Effect of propranolol on cyclic AMP excretion and plasma renin activity in labile essential hypertension

Labile hypertension is often associated with elevated cardiac output, increased plasma renin activity (PRA) and urinary cyclic AMP excretion in response to upright posture and to isoproterenol. The β-blocking agent propranolol was demonstrated to be an effective therapeutic agent in this condition. The effect of posture on cyclic AMP, PRA, pulse rate and blood pressure was therefore studied during the administration of propranolol and a placebo in patients with labile hypertension. With the patient on placebo, upright posture induced an increase in pulse rate, cyclic AMP excretion and PRA. Propranolol administration decreased the recumbent and upright blood pressures, pulse rate and PRA. Cyclic AMP excretion remained unchanged in the recumbent position but the postural increase was abolished. No appreciable changes in catecholamine excretion occurred during propranolol administration. Propranolol normalizes some humoral as well as hemodynamic abnormalities of labile hypertension and therefore may be of benefit in long-term treatment and possibly also in the prevention of stable hypertension.     

Aldosterone and renin in essential hypertension.

A review of some recent laboratory findings indicates definite disturbances in aldosterone metabolism and regulation in patients with mild essential hypertension: (a) a significant mean increase in plasma aldosterone concentration in patients with mild and stable essential hypertension, in contrast to the absence of any difference in patients with labile borderline essential hypertension when in a normotensive phase, compared with control subjects; and (b) a significant mean decrease in metabolic clearance rate of aldosterone, associated with a 12% decrease in hepatic blood flow and an increased binding of aldosterone to a transcortin-like plasma globulin. The secretion rate of 18-hydroxy-11-deoxycorticosterone is above the upper range of normal in 60% of patients with mild, uncomplicated essential hypertension. The incidence of low-renin hypertension, when age and race are taken into account, is much lower than previously assumed. Unless measurements are repeated over a long period, one or two low values of plasma renin cannot be considered a permanent marker indicating a special category of patients with essential hypertension. Tonin, a new enzyme discovered by Boucher, which forms angiotensin II directly from a plasma protein, from the tetradecapeptide substrate and from angiotensin I, is present in most tissues, but in highest concentration in the submaxillary gland. This enzyme is under the control of beta-adrenergic receptors.     

Effect of propranolol on plasma renin activity, renal cortex renin, and adrenal and brain isorenins in rats.

Propranolol administration to rats was studied for its effects on plasma renin activity, renal renin content, and adrenal and brain isorenins. Propranolol was given intraperitoneally at 6 and 30 mg/kg/day for a 15-day period. Pulse rate was significantly decreased. There were no effects on the isorenin content of adrenal or brain tissue or on renal renin content. Rats responded in two completely different ways with respect to plasma renin activity. Two-fifths had a total suppression of plasma renin activity; the rest had concentrations similar to those in controls. These observations are consistent with those seen during chronic administration of propranolol to hypertensive patients and suggest that its antihypertensive effect may in some patients be through the suppression of renin release. Its mechanism of action in most patients remains at present unclear.     

Plasma leptin levels strongly correlate with plasma renin activity in patients with essential hypertension.

Previous studies demonstrated elevated plasma leptin and angiotensinogen (PRA) levels in essential hypertension. However, a few studies investigated the relationship between leptin and angiotensinogen levels in both lean and overweight/ obese hypertensives. The aim of the present study was therefore to examine the relationship between blood pressure, leptin and plasma renin activity in normotensives and in both lean and overweight/obese patients with essential hypertension. Two groups of subjects who were carefully matched for age, gender, waist:hip ratio and body mass index (BMI) were studied: 28 normotensives (NT) (age: 40.1+/-9.1 years old, BMI: 28.1+/-3.6 kg/m2, male/female: 18/10) and 33 newly diagnosed mild to moderate essential hypertensives (EHT) (age: 38.9+/-10 years old, BMI: 27.9+/-4.8 kg/m2, male/female: 22/11). No significant differences in age, gender, waist:hip ratio, fasting blood glucose and BMI were detected between EHT and NT groups. However, systolic and diastolic pressures, mean arterial blood pressures, plasma leptin levels and PRA were significantly higher in EHT group than in NT group (P = 0.001). Plasma leptin levels were strongly correlated with BMI in EHT (r=0.67, P = 0.001) and NT groups (r=0.44, P = 0.001). Plasma leptin levels were correlated with plasma PRA levels in both EHT and NT groups (r = 0.66 and r = 0.44; both P < 0.05, respectively). There was no correlation between leptin or PRA and systolic, diastolic pressures, or mean arterial blood pressures. Furthermore, the patients were divided as lean (n=16) and overweight/obese (n = 17) and compared with BMI-matched controls. In both subgroups, plasma leptin and PRA levels were also higher than those of controls. Our results showed that elevated plasma leptin and PRA are associated with hypertension in both lean and overweight/obese hypertensives. Moreover, plasma leptin was significantly correlated with plasma angiotensinogen levels. These findings suggest that adipose mass is an important determinant of blood pressure, although the mechanism is not clear.     

Calcium metabolism in essential hypertension: relationship to altered renin system activity

Hypertensive disease is associated with various abnormalities of calcium metabolism although how these abnormalities relate to the elevated pressure remains unclear. Based on the use of renin-sodium profiling, we have defined heterogeneous deviations in circulating levels of ionized calcium and magnesium as well as of the calcium-regulating hormones parathyroid hormone, calcitonin, and 1,25-dihydroxyvitamin D (1,25D), which parallel similar deviations in plasma renin activity. Essential hypertensive subjects with a profile of low renin, lower ionized calcium, and elevated 1,25D respond best to the calcium channel blocker nifedipine, demonstrate an enhanced sensitivity to the blood pressure effects of dietary salt loading, and have significantly lower blood pressures in response to oral calcium supplementation. Hypertensive subjects with the opposite metabolic profile--higher renin activity, higher serum ionized calcium, and lower 1,25D levels--are relatively insensitive to the blood pressure effects of either dietary salt loading or nifedipine, and show no significant hypotensive response to calcium supplements. Altogether, these alterations of calcium ionic and hormonal metabolism suggest that the hormonal control of calcium metabolism is linked to renin system activity as well as to the pathophysiology of the hypertensive process.     

Relation between arterial pressure,dietary sodium intake,and renin system in essential hypertension.

Forty-one patients with mild essential hypertension, 36 patients with severe hypertension, and 28 normotensive subjects were studied on a high sodium intake of 350 mmol/day for five days and low sodium intake of 10 mmol/day for five days. The fall in mean arterial pressure on changing from the high-sodium to the low-sodium diet was 0.7 +/- 1.7 mm Hg in normotensive subjects, 8 +/- 1.4 mm Hg in patients with mild hypertension, and 14.5 +/- 1.4 mm Hg in patients with severe hypertension. The fall in blood pressure was not correlated with age. Highly significant correlations were obtained for all subjects between the ratio of the fall in mean arterial pressure to the fall in urinary sodium excretion on changing from a high- to a low-sodium diet and (a) the level of supine blood pressure on normal diet, (b) the rise in plasma renin activity, and (c) the rise in plasma aldosterone. In patients with essential hypertension the blood pressure is sensitive to alterations in sodium intake. This may be partly due to some change either produced by or associated directly with the hypertension. A decreased responsiveness of the renin-angiotensin-aldosterone system shown in the patients with essential hypertension could partly account for the results.     

Effect of somatostatin on plasma renin activity and blood pressure in patients with essential hypertension

The effects of somatostatin on plasma renin activity (PRA) and blood pressure were evaluated in patients with essential hypertension (EH) and in normotensive subjects. All subjects examined were hospitalized and placed on a diet containing 7-8 g/day sodium chloride and received an intravenous infusion of somatostatin (500 microgram/20 ml of saline, for 60 min) in the basal condition. During somatostatin infusion, the mean blood pressure (MBP) remained unaffected in all patients with EH and the normotensive subjects, while the PRA decreased slightly in the EH group. When the patients with EH were classified according to their renin levels (low, normal and high), parallel significant decreases in MBP and PRA were found only in the high renin group during the somatostatin infusion. No significant change in MBP and PRA was observed in the other groups including the normotensive subjects. To assess the activity of synthetic somatostatin, the plasma levels of growth hormone (GH) and cyclic AMP were measured. These levels were lowered significantly during the infusion and the GH levels showed a rebound 15 min after cessation of the infusion. The cyclic AMP returned to the basal levels, but no rebound was observed. The above data indicate that the fall in blood pressure in the high renin group in the basal condition was probably due in part to reduced renin release by somatostatin, and the maintenance of high blood pressure especially in high renin EH.     

Metabolic consequences of atenolol and propranolol in treatment of essential hypertension.

A six-month study of triglyceride, cholesterol, free fatty acid (FFA), glucose, insulin, growth hormone, and glucagon concentrations was carried out in asymptomatic hypertensive normal-weight men randomly allocated to treatment with atenolol or propranolol. A highly significant increase in the basal plasma triglyceride concentration was observed in propranolol-treated patients after three and six months'' treatment, with a smaller but significant increase in atenolol-treated subjects after six months'' treatment. The changes in triglyceride concentration could not be ascribed to variations in plasma insulin, growth hormone, or glucagon concentrations. Basal FFA concentrations were reduced during the first three months of treatment in both groups but returned to pretreatment levels after six months. Plasma cholesterol concentrations were unchanged by either agent.     

Changes of plasma renin and renal renin concentration in HgCl2 induced acute renal failure in rats.

Acute renal failure (ARF) was produced by the single intraperitoneal injection of 3 mg/kg mercuric chloride (HgCl2) in male Wistar rats. Immediately after, and in the 1st, 3rd, 6th, 24th and 48th hour after HgCl2 administration the following variables were monitored: plasma renin concentration (PRC), renal renin concentration (RRC) blood-urea nitrogen (BUN), plasma sodium (PNa), plasma creatinine (PCr) concentrations and haematocrit (Ht). Haematocrit and PNa increased during the first hour and returned to the control value in the 3rd hour. Thereafter, their level remained unchanged. Plasma renin concentration increased threefold during the first six hours after the HgCl2 injection, however, by the 48th hour it returned to the control value. In the first 24 hours of ARF, RRC remained unchanged. However, by the 48th hour its level increased four times the control value. After mercury injection BUN and PCr increased progressively. We were not able to establish any significant correlation between the changes of PRC and BUN. A gradual increase of RRC was observed in the course of ARF.     

Radioactive 86rubidium influx into red blood cells in essential hypertension in relation to the plasma renin activity

Changes in several mechanisms of sodium transport across the cell membranes are described in essential hypertension. We studied ouabain-sensitive and insensitive 86Rb+ influx into the red blood cells (RBC) of 16 healthy controls and 51 patients with essential hypertension (EH) divided according to their plasma renin activity (PRA) in 3 groups: 11 patients with high PRA (HREH), 18 patients with normal PRA (NREH) and 22 patients with low PRA (LREH). In addition to studying 86RB+ uptake by patients RBC, we tested also the effect of the patients' sera on 86Rb+ influx into the RBC of healthy subjects. Red blood cells of patients with HREH and NREH had lower ouabain-sensitive 86Rb+ influx in comparison with controls. No significant differences were found between these hypertensive groups. In contrast 86Rb+ uptake by the RBC of LREH patients was always higher than in controls or HREH and NREH. It was chiefly the ouabain-sensitive component that was raised, but some increase in ouabain-insensitive 86Rb+ influx also could be seen. The serum of patients with HREH and NREH, when incubated with RBC of healthy controls, lowered their ouabain-sensitive 86Rb+ influx. The decrease was more pronounced in NREH than in HREH group. Plasma from LREH patients increased both ouabain-sensitive and ouabain-insensitive 86Rb+ influx into the control RBC. These findings indicate that there may be differences in the sodium/potassium transport mechanisms across the cell membrane in various kinds of EH.(ABSTRACT TRUNCATED AT 250 WORDS)     

Captopril in essential hypertension; contrasting effects of adding hydrochlorothiazide or propranolol.

Twenty-four patients with moderate to severe hypertension were treated for four weeks with captopril, an oral inhibitor of angiotensin-converting enzyme. The fall in blood pressure with captopril alone correlated with pretreatment plasma renin activity. The effect of adding either hydrochlorothiazide or propranolol to the captopril treatment was then studied. The addition of hydrochlorothiazide to captopril produced a dose-dependent fall in blood pressure. At the higher dose of the diuretic this fall in blood pressure correlated with weight loss, suggesting that when the diuretic-induced compensatory rise in angiotensin II is prevented by captopril the fall in blood pressure becomes dependent on loss of sodium and water. In contrast, the addition of propranolol to captopril produced no further fall in blood pressure, suggesting that inhibition of angiotensin-converting enzyme prevents the blood pressure lowering effect of propranolol. This may have implications for the mechanism whereby beta-blockers alone lower blood pressure. These contrasting effects of hydrochlorothiazide and propranolol in the presence of captopril indicate that in patients whose hypertension is not controlled by captopril alone the addition of increasing doses of diuretic is likely to control the blood pressure. The addition of a beta-blocker, however, is less likely to be effective.     

The influence of plasma renin substrate on the relationship between plasma renin activity and plasma renin concentration. An experimental study in hyper- and hypothyroid rats

The effects of endogenous Plasma Renin Substrate (PRS) on the relationship between Plasma Renin Activity (PRA) and the Plasma Renin Concentration (PRC) have been studied in hyperthyroid rats, by I-triiodothyronine (T3) administration and in hypothyroid rats, by propylthiouracil (PTU) treatment, to clarify if PRA changes are an adequate index for evaluating the renin-angiotensin changes during the alterations in the thyroid function. Although in experimental situations studied the induced variation on PRC explains a 62 per cent of the changes in PRA, finding a good lineal correlation between both parameters (r = 0.79, P less than 0.001). Not only does PRS play an important role on the kinetic of the enzymatic reaction but also explains jointly with PRC up to a 85 per cent of PRA alterations. PRS changes become more important during thyrotoxicosis where they limit in a higher degree the velocity of reaction due to inverse relationship between PRC and PRS (r = 0.74, P less than 0.001).