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PubMed1996

Comparison of the effects of nicorandil, pinacidil and nitroglycerin on hypoxic and hypercapnic pulmonary vasoconstriction in the isolated perfused lung of rat.

1. The aims of this study were to compare in the rat isolated perfused lung preparation, the dilator actions of nicorandil, pinacidil and nitroglycerin on the hypoxic pulmonary pressure response with or without hypercapnic acidosis and to investigate the possible involvement of K channels and EDRF in these effects. 2. Isolated lungs from male Wistar rats (260-320 g) were ventilated with 21%O2 + 5%CO2 + 74%N2 (normoxia) or 5%CO2 + 95%N2 (hypoxia) and perfused with a salt solution supplemented with ficoll and gassed with 40%CO2 + 60%N2 to produce hypercapnic acidosis. Glibenclamide (1 microM), charybdotoxin (0.1 microM), NG-nitro-L-arginine methyl ester (L-NAME, 100 microM) and methylene blue (30 microM) were used to block KATP channels, KCa channels, EDRF synthesis and guanylate cyclase, respectively. 3. Hypoxic pressure response was significantly increased by hypercapnic acidosis (+115%, P < 0.001), L-NAME (+111%, P < 0.001), methylene blue (+100%, P < 0.05) but not by glibenclamide or charybdotoxin. In contrast none of these inhibitors affected the hypoxic hypercapnic acidosis response. 4. Nicorandil, pinacidil and nitroglycerin caused relaxation during the hypoxic pressure response and hypoxic hypercapnic acidosis response. Nicorandil was more potent in the latter. Glibenclamide inhibited the relaxant effects of nicorandil and pinacidil but not those of nitroglycerin during hypoxia alone. In contrast, glibenclamide inhibited the relaxant effects of the three drugs during hypoxia + hypercapnia. Charybdotoxin inhibited the relaxant effect of pinacidil during normocapnia and hypoxia but not those of nicorandil or nitroglycerin. Methylene blue inhibited partially the dilator response to pinacidil but did not modify the effects of nitroglycerin or nicorandil. 5. It is concluded that in the rat isolated lung preparation, EDRF limits hypoxic pulmonary vasoconstriction but not hypoxic vasoconstriction potentiated by hypercapnic acidosis, whereas KATP or KCa channels are not involved in either case. Nicorandil and pinacidil dilate pulmonary vessels mainly through KATP channels but the effects of pinacidil may also involve an additional mechanism of action through KCa channels. Finally it is suggested that nitroglycerin may partly exert its relaxant effects through KATP channels.

Acidosis↗

PubMed1981

Effect of a new vasodilator, pinacidil (P 1134), on potassium, noradrenaline and serotonin induced contractions in rabbit vascular tissues.

Ring preparations of rabbit aorta were contracted by potassium (127 mM). Pinacidil (P 1134), a new vasodilator ( 2.3 x 10(-5) M), the calcium antagonists verapamil (3.4 x 10(-7) M), nifedipine (3.4 x 10(-9) M) and hydralazine (1.9 x 10(-4) M) relaxed the preparation by 50%. 50% relaxation of noradrenaline-contracted tissues was obtained with pinacidil, 6.8 x 10(-5) M, verapamil, 2.4 x 10(-3) M. At 2 x 10(-7) M concentration nifedipine was almost inactive. In ring preparations of rabbit aorta exposed to calcium-free medium and then depolarized with potassium (127 mM), pinacidil, 5 x 10(-5) M and nifedipine, 10(-8) M significantly inhibited the contractions by cumulative addition of calcium. Hydralazine, 10(-3) M had no effect. Noradrenaline-induced contractions in calcium-free medium or in presence of increasing amounts of calcium were significantly inhibited by nifedipine, 10(-8) M and hydralazine, 10(-3) M. Pinacidil, 10(-4) M had no effect. Pinacidil, 1.3 x 10(-5) M and verapamil, 2.0 x 10(-5) M inhibited by 50% the serotonin-induced increase of perfusion pressure of isolated rabbit ear artery. The noradrenaline effect in this preparation were 50% inhibited by pinacidil, 2.4 x 10(-4) M and by verapamil, 8.8 x 10(-5) M. Hydralazine, 10(-3) M exerted minor inhibitory effect. It is suggested that interference with calcium influx contributes to the vasodilator activity of pinacidil.

Animals↗

PubMed1989

Pinacidil uptake and effects in the isolated rabbit heart.

The myocardial accumulation of pinacidil showed one-compartment characteristics with a half-time of 1.11 min., whereas the disposition followed three-compartment kinetics with half-times for the relevant two redistributory and the terminal phases of 0.39, 1.51 and 5.44 min., respectively. At a steady-state drug concentration in the perfusate of 6.12 nmol ml-1, the average concentration of pinacidil in the myocardium was 20.6 nmol g-1. The accumulated amount could predictically be referred with 57% to a central and 31 and 12% to two peripheral (deeper) drug pools. The pharmacodynamic effects of pinacidil in the isolated perfused rabbit heart were studied at stepwise increasing concentrations from 0.15 to 100 microM. Coronary flowrate increased initially up to 24.5% at 1.5 microM pinacidil and then gradually decreased. Amplitude and velocity of contraction were both inhibited in a biphasic way up to 92.7 and 94.1%, respectively. Apparent dynamic steady states developed within 13-15 min. The computer-derived inhibitory Em-values related to the first phase were 49.2 and 52.4% and those related to the second phase were 111.7 and 108.3%, respectively. Heart frequency decreased monophasically and exhibited an inhibitory Em-value of 19.6%. Oxygen consumption decreased at pinacidil concentrations higher than 15 microM and the Em-value was 69.7%. The frequency-corrected QT-interval decreased biphasically and the related inhibitory Em-values were 8.6 and 58.7%. The QRS-interval did not change and the PQ-interval only showed a minor increase at the highest pinacidil concentration. Our findings are compatible with the concept of pinacidil being a potassium channel opener.

Animals↗

PubMed1989

Effect of pinacidil on sympathetic neuroeffector transmission in rabbit blood vessels.

The effects of pinacidil on vascular sympathetic neuroeffector transmission were studied. Pinacidil (3 x 10(-7)-3 x 10(-4) M) inhibited the contractions of rabbit isolated pulmonary artery evoked by nerve stimulation. This was the case both in the absence and presence of cocaine plus corticosterone. The inhibition reached a steady state and was reversible. Pinacidil (10(-5) -3 x 10(-4) M), in the absence or presence of cocaine plus corticosterone, markedly enhanced the 3H-overflow evoked by electrical-field stimulation of the artery preloaded with 3H-noradrenaline (3H-NA). The enhancement was dependent on frequency (1-30 Hz) in a complex manner. Phentolamine (3 x 10(-6) M), but not rauwolscine (10(-6) M) prevented the enhancement. Pinacidil (10(-4) M) did not antagonize the alpha-methylnoradrenaline-induced inhibition of 3H-overflow evoked by stimulation. Pinacidil (10(-5)-3 x 10(-5) M) in a non-competitive manner antagonized the contractions of isolated aorta elicited by noradrenaline (3 x 10(-9)-3 x 10(-5) M), phenylephrine (2 x 10(-8)-3 x 10(-4) M), adrenaline (10(-9)-3 x 10(-5) M), histamine (10(-6) 6 x 10(-4) M), serotonin (10(-8)-10(-4)M), and potassium (10(-3) M). Pinacidil (10(-6)-3 x 10(-4) M) and methacholine (3 x 10(-8)-10(-6) M) relaxed aorta preconstricted with noradrenaline (10(-7) M). The relaxation caused by pinacidil was not dependent on the presence of endothelial cells, while that seen with methacholine was.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1983

Hemodynamic characterization of pinacidil in rats. Comparison with hydralazine.

Pinacidil (N"-cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine monohydrate; P1134) is a new vasodilator drug with a direct relaxant effect on vascular smooth muscle. Its hemodynamic properties, in comparison with those of hydralazine, were studied in conscious normotensive and spontaneously hypertensive rats; anesthetized normotensive rats; pithed normotensive rats; pithed normotensive rats subjected to electrical stimulation of the spinal cord. Radioligand binding studies on rat cerebral membranes were carried out to study a possible affinity for pinacidil towards alpha 1- and alpha 2-adrenoceptors, respectively. The observations made in conscious and anesthetized rats suggest that both pinacidil and hydralazine are predominantly arterial vasodilators. In conscious animals reflex tachycardia was elicited by both drugs. Neither pinacidil nor hydralazine possessed substantial affinity for alpha 1- or alpha 2-adrenoceptors, as concluded from radioligand binding studies. Pinacidil interferes with the pressor response to postsynaptic alpha 2-adrenoceptor stimulation in pithed rats, possibly reflecting weak calcium antagonistic activity of the drug. Pinacidil did not interfere with the electrically induced release of noradrenaline from presynaptic sites. All results suggest that pinacidil is a direct-acting arteriolar dilator, which on a molar base is somewhat more potent than hydralazine.

Animals↗

PubMed1989

Enhancement of potassium-sensitive current in heart cells by pinacidil. Evidence for modulation of the ATP-sensitive potassium channel.

Pinacidil belongs to a novel group of compounds that enhance the potassium permeability of vascular smooth muscle. Evidence also exists that this drug enhances the potassium permeability of cardiac tissue. The purpose of the present investigation was to determine if pinacidil alters potassium-channel activity in heart and, if so, which potassium channel is the target. We used the whole-cell arrangement of the patch voltage clamp to record membrane currents from isolated guinea pig ventricular cells. In solutions designed to isolate potassium currents, pinacidil enhances a time-independent current positive to the potassium equilibrium potential. Current measured at voltages negative to the potassium equilibrium potential are essentially unaltered by the drug. The potassium sensitivity of outward current indicates that the target for the drug is a potassium channel. Experiments designed to test for voltage-dependent channel gating strongly suggest that the pinacidil-sensitive current is not voltage gated. Pinacidil-sensitive current is blocked by externally applied Ba2+, Cs+, and tetraethylammonium ion. In addition, it is potently blocked after external application of 100 nM glibenclamide. Taken along with the time- and voltage-independent properties of pinacidil-sensitive current, this pharmacology strongly suggests that the target for pinacidil in heart is the ATP-sensitive potassium channel.

Adenosine Triphosphate↗

PubMed2000

Possible underestimation of the channel conductance underlying pinacidil-induced K+ currents using noise analysis in pig urethral myocytes.

Electrophysiological and pharmacological properties of the pinacidil-induced K+ currents in isolated cells from pig urethra were investigated using patch-clamp techniques. Pinacidil (100 microM) induced an outward current at -50 mV which gradually decreased. Under current-clamp conditions, 100 microM pinacidil induced a hyperpolarization that was sustained. This suggests that activation of only a few channels can hyperpolarize the membrane. At a holding potential of -50 mV, glibenclamide inhibited the pinacidil-induced current with a single exponential time course. Unitary current recordings in symmetrical 140 mM K+ conditions demonstrated that pinacidil activates a 43-pS, glibenclamide-sensitive K+ channel (i.e. K(ATP) channel). Analysis of the basal noise of the pinacidil-induced macroscopic currents from -90 mV to -30 mV yielded estimates of channel conductance (6 pS) which were much smaller, and probably an underestimate. These results indicate that pinacidil induces a glibenclamide-sensitive K+ current through only one type of K+ channel (K(ATP) channel) in pig urethra.

Animals↗

PubMed2003

Selective mitochondrial KATP channel activation by nicorandil and 3-pyridyl pinacidil results in antiarrhythmic effect in an anesthetized rabbit model of myocardial ischemia/reperfusion.

The roles of cardiomyocyte sarcolemmal ATP-sensitive K+ (KATP) and mitochondrial KATP channels in cardioprotection and antiarrhythmic activity induced by KATP channel openers remain obscure. However, it has been suggested that the mitochondrial KATP channels are involved as a subcellular mediator in cardioprotection afforded by ischemic preconditioning. In the present study, we investigated the effects of the administration of non-hypotensive doses of ATP-sensitive K+ channel (KATP) openers (nicorandil and 3-pyridyl pinacidil), a specific mitochondrial KATP channel blocker (5-hydroxydecanoate) and a specific sarcolemmal KATP channel blocker (HMR 1883; 1-[5-[2-(5-chloro-o-anisamido)ethyl]-2-methoxyphenyl]sulfonyl-3- methylthiourea) prior to and during coronary occlusion, as well as prior to and during post-ischemic reperfusion, on survival rate, ischemia-induced and reperfusion-induced arrhythmias and myocardial infarct size in anesthetized albino rabbits. The thorax was opened in the left 4th intercostal space and after pericardiotomy the heart was exposed. In Group I (n = 80), occlusion of the left main coronary artery and hence, myocardial ischemia-induced arrhythmias were achieved by tightening a previously placed loose silk ligature for 30 min. In Group II (n = 186), arrhythmias were induced by reperfusion following a 20 min ligation of the left main coronary artery. In both Group I and Group II, early intravenous infusion of nicorandil (100 micrograms/kg bolus + 10 micrograms/kg/min), 3-pyridyl pinacidil (3.0 micrograms/kg bolus + 1.0 microgram/kg/min), HMR 1883 (3 mg/kg)/nicorandil and HMR 1883 (3 mg/kg)/3-pyridyl pinacidil, just prior to and during ischemia, increased survival rate (75%, 67%, 86% and 75% vs. 60% in the control subgroup in Group I; 67%, 75%, 75% and 67% vs. 43% in the control subgroup in Group II), significantly decreased the incidence and severity of life-threatening arrhythmias and significantly decreased myocardial infarct size. However, late intravenous administration of nicorandil or 3-pyridyl pinacidil at the onset of and during reperfusion did not increase survival rate nor confer any antiarrhythmic or cardioprotective effects. The antiarrhythmic and cardioprotective effects of both nicorandil and 3-pyridyl pinacidil were abolished by pretreating the rabbits with 5-hydroxydecanoate (5 mg/kg, i.v. bolus), a selective mitochondrial KATP channel blocker, but not by pretreatment with HMR 1883 (3 mg/kg). In the present study, higher levels of malondialdehyde (MDA) and lower levels of reduced glutathione (GSH) and superoxide dismutase (SOD) in the necrotic zone of myocardium in all sixteen subgroups in Group II suggest little anti-free radical property of nicorandil and 3-pyridyl pinacidil. Therefore, we may conclude that intervention by intravenous administration of nicorandil and 3-pyridyl pinacidil (through the selective activation of mitochondrial KATP channels), increases survival rate and exhibits antiarrhythmic and cardioprotective effects during coronary occlusion and reperfusion in anesthetized rabbits, when administered prior to and during coronary occlusion. The mitochondrial KATP channel may be considered to be a potentially important site of cardioprotection and antiarrhythmic activity.

Animals↗

PubMed1988

Pinacidil. Preclinical investigations.

Routine pharmacological screening of thiourea compounds led to the selection of pyridyl cyanoguanidines for their antihypertensive effects. From this cyanoguanidine class of compounds, P 1134 (pinacidil) was synthesised. Pinacidil has an asymmetrical carbon atom in the pinacolyl radical and the (-) enantiomer is more active than the (+) enantiomer both in vitro and in vivo. Pinacidil is rapidly absorbed following oral administration with the time to peak plasma concentration being 0.5 to 1 hour and, for the extended release formulation, 1 to 3 and 5 to 7 hours. The antihypertensive effect of pinacidil is proportional to the dose administered. Pyridine-N-oxide is the principal metabolite and accounts for approximately half of the dose excreted in the urine within 24 hours. In hypertensive rats and dogs, the blood pressure-lowering effect of pinacidil is dose-dependent and linearly related to the baseline blood pressure. The haemodynamic profile is characterised by an increased cardiac output as a consequence of increased stroke volume. An increase in heart rate follows the depressor response. The fall in blood pressure is preceded and superseded by a fall in the total peripheral resistance. Preclinical haemodynamic studies suggest that pinacidil is a directly acting precapillary vasodilator. The resting membrane potential of smooth muscle cells is approximately -60mV whereas the equilibrium potential for potassium is more negative, between -80 and -90mV. Pinacidil opens K+ channels and allows potassium to attain its equilibrium potential, resulting in hyperpolarisation of the cell at rest. A hyperpolarised cell is less prone to depolarisation, and without depolarisation there is no activation of the voltage-operated Ca2+ channels and, hence, no muscle contraction.

Antihypertensive Agents↗

PubMed1988

Double-blind comparator trials with pinacidil, a potassium channel opener.

The antihypertensive effects of pinacidil, a potassium channel opener, were studied in 4, dose titration, double-blind trials. Patients had mild to severe hypertension, with supine diastolic arterial pressures between 91 and 150mm Hg during the qualification assessment. Efficacy was assessed using an 'intention-to-treat' analysis. In one study, pinacidil-treated patients had a response rate significantly greater than placebo-treated patients. In another study, the pinacidil group had a response rate significantly greater than the prazosin group (83% vs 75%, respectively). In a third study, the response rate in the pinacidil group was marginally greater than in the hydralazine group (77% vs 73%, respectively). In a 'step 2' trial, pinacidil was as effective as methyldopa and more effective than placebo. Adverse experiences with pinacidil were associated with vasodilatation. Electrocardiographic T wave changes occurred intermittently and may be related to its mechanism of action. These studies suggest that antihypertensive monotherapy with pinacidil was effective and generally well tolerated.

Antihypertensive Agents↗

PubMed1988

Pinacidil with and without hydrochlorothiazide. Dose-response relationships from results of a 4 x 3 factorial design study.

Utilising a modified fixed-dose, 4 x 3 factorial design, the antihypertensive effects of all combinations of 4 doses of pinacidil (0, 12.5, 25 and 37.5 mg bid) with 3 doses of hydrochlorothiazide (0, 12.5 and 25 mg bid) were studied in patients with supine diastolic blood pressure of 95 to 110mm Hg. The decreases in supine diastolic blood pressure from baseline were dose-related for both drugs. The response to the highest monotherapy dose of pinacidil was less in patients with oedema. When given in combination, hydrochlorothiazide blunted the differences among pinacidil doses so that 12.5 mg pinacidil with 12.5mg hydrochlorothiazide administered twice daily produced nearly maximal antihypertensive efficacy. For pinacidil monotherapy, the incidence of oedema was 3%, 26% and 47% at dosages of 12.5, 25, and 37.5mg bid, respectively, with significant attenuation of these effects at both hydrochlorothiazide dosage levels. Based upon these data, low (12.5-25mg bid) doses of pinacidil are effective and safe as monotherapy for hypertension. The optimal combination of pinacidil with hydrochlorothiazide given twice daily for hypertension contains 12.5mg of each drug.

Antihypertensive Agents↗

PubMed1998

Pinacidil suppression on 5-HT3 receptor-mediated contraction of guinea pig ileum in vitro.

AIM: To study the effects of the K+ channel opener pinacidil on 5-HT3 receptor-mediated contractions of the isolated guinea pig ileum (GPI) longitudinal muscle-myenteric plexus strip preparations. METHODS: GPI contractions were recorded with a chart recorder through isometric transducers. The effect of pinacidil on binding properties of 5-HT3 receptors was assessed using [3H]GR65630 binding assay in membrane preparations of rat entorhinal cortex. RESULTS: (1) A selective 5-HT3 receptor agonist 2-methyl-5-HT 0.1-300 mumol.L-1 and 5-HT 0.001-50 mumol.L-1 elicited GPI contractile responses in concentration-dependent manners, the EC50 values (and 95% confidence limits) for 2-methyl-5-HT and 5-HT were 10.0 (8.9-11.2) mumol.L-1 and 1.6 (1.3-1.9) mumol.L-1, respectively. Selective 5-HT3 receptor antagonist tropisetron 0.1 mumol.L-1 competitively inhibited the responses to 2-methyl-5-HT and 5-HT. (2) Pinacidil 0.5-5 mumol.L-1 inhibited 5-HT3 receptor-mediated contractions. (3) Pinacidil 1 mumol.L-1 enhanced the inhibitory effects of tropisetron 0.1 mumol.L-1 or another selective 5-HT3 receptor antagonist benesetron 1 mumol.L-1 on 5-HT-induced GPI contractile responses. (4) Pinacidil 1-5 mumol.L-1 did not affect GPI contractile responses evoked by a selective M-ACh receptor agonist carbachol 1 mumol.L-1. (5) Pinacidil 1-5 mumol.L-1 had no effect on binding properties of 5-HT3 receptors with selective 5-HT3 receptor radioligand [3H]GR65630 in the entorhinal cortex of rat brain. CONCLUSION: The inhibition by pinacidil of 5-HT3 receptor-mediated GPI contractile responses may be mediated through activation of ATP-sensitive K+ channels located in prejunctional myenteric neurons.

Animals↗

PubMed2005

[Effects of quinidine on pinacidil-induced transmural dispersion of repolarization in canine right ventricular wall].

OBJECTIVE: On the basis that pinacidil can produce an "all or none" repolarization in right ventricular wall of canine, to observe the effects of quinidine on the marked transmural dispersion of repolarization. Recent studies have shown that ventricular myocardium is composed of at least 3 electrophysiological distinct cell types: epicardial, endocardial, and midcardial cells. Differences in the response of the 3 cell types to pharmacologic agents and/or pathophysiological states often result in amplification of intrinsic electrical heterogeneities, thus providing a substrate as well as a trigger for the development of arrhythmias. The study was designed to observe the right ventricular transmural heterogeneity in vitro canine heart tissue preparation level. METHODS: The strips were isolated from the anterior wall of the right ventricular of canine. The preparations perfused with oxygenated (95%O(2)/5%CO(2)) Tyrode's solution. The tissues were stimulated at basic cycle lengths of 1000 ms. Standard microelectrode techniques were used. Transmembrane action potentials were recorded from epicardial, midcardial and endocardial cells respectively from right ventricular free wall of canine on different conditions [perusing with Tyrode's solution (Control), pinacidil (2.5 micromol/L), and quinidine (5 micromol/L) in turn]. RESULTS: Compared with that of endocardial cells, the action potentials of canine ventricular epicardial and midcardial cells had more obvious spike and dome morphology. Pinacidil (2.5 micromol/L) caused a loss of the dome of transmembrane action potentials and a marked abbreviation of the action potential duration (APD) in right ventricular epicardial and midcardial cells, especially in epicardial cells, but not in endocardial cells (n = 10). With pinacidil (2.5 micromol/L), in epicardial cells, phase 2 amplitude of action potentials decreased from (117.7 +/- 9.3) mV to (71.3 +/- 6.4) mV (P < 0.01), and 90% of the APD(90) decreased from (198.2 +/- 20.8) ms to (103.9 +/- 13.5) ms (P < 0.01). The transmural dispersion of action potential duration increased from (48.5 +/- 9.2) ms to (128.7 +/- 13.5) ms (P < 0.01). Quinidine (5 micromol/L) effectively prolonged the APD abbreviated by pinacidil, restored or partly restored the dome of transmembrane action potentials of epicardial and midcardial cells but not of endocardial cells (n = 10). In epicardial cells phase 2 amplitude increased from (71.3 +/- 6.4) mV to (106.6 +/- 7.7) mV (P < 0.01), and 90% of the APD(90) increased from (103.9 +/- 13.5) ms to (185.9 +/- 15.7) ms (P < 0.01). The transmural dispersion of action potential duration significantly decreased from (128.7 +/- 13.5) ms to (54.3 +/- 10.8) ms (P < 0.01). Quinidine reduced pinacidil-induced transmural dispersion of phase 2 amplitude and the APD in right ventricular wall of canine. CONCLUSION: By restoring the dome and the APD of the epicardial and midcardial cells action potentials, quinidine (5 micromol/L) could reduce the marked transmural dispersion of repolarization caused by pinacidil.

Action Potentials↗

PubMed2005

Pinacidil increases diclofenac antinociception in the formalin test.

Evidence suggests that the ATP-sensitive K+ channels are important in the peripheral antinociceptive effect of diclofenac. Combinations of nonsteroidal anti-inflammatory drugs (NSAIDs) with other different drugs are currently used in clinical practice to increase the analgesic efficacy and to reduce adverse events. We evaluated the effect of the combination of diclofenac and the activator of K+ channels pinacidil in the formalin test. Female Wistar rats (180-200 g) were injected in the dorsal surface of the right hind paw with 50 microl of formalin (1%). Nociception was quantified as the number of flinches of the injected paw during the next 60 mins, while reduction of flinches was considered antinociception. Ipsilateral, but not contralateral, pretreatment with diclofenac (25-200 microg/paw) or pinacidil (5-50 microg/paw) significantly reduced, in a dose-dependent manner the formalin-induced flinching behavior during the second phase of the test. To determine if pinacidil was able to increase the effect of diclofenac, noneffective increasing doses of pinacidil were coadministered with an ineffective dose of diclofenac (25 microg). The local co-administration of pinacidil and diclofenac produced a significant reduction in the number of flinches during phase 2, but not during phase 1 of the test compared to the effect of either drug alone. In conclusion, the combination of individually ineffective doses of diclofenac and pinacidil produce an antinociceptive effect in the formalin test. In addition, pinacidil increased the action of diclofenac, probably through the activation of K+ channels.

Animals↗

PubMed1990

Effects of cromakalim and pinacidil on large epicardial and small coronary arteries in conscious dogs.

The effects of i.v. bolus administration of cromakalim (1-10 micrograms/kg) and pinacidil (3-100 micrograms/kg) on large (circumflex artery) and small coronary arteries and on systemic hemodynamics were investigated in chronically instrumented conscious dogs and compared to those of nitroglycerin (0.03-10 micrograms/kg). Nitroglycerin, up to 0.3 micrograms/kg, selectively increased circumflex artery diameter (CxAD) without simultaneously affecting any other cardiac or systemic hemodynamic parameter. In contrast, cromakalim and pinacidil at all doses and nitroglycerin at doses higher than 0.3 micrograms/kg simultaneously and dose-dependently increased CxAD, coronary blood flow and heart rate and decreased coronary vascular resistance and aortic pressure. Cromakalim was approximately 8- to 9.5-fold more potent than pinacidil in increasing CxAD. Vasodilation of large and small coronary vessels and hypotension induced by cromakalim and pinacidil were not affected by prior combined beta adrenergic and muscarinic receptors blockade but drug-induced tachycardia was abolished. When circumflex artery blood flow was maintained constant, the increases in CxAD induced by cromakalim (10 micrograms/kg), pinacidil (30 micrograms/kg) and nitroglycerin (10 micrograms/kg) were reduced by 68 +/- 7, 54 +/- 9 and 1 +/- 1%, respectively. Thus, whereas nitroglycerin preferentially and flow-independently dilates large coronary arteries, cromakalim and pinacidil dilate both large and small coronary arteries and this effect is not dependent upon the simultaneous beta adrenoceptors-mediated rise in myocardial metabolic demand. Finally, two mechanisms at least, direct vasodilation and flow dependency, are involved in the cromakalim- and pinacidil-induced increase in CxAD.

Animals↗

PubMed1988

Cromakalim, a potassium channel activator: a comparison of its cardiovascular haemodynamic profile and tissue specificity with those of pinacidil and nicorandil.

Studies have been performed to compare the cardiovascular haemodynamic profiles of the potassium channel activator, cromakalim (BRL 34915), with those of pinacidil and nicorandil. In conscious renal hypertensive cats, cromakalim was 10 times more potent than pinacidil as an antihypertensive agent while nicorandil was 10 times less potent than pinacidil. Cromakalim and pinacidil had a similar duration of action while nicorandil was short acting. In anaesthetised cats, hypotension evoked by intravenous infusions of cromakalim, pinacidil, or nicorandil was associated with a decrease in mesenteric vascular resistance but only cromakalim produced a marked reduction in renal vascular resistance. Cromakalim, pinacidil, and nicorandil were highly specific as inhibitors of tension in vascular (rabbit portal vein) (IC50 = 2.1 x 10(-8), 4.6 x 10(-8), and 1.3 x 10(-6)M, respectively,) rather than cardiac (rabbit papillary muscle), tissue. In view of its antihypertensive efficacy, specificity for vascular tissue, and beneficial effect upon renal haemodynamics, the potassium channel activator, cromakalim, has advantages in its profile of activity compared to pinacidil and nicorandil.

Animals↗

PubMed1989

Anti-ischemic effects of the potassium channel activators pinacidil and cromakalim and the reversal of these effects with the potassium channel blocker glyburide.

The direct cardioprotective efficacy of the potassium channel activators pinacidil and cromakalim was determined in isolated globally ischemic rat hearts. Isolated buffer-perfused rat hearts were subjected to 25 min of ischemia followed by 30 min of reperfusion. These hearts were pretreated with 1 to 100 microM pinacidil, 1 to 7 microM cromakalim or vehicle. Pinacidil resulted in significant improvements in reperfusion function and cardiac compliance, though it did not significantly reduce lactate dehydrogenase release at any concentration. The protective effects of pinacidil were greatest at a 10 microns concentration and were slightly diminished at higher concentrations (30 and 100 microns). Although not affecting the severity of ischemia alone, 10 microM glyburide (potassium channel blocker) completely reversed the protective effects of pinacidil on reperfusion function and compliance. Cromakalim (7 microM) resulted in a greater than 50% improvement in reperfusion function and compliance and unlike pinacidil significantly reduced lactate dehydrogenase release by approximately 50%. At 1 microM, glyburide alone did not significantly affect the severity of ischemia but reversed the protective effects of cromakalim. Not only did glyburide reverse the protective effects of cromakalim, it resulted in a worsening of ischemia compared to vehicle, an effect not seen with glyburide alone. Thus, both pinacidil and cromakalim appear to have direct cardioprotective efficacy, though some differences between them may be possible. The mechanism of their protective effects appears to be via potassium channel opening as the potassium channel blocker glyburide reverses the protective effect of these compounds. Intracellular electrophysiological studies showed that ischemia-induced depolarization was reversed with cromakalim, which increased the resting potential nearly back to preischemic levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1995

Vasorelaxation by pinacidil in isolated perfused lungs is enhanced in rats with hypoxic pulmonary hypertension but is dependent on the constrictor.

The potassium channel opening drug, pinacidil, has been examined in isolated perfused lungs taken from rats with hypoxic pulmonary hypertension (housed in 10% oxygen for 7 days) and control rats. Inhibition by pinacidil (1 to 30 microM) of noradrenaline (NA)-induced vasoconstriction (NA infusions; beta-adrenoceptors blocked) and of hypoxic pulmonary vasoconstriction (HPV; ventilation for 3.5-4.5 min with 0-1% oxygen) were compared. The vasoconstrictor responses in preparations from control and hypoxic rats, respectively, were (mm Hg) NA 6.6 +/- 0.68 (6); 8.2 +/- 1.45 (9); HPV 7.8 +/- 1.03 (12); 8.8 +/- 0.93 (13). These responses were reversibly inhibited by pinacidil. In lungs from control rats pinacidil was 10-fold less potent against NA than against HPV, but in lungs from hypoxic rats it was equipotent against NA and HPV. When tested against NA, but not HPV, pinacidil was significantly more potent in lungs from hypoxic rats than control rats. It is postulated that NA-induced vasoconstriction in lungs from hypoxic rats, and HPV in both groups of rats, involve calcium influx through voltage-operated calcium channels. Consequently, these responses are readily inhibited by drugs such as pinacidil which open potassium channels and hyperpolarise the cell membrane. In contrast in lungs from control rats, NA-induced constriction may involve mainly intracellular calcium release and thus be less readily inhibited by the hyperpolarising effect of pinacidil.

Animals↗