Franz W. Amann

Plasma Catecholamines and Cardiac, Renal and Peripheral Vascular Adrenoceptor-Mediated Responses in Different Age Groups of Normal and Hypertensive Subjects

The role of the sympathetic nervous system in cardiac, renal and peripheral vascular adrenoceptor-mediated responses was investigated in patients with essential hypertension and age-matched normotensive subjects. Regardless of age plasma adrenaline was significantly higher in hypertensive when compared with normotensive subjects. This suggests a sympatho-adrenal factor in essential hypertension. Plasma noradrenaline tended to increase with age but its similarity between normotensive and hypertensive subjects points to similar postganglionic neural activity and/or similar overflow of noradrenaline into the circulation. On the other hand, beta-adrenoceptor-mediated tachycardia in response to exercise and intravenous isoproterenol as well as the forearm vasodilator response to intraarterial isoproterenol decreased in normal subjects with older age. In hypertensives this age-dependent beta-receptor-related effect tends to be enhanced as judged from the greater reduction of cardiac isoproterenol sensitivity and the blunted renin response to exercise stimulation. The dilator response to alpha-adrenoceptor blockade with phentolamine was not different in both groups. Therefore a qualitative rather than quantitative derangement of sympathetic control of vascular resistance - in which beta-dilator effects are reduced and alpha-constrictor mechanisms prevail - may contribute to the maintenance of established hypertension.

Antihypertensive and renal effects of captopril in relation to renin activity and bradykinin‐induced vasodilation

The effect of captopril on blood pressure and renal hemodynamics in relation to plasma renin activity (PRA) was assessed together with the vasodilator responses to brachial artery infusions of bradykinin (BK) and sodium nitroprusside (NP) before and after 4 wk of therapy with doses of up to 450 mglday in patients with essential hypertension. The average blood pressure reduction of captopril was from 174.4/110.6 to 155.3/96.6 mm Hg (n = 12, P < 0.001) without increases in heart rate or body weight. It was effective in the eight patients with normal renin, but showed little effect in the four with a low renin. There was a correlation between the changes in blood pressure after captopril and the pretreatment PRA (r = −0.82, P < 0.01 for mean pressure). Brachial artery infusions of BK and NP induced dose‐dependent rises in forearm blood flow (FBF), but this was not related to the captopril blood pressure‐lowering effect. Repeat measurements during captopril therapy showed a shift to the left of the BK/FBF, but not of the NP/FBF, dose‐response curve, indicating effective vascular kininase II inhibition. Captopril decreased renal vascular resistance. Our data are compatible with the view that captoprils antihypertensive action mainly involves blockade of the renin‐angiotensin‐aldosterone system and not cumulation of BK. The favorable effects on renal hemodynamics and the lack of tachycardia and volume retention after captopril make it a valuable drug for the treatment of hypertension.

Elevated adrenaline and increased alpha-adrenoceptor-mediated vasoconstriction in essential hypertension.

In patients with essential hypertension, plasma adrenaline, regardless of age, was consistently higher than in normotensive controls; adrenaline correlated with heart rate and the vasodilator response in the forearm circulation produced by postjunctional alpha 1-adrenoceptor blockade with prazosin. This dilator response to prazosin was greater in hypertensive patients. Together, this suggests elevated sympathetic activity and enforced vasoconstriction via postjunctional alpha 1-adrenoceptors in essential hypertension. beta-Adrenoceptor-mediated cardiovascular responses decrease with age and even more with high blood pressure, which contributes to unopposed alpha-adrenoceptor-mediated vasoconstriction. This could explain the transition from an early high cardiac output into a later high peripheral resistance form of hypertension.

Verapamil-induced vasodilation is enhanced in essential hypertension.

The dependency of arteriolar tone on calcium influx was studied in 11 patients with essential hypertension (EHT) and compared to 11 age-matched normotensive (NT) subjects by measuring the forearm blood flow (FAF) response to intraarterial infusion of the calcium channel blocker verapamil (Verap) and the nonspecific vasodilator sodium nitroprusside (Nip) with venous occlusion plethysmography. Verap in incremental dosages induced a greater increase in forearm blood flow (delta FAF) in EHTs than in NTs, whereas there was no significant difference in delta FAF following Nip. When delta FAF to Verap was adjusted for delta FAF to Nip, it was still greater in EHTs. In EHTs delta FAF to all dosages of Verap correlated positively with basal plasma epinephrine concentration, and at the two highest dosages of Verap, associated with a decrease in systemic blood pressure, it correlated negatively with plasma renin activity and plasma angiotensin II concentration. Thus, increased dependency of arteriolar tone on calcium influx is related to the activity of the sympathetic nervous system in EHT. This association may be due to a common derangement in transmembranous ionic fluxes in the vascular smooth muscle cells and sympathetic neurons in EHT.

Effects of a new long-acting beta-blocker bopindolol (LT 31-200) on blood pressure, plasma catecholamines, renin and cholesterol in patients with arterial hypertension

SummaryBopindolol (LT 31-200), a new, long-acting, non-selective beta-blocker, was given as monotherapy to 13 patients, 12 with essential hypertension and 1 with renovascular hypertension. After a placebo period of 4–6 weeks, bopindolol was given once daily, starting with 1 mg and subsequently increasing at two-weekly intervals to 2 and 4 mg once daily until a diastolic blood pressure⩽90 mmHg was achieved. The effective dose was continued for 12 weeks. In 10 patients plasma levels of renin, noradrenaline, adrenaline and cholesterol were measured during placebo and after 3 months of therapy. Blood pressure and heart rate were lowered significantly during bopindolol treatment. The mean effective dose was 2.2 mg per day. In 10/13 patients a diastolic blood pressure⩽90 mmHg was achieved. Side effects were minimal. Changes in plasma noradrenaline and adrenaline were small and not significant, but renin and cholesterol were significantly reduced. Thus, LT 31-200 is an effective and well tolerated beta-blocker when given in a once daily dosage.

Antihypertensive Response to Postsynaptic α-Blockade with Prazosin in Low- and Normal-Renin Hypertension

&NA; The antihypertensive response to postsynaptic &agr;‐blockade with prazosin monotherapy was assessed in 27 subjects with essential hypertension, 12 of whom were classified as low‐renin and 15 as normal‐renin hypertensives. Response was better in the low‐renin group (mean sitting blood pressure fell from 175 ± 5/110 ± 3 to 149 ± 4/93 ± 4 mm Hg) than in the normal‐renin group (183 ± 5/118 ± 3 to 166 ± 7/104 ± 4 mm Hg). The fall in diastolic pressure was ≤95 mm Hg in 8 of 12 low‐renin and 6 of 15 normal‐renin patients. Although mean plasma renin values did not change significantly in either group during prazosin therapy, there was a significant negative correlation between the individual change in plasma renin activity and the corresponding fall in diastolic pressure. In a further 9 patients treated with prazosin alone for 6 months, there was a significant fall in blood pressure after 2 months. Subsequent increase in dosage resulted in only a minor additional fall after 4 and 6 months and was associated with a slight, but significant, increase in body weight. Prazosin can be used alone for long‐term therapy. Its effects are rarely hampered by a reflex tachycardia, but its efficacy may be limited by sodium‐volume retention secondary to a reactive stimulation of the renin‐angiotension‐aldosterone system. For optimal effect, it may best be combined with a renin‐suppressing agent and/or a diuretic.

Verapamil-induced vasodilator response is enhanced in essential hypertension

Forearm blood flow response to the calcium channel inhibitor verapamil, 1 75 micrograms/100 ml tissue, as measured by venous occlusion plethysmography, was found to be significantly greater in 11 patients with essential hypertension as compared to 11 age-matched normotensive subjects whereas there was no significant difference in increase in forearm blood flow between both groups to non-specific vasodilatation with sodium nitroprusside (1.2 micrograms/100 ml tissue). The increase in forearm blood flow to verapamil correlated positively with basal plasma epinephrine concentration in hypertensives. These findings support the concept of an increased dependency of arteriolar tone on calcium influx in patients with essential hypertension, an abnormally related to the activity of the sympathetic nervous system.

The Role of Catecholamines and Calcium in the Regulation of Blood Flow in Normotensive Subjects and in Patients with Essential Hypertension

The role of catecholamines and calcium in the regulation of blood flow was assessed by measuring their contributions to vascular tone by pharmacological intervention in the forearm arterial circulation. Postjunctional α1- and α2-adrenoceptor blockade with prazosin and yohimbine, respectively, produced a greater increase in forearm blood flow (FAF; venous occlusion plethysmography) in patients with essential hypertension than in normotensive subjects. This suggests that the sympathetic nervous system contributes to the elevated vascular resistance in essential hypertension via an enhanced α-adrenoceptor-mediated vasoconstrictor component. Adrenaline induced vasoconstriction through stimulation of postjunctional α2-adrenoceptors was demonstrated and this may be important in conditions associated with high concentrations of circulating adrenaline. Under resting conditions the β-adrenoceptor-mediated vasodilator force as measured by vascular β-adrenoceptor blockade was small compared to its vasodilator potential: intraarterial infusion of isoproterenol increased FAF about 3.5 times, the vasodilator response decreasing with older age. Enhanced calcium influx dependent vasoconstriction in patients with essential hypertension was demonstrated by the greater increase in FAF to calcium entry blockade. Together with the elevated intracellular free calcium concentration in platelets of hypertensive patients, this points to a derangement in the handling of calcium at the subcellular level in essential hypertension. A link between the elevated intracellular free calcium concentration and enhanced calcium influx dependent vasoconstriction is suggested by the normalization of both during antihypertensive treatment. Increased adrenergic activity in essential hypertension as reflected by supranormal plasma adrenaline concentrations in about one-third of patients may contribute to enhanced cellular calcium influx through receptor-operated calcium channels, and this is supported by the direct relationship between plasma adrenaline concentrations and the increases in FAF to α-adrenoceptor as well as to calcium entry blockade. Increased sympathetic activity and enhanced cellular calcium influx thus greatly contribute to the elevated vascular resistance in essential hypertension.

Blunting of Beta-Adrenoceptor-Mediated Cardiovascular Responses and Increasing Alpha-Receptor-Mediated Vasoconstriction: An Age-Dependent Transformation of Essential Hypertension

The role of the sympathetic nervous system in cardiac, renal and peripheral vascular adrenoceptor-mediated responses was investigated in patients with essential hypertension and age-matched normotensive subjects. Regardless of age, plasma adrenaline was significantly higher in hypertensive when compared with normotensive subjects. This suggests a sympatho-adrenal factor in essential hypertension. Plasma noradrenaline tended to increase with age but its similarity between normotensive and hypertensive subjects points to similar postganglionic neural activity and/or similar overflow of noradrenaline into the circulation. On the other hand, beta-adrenoceptor-mediated tachycardia in response to exercise and intravenous isoproterenol as well as the forearm vasodilator response to intraarterial isoproterenol decreased in normal subjects with older age. In hypertensives this age-dependent beta-receptor-related effect tends to be enhanced as judged from the greater reduction of cardiac isoproterenol sensitivity and the blunted renin response to exercise stimulation.