pranidipine and Hypertension

Calcium channel blocker (CCB) is one of the most frequently prescribed cardiovascular drugs. Two main classes of CCBs, dihydropyridines and benzothiazepines, are now clinically available for the treatment of hypertension in Japan. Both drugs inhibit the inward current of calcium ions through the L-type calcium channels. However CCBs have markedly different chemical structures and different effects on cardiovascular system. Therefore, in the present paper, their pharmacokinetic properties and interactions with other drugs are reviewed, and newly developed CCB are also described.

Topics: Benzimidazoles; Calcium Channel Blockers; Dihydropyridines; Drug Interactions; Humans; Hypertension; Mibefradil; Nifedipine; Tetrahydronaphthalenes; Thiazoles

The antihypertensive effects and tolerance of once-daily (od), pranidipine, a novel dihydropyridine derivative with a long duration of action, were evaluated in a double-blind, placebo-controlled, parallel-group dose-finding study. A total of 199 patients, with a diastolic blood pressure (BP) of 95-115 mmHg, were included in the trial. After 4 weeks on placebo, patients were randomly assigned to either placebo or pranidipine at 1, 2, 4, or 8 mg od for a further 4 weeks. A dose response was seen in the reduction (delta) of diastolic BP: placebo, delta 1.7 mm Hg; 1 mg, delta 6.4 mmHg; 2 mg, delta 7.5 mmHg, p < 0.01; 4 mg, delta 11.5 mmHg, p < 0.01; and 8 mg, delta 10.6 mmHg, p < 0.01. There were no meaningful changes in heart rate. The number of responders (decrease of diastolic blood pressure to < 90 mmHg and by 10 mmHg or more from baseline value) in each group also revealed a dose-response relationship: placebo = 9%; 1 mg = 25%, n.s.; 2 mg = 27%, n.s.; 4 mg = 41.5%, p < 0.01; and 8 mg = 41%, p < 0.01 (compared with placebo). Plasma concentrations of pranidipine also demonstrated linear dose-response relationships. An increase in adverse events was observed within the 8 mg group. The degree of reduction in BP and the number of responders were not greater in the 8 mg group compared with the 4 mg group, although the plasma concentration (mean values, ng/dl) of pranidine in the 8 mg group was higher (2.2 on day 42; 2.3 on day 56) compared with the 4 mg group (1.4 on day 42; 1.6 on day 56). In conclusion, pranidipine is a well-tolerated and 24-hour effective novel calcium antagonist that reduces BP in a dose-related manner up to 4 mg od.

Topics: Adult; Aged; Calcium Channel Blockers; Dihydropyridines; Dose-Response Relationship, Drug; Double-Blind Method; Female; Hemodynamics; Humans; Hypertension; Male; Middle Aged

Pranidipine (OPC-13340), a new dihydropyridine calcium antagonist, was given to 9 elderly hypertensive inpatients aged 64-79 years. Once-daily administration of pranidipine (1-2 mg) for 1-2 weeks decreased the 24-h average BP significantly from 167/92 mmHg to 150/83 mmHg without any change in pulse rate (PR) or the variabilities of BP and PR. The reduction of BP was observed exclusively during daytime (171/95 mmHg to 153/86 mmHg, p < 0.01 for SBP, p < 0.05 for DBP), while BP reduction during nighttime was significant only for DBP (157/84 mmHg to 146/79 mmHg, p > 0.05 for SBP, p < 0.05 for DBP). The analysis of the circadian rhythm by the cosinor method revealed that the acrophases of BP and PR were not changed significantly by the treatment with pranidipine. No adverse effects such as flushing and headache developed during the treatment. These results suggest that once-daily treatment with pranidipine is safe and exerts a sufficient antihypertensive effect during daytime with mild reduction of nighttime BP in elderly hypertensives. Furthermore, it does not alter the circadian patterns or variabilities of BP and PR. Thus, pranidipine may be useful as a monotherapy for elderly hypertensives.

Topics: Aged; Blood Pressure; Blood Pressure Monitoring, Ambulatory; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Female; Heart Rate; Humans; Hypertension; Inpatients; Male; Middle Aged

Nitric oxide (NO) synthesis in vascular endothelium of patients with hypertension is altered. Calcium antagonists have been shown to improve endothelial function in hypertensive patients. Here we report that pranidipine, one of the latest long-acting calcium antagonists in the dihydropyridine group, enhances the actions of NO released from endothelial cells (ECs). Pranidipine significantly enhanced cGMP accumulation in vascular smooth muscle cells cocultured with ECs, whereas amlodipine and nifedipine had no significant effects. In addition, pranidipine also suppressed basal and thrombin-stimulated endothelin-1 production from ECs. Pranidipine also enhanced cGMP accumulation in rat aortic segments with endothelium but not in endothelium-denuded vessels. In contrast, pranidipine had no effect in the presence of N(G)-monomethyl-L-arginine, an inhibitor of NO synthesis. Pranidipine did not affect the basal expression of endothelial NO synthase in ECs. However, pranidipine upregulated the activity of superoxide dismutase in ECs. These findings suggest that pranidipine enhances NO action through inhibition of superoxide-induced NO decomposition in the vessel wall. Thus, pranidipine may be useful in the treatment of impaired endothelial function in patients with hypertension.

Topics: Amlodipine; Animals; Aorta, Thoracic; Calcium Channel Blockers; Cells, Cultured; Coculture Techniques; Cyclic GMP; Dihydropyridines; Endothelin-1; Endothelium, Vascular; Humans; Hypertension; Male; Muscle, Smooth, Vascular; Nifedipine; Nitric Oxide; Nitric Oxide Synthase; Nitric Oxide Synthase Type III; Rats; Rats, Wistar; Superoxide Dismutase

The effect of long-term treatment with dihydropyridine calcium antagonists (amlodipine, pranidipine, nicardipine) on the periarterial nerve function was investigated in the perfused mesenteric vascular bed isolated from spontaneously hypertensive rat (SHR). Male 8-week-old SHR received amlodipine (0.01% and 0.02%) and nicardipine (0.1%) in drinking water and pranidipine (0.0035% and 0.035%) in rat chow for 7 weeks. Mean blood pressure in SHR was significantly lowered by long-term treatment with each calcium antagonist. In mesenteric vascular preparations treated with each calcium antagonist, vasoconstriction induced by periarterial nerve stimulation (PNS; 4, 8 and 12 Hz) was significantly smaller than that in non-treated SHR. The PNS (8 Hz)-evoked norepinephrine (NE) overflow in the perfusate was significantly decreased by amlodipine and pranidipine treatment, whereas nicardipine-treatment significantly enhanced the overflow of NE. In preparations with active tone produced by methoxamine and guanethidine, the PNS-induced vasodilation mediated by calcitonin gene-related peptide (CGRP)-containing (CGRPergic) vasodilator nerves was not affected by these drugs. These results suggest that long-term treatment of SHR with long-acting drugs, amlodipine and pranidipine, reduces sympathetic adrenergic nerve function but calcium antagonists have no effect on CGRPergic nerve function.

Topics: Amlodipine; Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Drug Interactions; Hypertension; Male; Mesenteric Arteries; Nervous System; Nicardipine; Norepinephrine; Rats; Rats, Inbred SHR; Vasoconstrictor Agents; Vasodilator Agents

Pranidipine is an optically-active 1,4-dihydropyridine (DHP) voltage-dependent L-type calcium channel inhibitor. Certain enantiomeric pairs display opposite effects, i.e., inhibition and activation of the calcium channel while others exhibit the same qualitative actions. We investigated pranidipine, a new DHP, using a paradigm of vascular smooth muscle reactivity. In isolated rat aorta, depolarized with 80 mM KCl, both isomers of pranidipine caused a right-ward shift of the concentration-contraction curves for extracellular Ca2+. The apparent pA2, values of the S-isomer and R-isomer were 10.03 and 8.36, respectively, providing evidence that the calcium channel blocking action of the S-isomer was 50 times more potent than that of the R-isomer. Antihypertensive actions of these two isomers studied in pentobarbital-anaesthetized spontaneously hypertensive rats, revealed that the S-isomer, at doses of 3-30 microg/kg i.v. decreased blood pressure in a dose-dependent manner, while the R-isomer had no effect on blood pressure at those doses. We conclude that the pair of enantiomers of pranidipine qualitatively display the same Ca2+ channel blocking action and that neither isomer exhibits Bay K 8644-like activation. Pranidipine may be useful in studies on the architecture of the DHP receptor 'pocket'.

Topics: Analysis of Variance; Animals; Antihypertensive Agents; Aorta; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Hypertension; Male; Muscle Contraction; Muscle, Smooth, Vascular; Rats; Rats, Inbred SHR; Rats, Wistar; Stereoisomerism; Structure-Activity Relationship

Interest in the cardiovascular protective effects of calcium channel antagonists has increased in the past decade. We investigated prevention of vascular wall remodeling by the long-acting calcium channel antagonist pranidipine in 12-week-old Dahl salt-sensitive (SS) rats with high-salt-induced (4% NaCl) hypertension. Six-week pranidipine treatment (60 mg/kg chow) decreased systolic blood pressure (SBP) by 22% in SS rats. This BP reduction was associated with decreases in cardiac mass and weight of the aortic wall. Glomerular filtration rate (GFR) was increased by 33%, but this did not lead to a decrease in urinary protein or NAG excretion. Morphologic investigation demonstrated striking resolution of arterial injury (medial necrosis and/or hyperplasia, inflammatory cell infiltration, and thrombus formation) by 87% after pranidipine treatment. Glomerular sclerosis was also attenuated by 61%, whereas tubular injury was improved by only 28%. These morphologic changes were reflected in the findings that the capacity of kidney homogenate for generating lipid peroxides was significantly decreased and that collagen levels and pattern type became similar to those of normotensive salt-resistant (SR) rats. Pranidipine also attenuated hypertensive vasculopathy in small arteries of the middle cerebral arteries. Thus, the calcium channel antagonist pranidipine can attenuate the vascular injury that occurs in salt-induced hypertension, a promising property that implicates its clinical usage, particularly in essential hypertension with cardiovascular complications.

Topics: Animals; Blood Pressure; Calcium Channel Blockers; Dihydropyridines; Hemodynamics; Hypertension; Kidney; Kidney Diseases; Models, Biological; Potassium; Rats; Rats, Inbred Strains; Sodium; Sodium, Dietary

The duration and magnitude of the hypotensive effect of a new, once daily dihydropyridine calcium channel blocking drug, OPC-13340, was assessed in 14 patients with essential hypertension during normal daily activities and programmed exercise testing. Intra-arterial ambulatory blood pressure (BP) monitoring was performed before and after one month's treatment. Mean reduction in day-time BP was 27/14 mmHg and night-time BP 18/11 mmHg (P less than 0.001 and 0.05 respectively). There was no change in heart rate throughout the 24 h. Satisfactory day-time control of systolic and diastolic BP using the drug as monotherapy was achieved in 58% and 88% of patients respectively, although adequate control of nocturnal systolic and diastolic BP occurred in only 54% and 50% of patients respectively. No postural hypotension occurred during tilt testing, and there was a significant reduction in the peak BP observed during both dynamic and isometric exercise. Side effects were mild and transient. Thus OPC-13340, given once daily, is an effective and well tolerated anti-hypertensive drug, with a prolonged 24-h action.

Topics: Adult; Aged; Calcium Channel Blockers; Circadian Rhythm; Dihydropyridines; Drug Administration Schedule; Exercise; Female; Humans; Hypertension; Isometric Contraction; Male; Middle Aged; Monitoring, Physiologic