Wolfgang Kiowski

Blood pressure control by the renin-angiotensin system in normotensive subjects. Assessment by angiotensin converting enzyme and renin inhibition.

BackgroundThe participation of the renin-angiotensin system in the control of blood pressure in normal, sodium-replete subjects is not clear. The use of a specific inhibitor of human renin should allow a better delineation of the importance of this system. Methods and ResultsBlood pressure responses were measured 1 hour after randomized, double-blind administration of the renin inhibitor Ro 42-5892 (600 mg p.o.) or the angiotensin converting enzyme inhibitor captopril (50 mg p.o.) in 20 healthy men on an ad libitum sodium diet. Effective inhibition of the renin-angiotensin system by either compound was indicated by increases of immunoreactive renin associated with an increase of angiotensin I production rate of 67.8±33.6% after captopril and a decrease of 79.5±16.4% after Ro 42-5892. Furthermore, Ro 42-5892 decreased plasma renin activity by 64%. Whereas intra-arterial diastolic (60±5.1 to 51.4±7.2 mm Hg, p < 0.01) and mean arterial (77.7±6.0 to 71.4±8.5 mm Hg, p < 0.001) pressures decreased after captopril, they remained unchanged after Ro 42-5892. Captopril, but not Ro 42-5892, increased forearm blood flow (2.4±0.8 versus 1.9±0.8 ml/min/100 ml, p < 0.01) and significantly enhanced the increase of forearm blood flow to brachial artery infusions of bradykinin (0.15, 1.5, 5, 15, and 50 ng/min/100 ml; 5 minutes each) from 744±632% to 1,383±514% (p < 0.01). Furthermore, repeat bradykinin infusions resulted in further decreases of blood pressure (from mean pressure of 71.4±8.5 to 63.2±7.6 mm Hg, p < 0.01) only after captopril. Changes of blood pressure after captopril were unrelated to baseline plasma renin activity but correlated with captopril-induced enhancement of vasodilation to bradykinin (r = 0.68, p < 0.05) ConclusionsThe lack of blood pressure effects of renin inhibition in contrast to angiotensin converting enzyme inhibition suggests that the renin-angiotensin system does not contribute significantly to blood pressure control in normotensive, sodium-replete subjects. The hypotensive activity of angiotensin converting enzyme inhibitors may result from additional hormonal effects, for example, inhibition of bradykinin degradation and/or subsequent increases of vasodilating prostaglandins or endothelium-derived relaxing factor(s).

Acute and chronic sympathetic reflex activation and antihypertensive response to nifedipine

The importance of counterregulatory mechanisms triggered by arterial vasodilation for the antihypertensive response to the calcium entry blocking agent nifedipine was investigated in 13 men with mild to moderate essential hypertension. Blood pressure and systemic vascular resistance were significantly reduced 30 minutes after sublingual administration of 10 mg of nifedipine while heart rate, cardiac index and plasma norepinephrine concentrations increased (all p less than 0.01). Also, changes in mean blood pressure correlated inversely with arterial baroreflex sensitivity (r = -0.74, p less than 0.01), suggesting that arterial baroreflex mechanisms by means of sympathetic activation tend to limit the acute antihypertensive response. Blood pressure, but not systemic vascular resistance, decreased further (p less than 0.01) after 6 weeks of therapy with nifedipine 20 mg three times daily, while average heart rate, cardiac index and plasma norepinephrine concentrations had returned toward pretreatment values. Thus, a reduction of acutely increased sympathetic activity toward pretreatment values during long-term nifedipine therapy was associated with further decreases in blood pressure. The importance of sympathetic activity was also stressed by the finding of an inverse relation between chronic changes in heart rate and blood pressure (percent of control, r = -0.76, p less than 0.01). Blood volume did not change during long-term nifedipine therapy. The results suggest that the degree of sympathetic reflex activation in part determines the antihypertensive response to nifedipine monotherapy.

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.

Changing Role of Beta- and Alpha-Adrenoreceptor-Mediated Cardiovascular Responses in the Transition from High-Cardiac Output into a High-Peripheral Resistance Phase in Essential Hypertension

The concept that the sympathetic nervous system might be implicated in essential hypertension was initially founded on the antihypertensive efficacy of anti-adrenergic drugs. Direct measurement of sympathetic nerve activity is difficult in man and, therefore, indirect estimates have been sought. Plasma norepinephrine concentrations reflect the rate of norepinephrine release from postganglionic adrenergic nerve terminals (1). Only 10%–20% of norepinephrine appears in the plasma and has no appreciable effect on adrenergic receptors (2). Plasma epinephrine reflects the rate of epinephrine release from the adrenal medulla and thus splanchnic preganglionic nerve activity. Epinephrine acts as a neurohormone on postjunctional adrenergic receptors, particularly those of the beta-type; it can also be taken up by adrenergic nerve endings, thereby enhancing, via prejunctional beta-adreno-receptors, the rate of norepinephrine release (3).

Inhibition of the arteriolar smooth muscle Na+-K+-pump induces an enhanced vasoconstriction in borderline but not in established essential hypertension

1. The dependency of arteriolar tone on the activity of the Na+ -K+-pump was studied in 17 normotensive (NT) males, aged 20-71 yr, without heredity for essential hypertension and 28 male patients with essential hypertension, aged 18-63 yr, by measuring forearm blood flow response to intra-arterial infusion of the Na+-K+-pump inhibitor ouabain. 14 of the patients were classified as borderline essential hypertensives (BHT) and 14 as established essential hypertensives (EHT). 2. Ouabain in incremental dosages 0.4-16 micrograms/100 ml tissue induced a vasoconstrictive response in the forearm with a maximal effect to 8 micrograms/100 ml tissue, which was not associated with an increase in regional noradrenaline release. 3. The vasoconstriction to ouabain 8 micrograms/100 ml was 29.6 +/- 6.8% in NT (P less than 0.001); 51.9 +/- 8.4% in BHT (P less than 0.001) and 36.0 +/- 12.7% in EHT (P less than 0.05). This response was greater in BHT than in NT (P less than 0.05) but not different in NT and EHT and did not correlate with age either in NT or in BHT and EHT taken together. 4. Our findings suggest an increased activity of the arteriolar Na+ -K+-pump in the early phase of essential hypertension which may to some extent correct a raised intracellular Na+; the latter being the consequence of an increased passive permeability to Na+. The activity of the arteriolar Na+ -K+-pump appears to be decreased in the later as compared to the early phase of essential hypertension.

Blunting of Exercise‐Induced Tachycardia and Renin Release 24 Hours After a Single Dose of Sotalol

Sotalol significantly reduces resting and exercise-stimulated heart rate and plasma renin activity 2 hours and to a lesser degree also 24 hours after oral administration of a single 200-mg dose in healthy volunteers. Because of this 24-hour beta-adrenoceptor blocking effect, sotalol should be suitable for once-daily dosing in clinical practice.

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.

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.