Antihypertensive treatment and vessel wall properties of large arteries.

Atherosclerosis is an important cause of cardiovascular morbidity and mortality. A good arterial compliance has been suggested to protect large vessels from atherosclerosis. Arterial compliance is diminished in patients with essential hypertension. The influence of verapamil (calcium-antagonist) and nebivolol (beta-adrenoceptor antagonist) on the vessel-wall properties of the common carotid artery were investigated. The two drugs improved compliance of the common carotid artery. Results from other studies on arterial compliance and antihypertensive drugs are also discussed.

The influence of chronic treatment with verapamil on plasma atrial natriuretic peptide levels in young and elderly hypertensive patients.

In a double-blind, placebo-controlled cross-over study, the plasma atrial natriuretic peptide (ANP) levels of nine young and ten elderly hypertensive patients were compared after placebo and after treatment with 120 mg verapamil given three times daily over 4 weeks. During placebo, plasma ANP levels proved to be higher in elderly patients than in young subjects. Chronic treatment with verapamil induced a rise in ANP levels in both young and elderly patients with hypertension.

Verapamil and nebivolol improve carotid artery distensibility in hypertensive patients.

The effects of verapamil (a calcium antagonist) and nebivolol (a novel, selective beta 1-adrenoceptor blocker) on carotid artery distensibility and cross-sectional compliance were studied non-invasively in hypertensive patients with the use of a high-resolution multigate pulsed Doppler system. Arm blood pressure measurements were made with an automated device (Dinamap). After a 4-week washout period, 19 patients (aged 21-73 years) with essential hypertension entered a double-blind randomized placebo-controlled crossover study with 120 mg verapamil or placebo three times a day for 4 weeks. After the administration of verapamil, carotid artery distensibility and cross-sectional compliance were significantly larger (P less than 0.05) than after placebo. Using the same protocol, 29 patients (aged 25-70 years) were given 5 mg nebivolol or placebo once a day for 4 weeks. After the administration of nebivolol, carotid artery distensibility and cross-sectional compliance were significantly larger (P less than 0.05) than after placebo. In both studies no significant differences in diameter and pulse pressure were found between placebo and verapamil or nebivolol. Blood pressure was decreased similarly with both verapamil and nebivolol. These results indicate that both verapamil and nebivolol favourably influence carotid artery distensibility and cross-sectional compliance of the common carotid artery, resulting in a better management of the systolic pressure pulse. The improved carotid artery distensibility may help to protect the patient against atherosclerotic complications of hypertension.

A long-term study of plasma catecholamine levels and plasma renin activity in borderline hypertension.

Blood pressure and plasma catecholamine levels were followed up for a total of 7 years in 26 subjects with borderline hypertension and in 24 normotensive subjects. During the observation period, five subjects from the borderline hypertensive group became definitely hypertensive, 10 remained in the borderline hypertensive range and in 10, blood pressure fell below borderline hypertensive levels. Of the original 24 normotensive subjects, 15 remained in the normotensive range. In seven, blood pressure rose, but did not reach borderline hypertensive levels. Three subjects were lost to follow-up. In contrast with the subjects who remained normotensive and borderline hypertensive, those who became definitely hypertensive had consistently high plasma noradrenaline concentrations at rest. Plasma adrenaline levels and plasma noradrenaline concentrations during exercise did not differ, however. The study suggests that borderline hypertensive subjects who develop definite hypertension within a few years have consistently enhanced sympathetic activity.

Long-term antihypertensive therapy with beta-blockers: submaximal exercise capacity and metabolic effects during exercise.

The effects of long-term (6 months) antihypertensive treatment with three different types of beta-blockers (propranolol, nonselective without ISA; pindolol, nonselective with ISA; metoprolol, beta 1-selective without ISA) on submaximal exercise capacity and metabolic variables during submaximal endurance exercise were studied in seven subjects with essential hypertension. Exercise tests were performed on a bicycle ergometer at 70% of estimated VO2 max. Similar reductions of resting and exercise blood pressure and exercise heart rate were obtained with the three beta-blockers. Exercise time was significantly reduced by all three beta-blockers during chronic antihypertensive therapy. The reduction tended to be more pronounced after 5-6 months of treatment than after 1 week (P = 0.06). During exercise, the plasma glycerol and nonesterified fatty acid concentrations were reduced. Plasma glucose concentration was reduced at the end of the exercise test during propranolol treatment only. Plasma lactate concentrations tended to be increased, but the difference was significant during pindolol treatment only. Oxygen uptake tended to decrease and respiratory exchange ratio to increase. Plasma potassium concentrations during exercise were significantly increased with all three beta-blockers. The effects on the metabolic variables during exercise were similar after 1 week and during long-term (20/24 weeks) beta-blocker treatment. The study shows that submaximal endurance exercise capacity is impaired in patients with essential hypertension on beta-blocker therapy and that the impairment is maintained during long-term antihypertensive beta-blocker treatment.

Metabolic effects of verapamil and propranolol during submaximal endurance exercise in patients with essential hypertension.

In contrast to beta-adrenoceptor blocking agents, calcium channel blockers do not appear to affect exercise tolerance in hypertensive subjects. A possible explanation is a difference in the metabolic effects of both types of drugs. Therefore, the effects of 4-week treatment periods with verapamil and propranolol on metabolic parameters during an endurance bicycle ergometer test were studied in eight patients with mild to moderate essential hypertension. Patients exercised at a work load which increased the heart rate to 150 bts/min during placebo. A single-blind, placebo-controlled, randomized cross-over design was used. The dose of propranolol and verapamil was adjusted to lower standing diastolic blood pressure less than 90 mmHg. Average daily doses were 155 +/- 21 mg propranolol and 390 +/- 44 mg verapamil. Exercise heart rate was reduced during propranolol and verapamil (P less than 0.01), but the reduction was more pronounced during propranolol than during verapamil (P less than 0.05). Minute ventilation and oxygen consumption were unchanged during propranolol and verapamil. The respiratory exchange ratio tended to increase during propranolol. Plasma glucose and lactate concentrations were unchanged during propranolol and verapamil. In contrast, plasma glycerol and nonesterified fatty acids were reduced during propranolol (P less than 0.05), but unchanged during verapamil. Plasma potassium levels were increased during propranolol (P less than 0.05). Despite the important direct and indirect role of calcium ions in the regulation of many metabolic processes, no effect of verapamil on metabolic parameters during submaximal exercise was found. In contrast, propranolol had an effect on fat and potassium metabolism during exercise.

Studies on the antihypertensive effect of single doses of the angiotensin converting enzyme inhibitor ramipril (HOE 498) in man.

The time course of the blood pressure lowering effect and the dose-response relationship of the new angiotensin converting enzyme inhibitor ramipril (HOE 498) were studied in 8 patients, with essential hypertension. As compared with placebo, a single oral dose of 2.5 mg ramipril lowered systolic and diastolic blood pressure. The antihypertensive action of single oral doses of 5, 7.5 and 10 mg ramipril was more pronounced. No change in heart rate occurred. Angiotensin converting enzyme activity was suppressed after all doses of ramipril studied. Plasma renin activity increased after 2.5 mg and 5 mg ramipril. Plasma aldosterone was not affected by 2.5 mg, but it fell after 5 mg ramipril. Thus, ramipril produced prolonged inhibition (more than 12 hours) of angiotensin converting enzyme activity and lowered blood pressure in patients with essential hypertension.

Influence of physical exercise on the pharmacokinetics of propranolol.

The pharmacokinetics of propranolol after oral and intravenous administration was studied at rest and on an exercise day in 8 healthy subjects. On the exercise day the subjects performed physical exercise for 7 h, consisting of bicycle ergometer exercise at 50% of maximal work capacity and outdoor walking. Propranolol (80 mg p.o., or 0.2 mg/kg body weight i.v.) was administered 30 min before the start of the exercise. After oral administration the terminal phase halflife, (t1/2 beta) and area under the curve (AUC) were both significantly reduced on the exercise day compared to the rest day. The bioavailability of propranolol was reduced by prolonged physical exercise and plasma levels of propranolol were about 30% lower at the end of the exercise day than at the end of the rest day. After intravenous administration, t1/2 beta was also reduced on the exercise day as compared to the rest day. AUC, clearance and volume of distribution did not differ on the two days. On the other hand, indocyanine green (ICG) clearance was significantly reduced during the bicycle ergometry periods on the exercise day. The combination of reduced ICG clearance, suggesting a reduction in hepatic blood flow, and a decreased t1/2 beta and unchanged clearance of propranolol on the exercise day was unexpected.