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SUMMARY Aggregating platelets release serotonin, which induces contraction of most vascular smooth muscle by activation of Sj-serotoninergic receptors. Serotonin released in the circulation may contribute to the increase in peripheral resistance of hypertension as the responsiveness of blood vessels from hypertensive animals and humans to the vasoconstrictor action of the monoamine is augmented. The data obtained with the new antihypertensive agent ketanserin may favor that interpretation. Ketanserin is a selective S 2 -serotoniiiergic antagonist with additional ai-adrenergic blockmg properties. In humans, it has a terminal half-life of 12 to 25 hours and is eliminated predominantly by the liver. The hemodynamic profile of ketanserin is that of a vasodilator drug with actions on both resistance and capacitance vessels. On short-term intravenous administration, it lowers blood pressure in hypertensive patients with minimal reflex changes In cardiovascular function. When given orally long term to hypertensive patients, ketanserin causes a sustained reduction in arterial blood pressure, comparable to that obtained with either /3-adrenergic biockers or diuretics. Several studies have shown a greater efficacy in older (> 60 years of age) than in younger patients independent of starting pressure. Side effects mainly consist of dizziness, somnolence, and dry mouth, but they are usually not severe. The mechanism underlying the antihypertensive effect of ketanserin is unclear. It cannot be attributed to either S 2 -serotoninergic or a,-adrenergic blockade alone, but an interaction between the two effects appears to be required.

Calcium has been implicated in smooth muscle contraction, arterial resistance, and the pathophysiology of essential hypertension. Using the intracellularly trapped fluorescent dye quin2 , the free calcium concentration in platelets was found to be elevated in patients with borderline (n = 8, p less than 0.01) and established essential hypertension (n = 23, p less than 0.001) when compared with normotensive subjects (n = 30). There was a close correlation between intracellular free calcium and systolic blood pressure (n = 61, r = 0.882, p less than 0.001) as well as diastolic blood pressure (n = 61, r = 0.950, p less than 0.001). The slopes of the regression lines did not differ between the groups.

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1 Verapamil is a racemic mixture of two optical isomers, the (-)-form being the more active component. Recent studies indicate a rapid hepatic transformation of (-)-verapamil, which results in different concentration-effect relationships after oral and intravenous administration. In practice the important pharmacokinetic properties of verapamil are low bioavailability (20%), predominant elimination by metabolism (> 95%) and a relatively short half-life (tl/2,, is 3-5 h). After repeated dosing, the rate of hepatic drug clearance seems to decrease. 2 Slow release (SR) formulations of verapamil may offer certain therapeutic advantages during long-term treatment. A comparison of conventional (C) and SR tablets in a 1-week treatment of eight cardiac patients showed a relative bioavailability (AUCsR/AUCc) of 90 + 30%. More stable serum drug levels were maintained by 12-hourly administration of SR verapamil. 3 A further study using a new 240 mg SR preparation in patients with arterial hypertension showed that even a single daily dose can be sufficient for adequate blood pressure control over 24 h.

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1 The intent ofthis study was to determine whether or not increased calcium-influx-mediated vasoconstriction is a primary pathogenetic disturbance in essential hypertension. 2 Ten normotensive subjects (NT) (aged 45+12 years) and 23 patients with essential hypertension (EH) were studied. Twelve of the patients (aged 42 + 12 years) were classified as having mild EH and 11 patients (aged 49 +11 years) as having moderate EH. 3 Forearm blood flow and intra-arterial blood pressure were measured. Forearm vascular resistance (FVR) was calculated under basal conditions, during reperfusion following 10 min arterial occlusion, and after infusion into the brachial artery of sodium nitroprusside (0.15 and 0.6 ug min-' 100 ml-' tissue for 2 min each) and the calcium-influx inhibitors nicardipine (5 and 40 ug min-' 100 ml-' tissue for 1 min each) and verapamil (80 ug min-' 100 ml-' tissue for 1 min). 4 FVR after 10 min arterial occlusion was lower in mild EH than in moderate EH and still lower in NT. FVR was comparable in the three groups following infusion of maximal doses of sodium nitroprusside, nicardipine, and verapamil. 5 To allow for the vasodilator response to arterial occlusion, the decrease in FVR measured after each drug was divided by that obtained after arterial occlusion in each individual. The adjusted vasodilator response to nicardipine and verapamil, but not to sodium nitroprusside, was greater in moderate EH than in NT and mild EH. In the latter two groups the adjusted vasodilator responses were comparable. 6 Calcium-influx mediated vasoconstriction is thus enhanced in moderate (established) EH but not in mild EH and, therefore, is unlikely as a primary pathogenetic disturbance in essential hypertension.