Ramon Sivertsson

Haemodynamic Effects of Carvedilol, A New Beta-Adrenoceptor Blocker and Precapillary Vasodilator in Essential Hypertension

Carvedilol (BM 14190) is a new antihypertensive compound which combines beta-adrenoceptor blocking and precapillary vasodilating properties but is devoid of intrinsic sympathomimetic activity. The acute and long-term effects on blood pressure and regional haemodynamics (forearm plethysmography) were studied with carvedilol 25 mg b.i.d. or 50 mg b.i.d. Comparisons were made with propranolol 80 mg b.i.d. in a randomized double-blind placebo controlled trial comprised of 30 patients with essential hypertension. After a four-week placebo period active therapy was given for four weeks. Carvedilol administered acutely reduced blood pressure at both doses, delta 13/6 mmHg (P less than 0.001/P less than 0.01) and 17/10 mmHg (P less than 0.001/P less than 0.01). Resistance in the forearm fell significantly with the higher dose. This was in contrast to propranolol which only reduced heart rate acutely, and as expected caused a rise in forearm resistance. After four weeks both compounds had reduced blood pressure significantly and to the same extent. Blood flow was still significantly reduced with propranolol in contrast to the findings with carvedilol. We conclude that carvedilol given orally has a useful antihypertensive effect both acutely and during prolonged treatment. It is well tolerated and its haemodynamic profile is attractive.

Acute and Long-Term Hemodynamic Effects of Carvedilol, a Combined β-Adrenoceptor Blocking and Precapillary Vasodilating Agent, in Hypertensive Patients

Summary: The purpose of these studies was to investigate the hemodynamic effects of carvedilol, a compound with combined properties of nonselective &bgr;‐adrenoceptor blockade and precapillary vasodilatation. The acute effects were studied with invasive technique (dye dilution) in 10 patients taking 25 mg orally and noninvasively (forearm plethysmography) in 10 patients taking 25 mg and in 10 patients taking 50 mg orally, all with essential hypertension. Significant reductions of systolic and diastolic blood pressure (p < 0.05–0.001) were observed in all groups. Total peripheral resistance (TPR) did not change acutely whereas resistance in the forearm was reduced by 16% (p < 0.05; invasive group). When a comparison with propranolol (80 mg × 2) was made in a randomized double‐blind placebo controlled trial in 30 patients, carvedilol acutely reduced blood pressure significantly by 13/6 mg Hg (25 mg) and 17/10 mm Hg (50 mg) in contrast to propranolol. Resistance in the forearm fell significantly with 50 mg carvedilol, whereas propranolol caused a significant rise. After 4 weeks, both compounds had reduced blood pressure significantly. Blood flow was still reduced with propranolol in contrast to the findings with carvedilol. In conclusion, the summary of these studies shows that carvedilol given orally has a useful antihypertensive effect both acutely and during prolonged treatment, and it has an attractive hemodynamic profile, in agreement with the hemodynamic findings in essential hypertension.

Treatment of hypertension with beta-blockers with and without intrinsic sympathomimetic activity.

Summary In a randomized double-blind trial 36 patients with essential hypertension were treated with either metoprolol or pindolol for 6 months following a 6-week placebo period. At the end of the placebo period and after 6 weeks and 6 months of active therapy peripheral hemodynamics at rest and during maximal vasodilatation were studied. Exercise heart rate was reduced to the same extent with both metoprolol and pindolol, indicating that the doses used (metoprolol average 179 mg/day; pindolol average 12 mg/day) were equipotent as regards β-adrenoceptor blocking effect. The antihypertensive effect was identical with both compounds. However, metoprolol caused a significant reduction of heart rate at rest both at 6 weeks and 6 months. With pindolol the reduction in heart rate was not significant at 6 weeks, and it was clearly much less than with metoprolol. On the other hand, no change in calf vascular resistance was seen during metoprolol therapy, whereas a marked and statistically significant reduction was caused by pindolol. Resistance at maximal dilatation in the forearm did not change with metoprolol, but tended to fall with pindolol after 6 weeks and was significantly reduced after 6 months. This indicates that although metoprolol and pindolol have the same antihypertensive potency, the two agents appear to reduce blood pressure through different mechanisms. Thus, cardiac mechanisms seem to play the most important role with metoprolol, whereas pindolol mainly acts by a reduction in vascular resistance. It also seems that treatment with pindolol normalizes the structural arteriolar abnormality present in hypertension as indicated by the reduction in resistance at maximal vasodilatation.

Prediction of future hypertension by casual blood pressure or invasive hemodynamics? A 30-year follow-up study.

Blood pressure elevation in young age is associated with a risk of developing hypertension. However, not all subjects will progress to clinical hypertensives in need of pharmacological therapy. In younger subjects, there is essential to find clinical or experimental characteristics to predict the future risk of hypertension. In the present study, the long‐term relationship between casual blood pressure measurement and future hypertension has been examined. The initial study group consisted of 20‐year‐old men (n = 44) with mild blood pressure elevation and a normotensive male control group (n = 29). After 30 years, we re‐examined 32 (72%) of the subjects with previous mild blood pressure elevation and 21 (73%) of the controls. We further analyzed possible associations between blood pressure level at follow‐up and anthropometric data, and invasively measured hemodynamic variables at baseline. After 30 years, 38% in the group with blood pressure elevation at baseline had developed hypertension, as compared to 10% in the control group. There was a significant positive relationship between baseline systolic blood pressure (r = 0.56; p < 0.001) and diastolic blood pressure (r = 0.36; p < 0.01) and systolic blood pressure 30 years later. In further regression analyses, there were no associations between cardiac output, vascular resistance or anthropometric data at baseline and blood pressure at follow‐up. In conclusion, casual blood pressure measurements predict the risk of future hypertension, whereas invasive hemodynamic and anthropometric measurements do not in young men with mild blood pressure elevation.

Renal function and vascular resistance during long-term minoxidil treatment of severe hypertension.

Twenty-one patients with severe hypertension, refractory to treatment with diuretics, beta-adrenoreceptor blocking drugs, and hydralazine, were treated with minoxidil replacing hydralazine as the vasodilating component in triple-drug therapy. With minoxidil (average dose, 22 mg/day), blood pressure decreased from 208/118/ to 164/92 mm Hg without the appearance of orthostatic hypotension. There was no increase in pulse in pulse rate. Only 1 patient had to discontinue the minoxidil treatment because of severe headache, and I patient died during follow-up for 6–38 months. The glomerular filtration rate ([***Cr]EDTA clearance) was determined in 12 patients before and during long-term minoxidil therapy. No signification reduction was observed in 10 patients with primary hypertension, while 2 patients with chronic glomerulonephritis showed a slow reduction of filtration rate. Peripheral hemodynamic experiments on the calf muscle blood flow were made with venous occlusion plethysmography at rest and during hyperemia after arterial occlusion and superimposed muscle work. Systemic blood pressures ws recorded simultaneously with the flow determinations, and the vascular resistance at rest and during complete vasodilatation was calculated from the mean arterial pressure blood flow ratio. After the change to minoxidil a considerable increase in resting blood flow to the calf muscle was noted. This increase was associated with a significant decrease in calculated vascular resistance and was unaltered during 3 years of follow-up. No change was found in the resistance at maximal dilation, considered to reflect the average radius of the resistance vessels of the muscle tissue. Consequently, no sign of reversibility of the vascular abnormality was demonstrated after 3 years of good blood pressure control in patients previously refractory to antihypertensive treatment.