To determine the contribution of altered beta-receptor function in the vasculature to the increased peripheral vascular resistance seen in hypertension, the effects of intra-arterial infusions of isoproterenol and epinephrine on forearm blood flow were determined in 11 male normotensive subjects and 11 male hypertensive subjects during 10 and 250 mmol/day sodium diets. Increased sodium intake from 10 to 250 mmol produced contrasting effects in the hypertensive and normotensive subjects. In the hypertensive subjects, sensitivity to isoproterenol decreased when sodium intake increased (median effective dose increased from 39 [95% confidence limits, 30 to 50] to 70 [95% confidence limits, 42 to 116] ng/min, p less than 0.05). On the other hand, in the normotensive subjects increased sodium intake resulted in an increased sensitivity to isoproterenol induced vasodilation (median effective dose decreased from 52 [38 to 71] to 29 [22 to 38] ng/min, p less than 0.01). No change occurred in sensitivity to epinephrine or in the maximum vasodilatory response to ischemia during dietary changes. Changes in beta-receptors on lymphocyte membranes paralleled the changes seen in vascular sensitivity so that the proportion of receptors exhibiting high affinity for agonists, a reflection of receptor adenylate cyclase coupling, decreased in the hypertensive subjects from 38.0% +/- 3.8% when they were receiving 10 mmol/day sodium to 29.6% +/- 2.7% when they were receiving 250 mmol/day sodium (p less than 0.01). However, the proportion increased from 32.4% +/- 3.7% for normotensive subjects receiving 10 mmol/day sodium to 47.1% +/- 7.8% for normotensive subjects receiving 250 mmol/day sodium (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

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Ketanserin is a selective (S2) serotonin receptor antagonist currently under investigation as an antihypertensive. It has been suggested that the antihypertensive action of ketanserin might be principally due to alpha-adrenergic receptor antagonism rather than its effect on serotonin receptors. We therefore determined the contribution of alpha-adrenergic blockade to the hypotensive effects of ketanserin in six patients with hypertension and compared that with the alpha-adrenergic blockade produced by prazosin, a known alpha 1-adrenergic antagonist. Each patient received placebo, ketanserin (40 mg every 8 hours), and prazosin (5 mg every 8 hours). Each agent was administered for 4 weeks in random order. Both ketanserin and prazosin lowered blood pressure significantly and to a similar extent. The extent of alpha-adrenergic blockade was determined from the ability to inhibit the hypertensive effect of phenylephrine infusions. The dose of phenylephrine required to raise the blood pressure by 20 mm Hg was significantly higher during both ketanserin (1.41 +/- 0.27 micrograms/kg/min; p less than 0.05) and prazosin (4.99 +/- 0.77 micrograms/kg/min; p less than 0.01) administration compared with placebo (0.85 +/- 0.15 micrograms/kg/min). However, the dose ratio was more than fourfold higher during prazosin treatment (7.38 +/- 1.99; p less than 0.05) than during ketanserin (1.69 +/- 0.21). Thus at equipotent hypotensive doses the extent of alpha-blockade produced by ketanserin was more than fourfold lower than that of prazosin, implying that mechanisms other than alpha-blockade must contribute to the antihypertensive actions of ketanserin.

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