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PubMed2002

The role of myocardial KATP-channel blockade in the protective effects of glibenclamide against ischaemia in the rat heart.

Glibenclamide preserves postischaemic myocardial function in the isolated, erythrocyte perfused, working rat heart model. This study addresses the possible involvement of KATP channels in this beneficial action of glibenclamide. We hypothesized that if glibenclamide improved postischaemic cardiac function by blocking of KATP channels, opening of these KATP channels should result in the opposite, namely detrimental effects on postischaemic heart function. Postischaemic functional loss and coronary blood flow were recorded during treatment with glibenclamide (4 micromol x l(-1); n = 5), the KATP channel openers pinacidil (1 micromol x (l-1); n = 5) and diazoxide (30 micromol x l(-1); n = 5), the combination of glibenclamide with pinacidil (n = 5) and glibenclamide with diazoxide (n = 5), and vehicle (n = 8). Both pinacidil and diazoxide significantly increased coronary blood flow 2-3 times, which was abolished by glibenclamide pre- and postischaemically. This confirms that under both flow conditions glibenclamide significantly blocks KATP channels in the coronary vasculature. The 12 min. global ischaemic incident resulted in a cardiac functional loss of 22.2 +/- 2.9% during vehicle. Glibenclamide reduced the cardiac functional loss to 4.3 +/- 1.2% (P < 0.01). Interestingly, both pinacidil and diazoxide reduced the cardiac functional loss to 4.0 +/- 1.5% (P < 0.01) and 2.9 +/- 1.4% (P < 0.001), respectively. The combination pinacidil+glibenclamide resulted in additional protection compared with the individual components (0.6 +/- 0.1 versus 4.0 +/- 1.5%, P < 0.05). Thus, in contrast to its effect on coronary vascular tone, the glibenclamide-induced improvement of postischaemic cardiac function may not be mediated through blockade of the KATP channel. Alternative mechanisms may be operative, such as uncoupling of the mitochondrial respiratory chain, thereby preconditioning the hearts against stunning.

Animals↗

PubMed1998

Thiopental and propofol impair relaxation produced by ATP-sensitive potassium channel openers in the rat aorta.

ATP-sensitive potassium channel openers are used as vasodilators in the treatment of cardiovascular disorders. The effects of i.v. anaesthetics on arterial relaxation induced by ATP-sensitive potassium channel openers have not been studied. Therefore, in this study, we have examined if thiopental (thiopentone) and propofol affect the vascular response to the ATP-sensitive potassium channel openers, cromakalim and pinacidil, in the isolated rat aorta. Rings of rat thoracic aortas without endothelium were suspended for isometric force recording. Concentration-response curves were obtained in a cumulative manner. During submaximal contractions with phenylephrine 0.3 mumol litre-1, relaxation after cromakalim 0.1-30 mumol litre-1, pinacidil 0.1-30 mumol litre-1 and papaverine 0.1-300 mumol litre-1 was demonstrated. Thiopental 30-300 mumol litre-1, propofol 10-100 mumol litre-1, 10% Intralipid 45 microliters or glibenclamide 5 mumol litre-1 were applied 15 min before addition of phenylephrine. During contractions with phenylephrine, cromakalim and pinacidil induced concentration-dependent relaxation. A selective ATP-sensitive potassium channel antagonist, glibenclamide 5 mumol litre-1, abolished this relaxation, whereas it did not affect relaxation produced by papaverine. Thiopental concentrations > 30 mumol litre-1 significantly impaired relaxation produced by cromakalim or pinacidil. Propofol concentrations > 10 mumol litre-1 also significantly reduced relaxation produced by cromakalim or pinacidil, whereas Intralipid was ineffective. Thiopental 300 mumol litre-1 and propofol 100 mumol litre-1 did not alter relaxation produced by papaverine. These results suggest that the i.v. anaesthetics, thiopental and propofol, impaired vasodilatation mediated by ATP-sensitive potassium channels in vascular smooth muscle cells.

Adenosine Triphosphate↗

PubMed2002

Differential modulation of the cardiac adenosine triphosphate-sensitive potassium channel by isoflurane and halothane.

BACKGROUND: The cardiac adenosine triphosphate-sensitive potassium (K(ATP)) channel is activated during pathophysiological episodes such as ischemia and hypoxia and may lead to beneficial effects on cardiac function. Studies of volatile anesthetic interactions with the cardiac K(ATP) channel have been limited. The goal of this study was to investigate the ability of volatile anesthetics halothane and isoflurane to modulate the cardiac sarcolemmal K(ATP) channel. METHODS: The K(ATP) channel current (I(KATP)) was monitored using the whole cell configuration of the patch clamp technique from single ventricular cardiac myocytes enzymatically isolated from guinea pig hearts. I(KATP) was elicited by extracellular application of the potassium channel openers 2,4-dinitrophenol or pinacidil. RESULTS: Volatile anesthetics modulated I(KATP) in an anesthetic-dependent manner. Isoflurane facilitated the opening of the K(ATP) channel. Following initial activation of I(KATP) by 2,4-dinitrophenol, isoflurane at 0.5 and 1.3 mm further increased current amplitude by 40.4 +/- 11.1% and 58.4 +/- 20.6%, respectively. Similar results of isoflurane were obtained when pinacidil was used to activate I(KATP). However, isoflurane alone was unable to elicit K(ATP) channel opening. In contrast, halothane inhibited I(KATP) elicited by 2,4-dinitrophenol by 50.6 +/- 5.8% and 72.1 +/- 11.6% at 0.4 and 1.0 mm, respectively. When I(KATP) was activated by pinacidil, halothane had no significant effect on the current. CONCLUSIONS: The cardiac sarcolemmal K(ATP) channel is differentially modulated by volatile anesthetics. Isoflurane can facilitate the further opening of the K(ATP) channel following initial channel activation by 2,4-dinitrophenol or pinacidil. The effect of halothane was dependent on the method of channel activation, inhibiting I(KATP) activated by 2,4-dinitrophenol but not by pinacidil.

2,4-Dinitrophenol↗

PubMed2006

Relaxant responses to calcium channel antagonists and potassium channel opener in human saphenous vein.

1.-- As shown in a parallel study the magnitude of depolarization induced in human saphenous vein by raising external potassium ([K(+)](e)) falls markedly below the theoretical values predicted by the Goldman-Hodgkin-Katz equations. This anomaly prompted us to re-examine the relaxant actions of L-type (nifedipine) and T-type (mibefradil) Ca(2+) channel antagonists, and relaxant and electrophysiological effects of the K(+) channel opener, pinacidil, on saphenous veins contracted by the elevation of [K(+)](e). 2.-- Nifedipine produced concentration-dependent relaxations in tissues contracted at various high [K(+)](e). In tissues contracted with 20 mm [K(+)](e), the pIC(50) for nifedipine was significantly (8.20 +/- 0.05; n = 6; mean +/- SEM; P < 0.05) greater than in tissues contracted with > or =40 mm [K(+)](e). 3.-- Tissues contracted with 20 mm [K(+)](e) also relaxed in response to mibefradil (pIC(50) = 6.1 +/- 0.14) and pinacidil (pIC(50) = 6.45 +/- 0.08), the latter being almost completely reversed (93.4 +/- 9.9%) by addition of glibenclamide (10 microm). 4.-- The resting E(m) of smooth muscle cells of saphenous vein was -77.0 +/- 0.7 mV (n = 52), and 20 mm [K(+)](e) produced a modest but significant depolarization to -73.0 +/- 0.7 mV (n = 52). Incubation with pinacidil plus 20 mm [K(+)](e) resulted in a significant hyperpolarization of the E(m) to -82 +/- 0.6 mV (n = 52). 5.-- N(omega)-nitro-L-arginine methyl ester did not impede the relaxant responses of nifedipine, mibefradil or pinacidil. 6.-- In conclusion, the relaxant effects of nifedipine and pinacidil (i) occurred at an E(m) distinctly below the presumed threshold for the opening of the classic (Ca(V)1.3alpha(1)) L-type Ca(2+) channels, and (ii) did not depend on generation of nitric oxide.

Calcium Channel Blockers↗

PubMed1991

Comparison of the effects of several potassium-channel openers on rat bladder and rat portal vein in vitro.

1. The ability of several K-channel openers to inhibit KCl-induced contractions of rat bladder detrusor and spontaneous mechanical activity in rat portal vein was examined. 2. Lemakalim, pinacidil, Ro 31-6930, RP 49356, P1060 and S 0121 dose-dependently relaxed rat detrusor, precontracted with 20 mM KCl. With the exception of pinacidil, concentrations of these agents below 30 microM did not inhibit 80 mM KCl-included contractions. Pinacidil (10 microM) produced a small, but significant (P < 0.05) relaxation of 80 mM KCl-induced mechanical activity. Minoxidil sulphate and BRL 38226 produced some relaxation of 20 mM but not 80 mM KCl-induced contractions. 3. Glibenclamide (0.3-3 microM) antagonized the relaxant effects of lemakalim, pinacidil, Ro 31-6930, RP 49356, P1060 and S 0121 in a competitive manner (pA2 values 6.3-6.6). The effects of minoxidil sulphate and BRL 38226 were fully antagonized by 3 microM glibenclamide. 4. Lemakalim, pinacidil, S 0121, BRL 38226 and minoxidil sulphate were each approximately 8 times more potent as inhibitors of the spontaneous contractions of rat portal vein than KCl-induced contractions of the rat detrusor. Minoxidil sulphate was approximately 30 times more potent in the rat portal vein than in the bladder. This may indicate that either minoxidil sulphate is acting at different recognition sites in these two tissues, or that this compound has an additional mechanism of action in the portal vein. 5. With the exception of minoxidil sulphate, all the compounds tested stimulated 86Rb efflux and 42K efflux from preloaded rat detrusor strips. The stimulated 86Rb efflux was qualitatively but not quantitatively similar to the stimulated 42K efflux. Minoxidil sulphate stimulated 42K efflux from rat portal vein but not from rat bladder. 6. It is concluded that all the compounds tested cause relaxation of rat detrusor predominantly by Kchannel opening. Selectivity for bladder rather than vascular smooth muscle was not shown by any compound.

Animals↗

PubMed1992

Differential effects of endothelin-1 on the vasorelaxant properties of benzopyran and non-benzopyran potassium channel openers.

1. The effects of endothelin-1 (ET-1) on the vasorelaxant properties of structurally different potassium channel openers (PCOs), BRL-38227, Ro 31-6930, SDZ PCO 400, EMD-52692, RP-49356 and pinacidil, were studied. 2. All PCOs evoked concentration-related relaxations of ET-1 (10 nM) or KCl (20 mM) contracted rat isolated aortic rings denuded of endothelium. BRL-38227, EMD 52692, SDZ PCO 400 and Ro 31-6930 were 11-42 times less potent in relaxing contractions to ET-1 than KCl. In contrast, this differential potency was not observed with RP-49356 or pinacidil. 3. BRL-38227 (0.06-3.0 microM), RP-49356 (0.3-3.0 microM) and pinacidil (0.3-3.0 microM) displaced KCl concentration-response curves to the right of controls, without modifying the maximum response. A subcontractile concentration of ET-1 (0.1 nM) prevented the inhibitory effects of low concentrations of BRL-38227 (0.06-0.1 microM) on KCl responses, but failed to modify those to RP-49356, pinacidil or high concentrations of BRL-38227 (0.3-3.0 microM). The inhibitory effects of BRL-38227 (0.1 microM) were also not changed by ET-3 (1.0 nM) or angiotensin II (0.1 nM). 4. In anaesthetized spontaneously hypertensive rats (SHR), cumulative bolus intravenous administrations of BRL-38227 (1-1000 micrograms kg-1, i.v.), Ro 31-6930 (1-1000 micrograms kg-1, i.v.), RP-49356 (10-1000 micrograms kg-1, i.v.) or nitrendipine (0.1-30 micrograms kg-1, i.v.) produced dose-dependent falls in diastolic blood pressure (DBP).ET-1 (i.v.) evoked a transient fall in DBP (1 pg kg- = 58 + 1 mmHg) which returnedto pre-administration levels within 4 min.5. Pretreatment of anaesthetized SHR with ET-l (1 pg kg-', i.v.) significantly increased the ED,5 (dose to evoke a 15% fall in DBP) values for BRL-38227 and Ro 31-6930. However, ET-l failed to modify the ED,5 values for RP-49356 or nitrendipine. The ED50 values for all of the vasodilators studied were not modified by ET-1.6. Infusion of BRL-38227 (2 pgkg-'min-', i.v.) or RP-49356 (4 pgkg-'min', i.v.) to anaesthetized SHR evoked dose-related falls in DBP, with a corresponding increase in descending aortic blood flow (DABF) and a decrease in total lower body vascular resistance (TLBVR). Pretreatment with ET-1 (1 ptg kg-', i.v.) significantly attenuated the decreases in DBP and TLBVR observed with low doses of BRL-38227, but not RP-49356 or high doses of BRL-38227. In contrast, ET-3 (3 pig kg-, i.v.) failed to modify the effects of BRL-38227 on DBP or TLBVR.7. In conscious SHR, the fall in DBP to BRL-38227 (30 pgkg-', p.o.) was significantly reduced following ET-1 (1 pig kg-', i.a.) treatment. ET-1 (1 pg kg-', i.a.) pretreatment, however, failed to modify the decrease in DBP induced by an equieffective oral dose of RP-49356 (1001pgkg-1).8. In conclusion, ET-1 selectively attenuated the vasorelaxant effects of the potassium channel opener,BRL-38227 and other substituted benzopyrans. The results are compatible with the hypothesis that benzopyran PCOs and ET-1 have affinity for a site that does not recognise RP-49356 or pinacidil. Thus,ET-l can differentiate between structurally unrelated potassium channel openers. The cardiovascular effects of some, but not all, PCOs might be radically modified in the clinical setting by elevated endogenous levels of ET-1 associated with certain diseased states.

Animals↗

PubMed2005

Fasudil prevents KATP channel-induced improvement in postischemic functional recovery.

Whereas activation of ATP-dependent potassium (K(ATP)) channels greatly improves postischemic myocardial recovery, the final effector mechanism for K(ATP) channel-induced cardioprotection remains elusive. RhoA is a GTPase that regulates a variety of cellular processes known to be involved with K(ATP) channel cardioprotection. Our goal was to determine whether the activity of a key rhoA effector, rho kinase (ROCK), is required for K(ATP) channel-induced cardioprotection. Four groups of perfused rat hearts were subjected to 36 min of zero-flow ischemia and 44 min of reperfusion with continuous measurements of mechanical function and (31)P NMR high-energy phosphate data: 1) untreated, 2) pinacidil (10 microM) to activate K(ATP) channels, 3) fasudil (15 microM) to inhibit ROCK, and 4) both fasudil and pinacidil. Pinacidil significantly improved postischemic mechanical recovery [39 +/- 16 vs. 108 +/- 4 mmHg left ventricular diastolic pressure (LVDP), untreated and pinacidil, respectively]. Fasudil did not affect reperfusion LVDP (41 +/- 13 mmHg) but completely blocked the marked improvement in mechanical recovery that occurred with pinacidil treatment (54 +/- 15 mmHg). Substantial attenuation of the postischemic energetic recovery was also observed. These data support the hypothesis that ROCK activity plays a role in K(ATP) channel-induced cardioprotection.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗

PubMed1993

Ischemic cardioprotection by ATP-sensitive K+ channels involves high-energy phosphate preservation.

We previously demonstrated that ATP-sensitive K+ channels (KATP) protect the guinea pig myocardium against ischemia-reperfusion injury (Cole et al., Circ. Res. 69: 571-581, 1991), but the cellular alterations leading to ischemic injury affected by KATP remain to be defined. This study investigates the relationship between activation of KATP and preservation of high-energy phosphates during global no-flow ischemia in arterially perfused guinea pig right ventricular walls. Electrical and mechanical activity were recorded via intracellular microelectrodes and a force transducer. Glibenclamide (10 and 50 microM) and pinacidil (10 microM) were used to modulate KATP. ATP and creatine phosphate (CP) levels were determined at the end of no-flow ischemia by enzymatic analysis. Preparations were subjected to 1) 20 min no-flow +/- glibenclamide (10 or 50 microM), 2) 30 min no-flow +/- pinacidil (10 microM) or pinacidil (10 microM) and glibenclamide (50 microM), or 3) 40 or 50 min of control perfusion before rapid freezing in liquid nitrogen. Pinacidil (10 microM) enhanced ischemic shortening of action potential duration (APD) and early contractile failure, prevented ischemic contracture, and inhibited high-energy phosphate depletion during ischemia. Glibenclamide (50 microM) inhibited the effects of pinacidil (10 microM) on electromechanical function and preservation of ATP and CP. Glibenclamide (10 microM) alone inhibited the early decline in APD and produced earlier ischemic contracture but did not enhance ATP or CP depletion compared with untreated tissues during 20 min of no-flow. Glibenclamide (50 microM) produced a greater inhibition of APD shortening in early ischemia, further decreased the latency to ischemic contracture, and caused enhanced ischemic depletion of ATP. The data indicate the changes in electrical activity induced by KATP indirectly preserve high-energy phosphates and reduce injury associated with ischemia. However, the data also suggest the possible presence of additional mechanisms for cardioprotection by KATP.

Action Potentials↗

PubMed1996

ATP-sensitive potassium channels in cultured arterial segments.

Organ cultures of arteries have been used to study growth responses, proliferation, and contractility. However, the function of specific-ion channels in cultured arteries has not been investigated. ATP-sensitive K+ (KATP) channels play an important role in the control of arterial tone. The goal of this study was to determine the functional state of KATP channels in arteries kept in culture. Segments from rabbit mesenteric arteries were cultured in for 2-7 days. To explore the properties of KATP channels, the effects of KATP-channel modulators and other vasoactive substances on isometric force, density, and modulation of KATP currents in single smooth muscle cells isolated from cultured vessels were examined. Isometric contractions were measured with a resistance-vessel myograph. Whole cell KATP currents were recorded with the patch-clamp technique. Membrane capacitance and KATP-current density in single smooth muscle cells from freshly dissected (control) and cultured arteries were not altered. At -60 mV, glibenclamide-sensitive currents in the presence of the K(+)-channel opener pinacidil were -4.7 +/- 1.2, -4.7 +/- 0.6, and -4.6 +/- 0.7 pA/pF for control and 2- and 4-day arteries, respectively. Inhibitory modulation of KATP currents in arterial smooth muscle also remained intact for 4 days in culture; the vasoconstrictor histamine (10 microM) reduced glibenclamide-sensitive currents in the presence of pinacidil by 61.2 +/- 2.8, 42.4 +/- 10.1, and 41.2 +/- 6.1% for control and 2- and 4-day arteries, respectively. Pinacidil relaxed control and cultured arteries (1-7 days) in a dose-dependent manner. Half-maximal effective concentrations of pinacidil were 0.42, 0.24, 0.23, and 0.51 microM for control and 2-, 4-, and 7-day arteries, respectively, whereas maximal relaxations to pinacidil were 62.9, 47.5, 37.5, and 55.7% for control and 2-, 5-, and 7-day arteries, respectively. Histamine, norepinephrine, and serotonin constricted cultured arteries, although responses to histamine and norepinephrine diminished by 30-50% after 5 days in culture. The relaxant effect of acetylcholine was not maintained in cultured arteries. Sodium nitroprusside, however, effectively relaxed arteries cultured for 2-7 days. The data indicate that with the culture model described, KATP channels in arterial smooth muscle remained functional and contractile responses in arterial segments were maintained for up to 7 days. These results suggest that this approach can be used to study either long-term regulation of KATP channels or the role of this channel type in growth responses.

Acetylcholine↗

PubMedDate not supplied

Vascular pharmacology of ATP-sensitive K+ channels: interactions between glyburide and K+ channel openers.

This study in isolated rabbit superior artery (RMA) investigated the interactions between glyburide, a known blocker of vascular ATP-sensitive K+ channels (KATP), and several chemically diverse potassium channel openers (PCOs): minoxidil sulfate (MNXS; 5 microM), pinacidil (1 microM), cromakalim (0.5 microM) and RP-49356 (1 microM; a PCO from Rhône Poulenc). Relaxation time courses for these PCOs were obtained in norepinephrine (NE; 5 microM)-precontracted RMA, and the concentrations of PCOs found to be equipotent to each other in terms of the degree of maximum relaxation (about 80%) and the time course of relaxation (within 15 min) were chosen for further study. This was taken as a functional indicator of a similar degree as well as similar kinetics of K+ channel opening by these PCOs. Pretreatment with glyburide (10-500 nM) produced a dose-dependent inhibition of the PCO relaxation time course. The glyburide IC50s against pinacidil, MNXS and RP-49356 were statistically similar and ranged from 72-79 nM. The glyburide IC50 against cromakalim was a modest 2-fold higher, at 148 nM. In contrast, pretreatment with charybdotoxin (200 nM) produced no significant inhibition of the maximum relaxation produced by these PCOs. Furthermore, glipizide, a sulfonylurea that is 10- to 25-fold less potent than glyburide for insulin secretion, was found to be 20- to 30-fold less potent than glyburide as a vascular KATP antagonist. These data suggest a mechanistic model in which these structurally diverse PCOs share a common critical step in the sequence of events leading to the KATP opening, and that glyburide interferes with this common critical step to produce a similar type of blockade against all four PCOs. Interaction studies with glyburide and pinacidil demonstrated 15 min to be the optimal pretreatment time for glyburide to produce maximal inhibition. Glyburide also reversed existing pinacidil relaxation regardless of the degree of pre-existing relaxation. These data suggest that glyburide is able to produce its blockade regardless of the state of K+ channel activation. Studies on the effect of pH (6.4 vs. 7.3) showed that at acidic pH, pinacidil became less effective and the effectiveness of glyburide was significantly enhanced, whereas the actions of D600 remained unchanged. These data suggest the effects of both openers and blockers of the KATP are strongly pH dependent.

Animals↗

PubMed1991

ATP-regulated K+ channels protect the myocardium against ischemia/reperfusion damage.

The role of ATP-regulated K+ channels in protecting the myocardium against ischemia/reperfusion damage was explored using glibenclamide and pinacidil to block and activate the channels, respectively. Electrical and mechanical activity of arterially perfused guinea pig right ventricular walls was recorded simultaneously via an intracellular microelectrode and a force transducer. The preparations were subjected to either 1) 20 minutes of no-flow ischemia with or without glibenclamide (1 and 10 microM) followed by reperfusion, or 2) 30 minutes of no-flow ischemia with or without pinacidil (1 and 10 microM) followed by reperfusion. No-flow ischemia for 20 minutes produced changes in electrical and mechanical activity that were completely reversed on reperfusion; resting membrane potential declined by 13 +/- 1.2 mV, action potential duration at 90% repolarization (APD90) decreased by 62%, and developed tension fell by greater than 95%, but resting tension did not change significantly. Glibenclamide (10 microM) had no effect on activity during normal perfusion, but during ischemia, resting membrane potential fell slightly further (17 +/- 1.8 mV) and APD90 declined by only 24%. Developed tension declined more slowly and to a lesser extent, but resting tension rose significantly between 10 and 20 minutes of ischemia. Reperfusion of glibenclamide-treated tissues elicited arrhythmias (extrasystoles and tachycardia), and the preparations failed to recover mechanical function. Glibenclamide at 1 microM produced qualitatively similar effects, albeit less severe. After 30 minutes of no-flow ischemia in untreated tissues, resting tension increased by approximately 130% during the no-flow period. Reperfusion caused arrhythmias (extrasystoles, tachyarrhythmias, and fibrillation) and failed to restore resting or developed tension to preischemic levels. Pinacidil at 1 microM did not affect electrical or contractile function, but at 10 microM it had a negative inotropic effect, decreasing APD90 and developed tension by 5% and 18%, respectively. Both concentrations of the drug caused a faster and greater decline in APD90 during the no-flow period. Resting tension did not change during 30 minutes of no-flow ischemia in the presence of pinacidil, and reperfusion led to 85% and complete recovery of electrical and mechanical activity at 1 and 10 microM, respectively. The data indicate that glibenclamide enhances whereas pinacidil reduces myocardial damage caused by ischemia/reperfusion. The results are consistent with the hypothesis that activation of ATP-regulated K+ channels during ischemia is an important adaptive mechanism for protecting the myocardium when blood flow to the tissue is compromised.

Action Potentials↗

PubMed2001

Functional roles of cardiac and vascular ATP-sensitive potassium channels clarified by Kir6.2-knockout mice.

-ATP-sensitive potassium (K(ATP)) channels were discovered in ventricular cells, but their roles in the heart remain mysterious. K(ATP) channels have also been found in numerous other tissues, including vascular smooth muscle. Two pore-forming subunits, Kir6.1 and Kir6.2, contribute to the diversity of K(ATP) channels. To determine which subunits are operative in the cardiovascular system and their functional roles, we characterized the effects of pharmacological K(+) channel openers (KCOs, ie, pinacidil, P-1075, and diazoxide) in Kir6.2-deficient mice. Sarcolemmal K(ATP) channels could be recorded electrophysiologically in ventricular cells from Kir6.2(+/+) (wild-type [WT]) but not from Kir6.2(-/-) (knockout [KO]) mice. In WT ventricular cells, pinacidil induced an outward current and action potential shortening, effects that were blocked by glibenclamide, a K(ATP) channel blocker. KO ventricular cells exhibited no response to KCOs, but gene transfer of Kir6.2 into neonatal ventricular cells rescued the electrophysiological response to P-1075. In terms of contractile function, pinacidil decreased force generation in WT but not KO hearts. Pinacidil and diazoxide produced concentration-dependent relaxation in both WT and KO aortas precontracted with norepinephrine. In addition, pinacidil induced a glibenclamide-sensitive current of similar magnitude in WT and KO aortic smooth muscle cells and comparable levels of hypotension in anesthetized WT and KO mice. In both WT and KO aortas, only Kir6.1 mRNA was expressed. These findings indicate that the Kir6.2 subunit mediates the depression of cardiac excitability and contractility induced by KCOs; in contrast, Kir6.2 plays no discernible role in the arterial tree.

Adenosine Triphosphate↗

PubMed2002

Effect of adenosine triphosphate-sensitive potassium channel openers on lung preservation.

ATP-sensitive potassium channel (KATP) openers have been proven to be involved in ischemic preconditioning, which protects ischemic tissue. However, the effect of KATP openers on ischemia-reperfusion injury of the lungs remains unknown. We investigated whether a KATP opener, pinacidil, can attenuate ischemia-reperfusion injury using an ex vivo rat lung model. Heart-lung blocks were flushed and preserved with phosphate-buffered saline (control group) or with one of the solutions containing pinacidil (pinacidil group) or pinacidil + glibenclamide (a KATP blocker) (glibenclamide group). The control and glibenclamide groups showed significantly higher values with respect to shunt fraction, pulmonary arterial pressure, and peak inspiratory pressure than the pinacidil group. The concentrations of total adenine nucleotides and ATP in the lung after reperfusion became significantly lower in the control and glibenclamide groups than in the fresh group. Lipid peroxidation of the lungs increased significantly in the control and glibenclamide groups after reperfusion. State 3 mitochondrial respiration and State 3/4 ratios of mitochondrial respiration were significantly decreased in the lungs of the control and glibenclamide groups. These findings suggested that KATP openers would maintain the mitochondrial respiratory function during lung preservation, prevent lipid peroxidation after reperfusion, and attenuate ischemia-reperfusion injury.

Adenosine Triphosphate↗

PubMed2002

Characterisation of the effects of potassium channel modulating agents on mouse intestinal smooth muscle.

The actions of agents which modulate ATP-sensitive potassium (K(ATP)) channels in excitable cells were investigated in an in-vitro preparation of mouse ileum from which the mucosa was removed. A range of potassium channel openers of diverse structure, cromakalim (0.1-100 microM), pinacidil (0.1-200 microM) and its analogue P1060 (0.1-200 microM), SDZ PCO400 ((-)-(3S,4R)-3,4-dihydro-3-hydroxy-2,2-dimethyl-4-(3-oxo-cyclopent-1-enyloxy)-2H-1-benzopyran-6-carbonitrile) (0.3-60 microM), caused concentration-related reduction in twitch height of electrical field stimulated ileum. P1060 and SDZ PCO400 were the most potent agents; diazoxide (0.1-100 microM) was without effect. The order of inhibitory potency, based on EC50 values (concentration of a relaxant producing 50% of the maximum inhibition of twitch) was: P1060 = SDZ PCO400 > cromakalim > pinacidil. The relaxant effect of the potassium channel openers was antagonised by the sulfonylureas glibenclamide (0.1-1.0 microM) and glipizide (3-30 microM) but the nature of the antagonism differed. Antagonism of P1060 and SDZ PCO400 by glibenclamide appeared to be competitive whereas the antagonism of relaxation induced by cromakalim and pinacidil was apparently not competitive. Both phentolamine (1-10 microM) and tolbutamide (100-300 microM) showed competitive antagonism of the actions of pinacidil while yohimbine (1-20 microM) did not antagonise relaxation and appeared to have actions at sites other than the K(ATP) channel in this preparation. The relative effectiveness of the antagonists on pinacidil-induced relaxation was found to be: glibenclamide > phentolamine > tolbutamide > yohimbine, which is in agreement with studies in other tissues. The results show that many structurally diverse potassium channel openers are potent relaxants of mouse ileum. These observations are consistent with the existence of ATP-dependent K+ channels in murine intestinal muscle which, however, differ somewhat in properties from those reported for vascular muscle and pancreatic beta-cells.

Animals↗

PubMed1993

Potassium channel openers attenuate atrioventricular block by bupivacaine in isolated hearts.

Our purpose was to test if pinacidil and bimakalim (EMD 52692 or SR 44866), which are ATP-sensitive K+ (K+ATP) channel openers, can attenuate bupivacaine-induced atrioventricular (AV) block. Bupivacaine-induced AV block was studied in 24 isolated guinea pig hearts with or without either pinacidil or bimakalim. Hearts were perfused at 55 mm Hg with a modified Krebs' perfusate. Variables monitored were: heart rate, AV conduction time, left ventricular pressure, coronary flow, and myocardial oxygen extraction. Bupivacaine was infused at a constant concentration of 4 microM to induce first degree AV block and 15-25 microM to induce second degree heart block. During a stable AV block (e.g., first degree, 2:1, 3:2, or 4:3), K+ channel openers, pinacidil (up to 30 microM) or bimakalim (up to 2 microM) were added to perfusate containing bupivacaine. The effects of K+ channel openers were also examined in the presence of the selective K+ATP channel blocker, glibenclamide (2.2 microM). On the average, 4 microM bupivacaine prolonged AV conduction by 53%, and decreased heart rate by 13%, left ventricular pressure by 26%, coronary flow by 6%, and percent oxygen extraction by 7%. In the presence of bupivacaine, pinacidil and bimakalim additionally decreased left ventricular pressure and oxygen extraction, markedly increased coronary flow, and attenuated the prolongation of AV conduction by 20% with no further change in heart rate. The beneficial effect of bimakalim on AV block was reversed by glibenclamide. Second degree AV block produced by higher doses of bupivacaine was converted to first degree AV block by either pinacidil or bimakalim in 6 of 8 and 7 of 8 hearts, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2000

[Hyperpolarized cardiac arrest with ATP-sensitive potassium channel opener on myocardial protection during CPB].

OBJECTIVE: To investigate the myocardial protective effects of pinacidil-induced hyperpolarized arrest and compare them with those induced with depolarized hyperkalemic arrest. METHODS: 18 dogs were equally divided into three groups. In the hypothermic hyperpolarization group (LH group), after aortic cross-clamping, a single dose of 4 degrees C pinacidil containing St. Thomas cardioplegic was infused through the aortic root. Temperature during CPB was kept between 26 - 28 degrees C and warmed to 37 degrees C before aortic declamping. Global ischemia lasted 60 min and then reperfusion started for 30 min. In the normothermic hyperpolarized group (WH group), the same procedure was set as in the LH group, except maintaining temperature of 35 - 37 degrees C for CPB and pinacidil solution. In the control group (group C), no pinacidil in St. Thomas solution was the only difference to the other 2 groups. Cardiac arrest and its recovery, the ultrastructure of the myocardium and hemodynamic during ischemia and after reperfusion were observed in the 3 groups. RESULTS: (1) The percentages of normal mitochondria and glycogen were not changed significantly during ischemia and after reperfusion in the LH group, but declined markedly in the group C at ischemic 30, 60 min, and reperfusion for 20 min (P < 0.01). In the WH group, they were lower than those of the group LH, but higher than those of the group C before ischemia. (2) The recoveries of CO, SV, CI, LVSW, RVSW, MAP in the LH group were significantly better than those in the other two groups after reperfusion for 15 minutes and 30 minutes (P < 0.05 or 0.01). However, they were much better in the WH group than in the group C (P < 0.05 or 0.01). (3) The time from cardioplegic infusion to cardiac arrest was shorter in the group C and the group LH than in the group WH. CONCLUSIONS: Myocardial protection for global ischemia during CPB could be well achieved with hyperpolarized cardiac arrest induced by ATP-sensitive potassium channel opener, pinacidil, especially in the hypothermic state. The protection is weaker in normothermia but is still stronger than that with traditional depolarized arrest.

Adenosine Triphosphate↗

PubMed1992

Potassium channel openers dilate large epicardial coronary arteries in conscious dogs by an indirect, endothelium-dependent mechanism.

Cromakalim and pinacidil, two potassium channel openers, dilate both large and small coronary arteries in conscious dogs. Because flow-mediated dilation of large arteries is endothelium-dependent, the consequences of in vivo endothelium removal (balloon denudation) on the response of large epicardial coronary arteries to cromakalim (10 micrograms/kg) and pinacidil (30 micrograms/kg) were investigated in six dogs chronically instrumented for the measurement of arterial pressure, left circumflex coronary artery diameter and coronary blood flow. Endothelium removal abolished the dilation of large coronary arteries induced by acetylcholine (endothelium-dependent dilation) and reactive hyperemia (flow-mediated dilation), but only slightly reduced (-18%) that induced by nitroglycerin. Before endothelium removal, both cromakalim and pinacidil induced a significant decrease in coronary resistance (-71 +/- 2 and -63 +/- 2%, respectively) and a significant increase in coronary diameter (8.5 +/- 1.3 and 6.7 +/- 0.9%). After endothelium removal, the decreases in coronary resistance were unaffected, but the increases in coronary diameter were reduced by 93 and 98% as compared to predenudation responses with cromakalim and pinacidil, respectively (both P < .01). In contrast, in vitro studies performed in isolated large epicardial coronary arteries obtained from five additional dogs showed that cromakalim evoked relaxations that were not affected by prior in vivo endothelium removal. Thus, despite the presence of potassium channels in isolated denuded large coronary arteries, our data demonstrate that cromakalim- and pinacidil-induced dilation of large arteries in vivo is an indirect, flow-mediated effect which is entirely endothelium-dependent.

Acetylcholine↗

PubMedDate not supplied

[Effect of ATP-sensitive potassium channel modulators and intermittent hypoxia on mitochondrial respiration during stress].

The influence of activator of ATP-sensitive potassium channels (KATP) pinacidil and blocker glibenclamide after intermittent hypoxia in rats under stress condition on ADP-stimulated mitochondrial respiration by Chance and lipid peroxidation processes in liver have been investigated. We used next substrates of oxidation--0.35 mM succinate, 1 mM alpha-ketoglutarate, 3 mM glutamate, 3 mM pyruvate, 2.5 mM malate and inhibitor of the mitochondrial fermentative complex I (10 microM rotenone), succinate dehydrogenase inhibitor (2 mM malonate) and inhibitor of transamination (1 mM aminooxiacetate). We suggest that adaptation by intermittent hypoxia and application of a KATP opener pinacidil possess significant protective effect on mitochondrial energy support under stress condition. Combination of intermittent hypoxia with pinacidil causes more efficient consumption of oxygen and decrease of lipid peroxidation processes comparative to intermittent hypoxia or pinacidil injection used separately. We conclude about the existence of the functional link between nitric oxide which is being increased under intermittent hypoxia and KATP opener. Both intermittent hypoxia and pinacidil effectively decrease the negative results of mitochondrial dysfunction under stress condition.

Adenosine Triphosphate↗