Sodium and responses to infused noradrenaline and angiotensin II in subjects predisposed to hypertension

A disturbed adrenergic dependent blood pressure regulation may represent a familial component in the pathogenesis of essential hypertension; its possible relation to sodium metabolism is presently unknown. Body sodium, the cardiovascular pressor reactivity to infused noradrenaline or angiotensin II, plasma levels of noradrenaline, adrenalin, renin, angiotensin II, aldosterone and atrial natriuretic peptide were measured on a low or high sodium diet in 10 normotensive young subjects without and 13 normotensive subjects with familial predisposition to hypertension. On the low sodium diet, the two groups did not differ significantly in the considered parameters, while blood pressure was slightly higher in predisposed subjects (+7/+7 mmHg). The change from the low to the high sodium diet was associated with a significant increase in supine systolic blood pressure in predisposed but not in non-predisposed subjects (P less than 0.05). Exchangeable sodium, body weight atrial natriuretic peptide and the pressor reactivity to infused adrenalin or angiotensin II increased significantly while plasma catecholamines, renin, angiotensin II and aldosterone levels were suppressed to a comparable extent in the two groups. The findings of this investigation confirm that sodium has an important regulatory effect on cardiovascular pressor responsiveness. The disturbed noradrenergic-dependent regulation of predisposed subjects is not explained by an abnormal adaptation of sympathetic dependent mechanisms or of other pressor factors to variations in dietary sodium intake.     

Antihypertensive contribution of sodium depletion and the sympathetic axis during chronic angiotensin II converting enzyme inhibition

The known physiological adaptation of cardiovascular sensitivity to variations in angiotensin II (Ang II) levels would predict that the blood pressure (BP)-lowering effect of Ang II inhibition might be at least partly counterbalanced by enhanced Ang II reactivity. Therefore, factors other than Ang II inhibition per se may contribute to the antihypertensive mechanisms of angiotensin converting enzyme (ACE) inhibitors. In order to further investigate this, the body sodium-blood volume state as well as the pressor reactivity to infused Ang II or norepinephrine (NE) were assessed in 12 normal subjects and 16 patients with essential hypertension given a placebo, and after 6 weeks of intervention with enalapril (20-40 mg/day). Enalapril produced in both groups similar falls in plasma ACE activity (P less than 0.0001) and upright plasma aldosterone (P less than 0.01), and a rise in plasma renin activity (PRA; P less than 0.05). BP decreased from 156/107 +/- 3/2 (mean +/- s.e.m.) to 142/94 +/- 5/3 mmHg (P less than 0.001) in the hypertensives and from 118/84 +/- 4/2 to 111/73 +/- 4/3 mmHg (P less than 0.01) in the normal subjects. In the hypertensive patients only, the Ang II pressor reactivity relative to Ang II plasma levels during Ang II infusion was increased (P less than 0.01), while the NE pressor reactivity relative to NE plasma levels during NE infusion (P less than 0.01) as well as the exchangeable body sodium (-5%, P less than 0.001) were reduced significantly. Blood and plasma volume, levels of plasma atrial natriuretic factor and catecholamines, and the heart rate and its response to isoproterenol were unchanged in both groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Correction of altered noradrenaline reactivity in essential hypertension by indapamide.

Fourteen patients with untreated mild to moderate essential hypertension had on average an abnormally high cardiovascular reactivity to exogenous noradrenaline and angiotension II, while plasma noradrenaline, renin activity, exchangeable body sodium, and blood volume were normal. Treatment with a low dose of indapamide (2.5 mg/day) for six weeks decreased blood pressure by 10% in these hypertensive patients but not in 13 normal control subjects. Plasma or blood volume and exchangeable sodium were not changed significantly; nevertheless, the latter, and body weight, tended to be decreased slightly. Though a mild reduction in extracellular sodium in both normal and hypertensive subjects appears possible, it may not per se fully explain indapamide's blood pressure-lowering effect in essential hypertension. Indapamide induced a mild decrease in angiotensin II pressor responsiveness in normal or hypertensive subjects, but a possible depressor influence from this change was probably antagonised by a concomitant pronounced increase in plasma renin activity. In hypertensive patients, the abnormally high noradrenaline reactivity was corrected by indapamide without an accompanying increase in endogenous plasma noradrenaline levels. Indapamide-induced changes in blood pressure correlated with those in noradrenaline pressor dose. It was concluded, therefore, that indapamide may decrease blood pressure in essential hypertension at least in part by lowering an abnormally high cardiovascular noradrenaline reactivity without causing an equivalent increase in adrenergic nervous activity.     

Sodium-volume factor, cardiovascular reactivity and hypotensive mechanism of diuretic therapy in mild hypertension associated with diabetes mellitus

Diabetes mellitus is often associated with excess body sodium and frequently accompanied by hypertension. Relationships among blood pressure and various regulatory factors were studied before and after six weeks of diuretic therapy with chlorthalidone, 100 mg/day, in 17 diabetic subjects (aged 32 to 75 years) with borderline to moderate hypertension. Following a four-week placebo phase, mean supine blood pressure was 165/93 ± 26/15 (±SD) mm Hg and exchangeable sodium was increased (49 ± 4 versus 45 ± 4 meq/kg lean body mass in 90 normal subjects; p < 0.01). Blood volume, and supine and upright plasma renin, aldosterone, norepinephrine, epinephrine or dopamine levels were comparable to normal values. Measurements in eight diabetic subjects revealed an increased cardiovascular reactivity, as evidenced by decreased (p < 0.001) pressor doses of norepinephrine (68 ± 42 versus 151 ± 52 ng/kg/min) or angiotensin II (3.9 ± 1.2 versus 10.3 ± 5.5 ng/kg/min). Chlorthalidone decreased blood volume by 11 per cent, lowered body sodium (by 9 per cent) and cardiovascular sensitivity to norepinephrine (by 48 per cent) or angiotensin II (by 60 per cent) towards normal and reduced blood pressure by 11 per cent to 145/82 ± 13/12 mm Hg (11 per cent). Plasma renin and aldosterone were markedly increased by chlorthalidone, whereas plasma and urinary catecholamine levels were not significantly altered. These findings suggest that hypertension in patients with diabetes mellitus may partly depend on increased body sodium and/or an exaggerated cardiovascular reactivity to norepinephrine and angiotensin II. The blood pressure-lowering effect of diuretic therapy may be due to removal of excess sodium and the restoration of norepinephrine pressor sensitivity towards normal without an equivalent increase in adrenergic nervous activity.     

Blunted aldosterone responsiveness to angiotensin II in normotensive subjects with familial predisposition to essential hypertension

The responsiveness of plasma aldosterone to an angiotensin (Ang) II infusion was assessed in normotensive young men, nine without and 13 with a family history of essential hypertension, after 7 days of low (mean urinary sodium 12 +/- 10 mmol/24 h) and 7 days of high (269 +/- 92 mmol/day) sodium intake. Under both conditions, the two study groups did not differ in body weight, arterial pressure, heart rate, plasma or urinary sodium and potassium or plasma renin, aldosterone or Ang II levels. However, after both dietary periods, the relationship between plasma aldosterone and plasma Ang II concentrations had shifted significantly (P less than 0.01) to the right in predisposed compared to non-predisposed subjects. The sodium-related changes in adrenocortical sensitivity to Ang II were similar in the two groups. The pressor response to Ang II did not differ between the two groups of subjects. These findings suggest that, in addition to the known cardiovascular abnormalities of sympathetic, renal and ion transport mechanisms, a fourth area of disturbance involving the response of plasma aldosterone to Ang II may be present in normotensive subjects with familial predisposition to essential hypertension.     

Captopril in clinical hypertension. Changes in components of renin-angiotensin system and in body composition in relation to fall in blood pressure with a note on measurement of angiotensin II during converting enzyme inhibition.

The effect of the converting enzyme inhibitor captopril on arterial pressure, the components of the renin-angiotensin-aldosterone system, and body sodium and potassium content was studied in eight hypertensive patients with renal artery stenosis and, in conjunction with diuretics, in seven patients with hypertension unresponsive to previous treatment. Two hours after the first dose, captopril caused significant falls in systolic and diastolic pressures, plasma angiotensin II, and aldosterone, with converse increases in angiotensin I and both active and total renin; the initial fall in diastolic pressure was significantly related to the drop in plasma angiotensin II. The biochemical changes were sustained during prolonged treatment, even when diuretics were added. One untreated patient with renal artery occlusion had severe secondary aldosterone excess, was sodium and potassium depleted, and severely hyponatraemic and hypokalaemic; captopril restored blood pressure, plasma electrolyte concentrations, and exchangeable sodium and total body potassium to normal. In one man with renal artery stenosis and overall renal impairment captopril led to sodium retention, and blood pressure did not fall until a diuretic was added. In the remaining patients with renal artery stenosis, pretreatment renin, angio tensin II, and aldosterone concentrations were either normal or only modestly raised, and plasma electrolyte concentrations and body content of sodium and potassium were normal. Captopril alone controlled arterial pressure in all, three cases showing a gradual fall of pressure over the first six weeks of treatment; no significant changes in exchangeable sodium or total body potassium were seen. The group of patients with previously intractable hypertension were all controlled with a combination of captopril and diuretic.     

Alpha 1-adrenergic blockade and cardiovascular pressor responses in essential hypertension

The effects of selective alpha 1-adrenergic blockade with terazosin on blood pressure and cardiovascular pressor responsiveness were assessed in 17 subjects with mild to moderate essential hypertension (mean age, 48 +/- 2 [SEM] years). As compared with a 2-week placebo period, 8 weeks of terazosin treatment (mean dose, 10.5 +/- 1.7 mg/day) caused a fall of supine (from 153/103 +/- 3/2 to 143/96 +/- 4/2 mm Hg; p less than 0.025) and upright (from 145/106 +/- 4/2 to 131/94 +/- 5/3 mm Hg; p less than 0.01) arterial pressure; a marked blunting of cardiovascular pressor responsiveness to norepinephrine, as judged from the pressor dose (from 73 +/- 9 to 2156 +/- 496 ng/kg/min; p less than 0.02) and from the rightward shift (p less than 0.01) of the plasma concentration-blood pressure response curve; and a slight increase in plasma norepinephrine concentration (from 37.7 +/- 3.3 to 52.2 +/- 7.8 ng/dl; p less than 0.01). Heart rate, body weight, exchangeable sodium, blood volume, and norepinephrine plasma clearance; plasma epinephrine, renin, angiotensin II, and aldosterone levels; the relationships between angiotensin II-induced increases in arterial pressure or plasma aldosterone and the concomitant increments of plasma angiotensin II; and heart rate responsiveness to isoproterenol did not change significantly after terazosin treatment. These findings suggest that the fall of arterial pressure induced by selective alpha 1-adrenergic blockade in subjects with essential hypertension is associated with, and probably explained by, inhibition of alpha 1-mediated, noradrenergic-dependent vasoconstriction. alpha 1-Adrenergic receptor antagonism did not modify body sodium concentration, the adrenomedullary component of the sympathetic nervous system, angiotensin II levels, or beta-adrenergic dependent mechanisms.     

Endogenous angiotensin-aldosterone-pressure relationships during sodium restriction

The effects of moderate restriction of dietary sodium and potassium supplementation on plasma levels of renin, angiotensin II, aldosterone, and cortisol and on arterial pressure were studied in 12 patients with mild essential hypertension. To define hormone-blood pressure relationships, venous hormone levels were measured hourly and intra-arterial pressure continuously for 24 hours after 4 to 6 weeks of sodium restriction, 4 to 6 weeks of potassium supplementation, and a similar period of control diet. Our results show that compared with the control diet, moderate sodium restriction was associated with increased levels of aldosterone but no overall change in renin, angiotensin II, or cortisol levels. Further, slopes of regression lines relating log renin and log angiotensin II to aldosterone were increased, as were log cortisol/aldosterone regression lines. On the contrary, regression lines of log renin and log angiotensin II versus arterial pressure were unaltered by sodium restriction. Hormone and blood pressure relationships were not changed by the potassium supplemented diet. Although confirmatory data are needed, our findings suggest that moderate sodium restriction enhances aldosterone responsiveness to endogenous angiotensin II and adrenocorticotropic hormone without diminishing the pressor activity of endogenous angiotensin II. These results may explain in part the disappointingly small hypotensive effect of modest sodium restriction in mild essential hypertension.     

Captopril in the management of hypertension with renal artery stenosis: Its long-term effect as a predictor of surgical outcome

Fifteen patients with hypertension and unilateral renal artery disease were treated with captopril alone; 10 came to operation and were later assessed postoperatively with no drug treatment. Captopril caused both immediate and sustained decreases in plasma angiotensin II and aldosterone, with increases in plasma active renin and blood angiotensin I concentrations. Decrements in systolic and diastolic pressure 2 hours after the first dose of captopril were closely correlated with the initial decreases in plasma angiotensin II. Blood pressure was decreased by long-term captopril therapy irrespective of whether plasma angiotensin II was abnormally high before treatment. The long-term response of both systolic and diastolic pressure correlated well with the response to surgery. By contrast, the blood pressure decrease 2 hours after the initial dose of captopril variously underestimated and overestimated the decrease during prolonged use of the drug and did not relate to surgical outcome. In patients who, before treatment, had secondary aldosteronism, hyponatremia, hypokalemia and sodium and potassium deficiency, captopril corrected these abnormalities. In the remaining patients, long-term captopril therapy did not alter exchangeable sodium, plasma sodium or total body potassium, although plasma potassium levels increased.     

Body-sodium and blood volume in a patient with licorice-induced hypertension

A 68-year-old man a nine-year history of licorice ingestion had moderate hypertension and low plasma potassium. Exchangeable sodium and blood volume were increased to 128 and 111%, respectively of the expected values; plasma renin and aldosterone levels were suppressed. Plasma norepinephrine concentration was distinctly elevated but the pressor response to infused norepinephrine was normal. After licorice withdrawal, blood pressure, plasma potassium and blood volume reverted to normal levels within three weeks, exchangeable sodium and plasma renin within four months. Exchangeable sodium in our patient with licorice-induced hypertension was increased to a comparable extent as in primary hyperaldosteronism. Moreover, blood pressure in relation to body sodium or plasma potassium did not differ between the exogenous or the endogenous types of mineralocorticoid excess. This observation does not support the possibility that in primary hyperaldosteronism excess aldosterone secretion per se could play an important pressor role independently from sodium retention.     

Attenuation of the development of spontaneous hypertension in rats by chronic central administration of captopril

Captopril infused into the lateral ventricle (ICV) of adult spontaneously hypertensive rats (SHR) decreases blood pressure. The current study was designed to explore the effects of brain converting-enzyme inhibition in young animals before the development of established hypertension and to characterize changes induced by captopril in a variety of pressor systems that might be responsible for the development of hypertension in this strain. Captopril (1.25 micrograms/0.5 microliter/hr) was infused into male SHR starting at 7 weeks of age. Four weeks later systolic blood pressure was only 157 +/- 3.3 compared to 181 +/- 3.9 mm Hg in vehicle-infused controls, and the pressor effect of ICV-injected angiotensin I was attenuated by 50%. When the same dose of captopril was infused intravenously, hypertension progressed as in vehicle-treated rats. Serum angiotensin-converting enzyme activity (SACE) and plasma arginine vasopressin (AVP) concentration were significantly higher (p less than 0.001 and 0.05, respectively), in the ICV captopril group than in the ICV vehicle group, while plasma aldosterone concentration and renin activity, fluid intake, urine volume, and urinary sodium excretion were similar in the two groups. Peripheral sympathetic nervous system activity assessed in the resting state was not altered by captopril treatment. In addition, AVP content of the telencephalon, diencephalon, mesencephalon, and pons medulla were not altered by ICV captopril. Renin activity was elevated in the telencephalon of ICV captopril-treated animals but unaltered in the other brain regions examined. These data demonstrate that ICV administration of captopril attenuates the development of hypertension in young SHR by mechanisms apparently independent of altered fluid and sodium balance and the sympathoadrenal system. The effect on blood pressure occurs in the absence of changes in renin activity or AVP content of plasma or those brain regions most often associated with blood pressure control.     

Acute responses to urapidil in hypertensive persons

Urapidil is a new antihypertensive agent involving both a peripheral and a central mode of action. To evaluate the acute effects of this drug on renal vascular tone and on pressor systems a randomized placebo-controlled crossover study was conducted in 10 patients with uncomplicated essential hypertension. Each subject received, on 2 separate days 1 week apart, an intravenous injection of either placebo or urapidil (25 or, if necessary, 50 mg). Before and after this injection blood pressure and heart rate (Dinamap), renal plasma flow (125I-hippuran), active plasma renin concentration, angiotensin II, aldosterone and catecholamines in plasma were measured. The results show that urapidil, when compared with placebo, greatly reduced blood pressure, while increasing heart rate, renal blood flow, and noradrenaline and adrenaline levels. However, dopamine levels were suppressed. Whereas renin and angiotensin II were only mildly stimulated, aldosterone levels increased significantly. It is concluded that urapidil, given intravenously, has an immediate blood pressure-lowering effect associated with a decrease in renal vascular tone and an increase in renal perfusion. Consequently, both the sympathetic and renin-angiotensin systems are stimulated, although the latter only to a mild degree. The increase in aldosterone may be partially related to the decrease in dopamine levels.     

Effect of sodium loading and depletion on vascular reactivity and prostacyclin generation

In order to estimate the modulatory activity of Prostacyclin (PGI2) to the vascular reactivity, pressor responses to angiotensin II (A II) and noradrenaline (NA) and PGI2 generation aorta were measured using the rats of sodium loading or of sodium depletion. On the sodium loading, the blood pressure increased gradually and plasma renin activity (PRA) and plasma aldosterone concentration (PAC) were decreased. The pressor responses to A II and NA were enhanced by sodium loading. The PGI2 generation of aorta was enhanced at the initial stage of sodium loading and decreased thereafter. The increased generation of PGI2 may represent the adaptive mechanism for the attenuation of the sustained elevation in blood pressure. It sodium depletion, the pressor responses to A II and NA were decreased, and PRA and PAC were elevated. PGI2 generation of aorta was also increased. These findings suggested that PGI2 could participate in blood pressure control mechanism on sodium loading and depletion.     

Renin-angiotensin system in dogs following chronic bile-duct ligation. Relation to vascular reactivity

The pressor response to angiotensin II, blood volume, angiotensin II in arterial blood, renin substrate, renin concentration, renin activity and aldosterone in venous blood, liver function tests, kidney function tests, glucose, sodium, potassium, plasma osmolality and complete blood count were examined before and 1, 2, 3 and 5 weeks after ligation of bile ducts in nine conscious trained dogs. The pressor response to angiotensin II was markedly suppressed after bile-duct ligation, especially at 1-3 weeks postoperation. A maximal decrease in plasma renin substrate, and maximal increases in plasma renin concentration, plasma renin activity and aldosterone were noted at 1 week postoperatively. Plasma angiotensin II levels were elevated at 1 and 5 weeks postoperatively but were near normal 2 weeks postoperatively despite suppression of the angiotensin II pressor response. Endogenous levels did not correlate with suppression of the pressor response to exogenous angiotensin II.     

The Effects of Saralasin, an Angiotensin II Antagonist on Blood Pressure and the Renin-Angiotensin-Aldosterone System in Normal and Hypertensive Subjects

Summary: The effects of saralasin, an angiotensin II antagonist, on blood pressure and the renin-angiotensin-aldosterone system in recumbent normal and hypertensive subjects.
Blood pressure reduction with saralasin infusion was seen only in hypertensive patients with abnormally elevated basal plasma renin and angiotensin II levels, and after sodium depletion the reduction in blood pressure was more marked. In normal subjects, and in hypertensives with plasma renin and angiotensin II levels within the normal range, there was no marked fall in blood pressure across saralasin infusion regardless of the sodium status of the individual.
Plasma aldosterone concentration fell during saralasin infusion in those subjects with high baseline renin and angiotensin II levels. This fall occurred in the sodium replete and deplete states. In the normal subjects, and those hypertensives with normal plasma renin levels, there was no fall in aldosterone in the sodium replete state. However, after sodium depletion the expected rise in aldosterone was abolished during saralasin infusion, the plasma aldosterone falling to within the normal sodium replete range, rising again after the saralasin infusion was stopped.
This study supports the concept of a direct role for renin and angiotensin II in the maintenance of hypertension in those subjects with elevated basal plasma renin. Plasma aldosterone would appear to be controlled, at least in part, by the prevailing plasma angiotensin II level in those subjects with elevated basal levels of angiotensin II; that is in high renin hypertensives, and in normal subjects and normal renin hypertensives who are sodium deplete.     

Effects of prolonged and brief infusions of noradrenaline on arterial pressure and on the plasma concentrations of active renin, angiotensin II, aldosterone and potassium

Conscious male beagle dogs were given constant intravenous infusions of noradrenaline for 14 days, four receiving 125 ng/kg/min and four 250 ng/kg/min. Before, during and after these infusions dose-response studies were done in which additional noradrenaline was infused at 500, 1000 and 2000 ng/kg/min, each rate for 1 h. Blood samples were taken before and during infusions for measurement of haematocrit and plasma concentrations of noradrenaline, active renin, angiotensin II, aldosterone, sodium and potassium. Fourteen-day infusion of noradrenaline at 125 ng/kg/min did not raise blood pressure significantly though infusion at 250 ng/kg/min did, but for the first week of infusion only. Heart rate decreased significantly at both rates. Arterial pressure fell markedly and significantly on stopping infusion. Mean plasma concentrations of renin, angiotensin II and aldosterone tended to be lower during prolonged infusion of noradrenaline, but only the fall of renin during the second week was significant in one group of dogs. Noradrenaline at higher rates significantly raised blood pressure and increased plasma concentrations of renin and angiotensin II. Plasma aldosterone concentration did not rise significantly, perhaps because plasma potassium concentration decreased; in support of this theory changes of plasma aldosterone correlated with changes of plasma potassium but not with changes of angiotensin II. The rise in arterial pressure during dose-response studies was related to the increase of plasma noradrenaline. Prolonged infusion of noradrenaline did not alter the dose-response relation between plasma noradrenaline concentration and arterial pressure.     

Mechanism of the blood pressure and renal hemodynamic effects of captopril

This study was designed to investigate the mechanisms of captopril's chronic effect on arterial pressure and renal function. In dogs maintained on high sodium intake (250 mEq/day), 6 days of captopril infusion caused no change in arterial pressure, renal hemodynamics, sodium excretion or plasma aldosterone concentration. Infusion of captopril for 7 days also caused no significant changes in arterial pressure or renal function in dogs made hypertensive by chronic infusion of angiotensin II and high sodium intake, a model of hypertension in which plasma renin activity is undetectable and prostaglandin and bradykinin formation may be elevated. In dogs maintained on low sodium intake, chronic infusion of captopril decreased arterial pressure and plasma aldosterone concentration markedly while increasing effective renal plasma flow. Infusion of aldosterone (200 μg/day) for 8 days during captopril infusion restored plasma aldosterone concentration but did not significantly change arterial pressure or renal function, indicating that decreased plasma aldosterone concentration did not play a major role in the hypotensive and renal effects of captopril. However, angiotensin II infusion (10 ng/kg/min) for 8 days during captopril infusion restored arterial pressure, plasma aldosterone concentration and renal function toward control levels. These data suggest that the effects of captopril on arterial pressure, renal hemodynamics and electrolyte excretion are mediated primarily by decreased angiotensin II formation.     

Oral calcium treatment lowers blood pressure in renovascular hypertensive rats by suppressing the renin-angiotensin system

The effects of calcium supplementation on blood pressure and its mechanisms were investigated in two-kidney, one clip renovascular hypertensive rats. Two series of experiments were performed: one was begun just after renal artery constriction, the other after the onset of hypertension. Calcium supplementation significantly attenuated the development of hypertension (systolic blood pressure: 183 +/- 8 vs 130 +/- 2 mm Hg) and was found to abate existing renovascular hypertension (systolic blood pressure: from 183 +/- 8 to 151 +/- 4 mm Hg). Calcium treatment did not cause significant alterations in fluid intake, urine volume, or urinary sodium excretion in either study. However, increased plasma renin activity and plasma aldosterone concentration were suppressed to the basal levels at the end of 3 weeks of calcium treatment (14 +/- 3 vs 8 +/- 2 ng angiotensin I/ml/hr; 530 +/- 50 vs 380 +/- 40 pg/ml). Blood pressure of calcium-treated renovascular hypertensive rats responded poorly to blockade of the renin-angiotensin system with captopril injection and angiotensin II analogue (saralasin) infusion. Further, in rats with chronic established renovascular hypertension, calcium treatment attenuated the enhanced pressor response to norepinephrine, but not to angiotensin II. These results suggest that the blood pressure-lowering actions of calcium supplementation are related primarily to suppression of renin secretion and secondarily to alteration of pressor response to norepinephrine in two-kidney, one clip renovascular hypertensive rats.     

Effects of the Calcium Antagonist Felodipine on the Sympathetic and Renin-Angiotensin-Aldosterone Systems in Essential Hypertension

ABSTRACT Studies were performed in 10 male patients with untreated essential hypertension, WHO grade I-II, aged 25–62 years, to explore the acute (single dose) and long-term (8 weeks) effects of felodipine on sympathetic activity—evaluated by plasma and urinary catecholamines—as related to blood pressure, heart rate and the activity in the renin-angiotensin-aldosterone system. The patients were hospitalized for 8 (acute) and 6 (long-term) days and were maintained on a standardized daily intake of sodium (150 mmol), potassium (75 mmol) and water (2500 ml). Acute felodipine administration (10 mg) significantly reduced blood pressure and increased heart rate. Plasma and urinary noradrenaline, plasma renin activity and angiotensin II increased, whereas plasma and urinary adrenaline, dopamine, aldosterone and plasma vasopressin were unaltered. Long-term felodipine treatment, 10 mg twice daily, reduced blood pressure to a similar extent as acute felodipine administration, but heart rate was not significantly changed. Plasma noradrenaline 3 and 12 hours after the last dose and urinary noradrenaline were increased, whereas plasma and urinary adrenaline and dopamine were unchanged. Plasma renin activity and angiotensin II were increased 3 hours, but unchanged 12 hours after the last dose. Plasma aldosterone was unchanged but urinary aldosterone increased. Plasma vasopressin was unchanged. The changes in plasma noradrenaline as related to blood pressure, heart rate, plasma renin activity and angiotensin II during long-term felodipine treatment may reflect decreased cardiac and renal β-adrenoceptor-mediated responses. Increased renal clearance of aldosterone could partly explain the unaltered plasma aldosterone level in spite of increased plasma angiotensin II following long-term felodipine treatment.     

Enhanced aldosterone response to angiotensin II in human hypertension.

Adrenal and vascular responsiveness to graded doses of angiotensin II (A II) were recorded for seven normal subjects and 12 patients with essential hypertension while in balance on an intake of 200 mEq sodium/100 mEq potassium. Patients with essential hypertension had been previously studied and known to have normal responses of plasma renin activity to sodium restriction and upright posture. A II was administered for 30 minutes at rates of 0.1, 0.3, 1, and 3 ng/kg per minute and plasma aldosterone responses were assessed 20 and 30 minutes later; blood pressure was monitored at intervals of 1 minute during infusion of A II at each rate. A significant increment in plasma aldosterone occurred at an infusion rate of 0.3 ng/kg per minute in patients with hypertension. This change was not seen until the infusion rate reached 1.0 ng/kg per minute in the normotensive control subjects. Even at an A II infusion rate of 1 ng/kg per minute, the increment in plasma aldosterone levels in normotensive subjects (4.2 +/- 0.6 ng/dl) was significantly less (P less than 0.001) than that in patients with essential hypertension (19 +/- 3 ng/dl). In both groups, a significant rise in mean arterial blood pressure occurred at an A II dose of 0.3 ng/kg per minute, but the pressor response of the hypertensive group was significantly greater at the highest infusion rate (3 ng/kg per minute) (P less than 0.05). Thus, enhanced adrenal and pressor responsiveness to infused A II was observed in the hypertensive subjects, suggesting a change in A II receptor affinity.