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At least 19 recordsLinked to original sources
PubMed1994

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

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

Animals↗
PubMed1991

The diverse effects of cromakalim on tension and 86Rb efflux in canine arterial smooth muscle.

1. To characterize further the K+ channels opened by cromakalim in arterial smooth muscle, the effects of cromakalim on tension and 86Rb efflux were compared in endothelium-denuded strips of coronary, mesenteric and middle cerebral (MC) arteries of the dog. 2. Cromakalim relaxed strips precontracted with 20.9 mM K+. The maximum relaxation induced by cromakalim varied in the arteries used; 94% in the coronary artery, 60% in the mesenteric artery and only 38% in the MC artery. Cromakalim failed to relax arterial strips precontracted with 65.9 mM K+. 3. When the effects of cromakalim on 86Rb efflux were determined in 20.9 mM K(+)-contracted strips, cromakalim-induced relaxations were accompanied by a large increase in 86Rb efflux in the coronary artery, by a small increase in the mesenteric artery but by an apparent decrease in the MC artery. 4. When 10(-7) M nifedipine was added to 20.9 mM K(+)-contracted strips, to inactivate Ca2(+)-activated K+ (KCa) channels, cromakalim produced a greater increase (measured from the point at which cromakalim was administered) in 86Rb efflux than in the absence of nifedipine, suggesting that the effects of cromakalim on 86Rb efflux from the 20.9 mM K(+)-contracted strips may be the resultant of two opposing effects: an increased 86Rb efflux perhaps due to the opening of ATP-sensitive K+ (KATP) channels, and a decreased efflux due to the closing of KCa channels. 5. After the inactivation of Kca channels in 20.9mM K+-contracted strips, the cromakalim-induced increase in 86Rb efflux measured as area under the curve was eight times greater in the coronary artery than in the MC artery. The increase in 86Rb efflux in the mesenteric artery was intermediate between these extremes. 6. Cromakalim also increased the 86Rb efflux from 65.9 mm K+-contracted strips. This increase was not augmented by the addition of nifedipine. Under these conditions, a similar variation in efflux response (as area under the curve) for cromakalim was noted in the arteries used. 7. The relaxant responses of each artery to cromakalim were competitively antagonized by glibenclamide, a blocker of KATP channels. The cromakalim-induced increase in 86Rb efflux was also inhibited by glibenclamide. 8. These results suggest that cromakalim-opened K+ channels in the three arteries may differ in terms of their frequency of occurrence in the plasmalemma, their permeability to 86Rb and their ability to modulate tension development. On the other hand, the activities of Kca and voltage-sensitive K+ channels, estimated from the effects of nifedipine, were similar in the three arteries.

Animals↗
PubMed1994

Vasodilating actions of cromakalim in resting and contracting states of carotid arteries from spontaneously hypertensive rats.

To determine the properties of cromakalim-opened K+ channels in arterial smooth muscle of spontaneously hypertensive rats (SHR), the effects of cromakalim on tension and 86Rb efflux were compared in endothelium-denuded strips of carotid arteries from 13-week-old SHR and normotensive Wistar-Kyoto rats (WKY). The addition of cromakalim or of nifedipine to resting strips caused a relaxation only in SHR. When strips from both strains were contracted with 15.9 mM K+, the magnitude of the precontraction was greater in SHR than in WKY. Under these conditions, relaxant responses to lower concentrations of cromakalim were decreased and those to higher concentrations of cromakalim were increased in SHR. When strips from both strains were contracted with a different concentration of K+ to an equivalent magnitude (78% of the maximum) relaxant responses to cromakalim were greater in SHR than in WKY. When strips were contracted with 10(-7) M norepinephrine, the precontraction was similar between SHR and WKY, and relaxant responses to cromakalim were greater in SHR. In both strains, the relaxant responses to cromakalim were competitively antagonized by glibenclamide, a blocker of ATP-sensitive K+ (KATP) channels, with a pA2 value of approximately 7.3. Charybdotoxin (10(-7) M), a blocker of Ca(2+)-activated K+ (KCa) channels, did not inhibit the relaxant responses to cromakalim in both strains. Charybdotoxin alone elicited a contraction, which was greater in SHR than in WKY. In resting strips preloaded with 86Rb, the basal 86Rb efflux rate constant was higher in SHR than in WKY. The addition of cromakalim (10(-5) M) to the resting strips increased the 86Rb efflux rate constant in both strains to a similar peak value. The addition of nifedipine (10(-7) M) to the resting strips decreased the basal 86Rb efflux rate constant only in SHR, and concomitantly affected the action of cromakalim in SHR. The results suggest that (1) cromakalim caused arterial relaxation via the opening of KATP channels in both SHR and WKY, (2) although the relaxant effects of cromakalim tended to be greater in SHR than in WKY, the differences were rather small, depended on the precontraction tone and varied with the concentration of the vasoconstrictors, and (3) there was an increased basal Ca2+ influx and a high activation of KCa channels in the resting state of SHR arteries, and these changes might influence the effects of cromakalim.

Animals↗
PubMed1995

Cardioprotection with the KATP opener cromakalim is not correlated with ischemic myocardial action potential duration.

We endeavored to determine if the enhanced shortening of the myocardial action potential duration (APD) during ischemia can be dissociated from the cardioprotective effects of the adenosine triphosphate (ATP) sensitive potassium channel (KATP) opener cromakalim. To establish if there is a relationship between APD shortening and the cardioprotective effect of cromakalim, we determined the effect of a dose of the delayed rectifier (IKr) blocker dofetilide (which abolishes the APD shortening effect of cromakalim) on the cardioprotective activity of cromakalim. Cromakalim was infused at a previously determined cardioprotective dose (10 micrograms/kg + 0.3 micrograms/kg/min infusion i.c.), and we determined the effect of 1 mg/kg (followed by a 0.01 mg/kg/min i.v. infusion) dofetilide alone and in combination with cromakalim on APD shortening and infarct size (90-min coronary occlusion and 5-h reperfusion) in anesthetized dogs. Dofetilide completely abolished the APD shortening effects of cromakalim during ischemia such that APD was similar to preischemic values. Cromakalim only shortened the APD during ischemia, although this effect was attenuated late into ischemia. Cromakalim significantly reduced infarct size (40% reduction from vehicle group value), whereas dofetilide alone had no effect. Dofetilide, at a dose that prevented the cromakalim-induced shortening of APD in ischemic tissue, did not attenuate the cardioprotective effects of cromakalim. No differences in collateral blood flow for any of the groups were observed. Dofetilide did cause a slight bradycardia, but this effect is unlikely to affect the interpretation of the results. These data suggest that APD shortening observed with the KATP opener cromakalim is not correlated with its cardioprotective effects.

Action Potentials↗
PubMed1991

Effects of cromakalim on neurally-mediated responses of guinea-pig tracheal smooth muscle.

1. The ability of cromakalim to modulate several different types of neuroeffector transmission has been assessed in guinea-pig isolated trachea. 2. In trachea treated with propranolol (10(-6) M) and indomethacin (2.8 x 10(-6) M), stimulation of the extrinsic vagal nerves evoked contractions which were blocked by hexamethonium (5 x 10(-4) M) or by tetrodotoxin (TTX; 10(-6) M). Cromakalim (10(-5) M) caused a two fold rightward shift of the frequency-response curve. 3. In carinal trachea treated with propranolol and indomethacin, transmural stimulation evoked an initial, rapid contraction followed by a more sustained secondary contraction. The initial, rapid contractile response was virtually ablated by atropine (10(-6) M) or by TTX but was resistant to hexamethonium. Cromakalim (10(-8)-10(-5) M) caused a concentration-dependent rightward shift of the frequency-response curve for the initial contraction. 4. In carinal trachea treated with atropine, propranolol and indomethacin, transmural stimulation evoked only the secondary (non-adrenergic, non-cholinergic (NANC] contractile responses. These were markedly reduced by TTX but were resistant to hexamethonium. Cromakalim (10(-8)-10(-5) M) suppressed the NANC contractile responses in a concentration-dependent manner. This action could be offset by glibenclamide (10(-6) M). 5. In trachea treated with atropine, histamine (10(-4) M), propranolol and indomethacin, transmural stimulation evoked NANC relaxant responses. Cromakalim (up to 10(-5) M) was without effect on the frequency-response curve for the stimulation of NANC inhibitory nerves. 6. Tested on trachea bathed by drug-free Krebs solution, cromakalim (10(-7)-10(-5) M) caused concentration-dependent suppression of tracheal tone. In trachea treated with propranolol and indomethacin, cromakalim (10- 7-1O- 5 M) caused concentration-dependent antagonism of acetylcholine (ACh). In trachea treated with atropine, propranolol and indomethacin, cromakalim (up to 10- 5M) failed to antagonize effects of either histamine or substance P.7. It is concluded that cromakalim can inhibit cholinergic (excitatory) neuroeffector transmission in the trachea but only at a concentration having demonstrable inhibitory activity against the action of exogenous ACh and the spontaneous tone of the airways smooth muscle. In contrast, cromakalim may depress NANC excitatory (putative peptidergic) neuroeffector transmission at a concentration below that exerting inhibitory activity on airways smooth muscle. Cromakalim does not concurrently depress NANC inhibitory neuroeffector transmission. Depression of NANC excitatory neuroeffector transmission could explain the ability of cromakalim to suppress airway hyperreactivity or bronchial asthma at doses lacking direct relaxant effect on airways smooth muscle.

Animals↗
PubMed1992

Characteristics of the contractile response of rabbit aorta produced by cromakalim in calcium-free solution.

1 The effect of potassium channel opening compounds has been investigated in the smooth muscle of rabbit aorta under Ca-free conditions. Examination of the characteristics of the response has been performed using cromakalim as the prototype compound. 2 In order of potency, Ro 31-6930, cromakalim, minoxidil sulphate and pinacidil each produced a contraction in rabbit aortic strips bathed in Ca-free MOPS-buffered physiological salt solution (PSS). In contrast, forskolin, glyceryl trinitrate and nifedipine each failed to increase tension under identical conditions. Cromakalim also evoked contraction of bovine trachealis muscle bathed in Ca-free PSS. 3. The contractile response to cromakalim in rabbit aortic strips was of delayed onset (15-20 min) and reached a plateau after approximately 120 min (1.8 g maximum with 1 microM cromakalim). No cromakalim-induced tension changes were observed in either 1 mM or 2.5 mM Ca-containing PSS. 4. Raising the [KCl] of the Ca-free PSS to 65.9 mM fully inhibited the cromakalim-induced contraction in rabbit aortic strips. In addition, pretreatment of aortic strips with the sulphonylurea glibenclamide antagonized the subsequent mechanical response to cromakalim. 5. In Ca-free PSS, cromakalim (1 microM) stimulated 42K-efflux with a time-course corresponding to the contractile event. Glibenclamide (1 microM) inhibited this cromakalim-induced 42K-efflux. 6. In sharp microelectrode studies in bovine trachealis, cromakalim (10 microM) produced a sustained membrane hyperpolarization in normal PSS. In contrast, the cromakalim-induced hyperpolarization in Ca-free PSS was not sustained. The fading of the hyperpolarization was temporally correlated with the increase in tension under these experimental conditions. 7. It is concluded that the K-channel opener-induced smooth muscle contractile response revealed in Ca-free PSS is the consequence of K-channel opening. The nature of the detailed mechanism which underlies this contractile phenomenon remains to be determined.

Animals↗
PubMed1990

Possible involvement of ATP-sensitive K+ channels in the relaxant response of dog middle cerebral artery to cromakalim.

To determine the functions of ATP-sensitive K+ (KATP) channels in cerebral arterial smooth muscle, the effects of cromakalim, an opener of these channels, on tension and 86Rb efflux were investigated in endothelium-removed strips of dog middle cerebral arteries (MCAs). Cromakalim relaxed the strips that were precontracted with 20.9 mM K+ with a small maximum response. The relaxant responses to cromakalim were competitively antagonized by glibenclamide, a blocker of KATP channels. In strips precontracted with 65.9 mM K+, cromakalim failed to relax the strips. The addition of cromakalim to a resting strip caused a dose-dependent relaxation. In the resting strips of MCAs preloaded with 86Rb, cromakalim did not increase the 86Rb efflux. With 42K as the tracer ion, cromakalim still had no effect on the efflux from the resting strips. On the other hand, cromakalim increased the 86Rb and 42K efflux from the strips of dog coronary arteries (CAs). In 20.9 mM K(+)-contracted strips of MCAs, cromakalim significantly decreased the 86Rb efflux. However, after the inactivation of Ca(++)-activated K+ channels by the addition of 1 x 10(-7) M nifedipine to the 20.9 mM K(+)-contracted strips of MCAs, cromakalim produced a small but significant increase in the 86Rb efflux. Similarly, when the resting strips of MCAs were placed in the Ca(++)-free 12 mM-Mg(+)+ solution, cromakalim increased the 86Rb efflux. In 65.9 mM K(+)-contracted strips, cromakalim increased the 86Rb efflux from both arteries. However, the extent of the increase in 86Rb efflux was significantly smaller in the MCA than in the CA.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMedDate not supplied

Cardiovascular effects of KRN2391 in anesthetized dogs: a comparison with cromakalim and nitroglycerin.

The cardiovascular effects of KRN2391, N-cyano-N'-(2-nitroxyethyl)-3-pyridine carboximidamide monomethanesulfonate, were compared with those of cromakalim and nitroglycerin in anesthetized dogs. KRN2391 (3-30 micrograms/kg, i.v.), cromakalim (3-30 micrograms/kg, i.v.) and nitroglycerin (1-10 micrograms/kg, i.v.) produced a dose-related decrease of the mean blood pressure with concomitant increase in heart rate. The increase in heart rate caused by cromakalim was lower than that caused by KRN2391 and nitroglycerin. Left ventricular end-diastolic pressure was decreased by all doses of KRN2391 and nitroglycerin. Cromakalim at 3 and 10 micrograms/kg decreased this end-diastolic pressure but increased it at 30 micrograms/kg. Left ventricular dP/dt was increased by KRN2391 and nitroglycerin but was decreased by cromakalim. KRN2391 and cromakalim produced a dose-dependent increase in aortic and coronary blood flow. Nitroglycerin showed biphasic changes in aortic and coronary blood flow, i.e., an initial increase followed by a decrease. At equipotent hypotensive doses, the increase in coronary blood flow induced by KRN2391 was greater than that by cromakalim and nitroglycerin, and total peripheral and coronary vascular resistances were decreased by KRN2391 and cromakalim. Nitroglycerin showed biphasic changes in total peripheral and coronary vascular resistances, i.e., these resistance showed an initial decrease followed by an increase. The relative decrease of coronary vascular resistance compared to the total peripheral vascular resistance was greater for KRN2391 than for cromakalim and nitroglycerin. The changes in hemodynamic parameters caused by KRN2391 were inhibited by pretreatment with glibenclamide (5 mg/kg, i.v.). These results suggest that the hemodynamic profile of KRN2391 is closer to that of cromakalim than to that of nitroglycerin, but that the selectivity for the coronary vascular bed is higher for KRN2391 than for cromakalim. In addition, it is considered that, compared with KRN2391 and nitroglycerin, cromakalim has a low selectivity for the vasculature vs the myocardium.

Anesthesia↗
PubMed1993

[Cardioprotective effect of cromakalim, a K+ channel opener, on isolated globally ischemic and reperfused rat hearts].

Examination was made of cardioprotective effect related to the ATP-sensitive K+ (KATP) channel on isolated globally ischemic reperfused rat hearts using cromakalim, a putative ATP-sensitive K+ channel opener. The hearts were subjected to 20 min Langendorff perfusion with Krebs Henseleit Bicarbonate Buffer (KHBB) (70 cmH2O, 37 degrees C), followed by 30 min ischemia at 36 degrees C, and 30 min reperfusion with KHBB, with (cromakalim group) or without (control group) pretreatment by 10 microM cromakalim added to KHBB for 5 min prior to ischemia. Before ischemia, no significant change in heart rate (HR), left ventricular developed pressure (LVDP) or coronary flow (CF) by 10 microM cromakalim could be detected. The two groups were the same in CF during reperfusion, but recovery of HR and LVDP significantly improved in the cromakalim group. Creatine kinase (CK) leakage in the cromakalim group was significantly less than in the control group during reperfusion. Cromakalim is thus shown to reduce the myocardial injury during ischemia and reperfusion. Intracellular Ca2+ content of the cromakalim group appeared lower than that of the control group at 30 min of reperfusion. At 5-30 min of reperfusion, in the cromakalim group, intracellular Ca2+ storage was prevented, leading to a good recovery of cardiac function, while in the control group, intracellular Ca2+ increased and recovery of cardiac function was poor. After pretreatment with 10 microM cromakalim, intracellular K+ content of the cromakalim group was significantly lower than in the control group before ischemia. At 5 min of reperfusion, intracellular K+ content of the cromakalim group was slightly less than that of the control group.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Effect of cromakalim on KCl-, noradrenaline- and angiotensin II-induced contractions in the rat pulmonary artery.

The effect of cromakalim on vascular reactivity was studied in rat isolated pulmonary arterial strips. Cromakalim (0.1-1 microM) inhibited contractions induced by low (20-30 mM) KCl concentrations in a concentration-dependent manner. It had no effect on those elicited by 60-100 mM KCl. However, a higher concentration of cromakalim (10 microM) slightly decreased (-5 to -10%) KCl efficacy. Contractions induced by noradrenaline (NA, 0.01-1 microM) and angiotensin II (AII, 0.5-50 nM) were reduced by cromakalim (0.1-10 microM). The maximal response to NA and AII was decreased by 54 +/- 6.4% and 70 +/- 5.8% (n = 5), respectively, in the presence of 10 microM cromakalim. The inhibitory effect of cromakalim was not dependent on the presence of vascular endothelium. After blockade of calcium influx by verapamil (10 microM), cromakalim had no further effect on NA- and AII-induced contractions. Cromakalim (0.1-1 microM) had no effect on the amplitude of the transient contraction evoked by NA and AII in Ca(2+)-free solution. The inhibitory effect of cromakalim (1 microM) was reversed by glibenclamide (1-10 microM) and phentolamine (5-100 microM) which, however, did not alter the relaxant effect of verapamil (1 microM), papaverine (1 microM) or theophylline (1 mM). Contractions induced by NA and AII in the presence of tetraethylammonium (TEA, 10 mM) were also depressed by cromakalim. These results show that cromakalim is a potent anticonstrictor agent in the pulmonary circulation. As in other smooth muscles, its mechanism of action involves an interaction with potassium channels at the vascular smooth muscle cell membrane level.

Angiotensin II↗
PubMed1991

Some degree of overlap exists between the K(+)-channels opened by cromakalim and those opened by minoxidil sulphate in rat isolated aorta.

The effects of the K+ channel opening drugs minoxidil sulphate and cromakalim, on 42K+ and 86Rb+ efflux and on vasorelaxation in rat isolated aorta, were compared. In rat aortic rings precontracted with noradrenaline (100 nmol/l), minoxidil sulphate and cromakalim concentration-dependently inhibited induced tension by up to 90%, with pD2 values of 7.35 +/- 0.1 and 7.17 +/- 0.1, respectively. Glibenclamide (300 nmol/l), produced 2200- and 19-fold rightward shifts in the concentration-relaxation curves to minoxidil sulphate and cromakalim, respectively, without an effect on the maximum relaxation. Both minoxidil sulphate and cromakalim increased the efflux of 42K+ and 86Rb+ from aorta in a concentration-dependent manner, with midpoints in the mumol/l range; the maximum efflux induced by minoxidil sulphate being approximately one tenth of that induced by cromakalim. The ratio of stimulated 86Rb+/42K+ efflux increased from 0.22 to 0.48 with increasing cromakalim concentrations, but was approximately constant (approximately 0.39) when the minoxidil sulphate concentration was varied. In the presence of minoxidil sulphate, the effects of cromakalim on 42K+ and 86Rb+ efflux were inhibited in a concentration-dependent manner, by up to 60%. In the continuing presence of cromakalim (300 nmol/l), minoxidil sulphate (10 mumol/l)-induced increases in 42K+ and 86Rb+ efflux were inhibited by 45%, whereas conditioning with cromakalim (1 mumol/l) inhibited the 86Rb+ efflux stimulated by additional superfusion of cromakalim (1 mumol/l) by 85%. Glibenclamide inhibited minoxidil sulphate (10 mumol/l)- and cromakalim (1 mumol/l)-induced increases in 42K+ and 86Rb+ efflux in a concentration-dependent manner with IC50 values of approximately 80 nmol/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2000

Interaction of isoflurane and cromakalim, a KATP channel opener, on coronary and systemic haemodynamics in chronically instrumented dogs.

BACKGROUND: Although isoflurane has been shown to cause coronary and systemic vasodilation through KATP channel activation, the interaction of KATP channel openers and isoflurane has not been fully investigated. The present study was carried out to determine the haemodynamic actions of cromakalim, a KATP channel opener, under the conscious state and during isoflurane anaesthesia in chronically instrumented dogs. METHODS: Fourteen dogs were chronically instrumented to measure systemic and coronary haemodynamics. Each dog was randomly assigned to receive doses of either cromakalim, 4 and 10 microg x kg(-1) i.v., or isoflurane, 2.1% end-tidal (1.5 MAC), plus cromakalim, 4 and 10 microg x kg(-1) i.v. RESULTS: Cromakalim dose-relatedly decreased mean arterial pressure and systemic vascular resistance and increased coronary blood flow in both conscious and anaesthetized states. With isoflurane, the duration of effects of cromakalim were prolonged. Isoflurane exerted an additive effect on the increase in coronary blood flow induced by a low-dose cromakalim, whereas it did not influence the effect of a high-dose cromakalim. The maximum rate of increase in left ventricular pressure and segment shortening were increased by cromakalim in the conscious state but unchanged during isoflurane anaesthesia. CONCLUSION: The results suggest that the coronary vasodilating effects of isoflurane and cromakalim are basically additive until cromakalim exerts the maximal effect, and that the action of cromakalim on the coronary vasculature is prolonged by isoflurane.

ATP-Binding Cassette Transporters↗
PubMed1988

Anti-vasoconstrictor effects of the K+ channel opener cromakalim on the rabbit aorta--comparison with the calcium antagonist isradipine.

1. Contractile responses of rabbit aortic rings elicited by KCl-depolarization, angiotensin II (AII), 5-hydroxytryptamine (5-HT) and noradrenaline (NA) have been investigated in the presence of cromakalim (BRL 34915) and isradipine (PN 200-110). 2. Above 10(-6)M, cromakalim inhibited contractile responses to low (less than or equal to 32 mM) but not to higher KCl concentrations. The 5-HT and AII concentration-response curves were antagonized noncompetitively by cromakalim (10(-7)-10(-5)M) and the maximal responses were inhibited by 40 and 55%, respectively. 3. Isradipine caused less inhibition of AII and 5-HT contractile responses than cromakalim, and in the presence of isradipine (10(-7)M), cromakalim was still able to antagonize further the contractions to AII in this vessel. 4. NA-induced contractions were relatively insensitive to inhibition by cromakalim and isradipine, both drugs causing a small rightward shift of the NA concentration-response curve. This result suggests that NA utilizes different Ca2+ pools from those involved in AII- and 5-HT-induced contractions of this vessel. 5. The sustained (tonic) part of the NA response was inhibited in a concentration-dependent manner by cromakalim (10(-7)-10(-5)M), but not by isradipine. 6. In aortic rings partially depolarized with 3.5 x 10(-2)M KCl, the ability of cromakalim, but not of sodium nitroprusside, atriopeptin III or hydralazine, to inhibit AII- and tonic NA-induced contractions was abolished. 7. Antivasoconstrictor activity of cromakalim on the rabbit aorta appears to involve factors in addition to an indirect inhibition of Ca2+ entry through dihydropyridine-sensitive Ca2+ channels. 8. The ability of cromakalim to open K+ channels and thereby modify the membrane potential would appear to underlie these antivasoconstrictor effects. This mechanism of action of cromakalim clearly differs from that of other vasodilators such as sodium nitroprusside and hydralazine.

Angiotensin II↗
PubMed1991

Differences between the effects of cromakalim and nifedipine on agonist-induced responses in rabbit aorta.

1. The effects of cromakalim on endothelium-denuded rabbit aortic strips were compared with those of the calcium (Ca2+) entry blocking agent, nifedipine. 2. Pre-incubation with cromakalim or nifedipine had no significant effect on the initial phasic component of noradrenaline (NA)-induced responses. 3. Cromakalim (0.3-10 microM), but not nifedipine, inhibited the maintained tonic contractions produced by NA. The effects of cromakalim were antagonized by raising extracellular [K+] or by glibenclamide. 4. Nifedipine inhibited contractions produced by KCl (40 mM) whereas cromakalim had no effect. 5. In Ca2(+)-free physiological salt solution (PSS), cromakalim produced a significant inhibition of both the refilling of and the release of Ca2+ from NA-releasable Ca2+ stores, whereas nifedipine was ineffective. 6. In tissues preloaded with 42K+ cromakalim (0.3-10 microM) produced a concentration-dependent increase in the 42K+ efflux rate coefficient. NA (0.3 microM) also produced an increase in the rate of efflux of 42K+, an effect which was not antagonized by nifedipine (0.3 microM). 7. When microelectrodes were used, cromakalim (1-10 microM) produced a maintained concentration-dependent membrane hyperpolarization. However, low concentrations of cromakalim (less than 1 microM) which relaxed the aorta had no effect on membrane potential. NA had no significant effect on membrane potential. 9. It is concluded that the ability of cromakalim to relax NA-induced contractions in rabbit aorta is not exerted by the indirect closure of nifedipine-sensitive Ca2+ channels. Instead, cromakalim may exert a direct inhibitory action on Ca2+ uptake into and release from Ca2+ stores and additionally inhibit the pathway through which Ca2+ passes from the extracellular fluid to intracellular Ca2+ stores.

Animals↗
PubMed1994

Effect of cromakalim and glibenclamide on spontaneous and evoked motility of the guinea-pig isolated renal pelvis and ureter.

1. We have investigated the effect of the potassium (K) channel opener, cromakalim, on the spontaneous myogenic activity of the guinea-pig isolated renal pelvis and on myogenic contractions evoked by direct electrical stimulation of the guinea-pig isolated ureter. 2. In the presence of Bay K 8644 (1 microM), electrical stimulation of the guinea-pig ureter (10 Hz for 1 s, pulse width 5 ms, 60 V) produced regular tetrodotoxin-(1 microM) resistant phasic contractions which were suppressed by 3 microM cromakalim. Glibenclamide (0.1-3 microM), 4-aminopyridine (4-AP, 0.1-2 mM) and tetraethylammonium (TEA, 1-10 mM) produced a concentration-dependent inhibition of the effect of cromakalim with the rank order of potency (EC50 in parentheses): glibenclamide (0.64 microM) >> 4-AP (1.11 mM) > TEA (6.6 mM). Apamin (0.1-0.3 microM) was without effect. 3. Cromakalim (0.1-10 microM) produced concentration-dependent inhibition and suppression of spontaneous contractions of the guinea-pig isolated renal pelvis and of evoked contractions of the ureter with EC50 values of 0.71 and 0.47 microM, respectively. 4. Glibenclamide (1 microM) produced a rightward shift of the concentration-response curve to cromakalim in both the renal pelvis and ureter, without producing depression of the maximal inhibitory effect. Glibenclamide did not affect the spontaneous activity of the renal pelvis while it produced a slight enhancement (10-15% increase) of evoked contractions of the ureter. Glibenclamide did not affect the inhibitory action of the adenylate cyclase activator, forskolin, in the renal pelvis or ureter. 5. In electrophysiological experiments (sucrose gap), cromakalim (0.3 and 1 microM) produced hyperpolarization of ureter smooth muscle. Cromakalim also produced a transient suppression of action potentials and accompanying phasic contractions evoked by electrical stimulation. Before suppression of evoked contractions, a shortening of action potential duration was observed concomitant with the developing hyperpolarization produced by cromakalim. A lower concentration (0.1 MicroM) of cromakalim did not affect membrane potential but shortened action potential duration and reduced the evoked contraction.6. Glibenclamide (1 MicroM) inhibited the hyperpolarizing action of cromakalim and prevented its inhibitory action on evoked action potentials and contractions of the ureter. Glibenclamide also produced a slight prolongation of action potential duration and increased the amplitude and duration of the accompanying mechanical response.7. These findings demonstrate that activation of cromakalim- and glibenclamide-sensitive K channels produces a powerful mechanism for regulation of pyeloureteral motility and suppression of latent pacemakers of the ureter in guinea-pig. Glibenclamide-sensitive K channels take part in determining action potential shape and duration in the guinea-pig ureter.

Action Potentials↗
PubMed1991

Effect of cromakalim and lemakalim on slow waves and membrane currents in colonic smooth muscle.

The effects of cromakalim (BRL 34915) and its optical isomer lemakalim (BRL 38227) were investigated in intact tissue and freshly dispersed circular muscle cells from canine proximal colon. Cromakalim and lemakalim hyperpolarized resting membrane potential, shortened the duration of slow waves by abolishing the plateau phase, and decreased the frequency of slow waves. Glyburide, a K channel blocker, prevented the effect of cromakalim on slow-wave activity. The mechanisms of these alterations in slow-wave activity were studied in isolated myocytes under voltage-clamp conditions. Cromakalim and lemakalim increased the magnitude of a time-independent outward K current, but cromakalim also reduced the peak outward K current. Glyburide inhibited lemakalim stimulation of the time-independent background current. Nisoldipine also reduced the peak outward current, and in the presence of nisoldipine, cromakalim did not affect the peak outward component of current. This suggested that cromakalim may block a Ca-dependent component of the outward current. Lemakalim did not affect the peak outward current. We tested whether the effects of cromakalim on outward current might be indirect due to an effect on inward Ca current. Cromakalim, but not lemakalim, was found to inhibit L-type Ca channels; however, glyburide did not alter cromakalim inhibition of inward Ca current. We conclude that the effects of cromakalim and lemakalim on membrane potential and slow waves in colonic smooth muscle appear to result primarily from stimulation of a time-independent background K conductance. The effects of these compounds on channel activity may explain the inhibitory effect of these compounds on contractile activity.

Animals↗
PubMed1991

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

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

Animals↗
PubMed1990

The protective effects of cromakalim and pinacidil on reperfusion function and infarct size in isolated perfused rat hearts and anesthetized dogs.

The direct myocardial protective effects of intracoronary infusions of cromakalim and pinacidil were determined in an anesthetized canine model of coronary occlusion and reperfusion. The left circumflex coronary artery was occluded for 90 minutes and reperfused for 5 hours, at which time the infarct size was determined. Cromakalim (0.1 micrograms/kg/min) or pinacidil (0.09 micrograms/kg/min) were infused into the left circumflex coronary artery starting 10 minutes preischemia. Cromakalim significantly reduced infarct size as a percent of the left ventricular area at risk (25 +/- 5%) compared with vehicle controls (55 +/- 7%). Pinacidil did not reduce infarct size at an equimolar dose, but at the higher dose also significantly reduced infarct size. Collateral blood flow was not significantly altered by either drug, though reperfusion flow was significantly higher in cromakalim-treated animals, particularly in the subepicardial region. When the same dose of cromakalim was given starting 2 minutes before the initiation of reperfusion, no significant beneficial effect of cromakalim was observed. In another study, isolated buffer-perfused rat hearts were subjected to 25 minutes of global ischemia and 30 minutes of reperfusion. These hearts were treated with 7 microM cromakalim, either starting 10 minutes before ischemia or only during reperfusion, and its effect on reperfusion function and LDH release were determined. Cromakalim pretreatment (both when given throughout the experiment and when not present in the reperfusion buffer) resulted in significant improvements in the reperfusion function. Reperfusion contracture and LDH were also significantly reduced with this treatment. When given only during reperfusion, cromakalim did not reduce the severity of ischemia when compared with vehicle controls. Thus, both cromakalim and pinacidil reduce ischemic/reperfusion injury, though the timing of treatment may be important.

Animals↗