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At least 973 records · Page 54Linked to original sources
PubMed1993

Influence of Zaprinast on vascular tone and vasodilator responses in the cat pulmonary vascular bed.

The influence of Zaprinast (M&B 22948), a guanosine 3',5'-cyclic monophosphate (cGMP)-specific phosphodiesterase inhibitor, was investigated in the pulmonary vascular bed of the cat under conditions of controlled blood flow and constant left atrial pressure. Under baseline conditions, injections of Zaprinast into the perfused lobar artery produced small decreases in lobar arterial pressure without altering systemic arterial or left atrial pressure. When tone was increased with U-46619, Zaprinast caused larger dose-dependent decreases in lobar arterial pressure without altering left atrial pressure. The decreases in lobar arterial pressure were reduced significantly by treatment with the nitric oxide (NO) synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or the guanylate cyclase inhibitor methylene blue. Under elevated tone conditions, efferent vagal stimulation and intralobar injections of acetylcholine, substance P, NO solution, and the S-nitrosothiols [S-nitroso-N-acetylpenicillamine (SNAP) and S-nitroso-L-cysteine (CysNO)] decreased lobar arterial pressure in a frequency-dependent and dose-related manner. After treatment with Zaprinast, the decreases in lobar arterial pressure in response to efferent vagal stimulation, the endothelium-dependent vasodilators, and the nitrovasodilators were not changed, whereas the duration of the vasodilator responses as measured by the half times was increased significantly. Vasodilator responses to adenosine, albuterol, and pinacidil were not altered by Zaprinast. These data suggest that cGMP hydrolysis in the lung is rapid and that endothelium-derived NO is important in stimulating basal cGMP production and in regulating vascular tone.(ABSTRACT TRUNCATED AT 250 WORDS)

3',5'-Cyclic-GMP Phosphodiesterases↗
PubMed1997

ATP-sensitive and inwardly rectifying potassium channels in smooth muscle.

The properties and roles of ATP-sensitive (KATP) and inwardly rectifying (KIR) potassium channels are reviewed. Potassium channels regulate the membrane potential of smooth muscle, which controls calcium entry through voltage-dependent calcium channels, and thereby contractility through changes in intracellular calcium. The KATP channel is likely to be composed of members of the inward rectifier channel gene family (Kir6) and sulfonylurea receptor proteins. The KIR channels do not appear to be as widely distributed as KATP channels in smooth muscle and may provide a mechanism by which changes in extracellular K+ can alter smooth muscle membrane potential, and thereby arterial diameter. The KATP channels contribute to the resting membrane conductance of some types of smooth muscle and can open under situations of metabolic compromise. The KATP channels are targets of a wide variety of vasodilators and constrictors, which act, respectively, through adenosine 3',5'-cyclic monophosphate/protein kinase A and protein kinase C. The KATP channels are also activated by a number of synthetic vasodilators (e.g., diazoxide and pinacidil) and are inhibited by the oral hypoglycemic sulfonylurea drugs (e.g., glibenclamide). Together, KATP and KIR channels are important regulators of smooth muscle function and represent important therapeutic targets.

Adenosine Triphosphate↗
PubMed2006

Activating of ATP-dependent K+ channels comprised of K(ir) 6.2 and SUR 2B by PGE2 through EP2 receptor in cultured interstitial cells of Cajal from murine small intestine.

The interstitial cells of Cajal (ICC) are pacemaker cells in gastrointestinal tract and generate an electrical rhythm in gastrointestinal muscles. We investigated the possibility that PGE(2) might affect the electrical properties of cultured ICC by activating ATP-dependent K(+) channels and, the EP receptor subtypes and the subunits of ATP-dependent K(+) channels involved in these activities were identified. In addition, the regulation of intracellular Ca(2+) ([Ca(2+)](i)) mobilization may be involved the action of PGE(2) on ICC. Treatments of ICC with PGE(2) inhibited electrical pacemaker activities in the same manner as pinacidil, an ATP-dependent K(+) channel opener and PGE(2) had only a dose-dependent effect. Using RT-PCR technique, we found that ATP-dependent K(+) channels exist in ICC and that these are composed of K(ir) 6.2 and SUR 2B subunits. To characterize the specific membrane EP receptor subtypes in ICC, EP receptor agonists and RT-PCR were used: Butaprost (an EP(2) receptor agonist) showed the actions on pacemaker currents in the same manner as PGE(2). However sulprostone (a mixed EP(1) and EP(3) agonist) had no effects. In addition, RT-PCR results indicated the presence of the EP(2) receptor in ICC. To investigate cAMP involvement in the effects of PGE(2) on ICCs, SQ-22536 (an inhibitor of adenylate cyclase) and cAMP assays were used. SQ-22536 did not affect the effect of PGE(2) on pacemaker currents, and PGE(2) did not stimulate cAMP production. Also, we found PGE(2) inhibited the spontaneous [Ca(2+)](i) oscillations in cultured ICC. These observations indicate that PGE(2) alters pacemaker currents by activating the ATP-dependent K(+) channels comprised of K(ir) 6.2-SUR 2B in ICC and this action of PGE(2) are through EP(2) receptor subtype and also the activation of ATP-dependent K(+) channels involves intracellular Ca(2+) mobilization.

ATP-Binding Cassette Transporters↗
PubMed1991

Inhibition of aldosterone production and angiotensin action by drugs affecting potassium channels.

We screened potassium channel agonists and antagonists in a search for pharmacologic probes of the channels that mediate potassium's effects on adrenal zona glomerulosa cells. Suspensions of bovine cells were tested, and aldosterone was measured by radioimmunoassay. The most potent inhibitors were pinacidil, capsaicin, glyburide, and quinine. These reagents were more potent against aldosterone production than against cortisol production. Aldosterone produced under basal conditions, as well as that stimulated by potassium, angiotensin II, or dibutyryl cyclic AMP, was antagonized. The vasodilatory and aldosterone-inhibiting potencies of potassium channel reagents were very different. Candidate antihypertensives with potassium channel activity should be tested for adrenal inhibition.

Adenosine Triphosphate↗
PubMed1994

Antagonism of eicosanoid-induced contraction of rat aorta by sulphonylureas.

Glibenclamide and other sulphonylureas are extensively used as specific blockers for ATP-dependent potassium channels in vascular smooth muscle. However, glibenclamide has recently been shown to inhibit actions of some prostanoids in vascular smooth muscle. We extend our previous study by examining the relaxant actions of five different sulphonylureas in rat aorta. The inhibitory effects of sulphonylureas on the contractions induced by prostaglandins F2 alpha, E2 and D2, norepinephrine, 5-hydroxytryptamine (5-HT) or potassium chloride (KCl) were examined. Glibenclamide significantly inhibited the contractions produced by prostaglandins F2 alpha, E2 and D2 but was without effect on responses to norepinephrine, 5-HT or KCl. Glimepiride produced significant attenuation of the responses to all agents tested (5-HT, norepinephrine, KCl), although the inhibition of the responses to prostaglandin F2 alpha was most pronounced. Glipizide and tolbutamide had activities similar to that of glibenclamide, while chlorpropamide was devoid of any antagonist action in rat aorta. In rat aorta precontracted with norepinephrine, glibenclamide inhibited the relaxant responses to lemakalim and pinacidil. Thus, in addition to the effect on ATP-dependent potassium channels, glibenclamide inhibits responses to prostaglandins F2 alpha, E2 and D2 but not to other agents. This effect is shared by glimepiride, tolbutamide and glipizide.

Animals↗
PubMed1995

K-channel opening activity of ZD6169 and its analogs: effect on 86Rb efflux and 3H-P1075 binding in bladder smooth muscle.

Zeneca ZD6169, (S)-N-(4-benzoylphenyl)-3,3,3-trifluoro- 2-hydroxy-2-methylpropionamide, is a novel compound which relaxes urinary bladder smooth muscle in vitro. The effect of ZD6169 and two of its analogs on 86Rb efflux and 3H-P1075 binding in guinea pig bladder strips was investigated to characterize the K-channel opening properties of this compound. ZD6169 concentration dependently increased the rate of 86Rb efflux from guinea pig bladder strips. 86Rb efflux evoked by ZD6169 and its analogs was blocked by glibenclamide (30 muM) but not by charybdotoxin, apamin or alpha-dendrotoxin, suggesting that this compound activates KATP channels in guinea pig bladder. In addition, interaction of ZD6169 with KATP channels was also confirmed in human bladder smooth muscle cells. Specific binding of 3H-P1075, a potent opener of KATP channels, to guinea pig urinary bladder strips was observed. 3H-P1075 binding was inhibited by known KATP openers. ZD6169 inhibited binding of 3H-P1075 to urinary bladder strips like other structurally different KATP openers, e.g. cromakalim and pinacidil. Potencies for inhibition of 3H-P1075 binding by ZD6169 and other potassium channel openers correlate well with potencies for increase in 86Rb efflux and bladder muscle relaxation studies. It is concluded that Zeneca ZD6169 is a potassium channel opener which activates ATP-sensitive K-channels in guinea pig urinary bladder strips as well as in human bladder cells. Furthermore, binding studies suggest that the effects of ZD6169 and its analogs are mediated by binding to the site labeled by 3H-P1075 in guinea pig bladder strips.

Amides↗
PubMed1990

The potassium channel openers: a new class of vasorelaxants.

Cromakalim, pinacidil, nicorandil, diazoxide and RP-49356 belong to the class of drugs termed potassium channel openers. In rat portal vein diazoxide, like cromakalim, abolished spontaneous mechanical and electrical activity and in rat aorta caused an increase in 86Rb efflux and inhibited KCl(20 mM)-induced contractions. However, in contrast to cromakalim, diazoxide (greater than 100 microM) also inhibited mechanical responses evoked by 80 mM KCl in rat aorta suggesting that it possesses pharmacological properties in addition to K channel opening. Since glibenclamide can attenuate the effects of cromakalim and diazoxide in vascular tissues, it is possible that a channel resembling the ATP-sensitive K channel found in pancreatic beta-cells may be involved in the vasorelaxant effects of these agents. However, differences exist in the order of potency of cromakalim and diazoxide for producing smooth muscle relaxation and for decreasing insulin secretion in pancreatic beta-cells. Furthermore galanin (which opens ATP-sensitive K channels in beta-cells) increases mechanical activity in rat portal vein. It is anticipated that new chemical developments will produce K channel opening molecules with greater potency and tissue selectivity.

Animals↗
PubMed2004

Heterogeneous beta2-adrenoceptor expression and dilation in coronary arterioles across the left ventricular wall.

BACKGROUND: Previous in vivo studies have shown that beta-adrenoceptor agonists cause a redistribution of coronary flow away from the subendocardium; however, the underlying mechanism remains uncertain. We tested the hypothesis that a heterogeneous distribution of beta-adrenoceptors and their vasomotor responses exists in the coronary microcirculation across the left ventricular wall. METHODS AND RESULTS: Porcine subepicardial and subendocardial arterioles (<100 microm) were isolated from the left ventricle and pressurized for in vitro study of vasodilation to the nonselective beta-adrenoceptor agonist isoproterenol and the selective beta2-adrenoceptor agonist procaterol. Both vessel types developed a similar level of basal tone and dilated to isoproterenol and procaterol. However, subepicardial arterioles exhibited a much higher sensitivity and greater dilation capacity to both agonists. The isoproterenol-induced vasodilations were inhibited by glibenclamide, an ATP-sensitive potassium (K(ATP)) channel blocker. In contrast to isoproterenol, dilations of subepicardial and subendocardial arterioles to pinacidil, a K(ATP) channel opener, were similar. In both vessel types, isoproterenol-induced dilation was inhibited by the beta2-adrenoceptor blocker ICI-118,551 but was insensitive to the beta1-adrenoceptor blocker atenolol. Reverse transcription-polymerase chain reaction and immunohistochemical data revealed that beta2-adrenoceptor mRNA and protein expression, respectively, were markedly greater in subepicardial arterioles. CONCLUSIONS: This study demonstrates that selective activation of beta2-adrenoceptors elicits dilation of both subepicardial and subendocardial arterioles through opening of K(ATP) channels. The higher beta2-adrenoceptor expression in subepicardial arterioles may contribute to the greater dilation of these vessels to beta2-adrenoceptor activation.

Adrenergic beta-2 Receptor Agonists↗
PubMed1999

Cellular basis for the Brugada syndrome and other mechanisms of arrhythmogenesis associated with ST-segment elevation.

BACKGROUND: The Brugada syndrome is characterized by marked ST-segment elevation in the right precordial ECG leads and is associated with a high incidence of sudden and unexpected arrhythmic death. Our study examines the cellular basis for this syndrome. METHODS AND RESULTS: Using arterially perfused wedges of canine right ventricle (RV), we simultaneously recorded transmembrane action potentials from 2 epicardial and 1 endocardial sites, together with unipolar electrograms and a transmural ECG. Loss of the action potential dome in epicardium but not endocardium after exposure to pinacidil (2 to 5 micromol/L), a K(+) channel opener, or the combination of a Na(+) channel blocker (flecainide, 7 micromol/L) and acetylcholine (ACh, 2 to 3 micromol/L) resulted in an abbreviation of epicardial response and a transmural dispersion of repolarization, which caused an ST-segment elevation in the ECG. ACh facilitated loss of the action potential dome, whereas isoproterenol (0.1 to 1 micromol/L) restored the epicardial dome, thus reducing or eliminating the ST-segment elevation. Heterogeneous loss of the dome caused a marked dispersion of repolarization within the epicardium and transmurally, thus giving rise to phase 2 reentrant extrasystole, which precipitated ventricular tachycardia (VT) and ventricular fibrillation (VF). Transient outward current (I(to)) block with 4-aminopyridine (1 to 2 mmol/L) or quinidine (5 micromol/L) restored the dome, normalized the ST segment, and prevented VT/VF. Conclusions-Depression or loss of the action potential dome in RV epicardium creates a transmural voltage gradient that may be responsible for the ST-segment elevation observed in the Brugada syndrome and other syndromes exhibiting similar ECG manifestations. Our results also demonstrate that extrasystolic activity due to phase 2 reentry can arise in the intact wall of the canine RV and serve as the trigger for VT/VF. Our data point to I(to) block (4-aminopyridine, quinidine) as an effective pharmacological treatment.

Acetylcholine↗
PubMed1995

Glibenclamide, a selective inhibitor of ATP-sensitive K+ channels, attenuates metabolic coronary vasodilatation induced by pacing tachycardia in dogs.

BACKGROUND: We previously reported that glibenclamide (a selective inhibitor of ATP-sensitive K+ channels [K+ATP channels]) inhibited metabolic coronary vasodilatation induced by beta 1-adrenoceptor stimulation. However, the role of K+ATP channels in metabolic coronary vasodilatation induced by tachycardia is still unknown. This study aimed to determine whether glibenclamide attenuates metabolic coronary vasodilatation induced by pacing-induced tachycardia. METHODS AND RESULTS: In anesthetized dogs, increasing heart rate from 103 +/- 1 to 160 beats per minute with atrial pacing increased coronary blood flow without altering arterial pressure and left ventricular pressure. Intracoronary infusion of glibenclamide at 1.5 and 5.0 micrograms.kg-1.min-1 did not alter basal coronary blood flow but significantly attenuated (P < .01) the tachycardia-induced coronary vasodilatation without altering the tachycardia-induced increase in myocardial oxygen consumption (MVO2). In conscious dogs, intracoronary glibenclamide at 5.0 micrograms.kg-1.min-1 attenuated (P < .05) coronary vasodilatation induced by ventricular pacing from 85 +/- 6 to 150 beats per minute. Glibenclamide markedly attenuated coronary vasodilation evoked with the K+ATP channel opener pinacidil. CONCLUSIONS: These data indicate that blockade of coronary vascular K+ATP channels with glibenclamide inhibited metabolic coronary vasodilatation induced by pacing tachycardia in dogs, suggesting that K+ATP channels are involved in the mechanism mediating metabolic coronary vasodilatation associated with pacing tachycardia.

Adenosine Triphosphate↗
PubMed2006

Spontaneous coronary vasospasm in KATP mutant mice arises from a smooth muscle-extrinsic process.

In the vasculature, ATP-sensitive potassium channels (KATP) channels regulate vascular tone. Mice with targeted gene disruptions of KATP subunits expressed in vascular smooth muscle develop spontaneous coronary vascular spasm and sudden death. From these models, it was hypothesized that the loss of KATP channel activity in arterial vascular smooth muscle was responsible for coronary artery spasm. We now tested this hypothesis using a transgenic strategy where the full-length sulfonylurea receptor containing exon 40 was expressed under the control of a smooth muscle-specific SM22alpha promoter. Two transgenic founder lines were generated and independently bred to sulfonylurea receptor 2 (SUR2) null mice to generate mice that restored expression of KATP channels in vascular smooth muscle. Transgenic expression of the sulfonylurea receptor in vascular smooth muscle cells was confirmed by detecting mRNA and protein from the transgene. Functional restoration was determined by recording pinacidil-based KATP current by whole cell voltage clamping of isolated aortic vascular smooth muscle cells isolated from the transgenic restored mice. Despite successful restoration of KATP channels in vascular smooth muscle, transgene-restored SUR2 null mice continued to display frequent episodes of spontaneous ST segment elevation, identical to the phenotype seen in SUR2 null mice. As in SUR2 null mice, ST segment elevation was frequently followed by atrioventricular heart block. ST segment elevation and coronary perfusion pressure in the restored mice did not differ significantly between transgene-negative and transgene-positive SUR2 null mice. We conclude that spontaneous coronary vasospasm and sudden death in SUR2 null mice arises from a coronary artery vascular smooth muscle-extrinsic process.

ATP-Binding Cassette Transporters↗
PubMed1991

Specific block of the anti-ischemic actions of cromakalim by sodium 5-hydroxydecanoate.

The potassium channel activators cromakalim and pinacidil were recently shown to have anti-ischemic properties in isolated globally ischemic rat hearts. The effects of two reported blockers of ATP-sensitive potassium channels, glibenclamide (glyburide) and sodium 5-hydroxydecanoate, on the anti-ischemic efficacy of cromakalim were determined in this model. Buffer-perfused rat hearts were subjected to 25 minutes of ischemia followed by 30 minutes of reperfusion. Pretreatment of these hearts with 60 microM cromakalim significantly decreased indexes of contractile function but caused a significant improvement of postreperfusion function and a significant decrease in release of lactate dehydroxygenase and in end-diastolic pressure. Pretreatment with glibenclamide at concentrations that reversed the preischemic effects of cromakalim (0.05 and 1.0 microM) also significantly reversed its postischemic protective effects. Sodium 5-hydroxydecanoate (100 and 300 microM) had no effect on the preischemic (negative inotropic) effects of cromakalim but completely reversed its cardioprotective effects. Sodium 5-hydroxydecanoate did not reverse the cardioprotective effects of the calcium entry blocker diltiazem. In phenylephrine-contracted rat aorta, glibenclamide (0.1-10 microM) inhibited cromakalim-induced relaxation, whereas sodium 5-hydroxydecanoate (10-1,000 microM) had no effect. Similarly, the ability of cromakalim to shorten cardiac action potential duration in guinea pig papillary muscle and to increase outward whole-cell potassium currents in isolated myocytes was inhibited by glibenclamide, whereas sodium 5-hydroxydecanoate was without effect. Thus, both glibenclamide and sodium 5-hydroxydecanoate inhibited the effects of cromakalim after reperfusion; however, sodium 5-hydroxydecanoate, unlike glibenclamide, had no effect in nonischemic preparations. These results suggest that sodium 5-hydroxydecanoate is an ischemia-selective inhibitor of ATP-sensitive potassium channels.

Animals↗
PubMed1993

Modulation of Ca2+ cycling in cardiac myocytes by arachidonic acid.

It is believed that inotropic agents exert their effects in cardiac muscle via a modulation of Ca2+ cycling; however, the involvement of phospholipase activation and the biochemical pathways participating in inotropic responsiveness remain unclear. The aim of the current study was to determine whether arachidonic acid and/or eicosanoids participate in inotropic responses by modulating Ca2+ cycling in cardiac myocytes. Experiments were performed with populations of freshly isolated, fura-2-loaded adult rat ventricular myocytes. Arachidonic acid stimulated a transient increase in cytosolic free Ca2+, which was still present after addition of EGTA but was significantly reduced by pretreatment with caffeine. Addition of arachidonic acid to either electrically stimulated or quiescent myocytes enhanced the amplitude of the ATP-induced Ca2+ transient. This effect was still observed in the presence of inhibitors of cyclooxygenase, lipoxygenase, and epoxygenase pathways but was significantly diminished after pretreatment with inhibitors of protein kinase C. In contrast, arachidonic acid attenuated the amplitude of electrically induced Ca2+ transients. This effect was mimicked by eicosatetraynoic acid and by the K+ channel agonist pinacidil. The inhibitory effect of eicosatetraynoic acid and arachidonic acid was reversed by addition of fatty acid-free bovine serum albumin. Together, these results suggest that arachidonic acid may play a physiological role in cardiac muscle excitation-contraction coupling as a modulator of sarcolemmal ion channels and/or Ca2+ release from the sarcoplasmic reticulum.

Adenosine Triphosphate↗
PubMed1996

Modulation of endothelium-dependent hyperpolarization and relaxation to acetylcholine in rat mesenteric artery by cytochrome P450 enzyme activity.

Acetylcholine (ACh) induced hyperpolarization and relaxation in rat mesenteric arteries contracted with norepinephrine, as indicated from studies with simultaneous microelectrode and tension recordings. We tested whether the hyperpolarization to ACh was modified by induction and depletion of cytochrome P450 enzymes. Enzyme induction by treating the animals with 3-methylcholanthrene and beta-naphthoflavone for 3 days resulted in a significant increase in the endothelium-dependent hyperpolarization to a maximum of 22.7 +/- 1.0 mV from 13.9 +/- 0.4 mV in arteries from untreated animals. Enzyme depletion by treating the animals with CoCl2 for 2 days resulted in a significant reduction in the maximum hyperpolarization to 9.9 +/- 0.7 mV. When NO synthesis was inhibited by N omega-nitro-L-arginine, the relaxation was correlated to hyperpolarization. The N omega-nitro-L-arginine-resistant responses were significantly inhibited by clotrimazole. The relaxation to ACh was not altered by enzyme induction but was significantly reduced by enzyme depletion. In KCI-contracted arteries, modification of cytochrome P450 enzyme activity had no significant effect on the relaxation to ACh. Similarly, hyperpolarization and relaxation to pinacidil were not significantly affected. These results suggest that the hyperpolarization response to ACh is closely regulated by cytochrome P450-dependent enzymes.

Acetylcholine↗
PubMed2003

Mitochondrial ATP-sensitive potassium channel activation protects cerebellar granule neurons from apoptosis induced by oxidative stress.

BACKGROUND AND PURPOSE: Mitochondrial ATP-sensitive potassium (mitoK(ATP)) channels are present in the brain, and several reports have shown that mitoK(ATP) channel openers protect the brain against ischemic injury. However, the precise mechanisms of this protection are not well established. We hypothesized that mitoK(ATP) channel openers prevent apoptosis by preserving mitochondrial membrane potential. METHODS: We investigated the effect of mitoK(ATP) channel openers on apoptosis induced by oxidative stress using cultured cerebellar granule neurons. RESULTS: The mitoK(ATP) channel opener diazoxide (100 micromol/L) significantly suppressed the number of cells with terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL)-positive nuclei and the increase in caspase-3 activity induced by 20 micromol/L H2O2. Diazoxide and another opener, pinacidil, prevented the loss of mitochondrial inner membrane potential (Delta(Psi)m) induced by H2O2. These effects were abolished by 5-hydroxydecanoate (500 micromol/L), a mitoK(ATP) channel blocker. Cyclosporin A and bongkrekic acid, inhibitors of the mitochondrial permeability transition pore, also prevented Delta(Psi)m loss, confirming the involvement of the mitochondrial permeability transition in the apoptotic cascade in neurons. Furthermore, diazoxide prevented the increase in extracellular glutamate concentration induced by H2O2, but this effect was not attributable to activation of surface K(ATP) channels. CONCLUSIONS: MitoK(ATP) channel openers inhibited apoptosis by preserving mitochondrial inner membrane potential. These beneficial effects may suggest a possible new target for neuroprotection.

Adenosine Triphosphate↗
PubMed2003

Comparison of the effect of class IA antiarrhythmic drugs on transmembrane potassium currents in rabbit ventricular myocytes.

BACKGROUND: The blockade of cardiac transmembrane potassium channels, which is commonly seen with various antiarrhythmic drugs, plays an important role in their mechanism of action. We studied and compared the less-explored effects of three Class IA antiarrhythmics on the transient outward current (I(to)) and on the inward rectifier (I(kl)), ATP sensitive (I(KATP)), and delayed rectifier (I(K)) potassium currents in rabbit ventricular myocytes. METHODS AND RESULTS: Transmembrane currents were measured by applying the whole-cell configuration of the patch-clamp technique at 37 degrees C in myocytes enzymatically isolated from rabbit ventricular preparations. Quinidine (10 microM), disopyramide (10 microM), and procainamide (50 microM) were studied at concentrations close to or exceeding the therapeutic plasma level. All studied drugs significantly decreased the amplitude of I(KATP) (activated by 50 microM pinacidil) and I(K) currents. None of them influenced significantly I(kl). The amplitude of I(to) was decreased by quinidine and disopyramide but was not considerably altered by procainamide. The fast inactivation of I(to) was not changed by procainamide and was significantly accelerated by quinidine and disopyramide. CONCLUSION: Although quinidine, disopyramide, and procainamide are all classified as Class IA antiarrhythmics, these drugs had different effects on various potassium currents, which may partially explain their distinct effect on repolarization in various cardiac tissues and on cardiac arrhythmias in clinical settings.

Adenosine Triphosphate↗
PubMed1996

Differential Electrophysiologic Effects of Chronically Administered Amiodarone on Canine Purkinje Fibers versus Ventricular Muscle.

BACKGROUND: Acute and chronic treatment with amiodarone has been reported to cause different electrocardiographic changes in patients. The cellular electrophysiologic effects of chronic administration (50 mg/kg/day orally for 6 weeks) and acute superfusion (5 µM in the tissue bath) of amiodarone were therefore studied in dog cardiac ventricular muscle and Purkinje fibers using conventional microelectrode techniques. METHODS AND RESULTS: During stimulation at 1 Hz, chronic amiodarone treatment lengthened the ventricular muscle action potential duration (APD) from 227.8 +/- 6.3 ms (n = 20) to 262.3 +/- 5.2 ms (n = 21; P <.01), but shortened that of Purkinje fibers from 337.6 +/- 9.2 (n = 21) to 308.3 +/- 7.1 (n = 19; P <.05). Acute superfusion of 5 µM amiodarone in cardiac tissue obtained from chronically treated dogs did not change ventricular muscle APD but shortened Purkinje fiber AP from 309.7 +/- 13.6 ms to 281.9 +/- 11.9 ms (n = 8; P <.05). Neither the chronic nor the acute amiodarone exposure prevented the APD shortening in ventricular muscle evoked by 10 µM pinacidil, suggesting that amiodarone does not interfere with the ATP-dependent potassium channels. The normal difference in APD between ventricular muscle and Purkinje fibers in untreated, control preparations was 110 ms but decreased to 46 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in fibers obtained from dogs chronically treated with amiodarone and increased to 185 ms in the presence of 30 µM sotalol, a class III antiarrhythmic drug used for comparison. Amiodarone (5 µM) applied directly abolished early afterdepolarizations (EADs) (induced by 1 µM dofetilide + 20 µM BaCl(2) + 2 mM CsCl) in 5 of 6 experiments and caused strong use-dependent V(max) block with relatively fast onset kinetics (rate constant = 1.23 +/- 0.13 AP(-1), n = 5) and offset (time constant = 364 +/- 62.5 ms, n = 5). After chronic amiodarone treatment, in contrast with acute sotalol application (30 µM), no reverse use-dependent effect was observed on the APD in Purkinje fibers. CONCLUSIONS: These results provide further evidence that amiodarone differs from other recognized class III antiarrhythmic drugs (ie, it is a mixed type agent with acute fast kinetic class I [type B] and a unique class III antiarrhythmic action characterized by decreased dispersion of APDs between ventricular muscle and Purkinje fibers). Amiodarone can abolish EADs unlike other class III agents that are usually associated to induction of EADs. These features might be responsible not only for the antiarrhythmic efficacy, but also for the relative safety (low incidence of torsade de pointes) of amiodarone in clinical settings.

Journal Article↗
PubMed2004

Analysis of gamma-aminobutyric acid-mediated responses in the pulmonary vascular bed of the cat.

In this investigation, we sought to identify the role of gamma-aminobutyric acid (GABA)(A) and GABA(B) receptors in the feline pulmonary vascular bed. Using adult mongrel cats and in separate experiments, we investigated the effects of l-N(5)-(1-iminoethyl) ornithine hydrochloride (l-NIO) (a nitric oxide synthase inhibitor), glibenclamide (an adenosine triphosphate (ATP)-sensitive K(+) channel blocker), meclofenamate (a nonselective cyclooxygenase inhibitor), bicuculline (a GABA(A) receptor antagonist), and saclofen (a GABA(B) receptor antagonist) on pulmonary arterial responses to pinacidil (an ATP-sensitive K(+) channel activator), bradykinin (a nitric oxide synthase inducer), muscimol (a GABA(A) receptor agonist), and 3-aminopropyl(methyl)phosphinic acid, hydrochloride (SKF-97541; a GABA(B) receptor agonist). Under increased tone conditions in the isolated left lower lobe vascular bed of the cat, muscimol induced a dose-dependent vasodepressor response that was not significantly altered after the administration of l-NIO, glibenclamide, meclofenamate, and saclofen. SKF-97541-induced vasodepression was not significantly attenuated after the administration of l-NIO, meclofenamate, and bicuculline. Responses to SKF-97541 were significantly attenuated after the administration of glibenclamide and saclofen. Responses to muscimol were significantly reduced after the administration of bicuculline. The results suggest that muscimol and SKF-97541 have potent vasodepressor activity in the feline pulmonary vascular bed and that these responses are modulated by, respectively, GABA(A) and GABA(B) receptor-sensitive pathways. Further, SKF-97541-induced vasodepression is mediated or modulated by an ATP-sensitive K(+) channel.

Animals↗