Blood pressure control and haemodynamic adaptation with the dihydropyridine calcium antagonist isradipine: a controlled study in middle-aged hypertensive men

Twenty-three middle-aged men (59 ± 2 years) with sustained, essential hypertension (WHO Stage II) and with diastolic blood pressure exceeding 100mmHg during a run-in placebo month were included in a trial designed to assess the clinical and haemodynamic effects of isradipine, a novel dihydropyridine calcium antagonist. The study was double-blind with a placebo-controlled crossover design. Isradipine as monotherapy was titrated in three, 3- week periods in doses of 2.5, 5 and 7.5 mg twice daily, or as apparently identical placebo capsules. A 3-week placebo wash-out period separated the two phases of the study. Clinical characteristics were followed during each treatment phase and an invasive haemodynamic examination was performed on the last day of the final active or placebo dose. In the haemodynamic investigation, cardiac output was measured using a dye-dilution technique and blood pressure via a catheter in the brachial artery. Plasma renin activity (PRA) was assessed by radio-immunoassay of generated angiotensin I and arterial noradrenaline concentrations using high-performance liquid chromatography (HPLC). Baroreceptor sensitivity was calculated from R-R intervals of the ECG and beat-to-beat systolic blood pressure during increasing bolus injections of phenylephrine. During optimal therapy with isradipine (7.5 mg twice daily), highly significant decreases in supine systolic (from 174 ± 4 to 154±3mmHg) and diastolic blood pressures (from 104 ± 2 to 91 ± 1 mmHg) were observed. Heart rate was unchanged (79 ± 3 versus 81 ± 2 beats/min) during chronic therapy. Blood pressure was reduced significantly by a decrease in total peripheral resistance (36%) while cardiac output (5.9 ± 0.4 versus 6.6 ± 0.5l/min), heart rate (69 ± 4 versus 72 ± 3 beats/min), and hence stroke volume (84 ± 9 versus 90 ± 8 ml/beat) remained unchanged during isradipine treatment. Baroreceptor sensitivity was unaffected by treatment but the regression slopes of the R-R intervals and systolic blood pressure levels were shifted so that an identical blood pressure resulted in a lower heart rate. A significant increase of PRA from 0.51 ± 0.07 to 0.71 ± 0.1 ng/ml per h (P <0.04) was observed while circulating levels of noradrenaline showed a non-significant tendency to increase (0.35 ± 0.05 versus 0.48 ± 0.06nmol/l, P=0.06). In summary, monotherapy with isradipine was well tolerated with a highly significant decrease in blood pressure was observed. Isradipine was shown to be a potent vasodilator which did not induce tachycardia or sodium retention.