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PubMed1994

Therapeutic potential of potassium channel activators in coronary heart disease.

Potassium channel activators have the ability to open potassium channels in a variety of cells. Since most of their effects are antagonized by antidiabetic sulfonylureas, the ATP-sensitive potassium channel is their likely target. Opening of potassium channels leads to hyperpolarization of the surface membrane with consequent closure of voltage-dependent ion channels and reduction of free intracellular calcium ions. Currently available potassium channel activators, including aprikalim, bimakalim, cromakalim, emakalim, nicorandil, pinacidil etc., display a high affinity for potassium channels of vascular smooth muscle. Vasodilation and a reduction in systemic vascular resistance are their prominent pharmacological effects. Coronary and cerebral arteries are highly sensitive to potassium channel activator-induced dilation. Apart from treatment of hypertension, potassium channel activators appear to have therapeutic potential in coronary heart disease. They reduce cardiac afterload, increase native and collateral coronary blood flow and reduce the size of experimental myocardial infarcts. This last effort cannot be satisfactorily explained entirely by haemodynamic or coronary vascular actions of potassium channel activators and a cardioprotective effect is postulated. For these drugs ischaemia-induced and activator-induced opening of cardiac ATP-sensitive potassium channels appear to work in concert. Nicorandil combines the pharmacological properties of an organic nitrate with those of potassium channel activators. Experimental and clinical results characterize nicorandil as a unique and promising drug for the treatment of coronary heart disease.

Animals↗
PubMed1991

Evidence for distinct endothelin receptors in the pulmonary vascular bed in vivo.

The present study was undertaken to investigate the effects of endothelin (ET) isopeptides on the pulmonary vascular bed of the intact, spontaneously breathing cat under conditions of constant pulmonary blood flow and left atrial pressure. When pulmonary vasomotor tone was actively increased by intralobar infusion of U46619, intralobar bolus injections of ET-1 (1 micrograms), ET-2 (1 micrograms), and ET-3 (3 micrograms) produced marked reductions in pulmonary and systemic vascular resistances. The pulmonary vasodilator response to each ET isopeptide was not altered by atropine (1 mg/kg i.v.), indomethacin (2.5 mg/kg i.v.), or ICI 118551 (1 mg/kg i.v.), but was significantly inhibited by an intra-arterial (i.a.) infusion of glybenclamide at 5 mg/kg. This dose of glybenclamide significantly inhibited the decrease in lobar arterial and systemic arterial pressures in response to intralobar injection of pinacidil (30 and 100 micrograms), whereas the pulmonary vasodilator responses to acetylcholine (0.03 and 0.1 micrograms) and prostaglandin I2 (0.1 and 0.3 micrograms) were not altered. The systemic vasodilator response to each ET isopeptide was not changed by glybenclamide or by the other blocking agents studied. The present data demonstrate for the first time that ET-1, ET-2, and ET-3 dilate the pulmonary vascular bed in vivo. The present data suggest that the pulmonary vasodilator response to ET isopeptides depends, in part, on activation of potassium channels and is mediated differently from the systemic vasodilator response to these substances. Contrary to earlier work, the present data indicate the pulmonary vascular response to ET isopeptides depends on the pre-existing level of pulmonary vasomotor tone. Furthermore, the present data suggest that in the lung ET-1, ET-2, and ET-3 may serve as endogenous agonists for potassium channels, a newly described vasodilator mechanism in the pulmonary vascular bed of intact adult animals.

Animals↗
PubMed1991

Effects of SR 44866, a potassium channel opener, on action potentials of rabbit, guinea pig, and human heart fibers.

The effects of various concentrations (3 x 10(-8) - 1 x 10(-5) M) of SR 44866, a K+ channel opener, on action potential (AP) characteristics were investigated in isolated rabbit sinoatrial node (SAN), rabbit Purkinje fibers, guinea pig ventricle, human atrium, and human papillary muscle. SR 44866 (up to 1 x 10(-5) M), like cromakalim and pinacidil, did not modify SAN AP and automaticity of the rabbit heart. In atrial, Purkinje and ventricular fibers of animal and human hearts, SR 44866 did not significantly change membrane resting potential, AP amplitude, or maximum rate of phase 0 (dV/dtmax). The main AP modifications induced by SR 44866 were concentration-dependent reductions in plateau amplitude and AP duration (APD): IC50 2 x 10(-7), 7 x 10(-7), 1.4 x 10(-6), 2.5 x 10(-6), and much greater than 10(-5) M for human atrium, human ventricle, guinea pig ventricle, rabbit Purkinje, and rabbit atrium, respectively. In isolated guinea pig heart, SR 44866 induced decreases in contractions (IC50 1.7 x 10(-6) M) and coronary perfusion pressure (CPP) (IC50 2.1 x 10(-8) M) with a very slight reduction (5% at 1 x 10(-6) M) in spontaneous heart rate (HR). Negative inotropic effect (guinea pig) and APD shortenings (guinea pigs and humans) of SR 44866 (1 x 10(-6) and 3.10(-6) M) were antagonized by glibenclamide (3 x 10(-7) to 3 x 10(-6) M), a specific blocker of cardiac K+ATP channels. The data support the hypothesis that SR 44866 activates ATP-sensitive K+ channels, which are present in the atria and ventricles of the human heart but not in pacemaker cells of rabbit SAN.

Action Potentials↗
PubMed1991

Pharmacological evaluation of the angiotensin, kinin, and neurokinin receptors on the rabbit vena cava.

Angiotensin II, bradykinin, and substance P are powerful vasoconstrictors of venous smooth muscle. In this report, we have characterized the receptors and the cellular mechanisms of these vasoactive peptides on a new isolated smooth muscle preparation, the rabbit vena cava. Receptors were characterized using agonists and antagonists and were found to be of the AT, B2, and NK-1 types. The myotropic responses of the vein to KCl was completely abolished in calcium-free medium; in the presence of nicardipine, nifedipine, and verapamil, three calcium channel antagonists; and of trifluoperazine, a calmodulin antagonist. AT II-, BK-, and SP-induced responses were slightly attenuated in calcium-free medium and in the presence of nifedipine and trifluoperazine. Pinacidil inhibited the contractile response of KCl and the three peptides while lidocaine was active against KCl only. Staurosporine and cholera toxin strongly inhibited the contractile responses of the vein to AT II, BK, SP, and KCl, probably by a nonspecific effect. It is concluded that AT II-, BK-, and SP-induced contractions of the rabbit vena cava are mediated by specific receptors and in part by an influx of extracellular Ca2+ through dihydropyridine-insensitive channels. Opening of K+ channels and inhibition of the Ca(2+)-calmodulin complex appear to interfere with the smooth muscle response to the peptides.

Angiotensin II↗
PubMed1992

Molecular mechanism of action of nicorandil.

Nicorandil relaxes coronary vascular smooth muscle by stimulating guanylyl cyclase and increasing cyclic GMP (cGMP) levels (as shown first in our laboratory) as well as by a second mechanism resulting in activation of K+ channels and hyperpolarization. Therefore, we studied the relative contributions of either mechanism to the overall response in bovine circular strips of coronary arteries by simultaneously measuring changes in length and in cGMP levels through radioimmunoassay. Blockade by 10 microM methylene blue of the cGMP increases in strips precontracted by 1 microM of the thromboxane A2 analogue U46619 reduced nicorandil-induced relaxation to 30-50%, and there were no significant changes in cGMP levels. Suppression of the hyperpolarizing component of nicorandil by 80.4 mM K+ or 1 microM glibenclamide in precontracted strips reduced nicorandil relaxation to 50% (K+) or shifted the dose response to the right by a factor of two (glibenclamide) without alteration of increases in cGMP. A quantitative separation of both mechanisms of action was obtained by comparing the correlation between increases in cGMP and relaxation under conditions of inhibited versus noninhibited hyperpolarization. The results indicate that cGMP contributes to the total relaxing effect of nicorandil by 30-40% at low concentrations and 80-90% at high concentrations of nicorandil. From the experiments with glibenclamide, it can be concluded that the probable mechanism by which nicorandil hyperpolarizes is opening glibenclamide-sensitive K+ channels in coronary vascular smooth muscle and that this latter effect mimics those of other K+ channel openers such as cromakalim or pinacidil.

Animals↗
PubMed1993

Adenosine-5'-uronamides rapidly desensitize the adenosine A2 receptor in coronary artery.

This study examined the structure-activity-relationship (SAR) of adenosine analogs and their ability to induce tachyphylaxis in vascular smooth muscle. Adenosine-5'-uronamides,5'-N-ethylcarboxamidoadenosine (NECA), 5'-N-cyclopropylcarboxamidoadenosine (CPCA), and 2-[p-(2-carboxyethyl)phenethylamino]-5'-N-ethylcarboxamidoadenosin e (CGS 21680), evidenced rapid desensitization of the A2 vasorelaxant response in porcine coronary artery in vitro whereas adenosine, 2-chloroadenosine (CAD), or 2-[(2-cyclohexylethyl)-amino]adenosine (CGS 22492) failed to do so. Tissues with prior exposure to NECA exhibited mitigated relaxation responses to adenosine, CAD, and NECA but not to isoproterenol, forskolin, pinacidil, or sodium nitroprusside (SNP). The data suggest that adenosine-5'-uronamides homologously desensitize the A2 receptor in porcine coronary artery smooth muscle.

2-Chloroadenosine↗
PubMed1995

Cardioprotective profile of the cardiac-selective ATP-sensitive potassium channel opener BMS-180448.

ATP-sensitive potassium channel (KATP) openers have direct protective effects on ischemic myocardium that are independent of vasorelaxation. Because reference KATP openers (e.g., cromakalim, pinacidil) are potent relaxants of smooth muscle, their utility for treating myocardial ischemia may be limited by hypotension. Efforts aimed at development of a cardioprotective KATP opener with less vasorelaxant activity led to identification of the arylcyanoguanidine analogue BMS-180448. In globally ischemic rat hearts, BMS-180448 was cardioprotective (EC25 for increasing time to contracture = 2.5 microM), with potency equal to that of cromakalim (EC25 = 4.9 microM) despite being significantly less potent as a peripheral smooth muscle relaxant (methoxamine-constricted rat aorta). The cardioprotective effects of BMS-180448 in isolated perfused rat heart were abolished by the KATP blockers glyburide and sodium 5-hydroxydecanoate, indicating KATP involvement in its mechanism of action. Further confirmation was obtained by demonstration of single KATP opening by BMS-180448 in guinea pig cardiac myocytes. In anesthetized dogs, cromakalim was > 100-fold more potent than BMS-180448 in decreasing blood pressure (BP). In anesthetized dogs subjected to 90-min coronary occlusion/reperfusion, BMS-180448 reduced infarct size (IS) by 50% without hemodynamic effects. BMS-180448 provides the opportunity to explore the cardioprotective actions of this class of agents without the possible complications (hypotension, coronary steal) that may be caused by the currently available KATP openers.

Adenosine Triphosphate↗
PubMed2002

Effects of different tetra-n-alkylammonium ions on acetylcholine-induced endothelium-dependent hyperpolarization in rat mesenteric artery.

The effects of a series of symmetric tetra-n-alkylammonium (TAA) compounds with alkyl side chains of one to six carbons in length on acetylcholine-induced endothelium-dependent hyperpolarization were examined in rat mesenteric artery. All TAA compounds caused a concentration-dependent inhibition of the hyperpolarizing response to acetylcholine. The potency of TAAs showed a general trend to increase with the lengths of the alkyl side chains. The inhibitory effects of TAAs, excepting the smallest compound, on the acetylcholine response were reversible. However, TAAs with long alkyl side chains may act as antagonists at muscarinic receptors, because the suppressive effect on A23187-induced endothelium-dependent hyperpolarization was more marked with TAAs having smaller alkyl side chains. Conversely, the hyperpolarizing response to pinacidil, an ATP-sensitive K+ channel opener, was significantly prevented only by TAA compounds with long alkyl side chains. TAA compounds with one-to three-carbon alkyl side chains caused a modest and reversible depolarization of the membrane, whereas the depolarizing effects of the compounds with four-to six-carbon alkyl side chains were marked and irreversible. These results suggest that TAAs could gain access to the target K+ channels for endothelium-derived hyperpolarizing factor, the ATP-sensitive K+ channels, and the K+ channels responsible for the regulation of the resting membrane potential in different ways.

Acetylcholine↗
PubMed2003

Verapamil, a Ca2+ entry blocker, targets the pore-forming subunit of cardiac type KATP channel (Kir6.2).

This study investigated the mechanism by which verapamil, which blocks 10R1, l-type Ca2+ channel and the HERG channel, blocks ATP-sensitive K+ (K(ATP)) channels. In whole cell patch experiments, verapamil reversibly inhibited cardiac type K(ATP) (Kir6.2/SUR2A) channels previously activated by 100-micromol/L pinacidil. In inside-out patch experiments, verapamil inhibited the C-terminal truncated form of Kir6.2 (Kir6.2DeltaC36) in a concentration-dependent manner; half-maximal inhibition (IC(50)) was obtained at 11.5 +/- 2.8 micromol/L when Kir6.2DeltaC36 was expressed without SUR2A. Verapamil also inhibited Kir6.2/SUR2A with a similar potency; IC(50) was 8.9 +/- 2.1 micromol/L for Kir6.2/SUR2A (not statistically different from the value for Kir6.2DeltaC36 alone). Thus, verapamil appeared to target the pore-forming subunit Kir6.2 rather than SUR2A, a member of ABC superfamily. Verapamil did not decrease the single-channel conductance, but increased the closed time of Kir6.2/SUR2A. The mutations of Kir6.2DeltaC36 (Kir6.2DeltaC36-R50G, -K185Q, -G334D), which have much lower ATP sensitivity, had no significant effect on verapamil block, suggesting that the site at which verapamil mediates K(ATP) channel inhibition is not identical with that involved in ATP block.

Calcium Channel Blockers↗
PubMed1998

Mesenteric and skeletal muscle microvascular responsiveness in subacute sepsis.

This study was performed to assess the effects of subacute sepsis in rats on the in vitro reactivity of arterioles (internal diameter, 100-150 microm) to alpha1- and alpha2-adrenergic stimulation and to angiotensin II. Male Sprague-Dawley rats were rendered septic by intraperitoneal implantation of a gelatin capsule containing sterile rat feces and 1 x 10(6) viable colony forming units of Escherichia coli. Control rats underwent sham laparotomy and implantation of a gelatin capsule containing only sterile feces. In vitro reactivity of arterioles from mesentery and skeletal muscle were studied 48 h later in a pressurized (50 mmHg) no flow state using videomicroscopy. Subacute sepsis decreased the contractile response of nonprecontracted microvessels from both anatomical sites to phenylephrine (both p < .01 versus control) and blunted the relaxation response to staurosporine (both p < .01), an inhibitor of protein kinase C. The small contraction to angiotensin II of mesenteric vessels was inhibited by sepsis (p < .05) but was unaltered in the skeletal muscle microcirculation. In the precontracted mesenteric microvessels from septic rats, endothelium-dependent relaxation to clonidine and to adenosine 5'-diphosphate were decreased (both p < .01 versus control), whereas in skeletal muscle microvessels, clonidine and adenosine 5'-diphosphate elicited constriction (both p < .01). Relaxation to the endothelium independent vasodilators sodium nitroprusside and pinacidil was preserved across all vessels. In conclusion, mesenteric and skeletal muscle microvascular responses to angiotensin II and alpha1- and alpha2-adrenergic stimulation are altered in subacute sepsis. This may in part lead to systemic hypotension and altered organ perfusion during states of chronic sepsis.

Angiotensin II↗
PubMed2004

ATP-dependent potassium channels as a key target for the treatment of myocardial and vascular dysfunction.

PURPOSE OF REVIEW: The aim of this review is to highlight the most recent and interesting articles on the physiologic properties and functions of ATP-dependent potassium channels in the cardiovascular system and on the role of the potassium channel openers for the treatment of cardiovascular dysfunction. RECENT FINDINGS: The initial efforts in the development of potassium channel openers focused on the management of systemic hypertension. Lately, the range of possible indications for potassium channel openers has increased to include pulmonary hypertension and stable angina pectoris. The discovery of a connection between the mitochondrial ATP-dependent potassium channels and the phenomenon of cardiac preconditioning created potential new uses for potassium channel openers in myocardial ischemia, inn unstable angina, in preoperative and perioperative settings, and for the preservation of organs for transplant. SUMMARY: The most recent data on the physiologic roles of sarcolemmal and mitochondrial ATP-dependent potassium channels and the pharmacology of potassium channel openers in the cardiovascular system are summarized and discussed. Finally, the effects of potassium channel opener drugs including minoxidil, nicorandil, pinacidil, bimakalin, and levosimendan, a dual-action potassium channel opener and calcium sensitizer with inodilator and cardioprotective activity, are discussed.

Adenosine Triphosphate↗
PubMed2006

P-1075 exerts diverse modulatory effects on mitochondrial ATP-sensitive K+ channels in rabbit ventricular myocytes.

P-1075 was reported to be selective for sarcolemmal ATP-sensitive K (sarcKATP) channels because of its lack of mitochondria-oxidizing effect in isolated adult rabbit myocytes. Conflicting results however have been reported on the action of P-1075 on mitochondrial KATP (mitoKATP) channels. The aim of the present study was to reevaluate the effect of P-1075 on mitoKATP channels. Endogenous flavoprotein autofluorescence in isolated rabbit ventricular myocytes was measured to assay mitoKATP channel activity. The mitoKATP channel opener diazoxide (100 microM) oxidized the flavoprotein. P-1075 at a concentration of 30 microM significantly inhibited the oxidative effect of diazoxide from 48.6 +/- 7.1% to 28.2 +/- 5.2% of the maximum value induced by 2,4-dinitrophenol (DNP, 100 microM) (n = 4, P < 0.05). Additionally, P-1075 (30 microM) significantly inhibited the pinacidil (100 microM)-induced flavoprotein oxidation by 48.4 +/- 3.9% (n = 4, P < 0.05). The inhibitory effects of P-1075 on diazoxide-induced flavoprotein oxidation were observed in the micromolar range in a concentration dependent manner. P-1075 alone oxidized flavoprotein in the range 30 nM to 5 microM, and was nearly maximal at 150 nM (11.1 +/- 1.9% of the DN P value, n = 5). These results indicate that P-1075 exerts diverse effects on mitoKATP channel in rabbit ventricular myocytes: P-1075 has a partial agonist effect and weakly activates mitoKATP channels at low concentrations, whereas P-1075 rather inhibits the opening of mitoKATP channels in the micromolar concentration range.

2,4-Dinitrophenol↗
PubMed2007

Relaxation of human placental arteries and veins by ATP-sensitive potassium channel openers.

BACKGROUND: Adenosine triphosphate (ATP)-sensitive potassium channels (K(ATP)) are important modulators of vascular tone. Preliminary data from our laboratory suggests that K(ATP) channels are expressed in the fetoplacental vasculature where addition of pinacidil, a specific K(ATP) opener, promotes relaxation. We aimed to assess the effects of KRN2391 and KRN4884 on the fetoplacental vasculature, which are putative K(ATP) channel openers. MATERIALS AND METHODS: Functional activity of K(ATP) channels was assessed in chorionic plate arteries and veins using wire myography. Cromakalim-, KRN2391- and KRN4884-induced relaxations were assessed in the presence and absence of agonist-induced pretone. Cromakalim, an established K(ATP) channel opener, acted as control. RESULTS: KRN2391 evoked significantly greater relaxation of chorionic plate arteries and veins than either KRN4884 or cromakalim. KRN2391-induced relaxation of precontracted arteries and veins was reduced in the presence of inhibitors of the nitric oxide pathway (L-NNA or LY83583). With KRN4884, there was no contribution of nitric oxide to the induced relaxation. CONCLUSIONS: We conclude that K(ATP) channels play an important role in controlling placental vascular tone. KRN2391 induces relaxation of human placental blood vessels by activation of K(ATP) channels and via activation of nitric oxide-dependent pathways.

Adenosine Triphosphate↗
PubMed2000

Tolbutamide stimulates exocytosis of glucagon by inhibition of a mitochondrial-like ATP-sensitive K+ (KATP) conductance in rat pancreatic A-cells.

1. Capacitance measurements were used to examine the effects of the sulphonylurea tolbutamide on Ca2+-dependent exocytosis in isolated glucagon-secreting rat pancreatic A-cells. 2. When applied extracellularly, tolbutamide stimulated depolarization-evoked exocytosis 4.2-fold without affecting the whole-cell Ca2+ current. The concentration dependence of the stimulatory action was determined by intracellular application through the recording pipette. Tolbutamide produced a concentration-dependent increase in cell capacitance. Half-maximal stimulation was observed at 33 microM and the maximum stimulation corresponded to a 3.4-fold enhancement of exocytosis. 3. The stimulatory action of tolbutamide was dependent on protein kinase C activity. The action of tolbutamide was mimicked by the general K+ channel blockers TEA (10 mM) and quinine (10 microM). A similar stimulation was elicited by 5-hydroxydecanoate (5-HD; 10 microM), an inhibitor of mitochondrial ATP-sensitive K+ (KATP) channels. 4. Tolbutamide-stimulated, but not TEA-induced, exocytosis was antagonized by the K+ channel openers diazoxide, pinacidil and cromakalim. 5. Dissipating the transgranular K+ gradient with nigericin and valinomycin inhibited tolbutamide- and Ca2+-evoked exocytosis. Furthermore, tolbutamide- and Ca2+-induced exocytosis were abolished by the H+ ionophore FCCP or by arresting the vacuolar (V-type) H+-ATPase with bafilomycin A1 or DCCD. Finally, ammonium chloride stimulated exocytosis to a similar extent to that obtained with tolbutamide. 6. We propose that during granular maturation, a granular V-type H+-ATPase pumps H+ into the secretory granule leading to the generation of a pH gradient across the granular membrane and the development of a positive voltage inside the granules. The pumping of H+ is facilitated by the concomitant exit of K+ through granular K+ channels with pharmacological properties similar to those of mitochondrial KATP channels. Release of granules that have been primed is then facilitated by the addition of K+ channel blockers. The resulting increase in membrane potential promotes exocytosis by unknown mechanisms, possibly involving granular alkalinization.

Animals↗
PubMed2001

Two resting potential levels regulated by the inward-rectifier potassium channel in the guinea-pig spiral modiolar artery.

1. Intracellular in vitro recordings were made from 771 cells from the spiral modiolar artery (SMA). The initial resting potentials (RPs) displayed a bimodal distribution that was well modelled as a mixture of two Gaussian distributions. About half of the cells had an average RP of -74 mV, and were termed high-RP cells, whereas the other half had an average RP around -41 mV, and were termed low-RP cells. Preparations that were incubated for longer than 24 h contained significantly more high-RP cells than those incubated for less than 8 h. 2. When labelled with the fluorescent dye propidium iodide, 68 and 36 cells were identified as smooth muscle cells (SMC) and endothelial cells (EC), respectively. The RP and input resistance were not significantly different between these two types of cell. Dye coupling was observed only in ECs. Dual cell recordings with 0.2-1.0 mm separation demonstrated the simultaneous existence of high- and low-RP cells and a heterogeneous low-strength electrical coupling. 3. The high-RP cells were depolarized by ACh and by high extracellular potassium concentration (high K(+)). The low-RP cells were usually hyperpolarized by moderately high K(+) (7.5-20 mM) and by ACh. The high K(+)-induced hyperpolarization was suppressed by barium (Ba(2+), 10-50 microM). The putative gap junction blocker 18 beta-glycyrrhetinic acid suppressed the ACh-induced responses in SMCs, but not in ECs. 4. Low-RP cells could rapidly shift the membrane potential to a permanent high-RP state spontaneously or, more often, after a brief application of hyperpolarizing agents including high K(+), ACh, nitric oxide and pinacidil. Once shifted to a high-RP state, the responses of these cells to high K(+) and ACh became similar to those of the original high-RP cells. 5. High-RP cells occasionally shifted their potentials to a low-RP state either spontaneously or after a brief application of 10-50 microM Ba(2+) or 100 microM ouabain. Once shifted to the low-RP state, the response of these cells to high K(+) and ACh became a hyperpolarization. The shift between high- and low-RP states was largely mimicked by wash-in and wash-out of low concentrations of Ba(2+). The shift often showed a regenerative process as a fast phase in its middle course. 6. It is concluded that the cochlear SMA in vitro is composed of poorly and heterogeneously coupled SMCs and ECs, simultaneously resting in one of two distinct states, one a high-RP state and the other a low-RP state. The two RP states are exchangeable mainly due to all-or-none-like conductance changes of the inward-rectifier K(+) channel.

Acetylcholine↗
PubMed2001

Evidence for involvement of A-kinase anchoring protein in activation of rat arterial K(ATP) channels by protein kinase A.

1. We have investigated the possible role of A-kinase anchoring proteins (AKAPs) in protein kinase A (PKA) signalling to ATP-sensitive K+ (K(ATP)) channels of rat isolated mesenteric arterial smooth muscle cells using whole-cell patch clamp and peptides that inhibit PKA-AKAP binding. 2. Intracellular Ht31 peptide (20 microM), which inhibits the PKA-AKAP interaction, blocked K(ATP) current activation by either dibutyryl cAMP or calcitonin gene-related peptide. Ht31-proline (20 microM), which does not inhibit PKA binding to AKAP, did not block K(ATP) current activation. 3. Ht31 reduced K(ATP) current activated by pinacidil and also prevented its inhibition by Rp-cAMPS, effects consistent with Ht31 blocking steady-state K(ATP) channel activation by PKA. However, Ht31 did not prevent K(ATP) current activation by the catalytic subunit of PKA. 4. An antibody to the RII subunit of PKA showed localization of PKA near to the cell membrane. Our results provide evidence that both steady-state and receptor-driven activation of K(ATP) channels by PKA involve the localization of PKA by an AKAP.

Adenosine Triphosphate↗
PubMed1992

Potassium channel openers: pharmacological and clinical aspects.

Opening of plasmalemmal K+ channels leads to cellular hyperpolarization which, in excitable tissues possessing voltage-dependent Ca2+ channels, prevents the opening of such channels and thus prevents excitation. In the last few years, an increasing number of compounds have been identified which elicit their effects by opening K+ channels, preferentially in smooth muscle, but also in other excitable tissues. These include the novel benzpyrans, cromakalim and bimakalim, the thioformamide aprikalim, and also well known antihypertensives such as minoxidil sulphate, diazoxide and pinacidil. After a short overview of the various families of K+ channel openers (KCOs), their basic pharmacological properties, including inhibition by the sulfonyl ureas (such as glibenclamide) are presented. The actual discussion concerning the type of K+ channel(s) opened by these compounds and their mechanism(s) of vasorelaxation will be reported. The therapeutic potential of these compounds in the cardiovascular field (as antihypertensives and, in particular, as anti-ischemic agents in heart and skeletal muscle), and in asthma (where they reverse established airway hyperreactivity) will also be discussed. Improved tissue selectivity may be the essential pre-requisite for true clinical success of this class of compounds.

Animals↗
PubMed1991

Action of nicorandil on ATP-sensitive K+ channel in guinea-pig ventricular myocytes.

1. Patch-clamp techniques were used to study the effects of nicorandil (2-nicotinamiodethyl nitrate) on the adenosine 5'-triphosphate (ATP)-sensitive K+ channel current (IK.ATP) in guinea-pig ventricular myocytes. 2. Nicorandil activated the time-independent outward current. This effect was dependent on intracellular ATP concentration ([ATP]i) showing a larger effect at 2 mM than at 10 mM [ATP]i. The nicorandil-induced outward current was inhibited by application of 0.3 microM glibenclamide. 3. In the inside-out patch configuration, 0.3-1.0 mM nicorandil increased the open-stage probability of IK.ATP without a change in its conductance value (about 90pS). This effect was inhibited by glibenclamide. Analysis of the open and closed time distributions showed that nicorandil had no effect on open and closed distributions shorter than 5 ms. On the other hand, nicorandil increased the life time of bursts and decreased the interburst intervals. 4 The inward rectifier K+ channel current was not influenced by internal application of nicorandil. 5 Therefore, we conclude that IK.ATP is the only K+ current activated by nicorandil, and the main effect of nicorandil is on the kinetics of the IK.ATP bursting behaviour. These actions are similar to that of pinacidil on this preparation.

Adenosine Triphosphate↗