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Query: UMLS:C0020538 (hypertension)
 170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Pinacidil, an antihypertensive agent that opens potassium channels, lowers plasma aldosterone levels in hypertensive patients by an unknown mechanism. In the present study, pinacidil's direct effects on production of aldosterone were assessed using isolated cells from bovine adrenal glomerulosa. Pinacidil was found to inhibit aldosterone production, both basally and during stimulation with either potassium, angiotensin II (Ang II), or adrenocorticotropic hormone (p less than 0.001), with half maximal inhibition occurring at 10(-5) M. As assessed by the exclusion of trypan blue from cells, pinacidil did not inhibit secretion through injurious effects on glomerulosa cells. Also, washing of cells previously exposed to pinacidil restored secretory responsiveness. Pinacidil did not alter cytosolic calcium (Ca2+) concentrations when aequorin was used as a photoluminescent indicator of Ca2+ levels, suggesting that pinacidil acted by a non-Ca(2+)-mediated mechanism. Consistent with direct inhibition of the late pathway in steroidogenesis was that pinacidil decreased conversion of pregnenolone and corticosterone to aldosterone. Pinacidil did not block binding of Ang II to its receptor, nor did it appear to affect adrenocorticotropic hormone-receptor binding, since stimulation by cyclic AMP, the post-receptor second messenger of adrenocorticotropic hormone, was also inhibited. In summary, pinacidil inhibited directly the adrenal's production of aldosterone. The mechanism whereby the inhibition occurred was unclear.
Hypertension 1991 Oct
PMID:Inhibition of aldosterone production by pinacidil in vitro. 165 50

To study the systemic and regional hemodynamic effects of the new antihypertensive agent pinacidil, the authors administered intravenously two doses of pinacidil (0.1 mg/kg) to patients with hypertension after 3 days of randomized, double-blind pretreatment with either propranolol or placebo. Pinacidil administration decreased systemic arterial pressure and total peripheral vascular resistance in both groups of patients. It also decreased pulmonary artery wedge pressure, and increased cardiac output, heart rate, and plasma norepinephrine levels; the changes in cardiac output and heart rate were attenuated by propranolol pretreatment. In addition, propranolol-pretreated patients responded to pinacidil with a decrease in forearm blood flow. In contrast, pinacidil administration exerted no significant effects on right atrial pressure, stroke volume, or mean pulmonary arterial pressure alone or in combination with propranolol. The results show that pinacidil is a potent arterial dilator but has little effect on the venomotor tone in patients with hypertension.
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PMID:Acute hemodynamic effects of pinacidil in hypertensive patients with and without propranolol pretreatment. 203 5

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.
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PMID:Effects of pinacidil on serotonin-induced contractions and cyclic nucleotide levels in isolated rat aortae: comparison with nitroglycerin, minoxidil, and hydralazine. 243 46

Peripheral vasodilation has proved to be a successful method to control hypertension in recent years, as illustrated by the increasing number of marketed vasodilators like calcium antagonists, alpha-adrenergic antagonists, and angiotensin-converting enzyme inhibitors. A novel group of vasodilators showing excellent antihypertensive activity in spontaneously hypertensive rats and renal hypertensive dogs has been discovered. The first compounds of the group were pyridylthioureas. Chemical modification based on structure-activity studies involving a substitution of N-cyanoguanidine for the less active thiourea function has led to the synthesis of pinacidil, N'-cyano-N-(4-pyridyl)-N"-(1,2,2-trimethylpropyl) guanidine, recently introduced as the new antihypertensive drug, Pindac. Preclinical studies showed that pinacidil does not relax vascular smooth muscle by any known mechanism, but recent investigations indicate that the compound opens potassium channels in the cell membranes. The hyperpolarization that follows is responsible for the relaxation. Pinacidil is rapidly and almost completely absorbed after oral administration and produces a dose-dependent blood pressure fall in hypertensive animals and humans. The therapeutic plasma concentrations are in the range of those producing relaxation of isolated, noradrenalin-contracted human blood vessels in vitro. In dogs, pinacidil decreases vascular resistance in most tissues proportionally to the blood pressure fall, but elicits a specific increase in coronary blood flow at antihypertensive doses. The compound shows a selectivity for precapillary vessels. It is mainly eliminated by hepatic metabolism to pinacidil-N-oxide followed by renal excretion, and the N-oxidation is partly reversible. Pinacidil is relatively free of toxicity, and action-related side effects such as fluid retention and tachycardia are readily controlled with diuretics and beta-blockers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Pinacidil: history, basic pharmacology, and therapeutic implications. 246 72

In a double-blind, randomized, crossover study, the effects of intravenous pinacidil, 0.2 mg/kg, were compared with those of hydralazine, 0.3 mg/kg, before and after beta-adrenoceptor blockade in six subjects with hypertension. Both drugs equally reduced total peripheral resistance by about 40%. Pinacidil reduced mean blood pressure by an average of 30 mm Hg, while the reduction after hydralazine was 10 mm Hg. The difference in antihypertensive effect resulted from greater increases in heart rate, cardiac contractility (systolic time intervals), and cardiac index (thermodilution) after hydralazine. These effects after hydralazine could not be fully abolished by beta-blockade, as could the effects after pinacidil. Pinacidil decreased pulmonary blood pressure, whereas there was a slight rise in pulmonary blood pressure after hydralazine. Forearm blood flow (venous occlusion strain gauge plethysmography) increased equally after both drugs; thus pinacidil decreased forearm vascular resistance more than hydralazine did. Serum concentrations of both drugs were within the therapeutic range and correlated with the fall in mean blood pressure. Five subjects complained of side effects after hydralazine, but none were reported after pinacidil. Hydralazine increased myocardial oxygen consumption (as estimated from the rate-pressure product) by 35%; there was no change after pinacidil. It is suggested that hydralazine has direct cardiostimulatory effects that limit its antihypertensive effectiveness. These effects increase myocardial oxygen consumption and may be responsible for the common and sometimes severe cardiovascular side effects of hydralazine.
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PMID:Acute hemodynamic effects of pinacidil and hydralazine in essential hypertension. 285 1

Hypertrophy of the left ventricle in hypertension is associated with an increased risk of morbidity and mortality. Thus, the prevention of and regression of left ventricular hypertrophy should be essential goals of antihypertensive treatment. Some commonly used antihypertensive drugs do not have this ability, despite achieving adequate blood pressure control. In a double-blind randomised parallel group study, we evaluated the effects of adjunctive long term therapy with either pinacidil or nifedipine on blood pressure and left ventricular function and anatomy (echocardiography) in 22 patients with a diastolic blood pressure above 95mm Hg who were already receiving bendrofluazide 5mg daily. Pinacidil reduced left ventricular mass from 326.3 +/- 126.2g to 251.2 +/- 114.6g (p less than 0.001) compared with nifedipine, which reduced ventricular mass from 293.6 +/- 35.7g to 267.3 +/- 34.7 (p = 0.04). In this respect, pinacidil was more effective than nifedipine (p = 0.013). Pinacidil improved left ventricular diastolic function, measured by the isovolumetric relaxation time, whereas nifedipine did not affect this parameter. Global systolic function was little affected by either drug. However, the end systolic wall stress was significantly reduced by both therapeutic regimens. Pinacidil may, therefore, be a potentially valuable antihypertensive drug.
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PMID:Effects of long term treatment with pinacidil and nifedipine on left ventricular anatomy and function in patients with mild to moderate systemic hypertension. 325 31

We compared antihypertensive effects of monotherapy with pinacidil (N = 197) or prazosin (N = 204) in a randomized, parallel, double-blind dose-titration study in which hydrochlorothiazide or propranolol could be added for adverse events or lack of efficacy. Pinacidil (12.5 to 75 mg b.i.d.) was a more potent vasodilator, producing a mean decrease in supine diastolic blood pressure (baseline = 102 to 103 +/- 9 mm Hg) of 18.8 +/- 10.0 (SD) mm Hg compared with 15.5 +/- 9.2 mm Hg with prazosin (1 to 10 mg b.i.d.; p less than 0.001). Patients responding to each drug had similar average blood pressure levels during 12-hour monitoring (137/85 mm Hg). More patients taking pinacidil required hydrochlorothiazide for edema (p = 0.008) and more taking prazosin required hydrochlorothiazide and propranolol for lack of efficacy (p less than 0.001). Tachycardia (15% to 20%) and palpitation (13% to 15%) were frequent events with both drugs. Edema (38.2% vs 22.3%) was more frequent with pinacidil (p less than 0.001) and postural hypotension (4.7% vs 1.0%) and asthenia (20.2% vs 13.2%) were more frequent with prazosin (p = 0.025; 0.062). No significant laboratory toxicity was noted. In conclusion, both pinacidil and prazosin are effective as monotherapy for hypertension. Monotherapy with pinacidil is limited by adverse events related to vasodilatation and monotherapy with prazosin is limited by lack of efficacy.
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PMID:Vasodilator monotherapy in the treatment of hypertension: comparative efficacy and safety of pinacidil, a potassium channel opener, and prazosin. 329 5

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.
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PMID:Antihypertensive effects of pinacidil in patients with and without indomethacin pretreatment. 335 58

We studied the systemic and coronary hemodynamic effects of a new antihypertensive agent, pinacidil, in nine morphine-sedated chronically instrumented dogs with one-kidney renal hypertension and eight similarly treated sham-operated normotensive dogs. The renal hypertensive dogs exhibited higher mean aortic blood pressure, total peripheral vascular resistance, and plasma renin activity before pinacidil administration than the sham-operated animals. The renal hypertensive dogs also had a lower left ventricular norepinephrine content, but the two groups did not differ significantly in plasma norepinephrine levels, cardiac output, or heart rate. Pinacidil decreased mean aortic pressure and total peripheral vascular resistance and increased cardiac output and heart rate in both groups. The changes in aortic pressure, total peripheral vascular resistance, and cardiac output were similar between the two groups, but the increase in heart rate was attenuated in renal hypertension. The peak rate of rise of left ventricular pressure (dP/dt), the ratio of left ventricular dP/dt and the developed pressure during isovolumic contraction (dP/dt/P), myocardial oxygen consumption, and plasma norepinephrine levels increased after pinacidil administration in the sham-operated dogs, but did not change in the renal hypertension group. The two groups did not differ in their responses of left ventricular dP/dt to intravenous isoproterenol. Pinacidil also caused coronary vasodilation in both groups, as evidenced by an increase in coronary blood flow and decreases in coronary vascular resistance and myocardial oxygen extraction. The decrease in myocardial oxygen extraction was similar in the two groups, but the increase in coronary blood flow was significantly less (p less than 0.05), probably because of the absence of an increase in myocardial oxygen consumption in the renal hypertensive dogs.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension
PMID:Systemic and coronary hemodynamic effects of pinacidil in awake normotensive and hypertensive dogs. 389 13

Pinacidil is a new and potent vasodilator, which has recently been used in the treatment of various forms of hypertension. In this study pharmacokinetic parameters were determined following administration of intravenous (0.2 mg/kg) and capsule (12.5 mg) formulations of pinacidil to twelve healthy volunteers. The serum half-life (t1/2) and volume of distribution (Vd) of pinacidil were 2.04 +/- 0.40 h and 1.4 +/- 0.4 l/kg respectively, while the elimination rate constant (k el) was 0.34 +/- 0.07 h-1. The mean bioavailability of pinacidil (capsule formulation) was 57% +/- 16 S.D. Mild side-effects such as dizziness, headache and fatigue were noted in two volunteers following intravenous administration of pinacidil, while no side-effects were reported with the oral formulation.
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PMID:Pharmacokinetics and bioavailability of pinacidil capsules in human volunteers. 400 51


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