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In a group of 14 hypertensive patients a 10-week course of treatment with prazosin 3-7.5 mg/day produced a significant reduction in mean blood pressure without serious side effects. The fall in diastolic pressure exceeded the response to a placebo by 10 mm Hg or more in 9 patients. The average decrease in diastolic pressure was similar to that produced by methyldopa 750 mg/day or propranolol 120-160 mg/day but the fall in systolic pressure was comparatively smaller, consistent with reported experimental work showing that the drug causes vasodilatation. The hypotensive effect of prazosin 1.5-3 mg/day combined with propranolol was significantly greater than that of propranolol alone and resulted in good control of blood pressure.

1. Plasma drug levels and blood pressure changes produced by a single 2 mg oral dose of prazosin were determined in nine hypertensive patients. 2. Regression analysis showed that there was a high degree of correlation between plasma prazosin concentration and change in mean blood pressure. 3. There were marked differences between patients in their responsiveness to prazosin.

A randomized double-blind crossover trial was conducted in 20 patients with moderate to severe hypertension to compare the efficacy of labetalol, which combines alpha- and beta-adrenoceptor blocking properties, with that of metoprolol alone or in combination with prazosin. After placebo for 1 wk, active medication was given in two 6-wk phases. During one phase, metoprolol (100 to 400 mg/day) was given with prazosin (2 to 4 mg/day) as an option in the last 3 wk, whereas during the other phase, labetalol (200 to 1000 mg/day) was given alone. Satisfactory control of supine blood pressure was obtained in 10 patients with metoprolol and in another four patients after the addition of prazosin. During the labetalol phase, blood pressure control was achieved in 11 of 19 patients tested. Gastrointestinal disturbances, nasal congestion, impotence, failure to ejaculate, scalp tingling, and headache were more prevalent in the labetalol phase than in the other. In four cases these occurred in patients who did not require prazosin. Supine, erect, and exercise pulse rates were reduced by both metoprolol with or without prazosin and by labetalol; the effects were less in the labetalol phase. These differences could arise from an action of labetalol on cardiac presynaptic alpha-adrenoceptors. Adjunctive use of prazosin in nonresponders to metoprolol increases the response rate and avoids unnecessary deployment of alpha-adrenoceptor blockade in patients whose blood pressure can be controlled by beta-blockade alone.

Combined use of prazosin and beta-blockers in a hypertension clinic over a 3-year period was surveyed by means of a computerized record system. Of the 1,250 patients in the clinic, 171 (14%) had been treated with this combination for periods averaging 17 months. Prazosin was administered with a beta 1-selective beta-blocker in 94 cases and with a beta 1 + beta 2-blocker in 100 cases; 23 patients had received treatment with both combinations. Diuretics were given in 86% of cases and other antihypertensive drugs in 19%. The population treated had a high incidence of severe hypertension, with initial diastolic pressure greater than 120 mm Hg in 38% and between 100 and 120 mm Hg in 50%. The percentage of patients with diastolic pressure less than 100 mm Hg was 12% initially and 79% at the end of the treatment period. Side effects necessitated withdrawal of therapy in 35 cases. These were referable in 19 cases to prazosin and in 16 to beta-blockers. Prazosin was found to be more effective in lowering blood pressure in combination with beta 1-blockers than with beta 1 + beta 2-blockers, although there were fewer severe side effects with beta 1-blockers.

1. The effects on blood pressure and heart rate of prazosin and a structurally-related congener, BL-5111A, were compared in conscious and anaesthetized rats. 2. Both agents induced dose-related falls in systolic and diastolic blood pressure, with relatively little effect on heart rate. The hypotensive potency of prazosin was twenty-fold greater than that of BL-5111A. 3. The hypotensive activity of prazosin was abolished by pretreatment with the ganglionic blocking agent, pentolinium, or the alpha-adenoceptor blocking agent, phentolamine, whereas BL-5111A retained significant hypotensive activity (up to 28%) after either pretreatment. 4. Both prazosin and BL-5111A attenuated pressor responses to noradrenaline, and reversed the responses to adrenaline, prazosin being, in this respect, 6 times more potent than BL-5111A. There was a highly significant relationship between the alpha-adrenoceptor blocking activity of either agents and its hypotensive effect. 5. BL-5111A differed from prazosin in possessing, in addition to its predominant alpha-adrenoceptor blocking action, a minor component of action attributable to direct vasodilatation.

The vasodilatory and alpha adrenergic blocking properties of prazosin were studied in anesthetized rats and compared with the direct-acting vasodilator, diazoside. The hypotensive activity of diazoxide was unimpaired after ganglion blockade with pentolinium or alpha adrenoreceptor blockade with phentolamine; diazoxide also significantly attenuated angiotensin II pressor responses. In contrast, the hypotensive action of prazosin was completely abolished, over a 10(4)-fold dose range, after ganglion or alpha adrenoreceptor blockade, and this agent failed, even in maximal hypotensive doses, to attenuate angiotensin II pressor responses. In addition, prazosin was shown to possess potent alpha adrenoreceptor blocking properties, significantly attenuating norepinephrine pressor responses and causing reversal of epinephrine pressor responses. These studies in the rat indicate that the hypotensive action of prazosin is not due to a direct relaxant effect upon vascular smooth muscle, but is attributable to alpha adrenoreceptor blockade.

1. Prazosin, clonidine, hydrallazine and diazoxide were administered intravenously, alone or in various combinations, to anaesthetized rats. 2. Prazosin and clonidine were equipotent. Their combined hypotensive effects in no instance exceeded the maximum effect attainable with either agent alone. The hypotensive effects of hydrallazine or diazoxide were, in contrast, additive to those of either prazosin or clonidine. 3. Pressor responses to clonidine were antagonized by prazosin. Prazosin may prove useful in hypertensive crises provoked by clonidine.

The mechanism of action of prazosin was studied in anesthetized rats by comparison with the peripherally-acting anti-hypertensive agents, indoramin, hydralazine and diazoxide. Hydralazine and diazoxide retained full hypotensive potency after ganglionic blockade with pentolinium or alpha adrenoceptor blockade with phentolamine. Hydralzaine and diazoxide also attenuated angiotensin II pressor responses. In contrast, the hypotensive activity of prazosin was completely abolished, and that of indoramin was almost abolished by either pentolinium or phentolamine pre-treatment. Neither prazosin nor indoramin caused impairment of angiotensin II responsivity, but each was shown to possess alpha adrenoceptor blocking properties. Both agents antagonized the pressor action of norepinephrine and reversed responses to epinephrine. Thus, while hydralazine and diazoxide act directly upon the vasculature by mechanisms independent of sympathetic vasomotor tone, prazosin, like indoramin, acts as an alpha adrenoceptor blocking agent.

Blood-pressure responses and changes in plasma drug concentration were studied in 11 hypertensive patients after an initial oral dose of 2 mg of prazosin. Subsequently, blood pressure was monitored during long-term treatment with prazosin. The prazosin reactivity index, a value derived during the first-dose study, appeared to predict the long-term antihypertensive effect of prazosin alone or prazosin combined with bendrofluazide.

The effects of the first dose of prazosin were assessed in hypertensive patients on different sodium intakes. Patients received 250, 100, or 30 mmol sodium per 24 hours for a week before taking 2 mg or 0-5 mg prazosin. The acute effects of prazosin on blood pressure and pulse rate were milder with a high sodium intake. On the 100-mmol intake symptomatic postural hypotension occurred in five out of seven patients given 2 mg prazosin and in two out of four given a 0-5-mg dose, whereas those taking 2 mg or 0-5 mg and a 250-mmol sodium intake experienced no postural symptoms. These findings indicate that particular care should be taken in starting prazosin treatment in sodium-depleted patients.

1. The fall in blood pressure produced by a test dose of prazosin was greater in a group of patients with chronic renal failure than in a group with normal renal function. 2. This difference could not be attributed to increased reactivity, measured as the slope of the regression line relating mean blood pressure and plasma prazosin concentration, nor to retarded elimination of the drug. 3. The enhanced antihypertensive effect of prazosin in renal failure appears to reflect changes in the bioavailability or distribution of the drug, which result in higher drug concentrations for a given dose.

Parzosin, 0.001 to 10 mg/kg, was administered intravenously to anesthetized normal rats. In the dose range 0.001 to 0.01 mg/kg, the drug induced highly significant, dose-related falls in blood pressure, pulse pressure and heart rate. With doses above 0.01 mg/kg, there was a plateau in hypotensive efficacy and a diminution in negative chronotropic activity. Both actions of prazosin (0.01 mg/kg) were unaffected by vagal blockade with atropine, while hypotensive potency was unimpaired after beta-adrenoreceptor blockade. The vasodilator, diazoxide, lowered blood pressure, widened pulse pressure and caused tachycardia in rats pre-treated with pentolinium. In contrast, all effects of prazosin were abolished by ganglion blockade. These findings, together with the absence of compensatory tachycardia or gross renin hypersecretion during prazosin-induced hypotension, are compatible with an antisympathotonic mode of action for the drug. However, consistent with its effects on cyclic nucleotide distribution, prazosin appears to enhance isoprenaline-induced beta-receptor stimulation.