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PubMed1994

Calcium entry and myogenic phenomena in skeletal muscle arterioles.

Studies were conducted to examine Ca2+ entry in several vasomotor situations related to myogenic properties of arterioles (basal tone, vasomotion, and responsiveness to alterations in intravascular pressure). In vivo studies were performed on small cremaster muscle arterioles of anesthetized rats. Intravascular pressure was increased using the pressure-box technique. Voltage-operated Ca2+ channel (VOC) activity was inhibited by nifedipine or methoxyverapamil and was stimulated with BAY K 8644. To examine the effect of hyperpolarization, studies were performed in the presence of pinacidil. Nifedipine and methoxyverapamil exhibited a trend toward dose-dependent dilation; however, neither agent caused dilation comparable to adenosine (10(-4) M). BAY K 8644 produced a biphasic effect, constriction below 10(-8) M, and dilation at higher levels. These data indicate that basal tone can be modulated by agents acting on VOCs; however, as high concentrations of nifedipine do not abolish tone, other mechanisms contribute. At similar concentrations, the Ca2+ channel antagonist significantly inhibited vasomotion, abolishing vasomotion at concentrations above 5 x 10(-6) M. In contrast, BAY K 8644 caused a dose-dependent increase in vasomotion amplitude (e.g., 269 +/- 52% of basal at 10(-7) M). Thus vasomotion appears highly dependent on VOCs. Experiments performed in the presence of the antagonists/agonists indicated that VOCs are not the prime determinant of constrictor responses to acute increases in intravascular pressure. Exposure to pinacidil resulted in dose-dependent vasodilatation and inhibition of vasomotion while showing little effect on acute myogenic responses. Similar effects of pinacidil were observed in isolated, cannulated, cremaster arterioles.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2000

Transmural difference in coronary arteriolar dilation to adenosine: effect of luminal pressure and K(ATP) channels.

Coronary blood flow in the subendocardium is preferentially increased by adenosine but is redistributed to the subepicardium during ischemia in association with coronary pressure reduction. The mechanism for this flow redistribution remains unclear. Since adenosine is released during ischemia, it is possible that the coronary microcirculation exhibits a transmural difference in vasomotor responsiveness to adenosine at various intraluminal pressures. Although the ATP-sensitive K(+) (K(ATP)) channel has been shown to be involved in coronary arteriolar dilation to adenosine, its role in the transmural adenosine response remains elusive. To address these issues, pig subepicardial and subendocardial arterioles (60-120 micrometer) were isolated, cannulated, and pressurized to 20, 40, 60, or 80 cmH(2)O without flow for in vitro study. At each of these pressures, vessels developed basal tone and dilated concentration dependently to adenosine and the K(ATP) channel opener pinacidil. Subepicardial and subendocardial arterioles dilated equally to adenosine and pinacidil at 60 and 80 cmH(2)O luminal pressure. At lower luminal pressures (i.e., 20 and 40 cmH(2)O), vasodilation in both vessel types was enhanced. Enhanced vasodilatory responses were not affected by removal of endothelium but were abolished by the K(ATP) channel inhibitor glibenclamide. In a manner similar to reducing pressure, a subthreshold dose of pinacidil potentiated vasodilation to adenosine. In contrast to adenosine, dilation of coronary arterioles to sodium nitroprusside was independent of pressure changes. These results indicate that coronary microvascular dilation to adenosine is enhanced at lower intraluminal pressures by selective activation of smooth muscle K(ATP) channels. Since microvascular pressure has been shown to be consistently lower in the subendocardium than in the subepicardium, it is likely that the inherent pressure gradient in the coronary microcirculation across the ventricular wall may be an important determinant of transmural flow in vivo during resting conditions or under metabolic stress with adenosine release.

Adenosine↗
PubMed2001

ATP consumption by uncoupled mitochondria activates sarcolemmal K(ATP) channels in cardiac myocytes.

We tested whether close coupling exists between mitochondria and sarcolemma by monitoring whole cell ATP-sensitive K(+) (K(ATP)) current (I(K,ATP)) as an index of subsarcolemmal energy state during mitochondrial perturbation. In rabbit ventricular myocytes, either pinacidil or the mitochondrial uncoupler dinitrophenol (DNP), which rapidly switches mitochondria from net ATP synthesis to net ATP hydrolysis, had little immediate effect on I(K,ATP). In contrast, in the presence of pinacidil, exposure to 100 microM DNP rapidly activated I(K,ATP) with complex kinetics consisting of a quick rise [time constant of I(K,ATP) increase (tau) = 0.13 +/- 0.01 min], an early partial recovery (tau = 0.43 +/- 0.04 min), and then a more gradual increase. This DNP-induced activation of I(K,ATP) was reversible and accompanied by mitochondrial flavoprotein oxidation. The F(1)F(0)-ATPase inhibitor oligomycin abolished the DNP-induced activation of I(K,ATP). The initial rapid rise in I(K,ATP) was blunted by atractyloside (an adenine nucleotide translocator inhibitor), leaving only a slow increase (tau = 0.66 +/- 0.17 min, P < 0.01). 2,4-Dinitrofluorobenzene (a creatine kinase inhibitor) slowed both the rapid rise (tau = 0.20 +/- 0.01 min, P < 0.05) and the subsequent declining phase (tau = 0.88 +/- 0.19 min, P < 0.05). From single K(ATP) channel recordings, we excluded a direct effect of DNP on K(ATP) channels. Taken together, these results indicate that rapid changes in F(1)F(0)-ATPase function dramatically alter subsarcolemmal energy charge, as reported by pinacidil-primed K(ATP) channel activity, revealing cross-talk between mitochondria and sarcolemma. The effects of mitochondrial ATP hydrolysis on sarcolemmal K(ATP) channels can be rationalized by reversal of F(1)F(0)-ATPase and the facilitation of coupling by the creatine kinase system.

Adenosine Triphosphate↗
PubMedDate not supplied

Relaxation in different-sized rat blood vessels mediated by endothelium-derived hyperpolarizing factor: importance of processes mediating precontractions.

To clarify the mechanisms involved in relaxations mediated by endothelium-derived hyperpolarizing factor (EDHF), acetylcholine (ACh)-induced endothelium-dependent relaxations and hyperpolarizations were examined in the rat aorta, the main branch of the mesenteric artery (MBMA) and the first branch of the mesenteric aftery (FBMA). In the presence of 100 microM N(G)-nitro-L-arginine (L-NNA) and 10 microM indomethacin, ACh (1 nM to 100 microM) produced no relaxation in the phenylephrine-precontracted aorta. The L-NNA-resistant relaxations by ACh in MBMA precontracted with phenylephrine were eliminated in the presence of 1 microM nifedipine where contractions were independent of L-type Ca(2+) channel activation. In FBMA precontracted with phenylephrine, the L-NNA-resistant relaxations were only partially inhibited by nifedipine. When vessels had been contracted with 300 nM phorbol-12,13-dibutyrate in the presence of nifedipine, ACh-induced L-NNA-resistant relaxations were observed in FBMA only. Pinacidil produced relaxations in all different-sized blood vessels, although sensitivity was inversely related to vessel size. The extent of the ACh hyperpolarizing responses was much smaller than that by pinacidil in the aorta. The membrane potential changes by ACh and pinacidil were almost the same in FBMA. These results indicate that the contribution of EDHF to endothelium-dependent relaxations increases as the vessel size decreases. This may be partly explained by precontractile processes dependent on Ca(2+) entry through L-type Ca(2+) channels, because Ca(2+) channel deactivation seems to be involved as a major mechanism of EDHF-mediated vasorelaxations. However, EDHF may also generate vasorelaxations by an additional mechanism, probably a reduced Ca(2+) sensitivity of contractile elements, as proposed for ATP-sensitive K(+) channel openers.

Analysis of Variance↗
PubMed2002

Effect of 17beta-estradiol exposure on vasorelaxation induced by K(+) channel openers and Ca(2+) channel blockers.

17beta-Estradiol has been shown to relax blood vessels partly through inhibition of Ca(2+) channels at supraphysiological concentrations; however, it is unknown whether acute exposure of the isolated artery rings to near physiological concentrations of sex steroid hormones could modulate the ionic channels that are involved in regulation of vascular tone. Brief incubation (20 min) with 17beta-estradiol (1-3 nmol/l) did not alter the relaxant response to three blocking agents of L-type voltage-sensitive Ca(2+) channels, nifedipine, diltiazem and verapamil in either endothelium-intact or endothelium-denuded rat mesenteric artery rings. In contrast, 17beta-estradiol at 3 nmol/l significantly attenuated the relaxation induced by K(+) channel openers, cromakalim and pinacidil in endothelium-denuded rings. Similarly, preincubation with progesterone (3 nmol/l) inhibited pinacidil-induced relaxation with much less effect on cromakalim-induced relaxation. It appears that 17beta-estradiol and progesterone attenuated the cromakalim- and pinacidil-induced relaxation in a different manner. These results suggest that acute exposure to female sex steroid hormones at near physiological levels may reduce the activity of ATP-sensitive K(+) channels in the rat arteries.

Animals↗
PubMed2005

Effects of pharmacological modulation of the ATP-sensitive potassium channels on the development of warm-up angina pectoris.

The aim of this study was to examine the effect of pharmacological modulation of the ATP-sensitive potassium channels in the development of warm-up angina pectoris. Thirty-one patients with stable angina pectoris, a positive exercise test and angiographically documented coronary artery disease underwent three exercise tests 90 min after receiving either glibenclamide 10.5 mg (an ATP-sensitive potassium channel blocker), pinacidil 25 mg (an ATP-sensitive potassium channel opener) or placebo in a blinded fashion. There was a 30-min recovery period between the first and the second test and 60 min between the second and the third test. The rate-pressure product at 1-mm ST-segment depression (ischemic threshold) and the maximum ST-segment depression (STD) adjusted to the highest rate-pressure product common to the three tests were analyzed. In the placebo group, there was a significant increase in the ischemic threshold during the second and third test and a significant decrease in the maximum adjusted STD during the second test which was lost during the third test. This apparent adaptation to exercise-induced ischemia was not seen in the glibenclamide-treated patients. In the pinacidil-treated patients, there was a paradoxical decrease in ischemic threshold during the second test with no change in maximum adjusted STD which tended to be lower than in the placebo-treated patients on each exercise test. This study confirms that the warm-up phenomenon can be induced during repeated exercise testing. The blockade of this phenomenon by glibenclamide suggests that the ATP-sensitive potassium channels may be involved in this potential protective mechanism. At the same time, the paradoxical response in the pinacidil-treated patients flags a warning that drugs acting on the sarcolemmal ATP-sensitive potassium channels may have a direct effect on the ST-segment that may interfere with the interpretation of the electrocardiogram.

Adenosine Triphosphate↗
PubMed1998

Recombinant cardiac ATP-sensitive K+ channel subunits confer resistance to chemical hypoxia-reoxygenation injury.

BACKGROUND: Opening of cardiac ATP-sensitive K+ (KATP) channels has emerged as a promising but still controversial cardioprotective mechanism. Defining KATP channel function at the level of recombinant channel proteins is a necessary step toward further evaluation of the cardioprotective significance of this ion conductance. METHODS AND RESULTS: KATP channel deficient COS-7 cells were found to be vulnerable to chemical hypoxia-reoxygenation injury that induced significant cytosolic Ca2+ loading (from 97+/-3 to 236+/-11 nmol/L). In these cells, the potassium channel opener pinacidil (10 micromol/L) did not prevent Ca2+ loading (from 96+/-3 nmol/L before to 233+/-12 nmol/L after reoxygenation) or evoked membrane current. Cotransfection with Kir6.2/SUR2A genes, which encode cardiac KATP channel subunits, resulted in a cellular phenotype that, in the presence of pinacidil (10 micromol/L), expressed K+ current and gained resistance to hypoxia-reoxygenation (Ca2+ concentration from 99+/-7 to 127+/-11 nmol/L; P>0.05). Both properties were abolished by the KATP channel blocker glyburide (1 micromol/L). In COS-7 cells transfected with individual channel subunits Kir6.2 or SUR2A, which alone do not form functional cardiac KATP channels, pinacidil did not protect against hypoxia-reoxygenation. CONCLUSIONS: The fact that transfer of cardiac KATP channel subunits protected natively KATP channel deficient cells provides direct evidence that the cardiac KATP channel protein complex harbors intrinsic cytoprotective properties. These findings validate the concept that targeting cardiac KATP channels should be considered a valuable approach to protect the myocardium against injury.

Adenosine Triphosphate↗
PubMed1993

Mechanosensitive gating of atrial ATP-sensitive potassium channels.

Cell-attached and inside-out excised-patch recording techniques were used to search for mechanosensitive ion channels in neonatal and adult rat atrial myocytes. A channel activated by negative pressure applied to the patch, with a single-channel conductance of 52 pS in symmetric potassium solutions, was frequently observed. This channel has been identified as the atrial ATP-sensitive potassium (KATP) channel on the basis of its potassium selectivity, as well as its inhibition by ATP or tolbutamide in the inside-out excised patch. Mechanosensitive modulation of the KATP channel has not previously been reported. In the presence of 1 mM ATP, 10-50 microM pinacidil (a specific KATP channel agonist) does not significantly increase basal KATP channel activity; however, these concentrations of pinacidil potentiated the mechanosensitive modulation of the KATP channel. A hypotonic swelling protocol (a mechanical stimulus) was used in an effort to determine whether mechanosensitive modulation of this channel can generate significant whole-cell currents. Under perforated-patch whole-cell recording conditions, superfusion of atrial myocytes with a 240 mosm/kg solution (control solution, 290 mosm/kg) stimulated whole-cell currents with a magnitude similar to those activated by 10 microM pinacidil. These results demonstrate that the gating of the atrial KATP channel is mechanosensitive and suggest that mechanosensitive modulation may be an additional and significant mechanism, modulating channel activity under both physiological and pathological conditions.

Adenosine Triphosphate↗
PubMed2004

Uncomplicated rapid posthypothermic rewarming alters cerebrovascular responsiveness.

BACKGROUND AND PURPOSE: Recently, we focused on the cerebrovascular protective effects of moderate hypothermia after traumatic brain injury, noting that the efficacy of posttraumatic hypothermia is related to the rate of posthypothermic rewarming. In the current communication, we revisit the use of hypothermia with varying degrees of rewarming to ascertain whether, in the normal cerebral vasculature, varying rates of rewarming can differentially affect cerebrovascular responsiveness. METHODS: Pentobarbital-anesthetized rats equipped with a cranial window were randomized to 3 groups. In 1 group, a 1-hour period of hypothermia (32 degrees C) followed by slow rewarming (over 90 minutes) was used. In the remaining 2 groups, either a 1- or 2-hour period of hypothermia was followed by rapid rewarming (within 30 minutes). Vasoreactivity to hypercapnia and acetylcholine was assessed before, during, and after hypothermia. Additionally, the vascular responses to sodium nitroprusside (SNP) and pinacidil, a K(ATP) channel opener, were also examined. RESULTS: Hypothermia itself generated modest vasodilation and reduced vasoreactivity to all utilized agents. The slow rewarming group showed restoration of normal vascular responsivity. In contrast, hypothermia followed by rapid rewarming was associated with continued impaired responsiveness to acetylcholine and arterial hypercapnia. These abnormalities persisted even with the use of more prolonged (2-hour) hypothermia. Furthermore, posthypothermic rapid rewarming impaired the dilator responses of SNP and pinacidil. CONCLUSIONS: Posthypothermic rapid rewarming caused cerebral vascular abnormalities, including a diminished response to acetylcholine, hypercapnia, pinacidil, and SNP. Our data with acetylcholine and SNP suggest that rapid rewarming most likely causes abnormality at both the vascular smooth muscle and endothelial levels.

Acetylcholine↗
PubMed2006

Role of ATP-dependent potassium channels in pulmonary vascular tone of fetal lambs with congenital diaphragmatic hernia.

High mortality in newborn babies with congenital diaphragmatic hernia (CDH) is principally due to persistent pulmonary hypertension. ATP-dependent potassium (K(ATP)) channels might modulate pulmonary vascular tone. We have assessed the effects of Pinacidil, a K(ATP) channel opener, and glibenclamide (GLI), a K(ATP) channel blocker, in near full-term lambs with and without CDH. In vivo, pulmonary hemodynamics were assessed by means of pressure and blood flow catheters. In vitro, we used isolated pulmonary vessels and immunohistochemistry to detect the presence of K(ATP) channels in pulmonary tissue. In vivo, pinacidil (2 mg) significantly reduced pulmonary vascular resistance (PVR) in both controls and CDH animals. GLI (30 mg) significantly increased pulmonary arterial pressure (PAP) and PVR in control animals only. In vitro, pinacidil (10 microM) relaxed, precontracted arteries from lambs with and without CDH. GLI (10(-5) microM) did not raise the basal tone of vessels. We conclude that activation of K(ATP) channels could be of interest to reduce pulmonary vascular tone in fetal lambs with CDH, a condition often associated with persistent pulmonary hypertension of the newborn.

Adenosine Triphosphate↗
PubMed1995

Effects of potassium channel openers in isolated human cerebral arteries.

The objective of this study was to compare the relaxant effects of the K+ channel openers pinacidil and lemakalim in isolated human pial arteries with the effects of the dihydropyridines nifedipine and nimodipine and the prostacyclin analog iloprost. Relaxation was measured in vessels contracted by 40 mmol/L K+. In contrast to the potent and consistent relaxant effects of nifedipine, nimodipine, and iloprost, the potency of pinacidil and lemakalim proved to be highly variable and inversely correlated with the onset velocity of the preceding contractions of K+ as well as with the endothelium-dependent relaxation of carbachol. Thus, in contrast to dihydropyridines and iloprost, pinacidil and lemakalim selectively elicited potent relaxations in those arteries that exhibited signs of altered vascular wall functions.

Benzopyrans↗
PubMed1996

Synthesis and structure-activity relationships of novel phenylcyanoguanidine derivatives as potassium channel openers.

3,5-Di-substituted phenylcyanoguanidine derivatives with halogen, cyano and/or nitro groups at the 3- and 5-positions of the benzene ring exhibited very strong smooth muscle relaxation activity in vitro, as compared to pinacidil. Among them, N-(3-chloro-5-cyanophenyl)-N'-cyano-N" -tert-pentylguanidine (5s) showed 27-fold more potent activity than pinacidil, and exhibited a stronger and more lasting antihypertensive effect than pinacidil by oral administration to spontaneously hypertensive rats. We propose a new pharmacophore model in which the essential factors for binding to the potassium channel are an NH and a bulky alkyl group.

Animals↗
PubMed1990

Specific antagonism by glibenclamide of negative inotropic effects of potassium channel openers in canine atrial muscle.

The mode of antagonism by glibenclamide, a potassium channel blocker, of the negative inotropic effects of potassium channel openers, cromakalim, pinacidil and nicorandil, was investigated in canine atrial muscle. Glibenclamide shifted the concentration-negative inotropic effect curves for cromakalim, pinacidil and nicorandil to the right without affecting the basal force of contraction. Schild analysis yielded uniform pA2 values of 6.06-6.35 for glibenclamide against the three potassium channel openers. The force of contraction of atrial muscles previously reduced by cromakalim was also antagonized by increasing concentrations of glibenclamide. Glibenclamide affected neither the concentration-negative inotropic effect curves for carbachol, an opener of the muscarinic receptor-coupled potassium channel, nor those for nifedipine, a calcium channel blocker. From these results, it became evident that glibenclamide behaved as a pharmacological antagonist of cromakalim, pinacidil and nicorandil in cardiac inotropy. The antagonism seems to involve competition of glibenclamide and these potassium channel openers, presumably at the ATP-sensitive channel in canine right atrial muscles.

Animals↗
PubMedDate not supplied

K+ channel blockers: natriuretic potency correlates to vascular ATP-sensitive K+ channel blockade.

Using analogs of known vascular ATP-sensitive K+ channel (KATP) blockers, we identified compounds with a wide range of potencies (over 500-fold) in their capacity to block the hypotensive response of 0.2 mg/kg pinacidil in rats. The most potent of these, U-97025E, belongs to a newly disclosed class of compounds, the cyanoguanidines. U-97025E at 0.04 mg/kg blocked 50% of the depressor response induced by 0.2 mg/kg pinacidil. The maximal natriuresis induced by U-97025E (0.4 mg/kg i.v.) increased Na+ excretion by approximately 60%. This natriuresis is of the same magnitude as that induced by thiazide without any effect on K+ excretion. We found a high degree of correlation between natriuretic potency and the capacity to block the blood pressure lowering effects of pinacidil, both among closely related analogs and dissimilar compounds. These findings imply an obligatory rather than incidental relationship between vascular KATP blockade and natriuresis. The exact molecular link of the vascular and renal effects remains to be determined.

ATP-Binding Cassette Transporters↗
PubMed1996

Inhibition of contractile responses of human myometrium and intramyometrial arteries by potassium channel openers.

OBJECTIVES: The effects of cromakalim and pinacidil on the contractile activity of the isolated human myometrium and intramyometrial arteries were studied. MATERIAL AND METHOD: Myometrial strips and pieces of uterine arteries were obtained from women undergoing hysterectomy. Contractions were recorded under isometric conditions. RESULTS: Both compounds (10(-9) M-5 x 10(-6) M) inhibited the spontaneous activity of the myometrium and vasopressin induced contractions of myometrium and intramyometrial arteries. There was no statistically significant difference in the responses of both tissues to cromakalim or pinacidil. Both compounds reduced responses of myometrium and intramyometrial arteries to low concentration of K+ (< 40 mM) but did not decrease contractions induced by 40 mM and 80 mM. CONCLUSION: The combined effect on the uterus and intrauterine vasculature would suggest a potential in the use of cromakalim or pinacidil for the treatment of dysmenorrhea.

Adult↗
PubMed1994

Influence of K+ channel openers on interferon-gamma dependent immune response in experimental allergic neuritis (EAN).

We examined the influence of the K+ channel opening drugs BRL 38227, pinacidil and diazoxide on cellular immune response and clinical course of experimental allergic neuritis (EAN) actively induced in Lewis rats by bovine peripheral myelin (BPM). T cell functions of EAN lymph node cells were assessed by measurement of proliferation and by counting of interferon-gamma secreting cells (IFN-gamma sc) in response to the specific antigen BPM and the T cell mitogen phytohemagglutinin (PHA). BRL 38227 and diazoxide at concentrations of 10(-5)M-10(-6)M and pinacidil at concentrations of 10(-5)M-10(-7)M enhanced the proliferative response to both BPM and PHA. The number of IFN-gamma sc was suppressed by the K+ channel openers in the same concentration range. There was a tendency of stronger suppression of cultures with high numbers of BPM-reactive IFN-gamma sc than of cultures with low numbers of BPM-reactive IFN-gamma sc. The applied K+ channel openers are primarily acting on ATP-sensitive K+ channels, which have not been found in T cells so far. The drugs may, therefore, exert non-selective effects on conventional voltage- and/or Ca(++)-dependent channels of T cells. A first trial with in vivo administration of 2.5 mg/kg x day of the drugs resulted in more severe neurological deficits in the early phase of EAN with BRL 38227, whereas pinacidil and diazoxide had no significant effects.

Animals↗
PubMed1995

Involvement of K+ channels in the relaxant responses to various agonists in estrogen primed rat uterus.

The present investigation was undertaken to study the effects of K+ channel openers in the relaxant responses to various agonists in estrogen primed rat uterus. Adrenaline and isoprenaline produced a dose-dependent relaxation in the estrogen primed rat uterus. The relaxant responses were found to be significantly potentiated when the preparations were exposed to PSS devoid of calcium. The responses to isoprenaline were found to be greater in the preparations depolarized with 40 mM KCl instead of 80 mM KCl. KCl failed to produce any contractile effect in the presence of D-600. Further, the addition of D-600 completely relaxed the KCl depolarized rat uterus. Pinacidil and cromakalim failed to relax 80 mM KCl depolarized rat uterus. However, they produced dose-dependent relaxation in the preparations depolarized with 40 mM KCl. The relaxant responses to pinacidil and cromakalim were competitively blocked by procaine. However, they were not altered by either propranolol or cimetidine. The relaxant responses to isoprenaline and histamine were found to be potentiated by pinacidil and cromakalim. These results indicate that in rat uterus in addition to adenylate cyclase c-AMP, potassium channels are also involved in the relaxant responses to isoprenaline and histamine.

Animals↗
PubMed2001

The effect of K(atp)channel activation on myocardial cationic and energetic status during ischemia and reperfusion: role in cardioprotection.

The role of cation and cellular energy homeostasis in ATP-sensitive K(+)(K(ATP)) channel-induced cardioprotection is poorly understood. To evaluate this, rapidly interleaved(23)Na and(31)P NMR spectra were acquired from isolated rat hearts exposed to direct K(ATP)channel activation from nicorandil or pinacidil. Nicorandil attenuated ATP depletion and intracellular Na(+)(Na(+)(i)) accumulation, delayed the progression of acidosis during zero-flow ischemia and prevented ischemic contracture. The K(ATP)channel inhibitor 5-hydroxydecanoate abolished these effects. Pinacidil did not alter Na(+)(i)accumulation, ATP depletion or pH during ischemia under the conditions employed. Both agonists greatly improved the post-ischemic functional recovery. Both agonists also dramatically improved the rate and extent of the reperfusion recoveries of Na(+)(i), PCr and ATP. The Na(+)(i)and PCr reperfusion recovery rates were tightly correlated, suggesting a causal relationship. Separate atomic absorption tissue Ca(2+)measurements revealed a marked reperfusion Ca(2+)uptake, which was reduced two-fold by pinacidil. In conclusion, these results clearly indicate that while K(ATP)channel-induced metabolic alterations can vary, the functional cardioprotection resulting from this form of pharmacological preconditioning does not require attenuation of acidosis, cellular energy depletion, or Na(+)(i)accumulation during ischemia. Rather than preservation of cationic/energetic status during ischemia, the cardioprotective processes may involve a preserved capability for its rapid restoration during reperfusion. The enhanced reperfusion Na(+)(i)recovery may be enabled by the improved reperfusion cellular energy state. This accelerated Na(+)(i)recovery could play an important cardioprotective role via a potential causal relationship with the reduction of reperfusion tissue Ca(2+)uptake and resultant reperfusion injury.

Adenosine Triphosphate↗