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PubMed1998

Cardioprotective effects of pinacidil pretreatment and lazaroid (U74500A) preservation in isolated rat hearts after 12-hour hypothermic storage.

BACKGROUND: Two important processes in the preservation of the function of donor hearts are the maintenance of ATP-sensitive potassium channel activity during myocardial ischemia and the scavenging of reactive oxygen species formed during reperfusion. The aim of this study was to compare the effect of three protocols on the preservation of hemodynamic function in isolated rat hearts after hypothermic storage. These protocols were: (1) pretreatment of the heart with a potassium channel opener (200 microM pinacidil); (2) storage of the heart in an aspartate-enriched extracellular cardioplegic solution containing the lazaroid antioxidant, U74500A (30 microM); and (3) a combination of protocols 1 and 2. METHODS: Hearts from Wistar rats were perfused on a Langendorff apparatus. After stabilization in working mode, baseline measurements of heart rate, coronary and aortic flow, and cardiac output were performed. Hearts (n=6 in each group) were then randomized to protocols 1-3, untreated controls, or vehicle-treated controls. Hearts were stored in extracellular-based preservation solution for 12 hr at 2-3 degrees C, remounted on the perfusion apparatus, and stabilized as before; hemodynamic measurements were then repeated. RESULTS: Recovery of hemodynamic function was enhanced by pinacidil pretreatment or incorporation of lazaroid in the storage solution, but the combination of these two treatments produced the best results. CONCLUSIONS: Combined pharmacological activation of ATP-sensitive potassium channels before cardioplegia and the addition of U74500A to the preservation solution is associated with significantly enhanced hemodynamic function in the isolated rat heart after 12 hr of hypothermic storage. These data suggest a novel use for these agents in the transplantation context.

Animals↗

PubMed1983

Preliminary evaluation of pinacidil in hypertension.

In a balanced single-blind placebo controlled study in six hypertensive patients treated with diuretic and beta-adrenoceptor blocker, a single oral dose of 10 mg pinacidil lowered blood pressure significantly, by a maximum of 26/13 mm Hg lying and 15/12 mm Hg standing at 3 h. The duration of action was less than 6 h. Chronic treatment of four patients (mean dose 20 mg twice daily for 3--7 weeks) lowered blood pressure by only 15/7 mm Hg. All four patients experienced side-effects of the type often observed during treatment with potent vasodilators. In the formulation studied pinacidil is unlikely to offer any advantage over the antihypertensive drugs currently available.

Antihypertensive Agents↗

PubMed1986

Acute haemodynamic effects of pinacidil in man.

The acute haemodynamic effects of i.v. pinacidil 0.2 mg kg-1 infused over 8 min were studied in 10 normotensive patients undergoing cardiac catheterisation. Mean arterial pressure fell from 94 +/- 3 mmHg (mean +/- s.e. mean) before infusion to 74 +/- 3 mmHg at 10 min after commencing infusion (P less than 0.001) and during this time heart rate increased from 75 +/- 4 to 106 +/- 7 beats min-1 (P less than 0.001). Significant changes were recorded until the end of the observation period (70 min after commencing infusion). Cardiac index increased from 3.2 +/- 0.2 to 4.0 +/- 0.2 l min-1 m-2 (P less than 0.001) and systemic vascular resistance fell from 16 +/- 1 to 10 +/- 1 units (P less than 0.001) at 10 min after commencing infusion. By the end of the observation period, the values had returned to pre-infusion levels. Only small changes in pulmonary haemodynamics were observed. These results indicate that pinacidil acts as a peripheral arteriolar vasodilator, and as such may have a role in the treatment of arterial hypertension and of cardiac failure.

Adult↗

PubMed1997

Evaluation of bosentan, pinacidil and nitroprusside on human pulmonary arteries: comparison with rat pulmonary arteries.

Bosentan (endothelin ETA/ETB antagonist), pinacidil (potassium channel opener) and nitroprusside (nitric oxide donor) were examined on isolated ring preparations of human intralobar pulmonary artery (3rd-5th generation, internal radius > or = 1 mm), rat main pulmonary artery (1st generation; internal radius > or = 1 mm) and rat intralobar pulmonary artery (3rd generation; internal radius 0.1-0.3 mm). The potency of endothelin-1 was the same in all three artery types. In human intralobar artery and rat main pulmonary artery, bosentan (3 and 10 microM) shifted the endothelin-1 concentration response curve to a higher concentration range (endothelin-1 concentration ratios, in human intralobar and rat main pulmonary artery, respectively: 3 microM bosentan, 4.5 and 8.1; 10 microM bosentan, 13.5 and 19.5), but caused no significant block of endothelin-1 in rat intralobar artery. The latter finding may be due to the reported presence of ETB receptors in rat intralobar arteries and the higher potency of bosentan on ETA than on ETB receptors. In contrast, the potencies of nitroprusside and pinacidil (relaxation of submaximal contractions to the thromboxane-mimetic, U46619) agreed on human and rat intralobar arteries but were 6 to 16-fold lower than on rat main pulmonary artery. We conclude that data obtained on pulmonary arteries from rats can be useful in predicting the effects of vasoactive drugs in human pulmonary arteries but selection of the most appropriate rat artery for study will depend on the drug group under investigation. For potassium channel openers and nitric oxide donors, good agreement between human and rat data will be found when using pulmonary arteries from the same anatomical location even though they differ markedly in size. In contrast, for endothelin antagonists, agreement is more likely to be found in arteries of comparable size, despite their different anatomical locations.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗

PubMed1988

Similarity of relaxations evoked by BRL 34915, pinacidil and field-stimulation in rat oesophageal tunica muscularis mucosae.

1. In the rat oesophageal tunica muscularis mucosae (TMM) the potassium channel openers, BRL 34915 and pinacidil, raised the threshold for concentration-dependent K+ contractions, suppressed contractions evoked by field stimulation of the TMM in the presence of tetrodotoxin (TTX) and tetraethylammonium (TEA), and relaxed tonic contractions resulting from muscarinic cholinoceptor stimulation. 2. BRL 34915 and both (+)- and (--)-pinacidil increased 86Rb efflux from tracer-loaded tissues; nifedipine abolished this effect. 3. Relaxations produced by potassium channel openers were inhibited by a temperature drop from 37 degrees C to 26.5 degrees C, an increase in extracellular K+ concentration to 64 mM, and treatment with the calcium channel antagonist, nifedipine. The same treatments also blocked field stimulation-evoked TTX-insensitive relaxations. 4. It is concluded that field stimulation of rat oesophageal smooth muscle in the presence of cholinoceptor-induced tone results in an increase in K+ permeability that is directly or indirectly coupled to Ca2+ influx through potential-operated channels.

Animals↗

PubMed1993

A comparison of the inhibitory effects of sodium nitroprusside, pinacidil and nifedipine on pressor response to NG-nitro-L-arginine.

1. The inhibitory effects of sodium nitroprusside (SNP), a nitric oxide (NO) donor, on mean arterial pressure (MAP) responses to NG-nitro-L-arginine (L-NNA) (NO synthase inhibitor), angiotensin II (AII) and noradrenaline (NA) were compared with those of pinacidil (KATP channel opener) and nifedipine (L-type calcium antagonist) in conscious, unrestrained rats. 2. Intravenous bolus injections of L-NNA (1-64 mg kg-1), AII (0.02-1.28 micrograms kg-1) and NA (0.25-16 micrograms kg-1) dose-dependently increased MAP to similar maxima. Intravenous infusions of SNP (1, 4 and 16 micrograms kg-1 min-1) dose-dependently increased ED20S of L-NNA, AII and NA. However, the maximum response evoked by L-NNA, but not by AII nor NA, was dose-dependently reduced by SNP. Moreover, the inhibitory effect of SNP on the pressor response to L-NNA ceased when the infusion of SNP was terminated. 3. Pinacidil (80 micrograms kg-1 min-1 for 30 min followed by 5 micrograms kg-1 min-1) increased ED50S of L-NNA, AII and NA but did not decrease the maximum responses to any of these agents. 4. Nifedipine (1 mg kg-1 min-1) non-selectively reduced maximum responses to L-NNA, AII and NA to similar levels and increased ED50S of AII and NA but not L-NNA. 5. The results show that SNP causes a selective, non-competitive and reversible inhibition of the pressor response to L-NNA. This inhibition by SNP is unlikely to be related to hypotension, the opening of ATP-sensitive potassium channels or blockade of L-type calcium channels.

Angiotensin II↗

PubMed1990

Mechanism of the vasodilator action of pinacidil.

The mechanism of the vasodilator action of pinacidil has been studied in rat mesenteric small arteries. The results show, first, that the use of flux studies to make measurements of ion permeability requires knowledge of the membrane potential, especially as regards K+ permeability. Second, the results confirm that the vasodilator effect of pinacidil is due to an increase in K+ permeability. Lastly, the results suggest that the K+ channels involved are sensitive to glibenclamide.

Animals↗

PubMedDate not supplied

Effects of pinacidil on serum lipid, lipoprotein, and apolipoprotein levels in patients with mild to moderate hypertension.

Twenty-two patients with mild to moderate hypertension received 20 mg of pinacidil daily for six weeks, followed by 40 mg daily for another six weeks. Levels of serum triglyceride and apolipoproteins C-II and C-III decreased significantly; high-density lipoprotein cholesterol levels increased significantly during treatment. These changes were more prominent in patients with total triglyceride levels of 150 mg/dl or over. The results suggest that pinacidil has a preferential action on triglyceride-rich lipoprotein metabolism.

Adult↗

PubMed1987

Comparative effects of pinacidil and prazosin on blood pressure, weight, plasma volume, the renin-angiotensin-aldosterone system, and the renal kallikrein-kinin system in patients with essential hypertension.

Patients with essential hypertension were randomized to treatment with either prazosin or pinacidil, a new direct-acting vasodilator. Factors that might modulate the antihypertensive response and result in pseudotolerance to these drugs were measured before initiation of therapy and following 12 weeks of treatment. Despite significant reductions in blood pressure, pinacidil and prazosin did not produce an increase in plasma volume, did not activate the renin-angiotensin-aldosterone system, and did not interfere with the renal kallikrein-kinin system. The data fail to reveal evidence of physiologic compensatory changes that would lead to the development of pseudotolerance.

Adolescent↗

PubMed2001

Activation of Na(+), K(+), Cl(-)-cotransport mediates intracellular Ca(2+) increase and apoptosis induced by Pinacidil in HepG2 human hepatoblastoma cells.

The role of Na(+), K(+), Cl(-)-cotransport (NKCC) in apoptosis of HepG2 human hepatoblastoma cells was investigated. Pinacidil (Pin), an activator of ATP-sensitive K(+) (K(ATP)) channels, induced apoptosis in a dose- and time-dependent manner in HepG2 cells. Pin increased intracellular K(+) concentration ([K(+)](i)). Bumetanide and furosemide, NKCC inhibitors, significantly inhibited the Pin-induced increased [K(+)](i) and apoptosis, whereas K(ATP) inhibitors (glibenclamide and tolbutamide) had no effects. The Pin-induced [K(+)](i) increase was significantly prevented by reducing extracellular Cl(-) concentration, and Pin also increased intracellular Na(+) concentration ([Na(+)](i)), further indicating that these effects of Pin may be due to NKCC activation. In addition, Pin induced a rapid and sustained increase in intracellular Ca(2+) concentration ([Ca(2+)](i)), which was completely prevented by the NKCC inhibitors. Treatment with EGTA or BAPTA/AM markedly inhibited the Pin-induced apoptosis. Inhibitors of Na(+), Ca(2+)-exchanger, bepridil, and benzamil significantly prevented both [Ca(2+)](i) increase and apoptosis induced by Pin. Taken together, these results suggest that Pin increases [Na(+)](i) through NKCC activation, which leads to stimulation of reverse-mode of Na(+), Ca(2+) exchanger, resulting in [Ca(2+)](i) increase, and in turn, apoptosis. These results further suggest that NKCC may be a good target for induction of apoptosis in human hepatoma cells.

Adenosine Triphosphate↗

PubMed2003

Pinacidil-induced opening, like glibenclamide-induced closure of cardiac KATP channels, protects cardiac function against ischemia in isolated, working, erythrocyte perfused rat hearts.

Glibenclamide-induced closure of ATP-dependent potassium (KATP) channels decreases coronary blood flow during normoxic and post-ischemic conditions. We have found that post-ischemic cardiac function is improved after glibenclamide treatment. Our theory was that this is a result of higher intracellular calcium concentrations due to reduction in ischemia-mediated hyperpolarization of the myocardial cell membrane. We hypothesized therefore that opening KATP channels would reduce post-ischemic function in our isolated, erythrocyte perfused, working rat heart model. During treatment with 1 or 12 mumol.L-1 pinacidil (protein unbound concentration) both before and after 12 minutes global ischemia coronary blood flow increased 2-3 fold compared with vehicle, while cardiac functional recovery post-ischemically was improved with both concentrations. Because closing and opening cardiac KATP channels both improve post-ischemic function, our calcium theory above can be discounted. The protective effect of glibenclamide may possibly be ascribed to metabolic effects such as preservation of ATP levels during ischemia.

Animals↗

PubMed1989

Hypotensive and peripheral vascular effects in healthy volunteers of repeated oral administration of pinacidil.

The hypotensive and peripheral vascular effects of two different oral formulations of pinacidil were investigated in twelve healthy male volunteers. Arterial blood pressure, heart rate and calf blood flow were measured on Days 1 and 7. The vasodilator activity of both formulations was confirmed by a significant increase in calf blood flow on both days, which was correlated with a significant decrease in diastolic blood pressure. There was no differences between the tablet and the pellet.

Adult↗

PubMed1987

Pinacidil increases the background potassium current in single ventricular cells.

Pinacidil, a new antihypertensive agent, increased the background (inward rectifier) potassium current and abolished its negative slope, and did not change the time-dependent component of the outward (delayed outward) current in single ventricular cells isolated from the guinea-pig heart. These effects must be responsible for the negative inotropic action of this drug.

Animals↗

PubMed1992

Pinacidil potentiates morphine analgesia.

The opening of K+ channels in the membrane of target neurons is a key mechanism of the effect of opioids. Here we show that the K+ channel opener, pinacidil, i.c.v. injected at doses of 50, 100 or 150 micrograms/rat, significantly increases and prolongs the effect of morphine on the thermal pain threshold (hot-plate and tail-flick tests). These data may suggest a novel approach to the management of pain.

Analgesia↗

PubMed2006

K(+)-evoked [(3)H]-norepinephrine release in human brain slices from epileptic and non-epileptic patients is differentially modulated by gabapentin and pinacidil.

The modulation of K(+)-evoked [(3)H]-norepinephrine ([(3)H]-NE) release by gabapentin (GBP) and pinacidil (PIN), a known K(ATP) agonist, was examined in human brain slices. We compared the pharmacological effects on NE-release in human epileptic neocortex and epileptic hippocampus to non-epileptic neocortex. GBP (100 microM) decreased [(3)H]-NE release by 22% in non-epileptic neocortical slices, whereas this inhibition was absent in slices from epileptic hippocampus and epileptic neocortex. PIN (10 microM) also reduced [(3)H]-NE release by 30% in non-epileptic neocortical slices and only by 5% in epileptic hippocampal slices. The blockade of voltage-gated calcium channels by omega-conotoxins MVIIA and MVIIC (0.1 microM) reduced [(3)H]-NE release in epileptic and non-epileptic neocortical slices to the same extend. The data show a marked reduction in K(+)-evoked [(3)H]-NE release by GBP and PIN in epileptic hippocampus and neocortex, suggesting an alteration of K(ATP) channel function, whereas the effects of the calcium channel modulators omega-conotoxins MVIIA and MVIIC are similar in both epileptic and non-epileptic neocortex.

Adrenergic alpha-Agonists↗

PubMed2003

K-ATP channel independent effects of pinacidil on ATP production in isolated cardiomyocyte or pancreatic beta-cell mitochondria.

Evidence has been presented that mitochondria contain ATP sensitive potassium channels (mK-ATP channels), which may confer tissue protection upon activation. It is, however, not known whether activation of mK-ATP channels has a direct effect on mitochondrial ATP production. This study was performed to define the effect of pinacidil (PIN) on ATP production by oxidative phosphorylation in isolated cardiomyocyte or pancreatic beta-cell mitochondria. Cardiomyocyte mitochondria produced seven times more ATP than beta-cell mitochondria in the presence of pyruvate/malate. PIN inhibited pyruvate/malate-induced mitochondrial ATP production with half maximal effect at 360 microM in both cell types. The inclusion of 5-hydroxydecanoate (5-HD) did not prevent this inhibition. Succinate induced a similar ATP production in cardiomyocyte or beta-cell mitochondria. In beta-cell mitochondria succinate-induced ATP production was inhibited by PIN with half maximal effects at 500 microM PIN. However, in cardiomyocyte mitochondria PIN stimulated succinate-induced ATP production 3-fold with half maximal effect at 100 microM and maximal effect at 200 microM. This PIN-dependent stimulation was mimicked by rotenone. The inclusion of 5-HD could not prevent these PIN effects. In conclusion, PIN may inhibit complex 1 of the respiratory chain without indications of opening mK-ATP channels. In cardiomyocytes with metabolically inhibited succinate dehydrogenase this results in a stimulation of ATP production conferring tissue protection. In beta-cells without a metabolically inhibited succinate dehydrogenase, there is no stimulation by PIN and tissue protection by PIN is not to be expected.

Adenosine Triphosphate↗

PubMed1990

Effects of cromakalim (BRL 34915) and pinacidil on normal and hypertrophied rat detrusor in vitro.

Normal and hypertrophied rat detrusor were investigated in vitro with regard to effects of the K(+)-channel openers pinacidil and cromakalim. Both drugs abolished spontaneous contractile activity and induced a relaxation of normal and hypertrophied detrusor preparations. In both types of preparation, contractions elicited by K+, carbachol or electrical field stimulation were depressed in the presence of the K(+)-channel openers. Responses induced by K+ or electrical stimulation were more reduced in the hypertrophied than in the normal detrusor. Both K(+)-channel openers increased the efflux of 86Rb+ in a concentration-dependent way and this increase was similar in normal and hypertrophied detrusor. If applicable to man, this data suggest that K(+)-channel openers may be effective in the treatment of bladder instability secondary to outflow obstruction.

Animals↗

PubMed1997

Denervation-induced supersensitivity to forskolin and pinacidil is not related to changes in the adenylate cyclase transduction pathway in the rabbit femoral artery.

1. The present study investigates whether chemical sympathectomy compromises the relaxation of the rabbit femoral artery precontracted with serotonin. The vasodilating agents promoted cyclic adenosine monophosphate (cAMP) accumulation or opening of the potassium channels. The effect of denervation on the adenylyl cyclase transduction pathway was also studied. 2. 6-Hydroxydopamine treatment did not impair the relaxation to adenosine, 8-bromoadenosine-cAMP (a membrane-permeable analog of cAMP) and 3-isobutyl-1-methylxanthine (a cAMP phosphodiesterase inhibitor). Moreover, denervation enhanced the relaxation to forskolin (a direct Gs-type protein activator) and pinacidil (a potassium channel opener). 3. Denervation modified neither adenosine diphosphate ribosylation of Gs- and Gi-proteins nor adenylyl cyclase activity.

1-Methyl-3-isobutylxanthine↗