Andrew J. Zweifler

Suppression of sympathetic nervous function in low-renin essential hypertension.

Study of general haemodynamics in 15 patients with low-renin essential hypertension showed haemodynamic and pathophysiological heterogeneity. However, there was suppression of sympathetic nervous system function in all low-renin patients, regardless of haemodynamic pattern. Subnormal sympathetic nervous activity was manifested by a low normal mean plasma-noradrenaline concentration at rest, diminished noradrenaline responsiveness to postural stimulation, and a reduced blood-pressure response to the indirectly acting sympathomimetic amine tyramine. It is proposed that the syndrome of low-renin essential hypertension is of diverse aetiology, but with secondary sympathetic nervous system underactivity as a feature common to the various forms. The low plasma-renin activity is probably an expression of defective sympathetic nervous system stimulation of renin release.

Pathophysiologic and pharmacokinetic determinants of the antihypertensive response to propranolol

The tendency for patients with essential hypertension to differ markedly in antihypertensive response to propranolol could arise from pathophysiologic or pharmacokinetic differences between them. This possibility was investigated in 23 men with mild to moderately severe essential hypertension. At each of three propranolol doses, 40 mg, 80 mg, and 320 mg daily, approximately a 20‐fold range in steady‐state plasma propranolol concentrations was observed. Clinical response however was unrelated to plasma propranolol: oral dose ratio, since patients with higher plasma levels were less sensitive to the existing plasma drug concentration. When falls in blood pressure and plasma propranolol concentration were compared overall, a biphasic dose‐response relationship was noted, with a first component at plasma propranolol concentrations of 3 to 30 ng Iml and a second at concentrations above 30 ng Iml. Only patients with increased sympathetic nervous system activity and high plasma renin activity (PRA) had substantial falls in pressure at propranolol levels of 3 to 30 nglml. Cardiac beta adrenergic receptor blockade, not suppression of PRA, seemed to be the antihypertenisve mechanism. This relation of pretreatment sympathetic nervous activity and PRA to antihypertensive response existed only at lower plasma propranolol concentrations. With a propranolol dose of 320 mg daily, both plasma norepinephrine concentration and PRA were unrelated to the clinical response.

Increased platelet catecholamine content in pheochromocytoma: a diagnostic test in patients with elevated plasma catecholamines.

Platelet catecholamine content was determined by radioenzymatic assay in 16 patients with elevated plasma norepinephrine or epinephrine or both and a clinical picture suggesting pheochromocytoma. Twenty-two normal subjects served as controls. Pheochromocytoma was documented in 10 patients, all of whom had markedly elevated platelet catecholamines. The other six patients had no tumor, and their platelet catecholamine levels were normal. Platelet catecholamines tended to return to normal more slowly than plasma catecholamines after removal of the pheochromocytoma, suggesting that platelets were rich in stored catecholamines. Determination of platelet catecholamine content is a helpful aid to the diagnosis of pheochromocytoma in patients with suggestive but not diagnostic elevations of the plasma catecholamine concentration.

Sympathetic Nervous System Involvement in Essential Hypertension: Increased Platelet Noradrenaline Coincides with Decreased β-Adrenoreceptor Responsiveness

Platelet catecholamine content may reflect integrated plasma catecholamine concentrations over time. The present study aimed at examining sympathetic nervous system (SNS) involvment in essential hypertension by assessing platelet noradrenaline (NA) and typically β-adrenoreceptor mediated responses to adrenaline (A) infusion as indices of sympathetic tone. Healthy white men were recruited by public advertising and screening (mean ± SD): Hypertensives (n = 13, sitting blood pressure [BP] 153 ± 13/106 ± 7 mmHg, age 34 ± 5 years, weight 83 ± 10 kg) were compared to normotensives (n = 13, sitting BP 114 ± 9/75 ± 9 mmHg, age 30 ± 6 years [n.s.], weight 82 ± 9 kg [n.s.]). Loss of platelet granular contents (including NA) prior to analysis was minimized by studying young subjects (age range 20–40 years, minimal atherosclerosis), using arterial blood sampling, and processing blood immediately. These procedures resulted in plasma β-thromboglobulin and platelet factor 4 levels which were not significantly different ...

EVIDENCE AGAINST AN INTERACTION OF ANGIOTENSIN II WITH THE SYMPATHETIC NERVOUS SYSTEM IN MAN

Animal experiments indicate that angiotensin II can, under some circumstances stimulate the sympathetic nervous system at a number of different sites. In order to determine whether such a relationship of the renin‐angiotensin and sympathetic nervous system exists in man, we increased (by intravenous infusion), or decreased (by administering the oral converting enzyme inhibitor captopril) circulating angiotensin II levels and monitored plasma adrenaline and nor‐adrenaline responses. Angiotensin II infusions did not increase plasma catechol‐amines, and lowering of angiotensin II by captopril treatment in patients with severe hypertension or congestive heart failure failed to alter plasma adrenaline or nor‐adrenaline levels. Whether physiological levels of angiotensin II are capable of interacting directly with the sympathetic nervous system in man remains to be demonstrated.

Importance of overweight in studies of left ventricular hypertrophy and diastolic function in mild systemic hypertension.

The relations of Metropolitan Life Insurance Co. Relative Weight values and blood pressure (BP) to minimal forearm vascular resistance, ventricular septal and posterior wall thickness, left ventricular (LV) mass index and cardiac diastolic function were assessed in 31 men, 37 +/- 2 (mean +/- standard error of the mean) years of age. Eighteen patients with untreated mild hypertension were compared with 13 normotensive control subjects of similar age and weight. The hypertensives had higher clinic (137 +/- 3/96 +/- 2 vs 121 +/- 4/81 +/- 3 mm Hg, p less than 0.001/less than 0.001) and home (p less than 0.001) BP. Despite higher BP, the hypertensives did not have significantly greater values than normotensives, respectively, for minimal forearm vascular resistance (2.20 +/- 0.12 vs 2.04 +/- 0.11 U), ventricular septal (9.9 +/- 0.5 vs 10.2 +/- 0.3 mm) and posterior wall thickness (10.2 +/- 0.4 vs 10.0 +/- 0.3 mm) or LV mass index (106 +/- 6 vs 107 +/- 6 g/m2). Furthermore, diastolic peak filling rate, an index of LV diastolic function, was virtually identical in the 2 groups (2.71 +/- 0.14 vs 2.69 +/- 0.07 liters/s, difference not significant). Correlates of peak filling rate included relative weight (r = -0.62, p less than 0.001), posterior wall thickness (r = -0.51, p less than 0.01) and age (r = -0.45, p less than 0.05). Relative weight also correlated significantly with posterior wall (r = 0.59, p less than 0.005), ventricular septal (r = 0.47, p less than 0.005) and LV mass index (r = 0.38, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Diminished finger volume pulse in borderline hypertension: Evidence for early structural vascular abnomality

Digital volume pulse maximum dilation was determined in 27 patients with borderline essential hypertension (BHT) and 28 age-matched normotensive controls (NT). Finger pulse volume (PV) and finger systolic pressure (SBP) were measured by pneumoplethysmography during vasodilation induced by combining direct and reflex heat dilation and reactive hyperemia. Finger SBP was higher (p less than 0.01) in BHT than in NT (120 +/- 18.7 vs. 104 +/- 14.8 mm Hg, respectively); PV was lower (p less than 0.01) in BHT than in NT (9.7 +/- 4.2 vs. 15.3 +/- 6 ml/5 ml finger X 10(-3). Pulse volume correlated inversely with SBP in BHT (r = -0.40, p less than 0.05) but was unrelated to SBP in NT. Pulse volume was not altered by high or low sodium intake in BHT or NT despite significant changes in plasma renin activity (PRA). In BHT finger vessels are less distensible at a higher pressure than in NT. This abnormality is demonstrable during maneuvers to withdraw sympathetic tone and is not influenced by alteration of PRA. These data support the concept that BHT can produce structural vascular change, and demonstrate that this abnormality can be detected by a relatively simple method.

Blood pressure, renin activity and heart rate changes during propranolol therapy of hypertension

To investigate the importance of plasma renin activity in determining the antihypertensive action of propranolol and of heart rate in guiding propranolol therapy, the effect of a graded oral dose of propranolol on blood pressure, plasma renin and heart rate was studied in 24 men with essential hypertension and differing initial levels of renin activity. Although plasma renin decreased substantially in patients with normal and high renin levels tasking a small dose of propranolol (40 mg/day), blood pressure was unchanged in the normal renin group, and a small decrease in systolic pressure alone was noted in those with high plasma levels of renin. Patients with low renin levels had no reduction in blood pressure with small doses of propranolol, but as a group they responded well to a dose of 320 mg/day. Standing heart rate decreased maximally at plasma propranolol concentrations greater than 25 ng/ml, and did not exceed 72 beats/min with plasma concentrations above that level. Overall, the observed responses for plasma renin and heart were more pronounced at lower plasma propranolol concentrations than those for blood pressure.

Clonidine-induced suppression of plasma catecholamines in states of adrenal medulla hyperfunction

To assess adrenal medulla activity in states of hyperfunction, a single 0.3 mg oral dose of clonidine hydrochloride (Catapres®) was given to twelve patients with varying evidence of familial adrenal medullary hyperplasia and pheochromocytomas from kindreds with Multiple Endocrine Neoplasia type 2 syndrome (MEN-2), seven patients with sporadic pheochromocytomas and six normal subjects. Mean arterial blood pressure and plasma norepinephrine (NE) levels were lower than baseline values 2h after clonidine in the normal subjects. Plasma epinephrine (E) rose in one normal but fell in the remainder after clonidine administration. In sporadic pheochromocytoma patients, E fell slightly in 4 and NE fell in 3 while mean arterial blood pressure was not significantly lower than baseline values in 7 patients 2 h after clonidine. In MEN-2, mean arterial blood pressure fell and there was a variabile response of plasma E and NE to clonidine, which appears to be related to the presence of detectable anatomic (CT scan) and functional (131I-mIBG scintigraphy) abnormalities of the adrenal medulla. These findings are thus compatible with the spectrum of adrenal medulla dysfunction and the presumed development of pheochromocytoma in this syndrome.

Effect of phenoxybenzamine on cardiovascular and plasma catecholamine responses to clonidine

To determine whether the alpha‐adrenergic antagonist phenoxybenzamine would alter cardiovascular or plasma catecholamine response to the alpha‐adrenergic agonist clonidine, six patients with pheochromocytomas and eight with labile hypertension were studied. Clonidine, 0.3 mg, was given with and without 48 hr pretreatment with 30 mg/day phenoxybenzamine. The response to 10 mg diazepam was also observed in seven of the subjects who had labile hypertension. In the hypertensive patients, clonidine alone induced a fall in supine blood pressure from 137 ± 21/91 ± 14 to 109 ± 18/76 ± 17 mm Hg and, with phenoxybenzamine, clonidine reduced blood pressure from 141 ± 22/89 ± 10 to 107 ± 21/72 ± 11 mm Hg. Plasma norepinephrine fell from 179 ± 60 to 107 ± 79 pg/ml without phenoxybenzamine and from 229 ± 159 to 95 ± 46 pg/ml with phenoxybenzamine in hypertensive subjects. Responses with phenoxybenzamine did not differ from those without phenoxybenzamine and diazepam induced no cardiovascular or plasma catecholamine changes. Clonidine did not lower plasma catecholamines in patients with a pheochromocytoma in the presence or in the absence of phenoxybenzamine. Blood pressure tended to decline after clonidine in pheochromocytoma patients not taking phenoxybenzamine, but it was not reduced by clonidine when these patients were taking phenoxybenzamine. Phenoxybenzamine does not inhibit reduction in blood pressure and plasma catecholamines induced by clonidine in patients with essential hypertension or interfere with the clonidine suppression test in patients with pheochromocytomas.