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PubMedDate not supplied

Suppression of ventricular arrhythmias after coronary artery ligation by pinacidil, a vasodilator drug.

Pinacidil, a new vasodilator compound, has been shown to lower blood pressure in animals and humans by a direct vasodilator effect. We have studied the effects of pinacidil on experimental cardiac arrhythmias in dogs. Pinacidil did not exhibit antiarrhythmic activity on ouabain-induced arrhythmias. In contrast, verapamil had minor antiarrhythmic activity on the ouabain arrhythmia, restoring sinus rhythm in one-third of the dogs studied. Pinacidil suppressed the arrhythmia present 22-24 h after coronary artery ligation at doses which produced a significant reduction in mean arterial pressure. The antiarrhythmic action of pinacidil was not modified by pretreatment with propranolol but appeared to be blunted by the infusion of the alpha-agonist, phenylephrine. Other hypotensive agents, hydralazine and sodium nitroprusside, although producing similar reductions in mean arterial pressure to pinacidil, did not exhibit a consistent antiarrhythmic action in dogs 22-24 h after coronary artery ligation. The calcium antagonist verapamil did not display antiarrhythmic activity on this model. The mechanisms by which pinacidil exerted an antiarrhythmic action have not yet been elucidated. The results of the present study suggest that further studies with pinacidil on myocardial infarct size, myocardial perfusion, and experimental cardiac arrhythmias would be advantageous.

Animals↗

PubMedDate not supplied

Effects of pinacidil on serotonin-induced contractions and cyclic nucleotide levels in isolated rat aortae: comparison with nitroglycerin, minoxidil, and hydralazine.

Pinacidil is a novel, clinically effective vasodilator used for the treatment of hypertension whose mechanism of action has not been precisely defined. In vitro, pinacidil (ED50 = 0.3 microM) was approximately 30-fold less potent than nitroglycerin and 700-fold more potent than minoxidil or hydralazine in relaxing rat aortic strip preparations. Aortic relaxations produced by nitroglycerin and acetylcholine were dramatically antagonized by methylene blue (10(-5) M), an inhibitor of soluble guanylate cyclase. In contrast, relaxation to hydralazine or minoxidil was unaffected and relaxation to pinacidil was only modestly inhibited (approximately threefold) by methylene blue (10(-5) M). Furthermore, aortic relaxation to pinacidil was similar in preparations with and without an intact endothelium. Relaxation induced by pinacidil (10(-7)-10(-4) M) was not associated with any elevation in either cyclic AMP (cAMP) or cyclic GMP (cGMP) levels in vitro, although nitroglycerin (10(-6) M) but not minoxidil (10(-3) M) or hydralazine (10(-3) M) significantly elevated cGMP levels. Thus, pinacidil was a potent relaxant agonist in vitro, in contrast to minoxidil and hydralazine, which were considerably weaker in this regard. Vascular relaxation produced by pinacidil was independent of an intact endothelium and was not associated with elevations in either cAMP or cGMP. These data are consistent with the proposal that the antihypertensive activity of pinacidil is due to nonspecific arterial vasodilation.

Animals↗

PubMed1988

Similarities in the mechanism of action of two new vasodilator drugs: pinacidil and BRL 34915.

The present study compares the in vitro and in vivo activities of pinacidil with another new vasodilator drug, BRL 34915, claimed to act via the opening of K+ channels in vascular smooth muscle. In the rabbit aorta, BRL 34915 and pinacidil caused rightward shifts of the KCl concentration-response curve and noncompetitively antagonized angiotensin II contractions, yielding an IC50 of 5 and 10 microM, respectively. In 86Rb-loaded guinea pig portal veins, both BRL 34915 and pinacidil stimulated 86Rb+ efflux over the concentration range 0.3-30 microM. At saturating concentrations, the maximum efflux elicited by pinacidil was only one-third that of BRL 34915. Spontaneous activity measured simultaneously from the same vessels was inhibited by BRL 34915 and pinacidil with an IC50 of 12 and 32 nM, respectively. Effects on mechanical activity were thus observed at drug concentrations 100-fold lower than those required to stimulate 86Rb+ efflux. In anesthetized rats, both compounds rapidly lowered blood pressure, with BRL 34915 being threefold more potent than pinacidil in this respect. Tachycardia was more pronounced after BRL 34915 than after pinacidil. Angiotensin II pressor responses were poorly antagonized by these two vasodilators in rats, in marked contrast to the potent effects of Ca2+ antagonists on these responses at equieffective hypotensive doses. We conclude the pinacidil, like BRL 34915, is a potent antihypertensive that is able to enhance the K+ permeability of vascular smooth muscle. The similarities between these two drugs suggest they have a common mechanism of action. However, the discrepancy between the concentrations of these drugs necessary to stimulate 86Rb efflux, and those at which mechanical effects are seen in the portal vein, do not rule out the possibility that other actions may contribute to their vasodilator activities.

Animals↗

PubMed1990

Pinacidil opens ATP-dependent K+ channels in cardiac myocytes in an ATP- and temperature-dependent manner.

Pinacidil is an antihypertensive agent that has been found to increase potassium conductance. This study examined the type of K channel affected by pinacidil in cardiac myocytes. Pinacidil shortened the action potential duration in papillary muscle. The effect was reversible upon addition of glyburide, a known IKATP blocker. The effect of pinacidil was temperature-dependent. Action potential duration was shortened more rapidly and to a greater extent at 37 degrees C than at 23 degrees C. Whole-cell experiments showed that I-V curves lost rectification after pinacidil treatment. As with the action potential experiments, the effect was more rapid at 37 degrees C than at 23 degrees C. Rectification was restored after exposure to glyburide. The I-V curve generated after pinacidil exposure was similar to that observed by others after treatment with metabolic inhibitors that activate IKATP. The effect of pinacidil was also ATP-dependent. Addition of 5 mM ATP to the internal solution prevented activation of IKATP. These data indicate that pinacidil activates IKATP.

Action Potentials↗

PubMed1994

Antiarrhythmic agent, MS-551, protects against pinacidil + hypoxia-induced ventricular fibrillation in Langendorff-perfused rabbit isolated heart.

We studied the electrophysiologic and antifibrillatory effects of the class III agent MS-551 in a rabbit isolated heart model in which ventricular fibrillation (VF) occurs reproducibly under conditions of hypoxia/reoxygenation in the presence of the ATP-dependent potassium channel opener, pinacidil. Ten minutes after MS-551 or vehicle administration, addition of pinacidil (1.25 microM) to the buffer was followed by a 12-min hypoxic period and 40-min reoxygenation. At a low concentration of MS-551 (1.0 microM), VF occurred in 5 of 6 hearts, the same incidence as in the control group (5 of 6). In contrast 0 of 6 hearts treated with 15 microM MS-551 developed VF (p < 0.05 vs. vehicle). Ventricular effective refractory period (VERP) was determined in a separate group of isolated hearts (n = 13). Pinacidil alone, during normoxic perfusion, decreased VERP 48 +/- 11% (p < 0.05) 15 min after exposure. Five minutes of hypoxia alone also decreased VERP (57 +/- 8%, p < 0.05). Under normoxic conditions, MS-551 increased ERP 31 +/- 10% (p < 0.05 vs. baseline). VERP prolongation by MS-551 was reduced in the presence of pinacidil but remained 22 +/- 6% (p < 0.05) above baseline. The results suggest that VERP shortening owing to pinacidil-mediated ATP-dependent K+ channel opening is associated with development of VF in isolated heart. MS-551 attenuates the pinacidil-mediated decrease in VERP and prevents pinacidil+hypoxia-reoxygenation-induced VF. Because pinacidil and hypoxia open myocardial KATP channels, putatively decreasing VERP, MS-551 may exert its antifibrillatory effect through partial blockade of KATP channels.

Animals↗

PubMedDate not supplied

Comparative relaxant effects of cromakalim and pinacidil on the tonic contraction of canine coronary artery induced by phorbol 12,13-dibutylate.

1. Phorbol esters, activators of protein kinase C (PKC), have been widely used to investigate the role of PKC in the regulation of smooth muscle contraction. However, limited studies have so far been made of the sensitivity of the contraction induced by phorbol esters to relaxant drugs. We therefore examined the relaxant effects of the K+ channel openers, cromakalim and pinacidil, on the tonic contraction of canine isolated coronary artery rings induced by phorbol 12,13-dibutylate (PDBu). 2. In rings contracted with 10(-7) mol/L PDBu, cromakalim and pinacidil, as well as nifedipine, produced a concentration-dependent relaxation. At their maximum effects, both cromakalim and nifedipine caused a partial relaxation, whereas pinacidil produced nearly a full relaxation. 3. The relaxant effects of cromakalim and pinacidil were effectively antagonized by the ATP-sensitive K+ channel blocker, glibenclamide (10(-6) mol/L). 4. In the presence of nifedipine, high K+ was ineffective while PDBu (10(-7) mol/L) still induced a tonic contraction. This PDBu-induced contraction was inhibited by concentrations of cromakalim and pinacidil higher than those needed in the absence of nifedipine. 5. In rings partially depolarized with 35 mmol/L KCl, the ability of cromakalim to inhibit PDBu-induced contractions in the presence of nifedipine was completely abolished. Under the same conditions, the relaxant response to pinacidil, unlike cromakalim, was inhibited only partially. 6. These results suggest that cromakalim inhibits PDBu-induced contractions through an opening of K+ channels. Pinacidil does so by a mechanism shared with cromakalim as well as by another that is independent of this K+ channel opening action. These multiple modes of action may confer on pinacidil a vasorelaxant activity greater than that of cromakalim.

Animals↗

PubMed1999

Differential effects of pinacidil and levcromakalim on the contractions elicited electrically or by noradrenaline in the portal vein of the rabbit.

The present study was undertaken to examine the antivasoconstrictor effects of pinacidil and levcromakalim, two potassium channel openers (PCOs), on the isolated rabbit portal vein and to define the role for different subtypes of pre- and/or post-synaptic K+ channels in the antivasoconstrictor action of the PCOs. The vein strips were contracted by electrical field stimulation (EFS) or by exogenous noradrenaline (NA). The results of this study showed that pinacidil produced a more potent inhibition of the neurogenic contractions (pD2 = 6.04 +/- 0.05) than of contractions induced by exogenous NA (pD2 = 4.90 +/- 0.10). Glibenclamide (1 microM), a selective blocker of adenosine triphosphate (ATP)-sensitive K+ channels (K(ATP)), did not affect the pinacidil-induced inhibition of contractions evoked by exogenous NA. In contrast, glibenclamide (0.1-10 microM) significantly antagonized the effect of pinacidil on EFS evoked contractions in a noncompetitive manner. There was no difference between the inhibitory effects of levcromakalim on neurogenic contractions (pD2 = 7.58 +/- 0.05) and contractions evoked by exogenous NA (pD2 = 7.64 +/- 0.08). Glibenclamide (1 microM) antagonized in the same manner the levcromakalim-induced inhibition of neurogenic contractions and contractions evoked by exogenous NA. Moreover, glibenclamide competitively antagonized the effect of levcromakalim on EFS induced contractions of the rabbit portal vein (pA2 = 6.40 +/- 0.10). Charybdotoxin (0.4 microM) and apamin (0.1 microM) did not influence the inhibitory effects of pinacidil and levcromakalim, both on contractions evoked by EFS and contractions evoked by exogenous NA. These results suggest that the antivasoconstrictor effect of levcromakalim might be postsynaptic and associated with opening of the smooth muscle K(ATP) channels. In contrast, it is hypothesized that the effect of pinacidil on neurogenic contractions is due to an interference with K(ATP) channels in the neuromuscular synapse. It seems that the action of pinacidil on the NA contractions is mediated by another still undefined mechanisms of pinacidil.

Adrenergic alpha-Antagonists↗

PubMed1990

Cytoplasmic calcium and the relaxation of canine coronary arterial smooth muscle produced by cromakalim, pinacidil and nicorandil.

1. In order to investigate the vasodilator mechanisms of the K+ channel openers, cromakalim, pinacidil and nicorandil, we measured changes in cytoplasmic Ca2+ concentration [( Ca2+]i) simultaneously with force by a microfluorimetric method using fura-2, a calcium indicator, in canine coronary arterial smooth muscle cells. 2. The three K+ channel openers all produced a concentration-dependent reduction of [Ca2+]i in 5 and 30 mM KCl physiological salt solution (PSS) but failed to affect [Ca2+]i in 45 and 90 mM KCl-PSS. 3. Cromakalim only partly inhibited (-45%) the 30 mM KCl-induced contractures, whereas pinacidil and nicorandil nearly abolished contractions produced by 45 mM, 90 mM and 30 mM KCl-PSS. 4. Tetrabutylammonium (TBA), a nonselective K+ channel blocker, or glibenclamide, a supposed adenosine 5'-triphosphate (ATP)-sensitive K+ channel blocker, abolished the reduction of [Ca2+]i caused by the three K+ channel openers and the relaxant effect of cromakalim, whereas they only slightly attenuated the relaxant effects of pinacidil and nicorandil. 5. The increase in [Ca2+]i produced by 45 or 90 mM KCl-PSS in the presence of pinacidil or nicorandil was abolished by 10(-5) M verapamil, indicating that the increase in [Ca2+]i was caused by the influx of extracellular Ca2+ and that pinacidil and nicorandil did not affect the voltage-dependent Ca2+ channel directly. 6. The [Ca2+]i-force relationship in the presence of cromakalim was not distinguishable from that of control. 7. The [Ca2+]i-force curve was shifted to the right by pinacidil and nicorandil. 8. These results show that cromakalim is a more specific K+ channel opener than pinacidil and nicorandil, and that vasodilatation produced by cromakalim in this study is predominantly a result of a reduction of [Ca2+]i due to the closure of voltage-dependent Ca21 channels by hyperpolarization. In contrast, additional mechanisms are involved in the vasodilator actions of pinacidil and nicorandil. One of these is related to a reduction in the sensitivity of contractile proteins to Ca2 . The latter mechanism of nicorandil is akin to that of nitroglycerin. K+ channels opened by these K+ channel openers may be ATP-sensitive ones which are blocked by glibenclamide.

Adenosine Triphosphate↗

PubMed1990

Effects of pinacidil, RP 49356 and nicorandil on ATP-sensitive potassium channels in insulin-secreting cells.

1. The whole-cell patch-clamp technique has been used to investigate the effects of pinacidil, RP 49356 and nicorandil on membrane potential and adenosine 5'-triphosphate (ATP)-sensitive K+ channel currents in the insulin-secreting cell line RINm5F. Interactions between pinacidil, RP 49356, nicorandil, diazoxide and ATP have been studied in excised outside-out membrane patches and open-cells. 2. In RINm5F whole-cells (current-clamp mode) continually exposed to glucose, pinacidil, RP 49356 and nicorandil, at concentrations greater than 100 microM, consistently reversed the effects of the sugar by repolarizing the membrane and terminating voltage-gated Ca2+ spike-potentials. 3. The actions of pinacidil, RP 49356 and nicorandil on membrane potential may be explained by their effects on the opening of ATP-sensitive K+ channels, since all three compounds activated channels in whole-cells (voltage-clamp mode), excised outside-out membrane patches and open-cells, at concentrations greater than 100 microM. Below 100 microM the actions of pinacidil, RP 49356 and nicorandil were weak and inconsistent. 4. The mechanism of channel activation appears to depend on the presence of cytosolic ATP, since in its absence, pinacidil, RP 49356 and nicorandil (greater than 100 microM) had either no effects or inhibited K+ channels. 5. Pinacidil, nicorandil and RP 49356 (200-500 microM) also appeared to open K+ channels inhibited by quasi-physiological concentrations of ATP (4 mM) and ADP (1 mM). However, in comparison to diazoxide their effects were weak. 6. Since pinacidil, RP 49356 and nicorandil have been shown to have effects on smooth muscle preparations at concentrations of 30 microM and below, the data presented in this study may have important implications for any prospective therapeutic application of the drugs, since at the concentrations required to relax smooth muscle cells, hyperglycaemia will be avoided.

Adenoma, Islet Cell↗

PubMed1982

Comparison of the effects of a new vasodilator pinacidil and nifedipine on isolated blood vessels.

In isolated human crural veins studied in vitro pinacidil (0.038-380 microM) caused a concentration-related inhibition of noradrenaline, 18 microM (NA) and 127 mM K+-induced contractions. Pinacidil was more potent in inhibiting the NA-contraction than that induced by K+, whereas the reverse was seen for nifedipine. At the highest concentrations greater inhibitions of the NA-induced contractions could be obtained with pinacidil than with nifedipine. The inhibitory effect of pinacidil on the K+-induced contractions was eliminated during a 1 hr wash-out period. In contrast to this, the inhibitory effect of nifedipine could not be eliminated during 4 hrs repeated wash-out. Pinacidil was completely devoid of inhibitory effect on 45Ca net influx in rat aorta, whereas nifedipine caused a significant reduction of influx. The results indicate that both pinacidil and nifedipine are effective vasodilatators in human vessels. Pinacidil seems to be more effective in NA-induced contractions than does nifedipine. The mechanism of action of pinacidil cannot be attributed to an inhibitory effect on cellular calcium entry.

Adult↗

PubMed1995

Divergent mechanisms of ATP-sensitive K+ channel-induced vasodilation in renal afferent and efferent arterioles. Evidence of L-type Ca2+ channel-dependent and -independent actions of pinacidil.

K+ channel openers (PCOs), such as pinacidil, elicit vasodilation primarily by hyperpolarization-induced inhibition of L-type Ca2+ channel activation. The physiological role of other mechanisms suggested to contribute to PCO-induced vasodilation is not well established. In the renal microcirculation, L-type Ca2+ channels play a prominent role in vasoconstriction of the afferent arteriole (AA) but are absent or physiologically silent in the efferent arteriole (EA). Thus, L-type Ca2+ channel-dependent and -independent mechanisms can readily be distinguished in this model. In the present study, we found that pinacidil potently inhibited Bay K 8644-induced AA vasoconstriction. Pinacidil also preferentially inhibited angiotensin II-induced AA vasoconstriction (approximately ninefold greater potency than EA). These results are consistent with an AA effect of pinacidil on L-type Ca2+ channel activation. Unexpectedly, 10 mumol/L pinacidil inhibited AA and EA responses to similar extents (84 +/- 10% and 71 +/- 9%, respectively). In both AAs and EAs, glibenclamide restored normal reactivity, indicating an involvement of the ATP-sensitive K+ channels. In the EA, however, pretreatment with diltiazem did not alter the effects of pinacidil. Nevertheless, 45 mmol/L KCl reversed the EA actions of pinacidil, indicating an essential requirement for a normal K+ gradient. These findings suggest that the EA actions of pinacidil involve alterations in membrane potential but not changes in L-type Ca2+ channel activity. Overall, our findings do support the premise that L-type Ca2+ channel modulation is involved in PCO-induced vasodilation in the renal microcirculation.(ABSTRACT TRUNCATED AT 250 WORDS)

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

PubMed1996

Postjunctional effect of pinacidil on contractility of isolated bovine trachealis.

Potassium channel openers hyperpolarize the smooth muscle cell membrane and relax airway smooth muscle. In this study, pre- and postjunctional effects of pinacidil ((+/-) N-cyano-N'-(4-pyridil)-N"-(1,2,2-trimethylpropyl)-guanidine monohydrated), an adenosine triphosphate (ATP)-sensitive K(+)-channel opener, were determined in isolated bovine trachealis. The effects of pinacidil on the frequency-response to electrical field stimulation (EFS), 0.1-32 Hz, and on the concentration response to acetylcholine (ACh), 10(9)-10(-4) M, were compared in muscle strips from six animals. In addition, the effect of pinacidil on the inhibitory nonadrenergic noncholinergic (iNANC) system was evaluated in histamine-contracted muscle strips from another eight animals. Pinacidil (10(-6) or 10(-5) M) shifted both the EFS frequency-response and the ACh concentration-response curves significantly (p < 0.01) to the right. Glibenclamide (10(-7)-10(-5) M) antagonized these responses in a concentration-dependent manner. The inhibitory effects of pinacidil on contractions of the same magnitude induced by EFS or exogenous ACh were not significantly different (p = 0.11), suggesting that pinacidil had only a postjunctional effect. Pinacidil had no effect on iNANC-mediated muscle relaxation. We conclude that pinacidil attenuates the contraction of isolated bovine tracheal smooth muscle by postjunctional mechanisms.

Acetylcholine↗

PubMed1986

Effects of pinacidil on renal hemodynamics and function in anesthetized dogs.

We studied the effects of pinacidil on renal hemodynamics and function in anesthetized dogs. An intravenous injection of pinacidil, at a dose of 0.25 mg/kg, resulted in a rapid and marked reduction of the mean systemic blood pressure (MSBP) accompanied by a significant increase in renal blood flow (RBF). There were no significant changes in glomerular filtration rate (GFR), urine flow (UF) and urinary excretion of electrolytes (UEE). When pinacidil was administered at a dose of 0.5 mg/kg, the hypotensive effect was more potent. RBF did not change, but GFR, UF and UEE significantly decreased. These antidiuretic effects were not influenced by renal denervation. Hydralazine, at doses of 0.5 and 2.0 mg/kg, caused a significant and sustained reduction of MSBP, but the effects were much less potent than those seen with pinacidil. A sustained increase in RBF was observed after hydralazine at both doses. The lower dose elicited increases in UF and UEE, although the GFR remained unchanged. The higher dose of hydralazine caused a reduction of GFR, accompanied by decreases in UF and UEE. These antidiuretic effects were abolished by renal denervation. Intravenous injection of pinacidil or hydralazine produced a significant increase in the renin secretion rate. Intrarenal arterial infusion of pinacidil (2.0 micrograms/kg/min) produced a more marked diuretic effect than hydralazine (20 micrograms/kg/min). These findings indicated that the hypotensive activity of pinacidil is more potent than that of hydralazine, and suggested that the antidiuretic action of i.v. pinacidil (0.5 mg/kg) is due to a reduction of renal perfusion pressure. Furthermore, this drug may exert an additional action in the kidney to cause diuresis.

Animals↗

PubMed1994

Pinacidil attenuates positive inotropic but not chronotropic responses to norepinephrine in isolated dog atrial and ventricular preparations.

We investigated whether pinacidil, a K+ATP channel opener like acetylcholine and adenosine, attenuated the positive chronotropic and inotropic responses to norepinephrine in isolated, blood-perfused dog atrial and ventricular preparations. Pinacidil (0.01-0.3 mumol) decreased atrial and ventricular contractile force to a much greater extent than sinus rate in a dose-related manner. Pinacidil dose-dependently attenuated increases in atrial and ventricular forces induced by norepinephrine but not increases in sinus rate. Pinacidil similarly attenuated the positive atrial and ventricular inotropic responses to Bay k 8644 and CaCl2. The pinacidil doses producing a fifty percent decrease (ED50) of the atrial and ventricular contractile force were not significantly different from the respective pinacidil doses producing a fifty percent inhibition (ID50) of the positive inotropic responses to norepinephrine, Bay k 8644 and CaCl2. Ouabain (5 and 15 nmol) did not affect the decreases in atrial and ventricular contractile force in response to pinacidil. These results suggest that the K+ATP-channel activator pinacidil, unlike acetylcholine or adenosine, functionally attenuates increases in ventricular and atrial contractile force in the responses to norepinephrine and other cardiotonics due to shortening of the action potential duration induced by K+ATP-channel activation in the dog heart.

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

PubMed1988

Vasodilatation with pinacidil. Mode of action in rat resistance vessels.

Pinacidil is a newly developed antihypertensive vasodilator, proposed to belong to the new group of smooth muscle relaxants, the K+ channel openers. The in vitro effects of pinacidil on induced tone, smooth muscle membrane potential and 86Rb and 42K efflux from rat resistance vessels (internal diameter about 200 microns) were studied. Tone induced with noradrenaline was concentration-dependently inhibited by pinacidil. Responses to electrical field stimulation were also inhibited. However, tone induced with high K+ depolarisation, noradrenaline in the presence of high K+, caffeine-induced contractions and noradrenaline contractions in the presence of felodipine were little affected by pinacidil. Pinacidil caused concentration-dependent hyperpolarisation of the resting smooth muscle. Pinacidil caused only a small and transient increase of the 86Rb efflux rate constant, while the same concentrations of pinacidil produced a significant increase in the 42K efflux rate constant. Our results seem to indicate that the relaxant effect of pinacidil is the result of an increase in K+ permeability, thus causing hyperpolarisation and relaxation. The opened K+ channels appear to be selective for K+ over Rb+.

Animals↗

PubMed1988

Long term haemodynamic effects of pinacidil and hydralazine in arterial hypertension.

Eight patients with a diastolic blood pressure greater than or equal to 100mm Hg when treated with a diuretic and a beta-blocker participated in a randomised crossover study comparing the haemodynamic effects of adjunctive therapy with pinacidil or hydralazine. The vasodilator dose was increased until the diastolic blood pressure was less than 90mm Hg or the maximum dosage, hydralazine 100mg twice daily, or pinacidil 50mg twice daily, was reached. Treatment continued for 3 to 6 months and a haemodynamic study was performed. After washout, the patients received the alternative treatment. In the upright position, during supine rest and during isometric as well as dynamic exercise, pinacidil lowered blood pressure more effectively than hydralazine. No differences between the 2 treatments were found in heart rate, stroke index, cardiac index, end systolic wall stress or glomerular filtration rate. Pulmonary mean and wedge pressure were lower during treatment with pinacidil. Forearm blood flow was higher and forearm vascular resistance lower during treatment with pinacidil. Cardiac contractility, judged from the systolic time interval ratio PEP: LVET, was lower during treatment with pinacidil compared with hydralazine. The median daily dose of pinacidil was 50mg and that of hydralazine 200mg. It was also noted that during long term treatment, pinacidil seemed more effective in reducing blood pressure than hydralazine.

Antihypertensive Agents↗

PubMed1982

Metabolism of the new antihypertensive agent pinacidil in rat, dog and man.

1. The antihypertensive agent pinacidil is eliminated from the body mainly by biotransformation in the liver, followed principally by renal excretion of the metabolites. 2. The metabolism and elimination of pinacidil is similar in rat, dog and man, and is independent of the route of administration. 3. After an oral dose, the 24 h urinary excretion of unchanged pinacidil is 13, 4, and 5% in rat, dog and man, respectively. Faecal excretion in the rat and dog is 2 and 4%. 4. In rat, dog and man the main biotransformation product is the pyridine-N-oxide of pinacidil. Following oral administration of pinacidil, 40, 54 and 54%, respectively, is excreted in the urine as the N-oxide during the first 24 h, and less than 1% in the faeces in rat and dog. 5. Three unidentified minor metabolites were found in plasma, urine and faeces in rat and dog. 6. The major metabolite, the pyridine-N-oxide of pinacidil, has an anti-hypertensive potency about a quarter of that of pinacidil. In animals and human volunteers with normal kidney function, however, the plasma concn. of the N-oxide are always lower than those of the parent compound, so that the metabolite contributes little to the antihypertensive effect of pinacidil.

Adult↗

PubMed1988

Antihypertensive effects of pinacidil in patients with and without indomethacin pretreatment.

To determine the potential role of prostaglandins in mediating the hypotensive action of the new antihypertensive agent pinacidil, we measured the blood pressure, regional blood flow and neurohumoral responses to pinacidil in thirteen hypertensive patients randomly assigned to receive pretreatment with either indomethacin (75 mg) or placebo. After baseline measurements had been obtained, each patient received an oral dose of pinacidil to which he had previously demonstrated a therapeutic response. The doses of pinacidil administered between the two groups did not differ. Serial measurements of blood pressure and heart rate over two hours revealed no attenuation of the hypotensive effect of pinacidil in the indomethacin-pretreated patients (-12.7 +/- 4.1 mm Hg) compared to the placebo group (-9.3 +/- 3.2 mm Hg). While significant vasodilation was not observed in the forearm, renal vasodilation occurred and was not different between the two groups. Pinacidil had no effect on glomerular filtration rate. Neither did pinacidil significantly increase plasma catecholamines or renin activity. The results indicate that prostaglandins probably do not play a major role in the vasodilator action of pinacidil, and that therapeutic doses of the drug have a differential effect on regional blood flows that result in hypotension, but not significant neurohumoral stimulation, in patients with mild to moderate hypertension.

Adult↗