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At least 343 records · Page 19Linked to original sources
PubMed2002

Monolithic matrix type transdermal drug delivery systems of pinacidil monohydrate: in vitro characterisation.

The monolithic matrix type transdermal drug delivery systems of pinacidil monohydrate (PM) were prepared by film casting technique on mercury substrate and characterised in vitro by drug release studies using paddle over disc assembly, skin permeation studies using Keshary and Chein diffusion cell on albino rat skin and drug-excipient interaction analysis. Four formulations were developed which differed in the ratio of matrix forming polymers, Eudragit RL-100 and PVP K-30, i.e. 8:2, 4:6, 2:8 and 6:4 and were coded as B-1, B-2, B-3 and B-4, respectively. All the four formulations carried 20% w/w of PM, 5% w/w of plasticiser, PEG-400 and 5% w/w of DMSO (based on total polymer weight) in isopropyl alcohol: dichloromethane (40:60) solvent system. Cumulative % of drug released in 48 h from the four formulations was 63.96, 55.95, 52.26 and 92.18%. The corresponding values for cumulative amount of drug permeated for the said formulations were 57.28, 50.35, 46.38 and 86.54%, respectively. On the basis of in vitro drug release and skin permeation performance, formulation B-4 was found to be better than the other three formulations and it was selected as the optimised formulation. The interaction studies carried out by comparing the results of assay, ultraviolet, infrared and TLC analyses for the pure drug, medicated and placebo formulations indicated no chemical interaction between the drug and excipients.

Acrylic Resins↗
PubMed1993

Synthesis of and radioligand binding studies with a tritiated pinacidil analogue: receptor interactions of structurally different classes of potassium channel openers and blockers.

The synthesis of N-cyano-N'-[1,1-dimethyl-[2,2,3,3-3H]propyl]-N"-(3- pyridinyl)guanidine, [3H]-15, is described. The utility of this tritiated radioligand in characterizing the interactions of potassium channel openers and blockers with their receptors is demonstrated. Potassium channel openers of the pinacidil, cromakalim, aprikalim, diazoxide, and minoxidil types, as well as KATP channel blockers of the glibenclamide and eosine types, are all capable of displacing [3H]-15 from its receptor. The results indicate that all of these compounds interact with the same target protein, but that several different allosterically coupled receptor binding sites are probably involved. The highly significant correlation between the ability of the structurally diverse potassium channel openers to inhibit [3H]-15 binding and to relax vascular smooth muscle is consistent with their receptor binding sites being closely associated with the potassium channel protein which is the functional target of this class of drugs.

Animals↗
PubMed2002

The stereoenantiomers of a pinacidil analog open or close cloned ATP-sensitive K+ channels.

ATP-dependent K(+) channels (K(ATP) channels) are composed of pore-forming subunits Kir6.x and sulfonylurea receptors (SURs). Cyanoguanidines such as pinacidil and P1075 bind to SUR and enhance MgATP binding to and hydrolysis by SUR, thereby opening K(ATP) channels. In the vasculature, openers of K(ATP) channels produce vasorelaxation. Some novel cyanoguanidines, however, selectively reverse opener-induced vasorelaxation, suggesting that they might be K(ATP) channel blockers. Here we have analyzed the interaction of the enantiomers of a racemic cyanoguanidine blocker, PNU-94750, with Kir6.2/SUR channels. In patch clamp experiments, the R-enantiomer (PNU-96293) inhibited Kir6.2/SUR2 channels (IC(50) approximately 50 nm in the whole cell configuration), whereas the S-enantiomer (PNU-96179) was a weak opener. Radioligand binding studies showed that the R-enantiomer was more potent and that it was negatively allosterically coupled to MgATP binding, whereas the S-enantiomer was weaker and positively coupled. Binding experiments also suggested that both enantiomers bound to the P1075 site of SUR. This is the first report to show that the enantiomers of a K(ATP) channel modulator affect channel activity and coupling to MgATP binding in opposite directions and that these opposite effects are apparently mediated by binding to the same (opener) site of SUR.

Adenosine Triphosphate↗
PubMed1988

Cardiac electrophysiological effects of pinacidil and related pyridylcyanoguanidines: relationship to antihypertensive activity.

It has been suggested that certain direct acting vasodilators increase potassium conductance (gK) of smooth muscle membranes. A similar increase of gK in cardiac tissue would be expected to selectively shorten the action potential duration (APD). The present studies were conducted to determine whether a series of pyridylcyanoguanidine antihypertensive agents, including pinacidil, might shorten the APD of canine Purkinje fibers and ventricular muscle, and if so, whether this effect can be correlated with their antihypertensive activities in anesthetized spontaneously hypertensive rats (SHR). Cardiac Purkinje fiber APD was decreased by most compounds. P-1075, the most potent compound of the series (EC50 = 3.7 x 10(-8) M), reduced the APD of Purkinje fibers by a maximum of 91 +/- 2% at 10(-6) M with no change in the maximum rate of rise (Vmax) or conduction time of the action potential. Similar selective effects on APD were noted in ventricular muscle cells. Shortening of APD was not altered by muscarinic blockade with atropine (3 x 10(-6) M) or adenosine receptor blockade with isobutyl methylxanthine (3 x 10(-5) M). In chloralose-anesthetized SHR, the pyridylcyanoguanidines reduced mean arterial blood pressure (BP) and left ventricular dP/dtmax with an order of potency similar to their effect on APD95. The most potent compound was again P-1075 with an ED50 of 8 micrograms/kg i.v. for its effect on BP. When the ED50 for BP reduction in vivo was compared with the EC50 for Purkinje fiber APD shortening in vitro, an excellent correlation was obtained (r = 0.97, p less than 0.005).(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1984

Pinacidil monotherapy for hypertension.

Ten patients with mild to moderate hypertension were treated for 9 weeks with a tablet formulation of pinacidil. Mean supine blood pressure fell from 174/100 to 148/84 mm Hg and mean supine pulse increased by 3 beats/min. Daily dosage was 40-100 mg, given in two or three divided doses. Plasma urea increased significantly and mean weight increased by 1.1 kg. Side effects were frequent but mild, in the main being those typically associated with potent vasodilator drugs. No patient withdrew from the study, and all achieved target blood pressure.

Adult↗
PubMed1985

The effects of long-acting pinacidil on intra-arterial blood pressure.

We have tested the efficacy of a new long-acting preparation of pinacidil, an arterial vasodilator, using continuous intra-arterial ambulatory blood pressure recording. An acute dose produced a measurable effect lasting for 12 h. The duration of this effect was less during chronic twice daily drug administration. Side effects were common, causing two out of nine patients to withdraw from the study. Tilt testing produced no postural hypotension and there was no evidence of rebound hypertension on the withdrawal day.

Antihypertensive Agents↗
PubMed1990

Characterization of responses to cromakalim and pinacidil in smooth and cardiac muscle by use of selective antagonists.

1. In dog isolated coronary artery (precontracted with endothelin, 10 nM) cromakalim (0.1-30 microM) and pinacidil (1-30 microM) produced concentration-dependent vasorelaxant responses. The effects of these compounds could be blocked by glibenclamide (3 microM), phentolamine (30 microM) or alinidine (30 microM) to a similar extent, indicating that both agents alter vascular tone through the same mechanism in this preparation. 2. The ability of the antagonists glibenclamide, phentolamine and alinidine to block the response to cromakalim in a number of smooth muscle types from the guniea-pig was determined. Cromakalim (0.1-30 microM) produced concentration-dependent relaxant responses in thoracic aorta (precontracted with endothelin, 30 nM), ileum (precontracted with K+, 25 mM) and trachea (spontaneously contracted). Responses to cromakalim in all tissues could be blocked by the three antagonists. However, significantly higher concentrations of the antagonists were required to block responses in the thoracic aorta than in the ileum or trachea. Given that the rank order of potency of the antagonists was similar in all tissues (i.e. glibenclamide greater than phentolamine = alinidine), this result may suggest vascular K+ channels opened by cromakalim are quantitatively but not qualitatively different in vascular compared with non-vascular smooth muscle. Glibenclamide was approximately 10 times more potent than phentolamine or alinidine. 3. Cromakalim had minimal functional effects on the rat spontaneously beating right atrial (rate) or electrically driven left ventricular strip (force) preparations. Similarly the three antagonists studied failed to alter force generation in the right ventricular strip. However alinidine and phentolamine did produce a dose-related bradycardia in the spontaneously beating right atria. This effect appears to be unrelated to blockade of the K+ channel opened by cromakalim since glibenclamide, the most potent K+ channel antagonist studied, failed to produce the same response. 4. It would appear that the K+ channel opened by cromakalim is present in a number of vascular and non-vascular smooth muscle. Based on the potency of the three antagonists studied, there appears to be little heterogeneity in the process activated by cromakalim in vascular and non-vascular smooth muscle.

Animals↗
PubMed2000

Effects of pinacidil on coronary Ca(2+)-myosin phosphorylation in cold potassium cardioplegia model.

The effects of the potassium (K(+)) channel opener pinacidil (Pin) on the coronary smooth muscle Ca(2+)-myosin light chain (MLC) phosphorylation pathway under hypothermic K(+) cardioplegia were determined by use of an in vitro microvessel model. Rat coronary arterioles (100-260 microm in diameter) were subjected to 60 min of simulated hypothermic (20 degrees C) K(+) cardioplegic solutions (K(+) = 25 mM). We first characterized the time course of changes in intracellular Ca(2+) concentration, MLC phosphorylation, and diameter and observed that the K(+) cardioplegia-related vasoconstriction was associated with an activation of the Ca(2+)-MLC phosphorylation pathway. Supplementation with Pin effectively suppressed the Ca(2+) accumulation and MLC phosphorylation in a dose-dependent manner and subsequently maintained a small decrease in vasomotor tone. The ATP-sensitive K(+) (K(ATP))-channel blocker glibenclamide, but not the nitric oxide (NO) synthase inhibitor N(omega)-nitro-L-arginine methyl ester, significantly inhibited the effect of Pin. K(+) cardioplegia augments the coronary Ca(2+)-MLC pathway and results in vasoconstriction. Pin effectively prevents the activation of this pathway and maintains adequate vasorelaxation during K(+) cardioplegia through a K(ATP)-channel mechanism not coupled with the endothelium-derived NO signaling cascade.

Animals↗
PubMed1985

[Pharmacological studies on pinacidil, a new anti-hypertensive agent. 1. Antihypertensive effects in SHR and DOC/saline hypertensive rats].

Antihypertensive effects of pinacidil (PND) were compared with those of hydralazine (HDL) and nifedipine (NFD) by determining the systolic blood pressure of the caudal arteries of conscious SHR and desoxycorticosterone (DOC)/saline hypertensive rats at temperatures between 29 degrees C to 30 degrees C using a newly developed tail cuff method. 1) A dose-dependent antihypertensive effect of PND in male SHR was observed in a dose exceeding 1 mg/kg, p.o. Comparison of antihypertensive effects during 6 hr after oral administration of antihypertensive agents showed that relative potencies of HDL and NFD to PND (1.0) were approximately 0.8 and 0.3, respectively. 2) Although no difference was observed in the antihypertensive effect of HDL between male and female SHR, these effects by PND and NFD were more potent in female SHR. 3) No tolerance was observed in the antihypertensive effect of PND by the once a day oral administration for 5 weeks in male SHR and DOC/saline hypertensive rats. Dose-dependent antihypertensive effects of PND in doses above 1 mg/kg were always observed during experimental periods. 4) In spite of the potent antihypertensive effects, pathological changes such as hyperplasia and hyalinization of arterial walls in kidneys in DOC/saline hypertensive rats were not improved by continuous administration of PND or HDL.

Administration, Oral↗
PubMed1997

Differential effects of pinacidil, cromakalim, and NS 1619 on electrically evoked contractions in rat vas deferens.

AIM: To compare the inhibitory action of electrically evoked contractions of rat epididymal vas deferens by pinacidil (Pin), cromakalim (Cro), and NS 1619. METHODS: Monophasic contractions were evoked by electric field stimulation in rat isolated epididymal half of vas deferens. RESULTS: Newly developed ATP-sensitive K+ channel openers, Pin and Cro, concentration-dependently reduced the electrically evoked (0.3 Hz, 1 ms pulse duration, 60 V) contractions and glibenclamide but not charybdotoxin antagonized the inhibitory effects of both agents. Pin shifted the concentration-response curve for norepinephrine to the right with reducing the magnitude of the maximum contraction in a glibenclamide-sensitive fashion. The large-conductance Ca(2+)-activated K+ channel opener, NS 1619, inhibited the electrically evoked contractions in a concentration-dependent manner. Charybdotoxin (100 nmol.L-1) partially reduced the effect of NS 1619 but glibenclamide (10 mumol.L-1) showed no effect. None of these 3 agents affected the basal tension. CONCLUSION: Both ATP-sensitive and Ca(2+)-activated K+ channels presented in vas deferens smooth muscles involved in regulation of muscle contractility.

Animals↗
PubMed1992

The inhibitory effects of cromakalim and its active enantiomer BRL 38227 against various agonists in guinea pig and human airways: comparison with pinacidil and verapamil.

The effects of the potassium channel activators, cromakalim, BRL 38227 and pinacidil, and the calcium antagonist, verapamil, have been compared against various spasmogens on airway responses in vitro and in vivo in the guinea pig and also in human isolated bronchi. In guinea pig tracheal spirals, potassium channel activators generally had a greater inhibitory effect than verapamil against tone induced by a wide range of spasmogens (spontaneous, 5-hydroxytryptamine, leukotriene D4, prostaglandin E2). The potassium channel activators had very little effect against potassium chloride- and carbachol-induced tone in guinea pig tracheal spirals [e.g., cromakalim (20 microM) induced relaxations of 0.21 +/- 0.03 (relative to an isoprenaline maximum = 1.0, mean +/- S.E.M.) against carbachol, compared to 0.77 +/- 0.03 against histamine]. In vivo, the potassium channel activators prevented histamine and 5-hydroxytryptamine-induced bronchoconstrictions, but had little inhibitory effect against acetylcholine. In contrast, in human bronchi, cromakalim was capable of inducing powerful concentration-dependent relaxations against carbachol-induced tone [cromakalim (20 microM) induced relaxations of 0.77 +/- 0.09 (relative to isoprenaline = 1.0, mean +/- S.E.M.) against carbachol, compared to 0.95 +/- 0.04 against histamine]. In human bronchi, all the inhibitory agents were more potent and more effective, except that verapamil did not have an increased maximum response. We conclude that potassium channel activators should be effective at relaxing contractions induced by a wide range of spasmogens in man.

Animals↗
PubMed1990

The initial hemodynamic response to newer antihypertensive agents at rest and during exercise: review of visacor, doxazosin, nisoldipine, tiapamil, perindoprilat, pinacidil, dilevalol, and carvedilol.

Antihypertensive drugs may lower blood pressure through very different mechanisms, initially as well as during chronic use. This article is a review of the immediate hemodynamic changes induced by a beta blocker (visacor), an alpha-receptor blocker (doxazosin), two calcium antagonists (tiapamil and nisoldipine), an angiotensin-converting enzyme inhibitor (perindoprilat), two double-acting compounds (dilevalol and carvedilol), and placebo studied in 126 patients with mild to moderately severe essential hypertension. The patient populations of the different treatment groups were comparable. The invasive hemodynamic technique, including intraarterial blood pressure (BP) recording and measurements of cardiac output by cardiogreen, was the same in all studies. All antihypertensive compounds examined induced a rapid reduction in blood pressure both at rest and during exercise, while no significant changes occurred in the placebo group. This review shows the scope of hemodynamic responses, ranging from peripheral vasodilation to a reduction of heart rate and blood flow. Furthermore, different counterregulatory effects blunting the immediate BP reduction are demonstrated.

Adult↗
PubMed1981

Immediate central and peripheral haemodynamic effects of a new vasodilating agent Pinacidil (P1134) in hypertensive man.

The purpose of this study was to evaluate the immediate central and peripheral haemodynamic effects of a new vasodilating agent P 1134, in hypertensive man. After oral administration of 25 mg P 1134, the maximal haemodynamic changes were (mean +/- 1 SEM): mean blood pressure fell from 121.8 +/- 6.5 to 80.5 +/- 7.8 mmHg, heart rate increased 24.2 +/- 4.5 beats/min, cardiac output rose 2.9 +/- 0.3 1/min and forearm blood flow increased 1.0 +/- 0.1 ml/100 ml tissue/min. Stroke volume increased 17.0 +/- 2.1 ml and the inotropic state of the heart as judged from systolic time intervals increased. Total peripheral resistance and forearm vascular resistance were both reduced by approx. 50%. Linear correlations were found between the serum concentration of P 1134 and the change in mean blood pressure and total peripheral resistance. Changes in the other parameters mentioned above occurred progressively with changes in mean blood pressure and total peripheral resistance. It can be concluded that P 1134 is a very potent hypotensive agent with a haemodynamic profile identical to that seen with vasodilators with preferably act on precapillary resistance vessels. Potency and maximal efficacy exceeds that of hydralazine and seems like that of minoxidil. P 1134 is remarkably free from side-effects apart from causing water retention as all other vasodilators. It can be administered orally as well as intravenously. This makes P 1134 a very interesting compound in the treatment of moderate to severe hypertension, and further studies are well-founded.

Adult↗