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PubMed1989

Beneficial effects of pinacidil on blood lipids: comparisons with prazosin and placebo in patients with hypertension. Pinacidil-Prazosin and Pinacidil-Placebo Research Groups, Lilly Research Laboratories.

In two randomized, double-blind clinical trials comparing pinacidil with prazosin and with placebo in patients with hypertension, a number of statistically significant and potentially beneficial effects on blood lipids were detected in the patients taking pinacidil. Patients treated with pinacidil exhibited significant average decrements from baseline in concentrations of total and low-density lipoprotein cholesterol and triglycerides and a significant average increment in high-density lipoprotein cholesterol. The mean effects seen in the pinacidil group were significantly greater than those in the placebo group for both total cholesterol (-9.8 vs +4.2 mg/dl, p less than 0.001) and triglycerides (-21.6 vs +8.6 mg/dl, p less than 0.001). The effects seen in patients given pinacidil were also significantly greater than those seen in the patients treated with prazosin for both high-density lipoprotein cholesterol (+3.6 vs -1.0 mg/dl, p = 0.002) and triglycerides (-14.8 vs +30.3 mg/dl, p less than 0.001). Negative effects of hydrochlorothiazide and propranolol on blood lipids were not apparent in patients given pinacidil. Thus, pinacidil treatment of hypertension is associated with a beneficial effect on blood lipids, which may be of clinical significance.

Antihypertensive Agents↗

PubMed1993

Effect of activation of ATP-dependent potassium channels with (-)-pinacidil and (-)-3-pyridyl pinacidil on infarct size in a canine model of ischemia-reperfusion injury.

We tested the hypothesis that opening myocardial ATP-dependent K+ (ATP-K) channels by administration of (-)-pinacidil or (-)-3-pyridyl pinacidil intracoronarily (i.c.) either during ischemia or as pretreatment could decrease infarct size in a canine model of ischemia-reperfusion injury in anesthetized male hounds subjected to 90-min left circumflex coronary artery (LCX) occlusion followed by 5-h reperfusion. Drugs were administered by one of two protocols. In the postocclusion treatment protocol (protocol post), either vehicle or (-)-3-pyridyl pinacidil [0.25 micrograms/kg/min (low dose) or 1 micrograms/kg/min (high dose)] was infused i.c. distal to the site of coronary artery occlusion, through LCX beginning 10 min after LCX occlusion and continuing until 10 min after the beginning of reperfusion. In the preocclusion treatment protocol (protocol pre), vehicle, low dose (-)-3-pyridyl pinacidil, or (-)-pinacidil (1 micrograms/kg/min) was infused i.c. distal to the site of coronary artery occlusion through the LCX beginning 10 min before occlusion and continuing until the end of the experiment. In both protocols, (-)-pinacidil and (-)-3-pyridyl pinacidil failed to demonstrate a decrease in infarct size from that of the vehicle-treated groups. In protocol post, the mean sizes of the infarcts in the vehicle, low-dose, and high-dose (-)-3-pyridyl pinacidil-treated groups were 26.4 +/- 5.0, 35.6 +/- 6.6, and 28.9 +/- 6.1% of the area at risk, respectively. In protocol pre, the mean sizes of the infarcts in the vehicle, (-)-pinacidil, and low dose (-)-3-pyridyl pinacidil-treated groups were 29.4 +/- 1.7, 27.0 +/- 3.9, and 35.6 +/- 4.1% of the area at risk, respectively. Neither subepicardial nor subendocardial blood flow in the ischemic zone, measured by radioactive microspheres, was significantly different among groups in either protocol. In protocol post, however, the endocardial/epicardial blood flow ration in the nonischemic zone was decreased by (-)-3-pyridyl pinacidil. In addition, the ischemic zone (LCX)/nonischemic left anterior descending coronary artery (LAD) zone blood flow ratio in the subepicardial region were decreased by (-)-3-pyridyl pinacidil. These observations suggest that the drug may shift blood flow away from the ischemic zone in general and away from the endocardium in particular. In protocol pre, the LCX/LAD ratio tended to decrease with both drugs, but the difference achieved statistical significance only with (-)-3-pyridyl pinacidil (low dose).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1985

Serum concentrations and urinary excretion of pinacidil and its major metabolite, pinacidil pyridine-N-oxide following i.v. and oral administration in healthy volunteers.

Serum concentrations of pinacidil and its major metabolite pinacidil pyridine-N-oxide were determined following administration of both an intravenous solution and a sustained release oral preparation to healthy volunteers. Mean bioavailability of pinacidil was 57.1 +/- 13.7%. Following intravenous administration, the mean AUC0-8 h metabolite/AUC 0-8 h pinacidil ratio was 0.559 +/- 0.272 and after oral administration, 0.825 +/- 0.656. Only one subject had serum metabolite concentrations in excess of pinacidil during the intravenous study whereas three subjects achieved metabolite concentrations in excess of pinacidil during the oral study. The mean serum elimination half-life of metabolite was significantly longer than parent drug following intravenous administration (P less than 0.01) but not after oral administration. No significant difference was found in the maximum measured metabolite concentration (Cmax.m) between the studies. The time to Cmax.m was significantly delayed (P less than 0.001) following oral dosage. Twenty four hour urinary excretion of metabolite was significantly increased (P less than 0.001) following oral administration whilst that of pinacidil was decreased (P less than 0.02). These results suggest that pinacidil pyridine-N-oxide may be a 'first-pass' metabolite of pinacidil. In most patients pinacidil pyridine-N-oxide is unlikely to contribute significantly to the hypotensive effect of pinacidil.

Administration, Oral↗

PubMed1988

Accumulation of pinacidil N-oxide during chronic treatment with pinacidil.

The effects of acute and chronic administration of a slow-release preparation of pinacidil have been studied in eight normotensive volunteers aged 40-57 years. Continuous administration of 20 mg b.i.d. pinacidil had no effect on serum pinacidil concentrations measured as AUC (0-9 h), but accumulation of the principal metabolite, pinacidil pyridine-N-oxide was found to occur. There were no significant changes in erect and supine blood pressure and heart rate from the pretreatment levels on days 1,15 or 29. Chronic administration of pinacidil caused a significant increase in weight over the total period of study. There were also significant changes in mean sodium (+2.38 mmol/l) and alkaline phosphatase (+15.75 iU/l) from the start to the end of pinacidil therapy but values were within the normal ranges, except for one alkaline phosphatase. There were significant changes in the following haematological parameters over the period of pinacidil therapy; leukocytes (-1.49 x 10(9)/l), haemoglobin (-0.56 g/dl), MCH (-1.1 pg), MCHC (-1.22 g/dl), platelet MCV (-0.90 fl).

Adult↗

PubMed1993

Urinary metabolites of pinacidil. II. Species difference in the metabolism of pinacidil.

1. Pinacidil was given orally to rabbit (10 mg/kg), dog (10 mg/kg), monkey (10 mg/kg) and mouse (150 mg/kg), the urinary metabolites were separated by h.p.l.c. and their structures determined by mass spectrometry. 2. Three new metabolites, namely, omega-hydroxy-pinacidil-O-glucuronide (M-8), pinacidil-pyridine-N-oxide-O-glucuronide (M-9) and pinacidil-pyridine-N-glucuronide (M-10) were isolated from rabbit urine, and one new metabolite, namely, pinacidil-pyridine-phenolic-glucuronide (M-11) was isolated from mouse urine. 3. M-9 is a unique glucuronide because the glucuronic acid is linked to the oxygen of pyridine-N-oxide. 4. In man, similar to rat, dog and mouse, pinacidil-pyridine-N-oxide (M-1) was the main urinary metabolite, with pyridine-N-oxidation being the major metabolic pathway. On the other hand, M-8 and M-9 were the most abundant metabolites in monkey and rabbit urine, respectively. Therefore, rat, dog and mouse have similar metabolism of pinacidil to man, but monkey and rabbit are significantly different in their metabolism of the drug.

Adult↗

PubMed1986

Liquid chromatographic determination of pinacidil, a new antihypertensive drug, and its major metabolite, pinacidil N-oxide, in plasma.

Two procedures are described, one for the determination of pinacidil, the other for the determination of both pinacidil and its metabolite, pinacidil N-oxide, in plasma. When only parent drug levels are required, the plasma proteins are precipitated with acetonitrile, the solids discarded and the supernatant is evaporated to dryness. The residue is then reconstituted for analysis. For the determination of both drug and metabolite, the analytes are selectively retained from plasma on a solid-phase extraction column and eluted with methanol. After evaporation to dryness, the residue is reconstituted in mobile phase. Both procedures utilize reversed-phase liquid chromatographic separations with ultraviolet detection. The limits of detection are 10 ng/ml pinacidil in plasma and 5 ng/ml each of pinacidil and pinacidil N-oxide in plasma for the two procedures, respectively.

Antihypertensive Agents↗

PubMed1992

Quality of life on antihypertensive therapy: a double-blind trial comparing quality of life on pinacidil and nifedipine in combination with a thiazide diuretic. European Pinacidil Study Group.

The quality of life (QL) was evaluated in a 6 month double-blind trial in six European countries. Patients with a sustained supine diastolic blood pressure (SDBP), phase V, of 95 mm Hg or more on bendrofluazide, 5 mg daily (or an equivalent dose of a thiazide diuretic) were randomised to additional pinacidil (n = 127), 25 mg up to 100 mg daily, or nifedipine (n = 130), 20 mg up to 80 mg daily. The treatment groups were similar at entry for QL scores, average DBP of 103 +/- 6 (SD) mm Hg, and average age of 56 +/- 10 (SD) years. Eighteen patients on pinacidil and 12 on nifedipine withdrew due to side effects, such as oedema (both drugs) and flushing (nifedipine). The maximum antihypertensive effect was achieved within 6 weeks and maintained, resulting in a significant fall in SDBP of 13.7 mm Hg on pinacidil and 15.5 mm Hg on nifedipine at the end of the trial. There was no significant difference in the antihypertensive effect. The target SDBP was achieved in 57% of pinacidil-and 63% of nifedipine-treated patients. The average number of symptomatic complaints fell in both groups, with significant decreases in the reporting of blurred vision and headaches on nifedipine. Complaints of growth of body and facial hair increased on pinacidil but there were no significant between-drug comparisons with respect to side effects. In measures of psychological well being, patients on pinacidil showed a significant (p less than 0.05) improvement in total and cognitive function scores compared to nifedipine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1994

Pharmacokinetic-pharmacodynamic modeling between pinacidil or pinacidil-N-oxide plasma levels and systemic and regional hemodynamic effects in healthy volunteers.

Pinacidil (P) lowers blood pressure through peripheral vasodilation, but also induces dose-dependent side-effects. In a previous placebo-controlled, randomized, double-blind and crossover study, performed in six healthy male volunteers, we investigated the systemic and regional hemodynamic effects of a single oral administration of 25 mg of P (sustained-release form) and measured the plasma concentrations of P and of its active metabolite, pinacidil-N-oxide (PO). In the present study, our goal has been to investigate the relationships between P and/or PO plasma concentrations and P administration effects on systolic, diastolic and mean arterial pressures (SAP, DAP, MAP), heart rate (HR), cardiac output (CO), total peripheral resistance (TPR), brachial and carotid arteries' diameters (BAD, CAD), flows (BAF, CAF) and vascular resistances (BVR, CVR) which were assessed before and at different time intervals after drug intake. Concentration-effect relationships were investigated using both linear and log-linear multiple regression models with P, PO or both P and PO as independent variables (six models). Significant linear relationships were observed between P and/or PO and SAP, DAP, MAP, TPR, BAD, BAF, BVR, CAD and CVR. For example, TPR (dynes.s/cm5) = 1308-3.031 x P (ng/ml), R = 0.57, P = 0.0037; BVR (mmHg.s/ml) = 58-0.261 x P (ng/ml), R = 0.56, P = 0.0042. Almost similar R values were obtained using P, PO, or both P and PO. The use of log-linear models did not improve the fittings.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1985

[Pharmacological studies on pinacidil, a new antihypertensive agent. 2. Studies on the hypotensive mechanism of pinacidil].

Effects of pinacidil (PND) on the blood pressure of anesthetized cats and contraction of guinea-pig isolated hearts and blood vessels were compared with those of hydralazine (HDL) and nifedipine (NFD). PND showed a dose-dependent hypotensive effect and decrease of total peripheral resistance in a dose above 0.3 mg/kg (p.o.) in anesthetized cats. However, no involvement of the autonomic nervous system was presumed in the hypotensive effect of PND due to studies on autonomic responses. Although negative inotropic and chronotropic effects of PND in the isolated guinea-pig atria and heart (Langendorff method) were slight, PND caused a coronary vasodilation at a dose of 1 micrograms. PND inhibited the norepinephrine (NE) contracture of isolated guinea-pig thoracic aorta and portal vein at 10(-6)-10(-5) M, but concentrations of 10(-5)-10(-4) M were required for the inhibition of K contracture. In the isolated thoracic aorta, HDL markedly inhibited NE contracture, while NFD inhibited K contracture. These results suggest that the hypotensive effect of PND is more closely associated with the inhibition of Ca2+ influx caused by the receptor activation of Ca2+ release from intracellular storage sites than membrane potential-dependent Ca2+ influx.

Animals↗

PubMed1991

Characterization of K+ channel-dependent as well as -independent components of pinacidil-induced vasodilation.

The mechanisms of pinacidil-induced direct vasodilation were studied in vitro in RMA and RAO. In RMA, pinacidil produced dose-dependent relaxations of norepinephrine (5 microM)-induced contractions with an IC50 of 0.2 microM. This component of pinacidil relaxation appeared to be dependent on K+ conductance because pretreatment with tetraethylammonium (10 mM), Ba++ (0.5 mM), glyburide (1 microM) and 20 mM K+ all caused a rightward shift of the pinacidil dose-response curve (DRC) and a corresponding increase in the pinacidil IC50. However, additional relaxation effects of pinacidil were still evident in the presence of various K+ channel blockers. Pinacidil also showed a relaxation DRC under the condition of 80 mM K+ contraction in both RMA and RAO with IC50 values of 27 and 50 microM, respectively. Pinacidil could also produce maximal relaxation in RMA and RAO remained unaffected in 145 mM K+ (zero Na+) depolarizing solution suggesting a lack of dependence on Na(+)-Ca++ exchange mechanism for this action of pinacidil. Studies using 1 or 3 min pulse labeling with 45Ca showed an absence of an inhibitory effect of pinacidil (at 50 and 100 microM) on unidirectional 45Ca influx stimulated by high-K+. Net 45Ca uptake studies showed that pinacidil inhibited high-K+ stimulated 45Ca uptake at 100 but not at 50 microM. Ryanodine (10-100 microM) was used as a tool to investigate the role of sarcoplasmic reticulum (SR) in this action of pinacidil. Under the condition in which ryanodine (10-100 microM) treatment was found to cause the SR to be nonfunctional, pinacidil relaxation DRC remained unaltered, suggesting a lack of a stimulatory effect of pinacidil on SR Ca++ accumulation. These data thus show that the K+ channel-independent effect of pinacidil does not involve to any significant degree an effect of pinacidil on plasmalemmal voltage-sensitive Ca++ channels, SR Ca++ stores, Na(+)-Ca++ exchange or membrane hyperpolarization.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed2002

Effect of diabetes on pinacidil-induced antinociception in mice.

The antinociceptive effects of pinacidil, an adenosine triphosphate (ATP)-sensitive K(+)i (K(ATP)) channel opener, were examined using the tail-flick test in non-diabetic and diabetic mice. Pinacidil i.c.v. produced dose-dependent antinociception in both non-diabetic and diabetic mice. There was no significant difference between the antinociceptive effect of i.c.v. pinacidil in non-diabetic mice and diabetic mice. The i.t. administration of pinacidil also produced dose-dependent antinociception in both non-diabetic and diabetic mice, however, the antinociceptive effect of i.t. pinacidil in diabetic mice was significantly greater than that in non-diabetic mice. The antinociceptive effect of i.c.v. or i.t. pinacidil was significantly antagonized by i.c.v. or i.t. glibenclamide, a K(ATP) channel blocker in both non-diabetic and diabetic mice. In non-diabetic mice, the antinociceptive effect of i.c.v. or i.t. administration of pinacidil was significantly antagonized by beta-funaltrexamine, a mu-opioid receptor antagonist, 7-benzylidenenaltrexone, a delta1-opioid receptor antagonist, naltriben, a delta2-opioid receptor antagonist, and nor-binaltorphimine, a kappa-opioid receptor antagonist. In diabetic mice, the antinociceptive effect of i.c.v. pinacidil was significantly reduced by 7-benzylidenenaltrexone, naltriben, and nor-binaltorphimine. However, beta-funaltrexamine had no effect on antinociception induced by i.c.v. pinacidil in diabetic mice. On the other hand, the antinociceptive effect of i.t. pinacidil was significantly antagonized by beta-funaltrexamine, 7-benzylidenenaltrexone, naltriben, and nor-binaltorphimine in diabetic mice. These results indicated that pinacidil produced antinociception through the release of opioid peptides acting at mu-, delta- and kappa-opioid receptors in surpraspinal and spinal cord of non-diabetic mice. On the other hand, in diabetic mice, the antinociception-induced by pinacidil was mediated through the release of opioid peptides acting at delta- and kappa-opioid receptors supraspinally, whereas pinacidil produced antinociception through the release of opioid peptides acting at mu-, delta-, and kappa-opioid receptors spinally.

Animals↗

PubMed1994

Prejunctional effects of cromakalim, nicorandil and pinacidil on noradrenergic transmission in rat isolated mesenteric artery.

The present study investigated the effects of cromakalim, nicorandil and pinacidil on resting and stimulation-induced (S-I) effluxes of radioactivity from rat isolated mesenteric artery preparations in which the noradrenergic transmitter stores had been radiolabelled with [3H]-noradrenaline. The efflux of radioactivity evoked by field stimulation of peri-arterial sympathetic nerves (pulses at 2 Hz frequency in trains of 60 s duration) was taken as an index of transmitter noradrenaline release. Cromakalim (1-100 microM) and nicorandil (1-1000 microM) produced minor effects on resting and S-I effluxes of radioactivity, but these did not exhibit concentration-dependency. Pinacidil (1-1000 microM) produced concentration-dependent increases, in both resting and S-I effluxes of radioactivity. With 1000 microM pinacidil, resting and S-I effluxes were increased to approximately 348% and 358% of their respective control values. The effects of pinacidil on resting and S-I effluxes were unaltered when the neuronal amine transport system was inhibited by desipramine (1 microM). Inhibition of monoamine oxidase with pargyline (100 microM) treatment markedly reduced the enhancement of resting efflux by 1000 microM pinacidil but did not alter its effect on S-I efflux. It is proposed that the enhanced resting efflux produced by pinacidil without pargyline treatment consists of deaminated [3H]-noradrenaline metabolites formed from [3H]-noradrenaline displaced from transmitter storage vesicles by pinacidil. The enhancement of S-I efflux by pinacidil does not appear to involve disruption of alpha 2-adrenoceptor auto-inhibition of transmitter release since equi-effective concentrations of phentolamine (1 microM) and pinacidil (1000 microM) produced additive effects on S-I efflux, whereas increasing the concentration of phentolamine from 1 to 2M produced no further increases in S-I efflux. In conclusion, this study has provided no evidence of a prejunctional inhibitory effect of the potassium channel openers cromakalim, nicorandil and pinacidil on transmitter noradrenaline release. However, the findings with pinacidil suggest that, in high concentrations, pinacidil displaces noradrenaline from transmitter stores, such that deaminated noradrenaline metabolites are released from the nerve terminals. Furthermore, pinacidil enhances S-I transmitter noradrenaline release, possibly by blocking neuronal potassium channels.

Animals↗

PubMed1990

Evidence that pinacidil may promote the opening of ATP-sensitive K+ channels yet inhibit the opening of Ca2(+)-activated K+ channels in K(+)-contracted canine mesenteric artery.

1. The effects of cromakalim and pinacidil on contraction and 86Rb efflux were investigated in strips of canine mesenteric artery. 2. Cromakalim and pinacidil relaxed arterial strips precontracted with 20.9 mM K+ with pD2 values of 6.56 and 5.88, respectively. 3. High (above 10 microM) concentrations of pinacidil, but not cromakalim, relaxed arterial strips bathed by a medium containing 65.9 mM K+, and inhibited Ca2(+)-induced contractions in strips bathed by a medium containing 80 mM K+. These findings suggested that pinacidil may act as an inhibitor of Ca2+ influx. 4. In arterial strips preloaded with 86Rb, cromakalim and pinacidil increased the basal 86Rb efflux. 5. When the effects of cromakalim and pinacidil on 86Rb efflux were determined in arterial strips contracted with 65.9 mM K+, both drugs increased 86Rb efflux. The increase in 86Rb efflux induced by pinacidil was much smaller than that induced by cromakalim. Under the same conditions, nifedipine decreased 86Rb efflux. 6. After the addition of nifedipine to arterial strips contracted with 65.9 mM K+, pinacidil produced a greater increase in 86Rb efflux than in the absence of nifedipine, whereas the effects of cromakalim were the same for the two conditions. Therefore, the effects of pinacidil on 86Rb efflux may be the resultant of two opposing effects: an increased 86Rb efflux due to the opening of ATP-sensitive K+ channels, and a decreased efflux due to the closing of Ca2(+)-activated K+ channels. 7. In causing relaxation, cromakalim was competitively antagonized by glibenclamide with a pA2 value of 7.16. However, glibenclamide antagonism of pinacidil was not of the simple competitive type, suggesting that inhibition of Ca2 + influx may contribute to the relaxant action of pinacidil. 8. It may be concluded that although the ability of pinacidil to increase 86Rb efflux via ATP-sensitive K+ channel opening was similar to that of cromakalim, the inhibition of Ca2 + influx by pinacidil may reduce the opening of Ca2 +-activated K+ channels in K+-contracted arterial strips.

Adenosine Triphosphate↗

PubMed1990

Multiple actions of pinacidil on adenosine triphosphate-sensitive potassium channels in guinea-pig ventricular myocytes.

1. The patch-clamp method was used to study the effects of pinacidil on the adenosine 5'-triphosphate (ATP)-sensitive K+ channel current in guinea-pig ventricular myocytes. 2. In the inside-out configuration of the patch membranes, the channel activity revealed a nearly fully open state in the absence of ATP, whereas application of ATP (0.1-5 mM) markedly suppressed the channel opening. Addition of pinacidil (0.02-1.0 mM) antagonized the inhibitory action of ATP and induced channel opening without marked change in conductance. An increase in ATP concentration depressed the maximal effect of pinacidil. Consequently, the dose-response relationship of ATP inhibition was shifted to the right, but the shift approached a limiting value as pinacidil concentration was increased. The results indicate that the antagonism between pinacidil and ATP is not competitive. 3. The dose-response curve for activation of the channel by pinacidil examined at -50 mV showed a sigmoidal shape but at +50 mV it had a convex shape, revealing asymmetry in the activating effects of pinacidil at these two voltages. 4. In the absence of ATP, pinacidil produced a voltage-dependent block at positive voltages by decreasing the mean open time and increasing the mean closed time, whereas no such effects were observed at negative voltages. The concentration-block relation at a given voltage was fitted to a first-order Hill saturation function. The Kd (dissociation constant) decreased with depolarization from 2.2 mM at +20 mV to 0.15 mM at + 80 mV. 5. The kinetics of block and unblock by pinacidil were shown to be slow, and were expressed by a first-order transition model. The blocking and unblocking rate constants were voltage dependent. 6. The slow block of single-channel current showed an exponential decay in the ensemble current. The time constant of the decay was voltage dependent, reaching a maximal value at around +50 mV. 7. In the absence of ATP, the channel activity gradually decreased and eventually stopped within 12-20 min, a process known as run-down of channel activity. Calcium accelerated this run-down process. Application of pinacidil partially reactivated the channel. Such channel reactivation by pinacidil during the course of run-down depended upon the conditions of the patch and the time course of the run-down. Pretreatment of the channel with ATP markedly strengthened the reactivation effect of pinacidil. 8. These results indicate that there are multiple sites or processes for interaction of pinacidil with the ATP-sensitive K+ channel.

Action Potentials↗

PubMed1991

Chiral recognition of pinacidil and its 3-pyridyl isomer by canine cardiac and smooth muscle: antagonism by sulfonylureas.

Pinacidil, a potassium channel opener (PCO), relaxes vascular smooth muscle by increasing potassium ion membrane conductance, thereby causing membrane hyperpolarization. PCOs also act on cardiac muscle to decrease action potential duration (APD) selectively. To examine the enantiomeric selectivity of pinacidil, the stereoisomers of pinacidil (a 4-pyridylcyanoguanidine) and its 3-pyridyl isomer (LY222675) were synthesized and studied in canine Purkinje fibers and cephalic veins. The (-)-enantiomers of both pinacidil and LY222675 were more potent in relaxing phenylephrine-contracted cephalic veins and decreasing APD than were their corresponding (+)-enantiomers. The EC50 values for (-)-pinacidil and (-)-LY222675 in relaxing cephalic veins were 0.44 and 0.09 microM, respectively. In decreasing APD, the EC50 values were 3.2 microM for (-)-pinacidil and 0.43 microM for (-)-LY222675. The eudismic ratio was greater for the 3-pyridyl isomer than for pinacidil in both cardiac (71 vs. 22) and vascular (53 vs. 17) tissues. (-)-LY222675 and (-)-pinacidil (0.1-30 microM) also increased 86Rb efflux from cephalic veins to a greater extent than did their respective optical antipodes. The antidiabetic sulfonylurea, glyburide (1-30 microM), shifted the vascular concentration-response curve of (-)-pinacidil to the right by a similar extent at each inhibitor concentration. Glipizide also antagonized the response to (-)-pinacidil, but was about 1/10 as potent with a maximal shift occurring at 10 and 30 microM. Glyburide antagonized the vascular relaxant effects of 0.3 microM (-)-LY222675 (EC50, 2.3 microM) and reversed the decrease in APD caused by 3 microM (-)-LY222675 (EC50, 1.9 microM). Nitroprusside did not alter 86Rb efflux, and vascular relaxation induced by sodium nitroprusside was unaffected by sulfonylureas. Thus, the enantiomers of the 3-pyridyl isomer of pinacidil demonstrate enhanced stereospecificity in both canine cardiac and vascular tissues compared to the enantiomers of pinacidil. However, the relative selectivity of pinacidil and its 3-pyridyl isomer for cardiac and vascular smooth muscle remains unaltered. Sulfonylureas antagonize the more potent enantiomers in both tissues, supporting the involvement of an ATP-sensitive potassium channel in the action of PCOs; however, antagonism in canine vascular smooth muscle by sulfonylureas does not resemble classical competitive antagonism.

Adenosine Triphosphate↗

PubMed1990

Actions of pinacidil on membrane currents in canine ventricular myocytes and their modulation by intracellular ATP and cAMP.

We studied the effects of pinacidil (3-50 microM) on the membrane currents of canine ventricular myocytes, using the whole-cell variant of the patch-clamp technique, and the modulation of these effects by intracellular environment, using the pipette perfusion technique. The following observations were obtained: (1) pinacidil induced a dose-dependent outward shift in current at voltages positive to -70 mV; (2) the pinacidil-induced current was largely time-independent at voltages positive to -50 mV and displayed an increase in current fluctuations at more positive voltages, resembling the kinetic properties of current through the ATP-regulated K+ channels; (3) elevating the extracellular potassium concentration [( K+]o) caused a positive shift in the voltage where the pinacidil-induced current crossed the voltage axis and increased the slope conductance of this current; (4) the pinacidil-induced current was reduced by Ba2+ (0.5-1.5 mM) and abolished by intracellular Cs+ (125 mM); (5) glibenclamide reversibly reduced or abolished the pinacidil-induced current; (6) the action of pinacidil was decreased by elevating [ATP] in the pipette solution (from 1 to 10 mM); (7) the action of pinacidil was augmented by adding isoproterenol (1 microM) to the superfusate or adding cAMP (0.1 mM) to the pipette solution; (8) elevating temperature augmented, and accelerated the onset of pinacidil's action; (9) pinacidil reversibly decreased the Ca2(+)-independent transient outward current (Ito1) but augmented the Ca2(+)-dependent transient outward current (Ito2). Based on these observations, we reached the following conclusions: (1) the main effect of pinacidil is to increase an outward current through the ATP-regulated K+ channels; (2) pinacidil's action is modulated by an enzymatic reaction.

Adenosine Triphosphate↗

PubMed2003

Contribution of Na+ -Ca2+ exchanger to pinacidil-induced relaxation in the rat mesenteric artery.

1 Pinacidil relaxes blood vessels through opening the K(ATP) channels with a resultant membrane hyperpolarization and inhibition of Ca(2+) influx. The aim of this study was to examine the mechanisms thereby pinacidil induces K(+) channel-independent relaxation in isolated endothelium-denuded rat mesenteric artery. 2 Pinacidil-induced relaxation was inhibited by glibenclamide (1-10 micro M) in phenylephrine-preconstricted rings, but was unaffected by glibenclamide after inhibition of K(+) channels and VGCCs. Pinacidil-induced K(+) channel-independent relaxation remained unchanged after treatment with cyclopiazonic acid (10 micro M), thapsigargin (1 micro M), ouabain (100 micro M), propranolol (10 micro M), Rp-cAMPS triethylamine (30 micro M), L-NNA (100 micro M), or ODQ (10 micro M). 3 Pinacidil induced more relaxant effect in the presence of nifedipine than in the presence of 60 mM K(+) plus nifedipine. Pretreatment with Na(+)-Ca(2+) exchanger inhibitors, nickel (30-300 micro M) or benzamil (20 micro M) attenuated pinacidil-induced relaxation in normal or in nifedipine-containing solution. Pinacidil (1 micro M) produced less relaxant effect with decreasing extracellular Na(+) concentration. Na(+)-free condition abolished the inhibitory effect of benzamil. Both nickel and benzamil inhibited pinacidil-induced relaxation in the presence of glibenclamide (10 micro M). Nickel (300 micro M) did not affect the relaxant response to sodium nitroprusside. 4 Pinacidil relaxed the rings preconstricted by active phorbol and U46619 with similar potency. 5 The present results indicate that stimulation of the forward mode Na(+)-Ca(2+) exchange pathway is in part responsible for pinacidil-induced K(+) channel-independent vasorelaxation. Pinacidil also induces K(+) channel-dependent but VGCCs-independent relaxation. The PKC-mediated cellular pathway may be a target site for pinacidil only in higher concentrations.

Animals↗

PubMed1990

Profibrillatory actions of pinacidil in a conscious canine model of sudden coronary death.

Pinacidil is one of a number of new antihypertensive agents possessing an action that involves an enhanced potassium efflux in cardiac and vascular smooth muscle. An associated feature of pinacidil is a shortening of the cardiac action potential duration, which may constitute a potentially proarrhythmic effect. The present study evaluated pinacidil (0.3 mg/kg/h i.v. for 6 h) on the postinfarcted canine heart in a subset of dogs unresponsive to programmed electrical stimulation during the subacute phase of anterior myocardial infarction, and known to be at low risk of ventricular fibrillation in response to acute posterolateral ischemia. Results were compared with a comparable control group of vehicle-treated, noninducible animals. Nonsustained ventricular tachyarrhythmia developed in 2 of 15 pinacidil-treated animals as compared to the initiation of ventricular tachycardia in 1 of 16 postinfarcted hearts (p = 0.96) in the control group. Thus, pinacidil did not alter the responsiveness of the postinfarcted heart with respect to the electrical induction of tachyarrhythmias. The subsequent development of an acute ischemic event at a site remote from the previous myocardial infarction was associated with a greater incidence of ventricular fibrillation within 1 h from the onset of ischemia in the pinacidil-treated animals (9/15; 60%) as compared to the control group (1/15; 6.7%; p = 0.007). The 24-h cumulative mortality, likewise, was greater in the pinacidil-treated group [13/15 (87%)] as compared to the vehicle-treated control group 3/15; 20%; p = 0.001. Significant cardiovascular and electrophysiologic effects of pinacidil included an increase in heart rate (124 +/- 6-143 +/- 10 beats/min, p less than 0.05) and reductions in the refractory periods of normal (178 +/- 2-166 +/- 4 ms, p less than 0.05) and peri-infarcted (170 +/- 5-185 +/- 5 ms, p less than 0.01) myocardial regions. It is concluded that pinacidil does not alter the responsiveness of the postinfarcted heart to programmed electrical stimulation. However, in the presence of a superimposed acute ischemic event, pinacidil increases the potential for the development of ventricular fibrillation in a subset of postinfarcted animals that otherwise show a low risk with respect to the development of lethal arrhythmias. It is hypothesized that the increased tendency to develop ventricular fibrillation is associated with the pinacidil-induced reduction in the ventricular refractory period. This conclusion is consistent with the known ability of pinacidil to enhance potassium efflux during myocardial repolarization and to decrease the duration of the action potential.

Action Potentials↗