Murray D. Esler

Mild high-renin essential hypertension. Neurogenic human hypertension?

To determine whether the elevated plasma renin activity in some cases of mild essential hypertension expresses sympathetic-nervous-system over-activity, we compared indexes of sympathetic activity in 16 patients with mild high-renin essential hypertension, 15 hypertensive patients with normal plasma renin activity and 20 normal subjects. Patients with elevated activity exhibited a raised plasma norepinephrine concentration (P less than 0.05), a greater fall in cardiac output with cardiac beta-adrenergic blockade by intravenous propranolol (P less than 0.01), reduction in total peripheral vascular resistance with alpha-adrenergic blockade produced by intravenous phentolamine (P less than 0.01), and reduction to normal of blood pressure by total autonomic blockade (atropine, propranolol and phentolamine). On psychometric testing, patients with high-renin hypertension, but not those with normal plasma renin activity, exhibited suppressed hostility (P less than 0.01), a behavioral pattern linked to increased sympathetic activity. The hypertension in these patients with high renin activity is neurogenic and possibly psychosomatic in origin.

Autonomic nervous cardiovascular regulation in borderline hypertension.

Borderline hypertension attracts investigative interest since it is an early predictor of established hypertension and its sequelae. This condition offers the opportunity of studying arterial hypertension at its inception, before the development of secondary pressure-related changes. A number of abnormalities of the circulation have been described in borderline hypertension. The peripheral resistance is either elevated or inappropriately adjusted to the prevailing increased cardiac output and blood flow. Cardiac output, heart rate and stroke volume are elevated in a proportion of patients. Decreased plasma volume, enhanced pressor responsiveness and elevated plasma renin activity have also been noted. All these changes could hypothetically be explained by a neurogenic mechanism. Although the experimental evidence supporting a neurogenic origin of borderline hypertension is incomplete and often indirect, most findings point toward an abnormal autonomic control of the circulation in this disorder. It is postulated that in a subgroup of patients with borderline hypertension a neurogenic mechanism is in fact operative. There is a need for further characterization of this category of borderline hypertension and for description of its natural history, particularly in relation to the possible subsequent development of essential hypertension.

Altered cardiac responsiveness and regulation in the normal cardiac output type of borderlind hlpertension.

Of 145 patients with borderline hypertension, 30% had increased resting cardiac index (QI), whereas the remainder had normal values. The specific aim of this study was to investigate cardiac regulation in patients who had normal resting QI. Eighty-five control subjects were used for comparison. At rest, patients with normal QI showed evidence of decreased parasympathetic inhibition; the QI after injection of atropine increased less than in control subjects. After complete cardiac autonomic blockade with propranolol and atropine, QI and stroke volume were significantly lower in patients than in control subjects. The mechanism of this low QI was further analyzed. Central blood volume, which strongly correlates with stroke volume, was used as an estimate of the cardiac venous filling. After blockade, stroke volume was decreased in patients, but central blood volume was normal. Patients also showed a decreased heart rate and QI response to infusion of isoproterenol. It is therefore postulated that two components may be responsible for the low QI in the “denervated” heart: patients exhibit a decreased responsiveness to sympathetic stimulation, and they may also be less responsive to venous filling. Behind the facade of cardiac normality in these borderline hypertensive patients with normal cardiac output, there is evidence of altered autonomic control of the heart (decreased vagal inhibition) and of changed cardiac response to sympathetic stimulation and possibly to venous filling.

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.

Relation of renin status to neurogenic vascular resistance in borderline hypertension

The relation of renin-angiotensin status to general hemodynamics and to neurogenic vascular resistance was studied in patients with border-line hypertension. Plasma renin activity during standing was referred to a standard renin-urinary sodium nomogram derived from 18 normal subjects. Among 22 patients with borderline hypertension the renin level was high in 8, low in 4 and within normal limits in the remaining 10. In patients with borderline hypertension and high or normal levels of plasma renin activity, the blood pressure elevation was due to increased total peripheral vascular resistance. In contrast, in patients with low renin borderline hypertension, total peripheral resistance was not significantly elevated; the blood pressure elevation reflected a cardiac index 12 percent higher than that in normal subjects. The neurogenic contribution to total peripheral vascular resistance was assessed by studying the effects of alpha adrenergic blockade with phentolamine, after prior autonomic blockade of the heart with atropine (0.04 mg/kg body weight) and propranolol (0.2 mg/kg). Phentolamine (15 mg) produced an immediate reduction in total peripheral resistance of 12.0 +/- 6.7 percent in patients with high renin borderline hypertension (P less than 0.01) but no change in normal subjects or those with borderline hypertension and normal or low renin levels. Normalization of the blood pressure followed total autonomic blockade with atropine, propranolol or phentolamine only in patients with high renin borderline hypertension. It is concluded from these preliminary data that in high renin borderline hypertension the blood pressure elevation is sustained by neurogenic mechanisms. The elevated renin level in these patients is probably an expression of increased sympathetic nervous activity. Although the elevated plasma renin level may possibly be contributing to the generation of higher sympathetic tone, or data do not support a direct role of circulating angiotensin in the maintenance of the elevated vascular resistance.

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.

The Determinants of Plasma-Renin Activity in Essential Hypertension

Plasma-renin activity was studied, under different conditions of sitmulation, in normal subjects and patients with essential hypertension. In normal subjects, three components of renin release, basal, neural, and sodium-sensitive, could be delineated. Among the hypertensive patients, abnormal patterns of renin release were noted. The categorization of patients according to plasma-renin status, however, differed with the conditions of testing, being dependent both on the pathophysiology of the essential hypertension and the character of the renin-releasing stimulus, specifically whether this stimulus elevated plasma-renin activity through a predominantly neural (upright posture) or non-neural mechanism (dietary sodium deprivation). Abnormal plasma-renin activity in essential hypertension resulted in part from disordered sympathetic nervous system function. Patients with mild hypertension and elevated plasma-renin activity exhibited increased neural stimulation of renin release, whereas in patients with low plasma-renin values, all three components of renin release, including the neural element, were diminished.

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.

Factors influencing the choice of antihypertensive agents

Personal, social, and medical factors unique to individual patients have a bearing on the efficacy of specific antihypertensive agents and on the frequency and severity of side effects. The factors relate to age, sex, occupation, potential for adherence to a prescribed program of therapy, and associated health problems. The importance of a simple, inexpensive program is emphasized.

Patterns of Neurogenic Involvement in Borderline and Essential Hypertension

Publisher Summary This chapter Hemodynamics and indices of neurogenic tone are compared in 145 patients with borderline hypertension, 21 patients with essential hypertension, and 86 normal subjects. Some patients with borderline hypertension have an elevation of cardiac output that is fully neurogenic—cardiac output becomes normal after beta-adrenergic and parasympathetic cardiac blockade with intravenous propranolol and atropine. Sequential administration of propranolol and atropine in these patients reveals sympathetic cardiac stimulation and less vagal inhibition that points toward an altered integration of autonomic cardiac control. Analysis by renin status provides further insight. Based on the hemodynamic responses to propranolol and alpha-adrenergic blockade with phentolamine, borderline hypertensives with high plasma renin show evidence of increased adrenergic drive to the heart and resistance vessels. In these patients, the hypertension is entirely neurogenic, because a combined cardiac and vascular autonomic blockade elicits normotension. In borderline hypertensives with low plasma renin activity, there is no evidence of increased sympathetic tone. In mild established essential hypertension renin, categorization allows a similar differentiation. Essential hypertensives with high plasma renin activity have a faster heart rate, which is related to excess beta-adrenergic drive. Plasma norepinephrine concentration in these patients is elevated. Patients with low-renin essential hypertension does not show abnormality.