated. It has been suggested that activation of mitochondrial K(ATP) channels may prevent mitochondrial dysfunction associated with Ca(2+) overload during reperfusion. The purpose of this experiment was to study, in an isolated mitochondrial preparation, the effects of mitochondrial K(ATP) channel opening on mitochondrial function and to determine whether it protects mitochondria form Ca(2+) overload. Mitochondria (mito) were isolated from rat hearts by differential centrifugation (n = 5/group). Mito respiratory function was measured by polarography without (CONTROL) or with a potassium channel opener (PINACIDIL, 100 microM). Different Ca(2+) concentrations (0 to 5 x 10(-7) M) were used to simulate the effect of Ca(2+) overload; state 2, mito oxygen consumption with substrate only; state 3, oxygen consumption stimulated by ADP; state 4, oxygen consumption after cessation of ADP phosphorylation; respiratory control index (RCI: ratio of state 3 to state 4); rate of oxidative phosphorylation (ADP/Deltat); and ADP:O ratio were measured. PINACIDIL increased state 2 respiration and decreased RCI compared to CONTROL. Low Ca(2+) concentrations stimulated state 2 and state 4 respiration and decreased RCI and ADP:O ratios. High Ca(2+) concentrations increased state 2 and state 4 respiration and further decreased RCI, state 3, and ADP/Deltat. PINACIDIL improved state 3, ADP/Deltat, and RCI at high Ca(2+) concentrations compared to CONTROL. Pinacidil depolarized inner mitochondrial membrane, as evidenced by decreased RCI and increased state 2 at baseline. Depolarization may decrease Ca(2+) influx into mito, protecting mito from Ca(2+) overload, as evidenced by improved state 3 and RCI at high Ca(2+) concentrations. The myocardial protective effects resulting from activating K(ATP) channels either pharmacologically or by IPC may be the result of protecting mito from Ca(2+) overload.

Animals↗
PubMed1991

Modulation of intracellular calcium by potassium channel openers in vascular muscle.

We investigated two putative K+ channel openers, pinacidil and BRL34915 (cromakalim), and demonstrated their vasorelaxant effectiveness on rat artery contractions induced by K+, tetraethylammonium (TEA), or norepinephrine. The K+ channel opener-induced decrease in tension was rapid, even when tension was stimulated by 100 mmol/l K+. Measurements of intracellular free Ca++ (activity) by ultra-high sensitivity digital imaging microscopy was carried out by briefly loaded fura 2 (fluorescence ratio) quantitation in isolated, contracting cells of rat azygos vein. Submicron resolution was achieved by measuring cytoplasmic Ca(++)-sensitive fluorescence at each pixel, and size and intensity of areas with high Ca++ concentrations, called hot spots, were determined by a computer-generated, 3 lambda algorithm. Hot spots, which most likely represent the sites of Ca++ release and re-uptake by Ca(++)-regulatory organelles, increased in size and intensity upon addition of K+ or norepinephrine, reaching an early peak prior to the whole cell average peak in cytoplasmic Ca++ activity. Both norepinephrine and K(+)-induced stimulation resulted in Ca++ activity increases that were primarily due to Ca++ release from storage sites. Reduction of free Ca++ activity to resting or lower levels occurred upon addition of pinacidil or cromakalim. Intracellular Ca++ decreases due to K+ channel openers appeared abruptly beginning at the central portions of the cells, resulting in a pronounced early drop in central Ca++ activity while elevated Ca++ levels persisted at the periphery. While this late stage residual of peripheral Ca++ appears to be a significant step in the vascular muscle relaxant action of both K+ channel opener drugs, the level of Ca++ at peripheral sites was greater in response to pinacidil than to cromakalim. The results of this study suggest that in addition to increasing K+ conductance, pinacidil and cromakalim cause 1) decreased Ca++ activity in central regions of the myocytes, and 2) a shift in Ca++ distribution to primarily subsarcolemmal sites. These observations lead us to hypothesize separate control of peripheral and central Ca++ activity within a vascular muscle cell, with Ca++ redistribution that can be altered by vasorelaxants. We suggest that intracellular Ca++ redistribution may contribute the membrane potential-independent part of the vasorelaxant action of the K+ channel openers.

Animals↗
PubMed1991

K+ channel blocking and anti-muscarinic effects of a novel piperazine derivative, INO 2628, on the isolated dog atrium.

The effects of a novel piperazine derivative, INO 2628, on the negative inotropic and chronotropic responses to intracardiac parasympathetic nerve stimulation and carbachol, to adenosine and to the K+ channel openers, pinacidil and nicorandil, were investigated in isolated, blood-perfused dog heart preparations. INO 2628 (0.1-10 mumol) injected into the sinus node artery of the isolated atrium induced negative chronotropic and small positive inotropic responses in a dose-dependent manner. INO 2628 antagonized the negative chronotropic and inotropic responses to intracardiac vagus stimulation and carbachol in a dose-dependent manner, whereas INO 2628 did not antagonize the negative cardiac responses to adenosine. Pinacidil and nicorandil caused dose-dependent negative inotropic and small negative chronotropic responses in isolated atria and ventricles, suggesting that pinacidil-related K+ channels are much sparser in SA nodal pacemaker cells than in cardiac muscle cells. INO 2628 dose dependently antagonized the negative inotropic responses to pinacidil and nicorandil, but it did not modify the nicardipine-, pentobarbital- or G-strophanthin-induced cardiac responses. These results suggest that INO 2628 inhibits the negative cardiac effects of acetylcholine at muscarinic receptors and directly inhibits K+ channels in the isolated dog heart.

Adenosine↗
PubMed2005

Reduced effectiveness of HMR 1098 in blocking cardiac sarcolemmal K(ATP) channels during metabolic stress.

ATP-sensitive K(+) (K(ATP)) channels are involved in ischemic cardioprotection induced by preconditioning (IPC), though the relative role of sarcolemmal (sK(ATP)) and mitochondrial (mitoK(ATP)) channels remains controversial. The sK(ATP)-selective sulphonylthiourea HMR 1098 has often been reported to be without effect on ischemic cardioprotection, suggesting minimal involvement of sK(ATP). Since some sulphonylureas show reduced potency under conditions of metabolic stress, we used patch clamp to assess the ability of HMR 1098 to block sK(ATP) currents of adult rat ventricular myocytes activated by metabolic inhibition (MI, NaCN+iodoacetate). In contrast to the prototype sulphonylurea glibenclamide, HMR 1098 (10 muM) was without effect on sK(ATP) currents, and also did not inhibit MI-induced action potential shortening. However, HMR 1098 blocked sK(ATP) current induced by the K(ATP) opener pinacidil (IC(50)=0.36+/-0.02 muM), and reversed pinacidil-induced action potential shortening. In inside-out patches, block by HMR 1098 was relieved by increasing MgADP concentrations (1-100 muM). HMR 1098 inhibited pinacidil-activated recombinant Kir6.2/SUR2A channels with a similar IC(50) (0.30+/-0.04 muM), but was less effective when channels were activated by low intracellular ATP. HMR 1098 displaced binding of the pinacidil analogue [(3)H]P1075 to native cardiac membranes with a biphasic inhibition curve. Our results show that HMR 1098 becomes a much less effective inhibitor of sK(ATP) during metabolic stress, and suggest that the lack of effect of HMR 1098 on ischemic cardioprotection reported in some studies may represent loss of block by the drug under these conditions rather than a lack of involvement of sK(ATP) channels.

ATP-Binding Cassette Transporters↗
PubMed2000

Involvement of ATP-sensitive K(+) channels in the anti-tussive effect of moguisteine.

The effect of glibenclamide, an ATP-sensitive K(+) channel blocker, on the anti-tussive effect of moguisteine and of pinacidil, an ATP-sensitive K(+) channel opener in guinea pigs was studied. Pinacidil (1 and 5 mg/kg, subcutaneous (s.c.)) dose-dependently reduced the number of coughs. The anti-tussive effect of pinacidil was significantly and dose-dependently antagonized by pre-treatment with glibenclamide (3 and 10 mg/kg, i.p.). Moguisteine (1 and 5 mg/kg, s.c.) dose-dependently reduced the number of coughs. The anti-tussive effect of moguisteine was also reduced by pre-treatment with glibenclamide, in a dose-dependent manner. However, pre-treatment with glibenclamide had no effect on the anti-tussive effects of dihydrocodeine and dextromethorphan. Glibenclamide (10 mg/kg, i.p.), by itself, had no significant effect on the number of coughs. These results suggest that pinacidil and moguisteine may exert their anti-tussive effects through the activation of ATP-sensitive K(+) channels. Furthermore, it is possible that ATP-sensitive K(+) channels may be involved in the anti-tussive effect of peripherally acting non-narcotic anti-tussive drugs.

ATP-Binding Cassette Transporters↗
PubMed1997

KATP channel modulators increase survival rate during coronary occlusion-reperfusion in anaesthetized rats.

We investigated the effect of ATP-sensitive K+ channel (KATP) openers (pinacidil and cromakalim), and a KATP blocker (glibenclamide) on reperfusion-induced arrhythmias in pentobarbitone-anaesthetized rats. Arrhythmias were induced by reperfusion following a 6 min ligation of the left main coronary artery. Rats were pretreated with pinacidil (0.1 or 0.3 mg/kg), or cromakalim (28 or 56 micrograms/kg), or glibenclamide (5 mg/kg), or vehicle. Pinacidil and cromakalim produced dose-related reductions in blood pressure. Pinacidil (0.1 mg/kg) and cromakalim (56 micrograms/kg) significantly decreased the incidence of reperfusion-induced ventricular fibrillation and increased survival. Glibenclamide did not decrease ventricular fibrillation incidence, yet improved survival by increasing the possibility of recovery from ventricular fibrillation. The present study suggests that both opening and blocking KATP channels may increase survival during coronary occlusion and reperfusion in anaesthetized rats.

Action Potentials↗
PubMed1990

K(+)-channel openers for relaxation of isolated penile erectile tissue from rabbit.

The effects of the K(+)-channel openers (KCOs) cromakalim (BRL 34915) and pinacidil were investigated and compared with those of papaverine on isolated corpus cavernosum from rabbit. Preparations were mounted in organ baths and isometric tension was recorded. Spontaneous contractile activity was effectively abolished by the KCOs tested, cromakalim being the most potent of them. The KCOs concentration-dependently and effectively depressed electrically induced contractions and also contractions induced by exogenously applied noradrenaline and by low (less than or equal to 20 mM) concentrations of K+. Cromakalim was three to four times more potent than pinacidil. Pinacidil and cromakalim were shown to cause increases in the efflux of 86Rb from preloaded cavernous tissue. Papaverine also effectively depressed spontaneous contractile activity, and contractions evoked by electrical stimulation and noradrenaline. It had a potency 19 to 36 times lower than that of cromakalim. However, papaverine did not increase 86Rb efflux from preloaded tissue. The results show that cromakalim and pinacidil effectively relax penile erectile tissue, probably by the opening of K(+)-channels and subsequent hyperpolarization. Further investigations on human material seems motivated in order to elucidate if the principle of K(+)-channel opening offers any therapeutic advantages to other drugs in the diagnosis and treatment of penile erectile dysfunction.

Animals↗
PubMed2002

Nitric oxide induces hyperpolarization by opening ATP-sensitive K(+) channels in guinea pig spiral modiolar artery.

Nitric oxide (NO) hyperpolarizes vascular smooth muscle cells and dilates blood vessels of various beds, but little is known on cochlear vasculatures. Using in vitro preparations of the spiral modiolar artery (SMA), intracellular electrical recording and labeling techniques, we found that the NO donor DPTA-NONOate (10 microM) caused a hyperpolarization of approximately 9 mV in all the cells that had a low resting potential (RP) level near -40 mV. The hyperpolarization amplitude was concentration-dependent, with a 50% effect concentration (EC(50)) of 1 microM. The responses occur in both smooth muscle and endothelial cells, neither of which was blocked by 18beta-glycyrrhetinic acid. The induced hyperpolarization was completely blocked by glipizide, but not by charybdotoxin, apamin, barium, 4-aminopyridine or tetraethylammonium. The hyperpolarizing responses were imitated by pinacidil (EC(50)=30 microM). The pinacidil-induced response was also blocked by glipizide but not by the other K(+) channel blockers mentioned above. Both DPTA-NONOate and pinacidil had little membrane potential effect on cells that had a high RP level near -75 mV. However, when the high RP cells were depolarized to a level beyond -45 mV by barium, both DPTA-NONOate and pinacidil hyperpolarized these cells not differently from those that initially had a low RP. It is concluded that NO hyperpolarizes the SMA primarily by activating K(ATP) channels in both muscle and endothelial cells.

Adenosine Triphosphate↗
PubMed1999

ATP-sensitive potassium channel activation mimics the protective effect of ischaemic preconditioning in the rat isolated working heart after prolonged hypothermic storage.

1. Ischaemic preconditioning (IP) can significantly reduce the extent of infarct size, contractile dysfunction and necrosis in hearts from a number of animal species. Activation of ATP-sensitive potassium channels has been implicated in this process. The aims of the present study were to determine the extent to which IP preserves haemodynamic function in the rat isolated working heart model after prolonged hypothermic storage and to examine the involvement of activation of potassium channels in this process. 2. Hearts from Wistar rats were perfused on a Langendorff apparatus. After stabilization in working mode, baseline measurements of heart rate, aortic flow, coronary flow and cardiac output were performed. Hearts were randomized to one of six treatment groups: (i) untreated control; (ii) IP; (iii) 3 min perfusion with 200 mumol/L pinacidil; (iv) pinacidil vehicle; (v) 3 min perfusion with 10 mumol/L glibenclamide before IP; and (vi) 3 min perfusion with glibenclamide then pinacidil. Hearts were stored in an extracellular-based preservation solution for 6 or 12 h at 2-3 degrees C, remounted on the perfusion apparatus, stabilized as before and then haemodynamic measurements were repeated, after which time heart water contents were determined. 3. Recovery of haemodynamic function was markedly enhanced in the IP and pinacidil-treated groups compared with untreated and vehicle controls. These beneficial effects were completely blocked by glibenclamide. These results suggest that strategies for activating potassium channels in donor hearts may protect organs during hypothermic storage prior to transplantation.

Adenosine Triphosphate↗
PubMed1999

Regulation of vascular tone by endothelium-derived hyperpolarizing factor.

1. Endothelium-derived hyperpolarizing factor (EDHF) mediates the nitric oxide (NO)-independent component of the relaxation in rat mesenteric arteries. The relationship between hyperpolarization and vascular tone was studied by simultaneous recording of membrane potential with intracellular microelectrodes and tension in ring segments of rat mesenteric arteries. 2. By depolarizing arteries with high potassium solutions, it was determined that the threshold for contraction is approximately -46 mV. Maximum contraction was attained when the arteries were depolarized to -20 mV. Thus, 1 mV depolarization resulted in an approximate 4% increase in tone. This relationship was not altered in spontaneously hypertensive rats. 3. Noradrenaline (0.3 mumol/L) caused contraction and depolarized arteries by 13 mV. Acetylcholine caused endothelium-dependent relaxation and hyperpolarization up to 14 mV. In the presence of N omega-nitro-L-arginine, the EDHF-mediated relaxation was correlated to hyperpolarization. A hyperpolarization of 1 mV corresponded to a 4.3% decrease of the induced tone. 4. At concentrations (10 mumol/L) causing total relaxation, the maximum hyperpolarization induced by NO was only 7.6 mV. 5. A maximum relaxation of 88% was observed with pinacidil (3 mumol/L), despite a 25 mV hyperpolarization. Relaxations to NO and pinacidil were not correlated with hyperpolarization. At similar levels of hyperpolarization, NO and pinacidil elicited more relaxation than EDHF. 6. These studies show that vascular tone is very sensitive to membrane potential change in the range between -46 and -20 mV in the rat mesenteric artery. The relaxation response to EDHF, unlike that to NO and pinacidil, can be accounted for solely by its effect on the membrane potential.

Animals↗
PubMed1993

Effects of ATP-sensitive K+ channel openers on pacemaker activity in isolated single rabbit sino-atrial node cells.

Electrophysiologic effects of ATP-sensitive K+ channel openers (cromakalim, pinacidil, and nicorandil) in single rabbit sino-atrial (SA) node cells were examined by a whole-cell voltage- and current-clamp technique. Cromakalim (> 30 microM), pinacidil (> 1 microM), and nicorandil (> 500 microM) caused a negative chronotropic effect. At low concentrations, the maximum diastolic potential was hyperpolarized and the maximum rate of depolarization was enhanced, but at high concentrations, both were reversed and action potential amplitude (APA) was decreased significantly. Pinacidil (> 30 microM) and nicorandil (> 3 microM) prolonged AP duration (APD), but cromakalim did not affect it. In whole-cell voltage-clamp experiments, cromakalim (100 microM), pinacidil (> 30 microM), and nicorandil (> 300 microM) inhibited the Ca2+ current significantly but had little or no effect on the delayed rectifying K+ current and the hyperpolarization-activated inward current. Glibenclamide (1 microM) did not antagonize the effects of K+ channel openers on Ca2+ current and APs. These results indicate that the K+ channel openers have direct inhibitory actions on spontaneous APs and Ca2+ current in rabbit SA node cells (but K+ current was unaffected), resulting in decreased pacemaker activity.

Action Potentials↗
PubMed1995

Renal and vascular effects of chemically distinct ATP-sensitive K+ channel blockers in rats.

The ATP-sensitive K+ channel blocker U-37883A was given intravenously (i.v.) to rats to determine if pharmacologic diversity among ATP-sensitive K+ channels observed in vitro is also apparent in vivo. Vascular K+ channel blockade was quantified as inhibition of the decrease in blood pressure (BP) produced by a standard dose of the K+ channel opener pinacidil. Renal natriuretic effects were evaluated by an increase in urinary Na+ excretion. In both instances, effects of U-37883A, a guanidine, were compared with those of the sulfonylurea glyburide. In addition, the ability of these K+ channel blockers to lower plasma glucose levels was compared. U-37883A was nine times more potent than glyburide as a natriuretic and a comparable six times more potent than glyburide in blocking pinacidil, suggesting common features between ATP-sensitive K+ channels in vascular smooth muscle (VSM) and renal tubules. In contrast, a dose of U-37883A that blocked pinacidil and increased Na+ excretion had no effect on plasma glucose, whereas a dose of glyburide that was natriuretic and equally as effective against pinacidil as U-37883A decreased plasma glucose, suggesting that ATP-sensitive K+ channels in pancreatic beta cells and renal tubules have dissimilar binding sites and/or features. U-37883A appeared to be more renal/vascular selective, an observation entirely consistent with previous findings in vitro. Our results represent the first in vivo suggestion of structural differences among the channel and/or accessory proteins from this family of K(+)-selective channels.

Adamantane↗
PubMed2003

SNC-80-induced preconditioning: selective activation of the mitochondrial adenosine triphosphate-gated potassium channel.

Pharmacologic preconditioning by delta-opioid agonists occurs via activation of an adenosine triphosphate (ATP)-gated potassium channel (I(KATP)). Opening of mitochondrial I(KATP) confers pharmacologic preconditioning whereas opening the sarcolemmal I(KATP) shortens action potential duration and is proarrhythmic. This study investigated whether SNC-80, a selective delta-opioid agonist, is associated with development of ventricular arrhythmia due to activation of I(KATP). Rabbit isolated hearts were subjected to 12 min of hypoxia and 40 min of reoxygenation after pretreatment with SNC-80 (1 microM, n = 6), pinacidil (1.25 microM, n = 12), or BMS-191095 (6.0 microM, n = 4). Nine additional hearts served as controls. The cytoprotective effects of SNC-80 at a concentration of 1 microM were confirmed using 30 min of regional ischemia followed by 120 min of reperfusion. Ventricular fibrillation (VF) developed in 11 of 12 pinacidil-treated hearts whereas none of the SNC-80-treated (zero of six) hearts developed VF (P < 0.001 compared with pinacidil pretreatment) and zero of four BMS-191095-pretreated hearts developed VF. Similarly, zero of nine control hearts developed VF. SNC-80 reduced infarct size expressed as a percentage of the area at risk from 33 +/- 4% to 14 +/- 3% (P = 0.004) compared with control. SNC-80, which selectively activates the delta-opioid receptor, provided cytoprotection but did not induce VF after hypoxia reoxygenation. The results indicate that pinacidil-induced nonselective activation of I(KATP) results in proarrhythmia that is dependent on activation of the sarcolemmal I(KATP). Selectivity for the mitochondrial I(KATP) is necessary to prevent induction of a proarrhythmic state.

Adenosine Triphosphate↗
PubMed1989

Inhibition by sulphonylureas of vasorelaxation induced by K+ channel activators in vitro.

1. The effects of the sulphonylureas glibenclamide, glipizide and tolbutamide on relaxant responses to the K+ channel activator, cromakalim (BRL 34915), were investigated in rabbit isolated mesenteric artery. The interaction between glibenclamide and pinacidil, another K+ channel activator, was also studied. 2. Glibenclamide produced progressive parallel shifts to the right of the cromakalim and pinacidil concentration-response curves. The calculated pA2 values were 7.16 +/- 0.03 against cromakalim and 6.66 +/- 0.05 against pinacidil. 3. Glipizide and tolbutamide also produced parallel shifts to the right of the cromakalim concentration-response curve to yield pA2 values of 5.59 and 3.98 respectively. 4. Glibenclamide had little inhibitory effect upon vasorelaxant responses to the Ca2+ channel blocker, nifedipine. 5. The results suggest that cromakalim and pinacidil activate an ATP-sensitive K+ channel in vascular smooth muscle which may differ from that of the pancreatic beta-cells.

Animals↗
PubMed1992

Effects of potassium channel openers and calcium channel blockers on the force responses of the electrically driven rat right ventricle strip.

1. The effects of potassium channel openers (cromakalim and pinacidil) and of calcium channel blockers (verapamil, diltiazem and flunarizine) on the contractile responses of the rat right ventricle have been determined. 2. On the electrically driven rat right ventricle cromakalim at 3 x 10(-7), 10(-6), 3 x 10(-6) M and 10(-5) M, and pinacidil at 10(-6), 10(-5) and 3 x 10(-5) M had no effect on the force responses to cardiac stimulation or to isoprenaline. 3. Pinacidil at 10(-4) M in a vehicle of 0.7% ethanol reduced the force responses to cardiac stimulation. This inhibitory effect was solely due to the ethanol. Pinacidil in 5 x 10(-4) M HCl (which had no effect alone) potentiated some of the responses to isoprenaline. 4. Verapamil, greater than or equal to 10(-6) M, diltiazem, greater than or equal to 10(-5) M, and flunarizine, greater than or equal to 10(-6) M, reduced the force responses to cardiac stimulation and to isoprenaline. 5. The present study has shown that calcium channel blockers, but not potassium channel openers, have inhibitory effects on the rat right ventricle.

Animals↗