Trimazosin: relationships between hypotensive effect, vascular responsiveness, and drug and metabolite concentrations

The relationships between the effects on blood pressure and vascular responsiveness, and the whole blood concentration of the antihypertensive drug trimazosin and its major metabolite were investigated in six normotensive male volunteers following 100 mg i.v. and 200 mg p.o. administration. Pressor responses to intravenous phenylephrine and angiotensin II were evaluated 1-3 (early) and 5-7 h (late) after drug or vehicle administration. There was a fall in blood pressure in the erect position (maximum between 4 and 8 h) associated with a modest increase in heart rate. Following treatment with trimazosin, blood pressure fell to 100/63 mm Hg with intravenous administration and 92/63 mm Hg with oral treatment, compared with the placebo value of 114/83 mm Hg. Both oral and intravenous trimazosin caused a significant rightward shift of the phenylephrine pressor dose-response curve (p less than 0.05). There was no significant shift of the angiotensin II pressor dose responses. Using linear regression analysis, the concentration of trimazosin in whole blood showed a significant correlation with the dose ratios from the phenylephrine pressor dose responses following treatment with both intravenous (r = 0.73, p less than 0.02) and oral (r = 0.57, p less than 0.05) trimazosin. There was no such correlation using dose ratios from angiotensin II pressor dose responses. There was no correlation between the concentration of the metabolite 1-hydroxytrimazosin and dose ratios from either phenylephrine or angiotensin II pressor dose responses. These observations suggest that the predominant mechanism of action of trimazosin, at doses that reduce blood pressure in humans, is through blockade of peripheral postjunctional alpha 1-adrenoceptors.