A F Lever

Angiotensin II causes vascular hypertrophy in part by a non-pressor mechanism.

Angiotensin II, when given in low doses, raises blood pressure slowly. When tested in vitro on vascular smooth muscle cells, it has mitogenic and trophic effects; it is not known if it has these effects in vivo. Our purpose was to determine whether vascular hypertrophy develops during slow pressor infusion of angiotensin II and, if so, whether it is pressure induced. Three experiments were done in rats infused subcutaneously with angiotensin II (200 ng/kg/min) by minipump for 10-12 days. Experiment 1: Angiotensin II gradually raised systolic blood pressure (measured in the tail) from 143±2 to 208±8 mm Hg (mean±SEM), significantly suppressing plasma renin and increasing threefold (NS) plasma angiotensin II. There was no loss of peptide in the pump infusate when tested at the end of the experiment. Experiment 2: In the perfused mesenteric circulation, vasoconstrictor responses to norepinephrine, vasopressin, and KC1 were enhanced in rats given a slow pressor infusion of angiotensin II, but sensitivity of responses was not altered. This combination of changes suggests that vascular hypertrophy develops during slow pressor infusion of angiotensin II. Experiment 3: Vessel myography was done after angiotensin II infusion with and without a pressor response. Angiotensin II raised systolic blood pressure, increased heart weight, and produced myographic changes of vascular hypertrophy in the mesenteric circulation, increasing media width, media cross-sectional area, and media/lumen ratio. Hydralazine given with angiotensin II prevented the rise of pressure and the cardiac effect but not the vascular changes. Two-way analysis of variance showed that angiotensin II significantly increased media width, media cross-sectional area, and media/lumen ratio, all independent of hydralazine. Thus, although hydralazine inhibits the pressor and cardiac effects of angiotensin II, suggesting a pressor mechanism for the cardiac change, it does not inhibit structural vascular change, which suggests that at least part of the effect has a non-pressor mechanism.

Brief angiotensin converting enzyme inhibitor treatment in young spontaneously hypertensive rats reduces blood pressure long-term.

Our study examines the long-term cardiovascular effects after a brief period of angiotensin converting enzyme (ACE) inhibitor treatment in young spontaneously hypertensive rats (SHR). SHR were treated with perindopril (3 mg/kg/day) by gavage from 2 to 6, from 6 to 10, or from 2 to 10 weeks of age. Systolic blood pressure was measured in the tail weekly until 25 weeks of age. Corresponding control groups received distilled water for the same periods. In each treatment group blood pressure was reduced significantly during treatment, rose when treatment stopped, but plateaued significantly below control SHR thereafter. This difference in blood pressure at 25 weeks of age was due to reduced total peripheral resistance as determined by microsphere methods, but plasma renin activity and angiotensin II concentrations were not different Cardiac hypertrophy was also reduced in treated SHR. In a separate experiment, perindopril treatment from 6 to 10 weeks of age resulted in a significant reduction in the media/ lumen ratios of mesenteric resistance vessels at 32 weeks of age. Concomitant administration of angiotensin II with perindopril from 6 to 10 weeks of age not only prevented the long-term effects on blood pressure seen with perindopril treatment alone but was associated with cardiovascular hypertrophy in excess of untreated control SHR. Finally, perindopril given for a shorter period (6 to 7 weeks) or later in life (20 to 24 weeks) had no significant long-term effects on blood pressure. These results demonstrate that a 4-week period of ACE inhibitor treatment in young SHR is sufficient to prevent the full expression of genetic hypertension and cardiovascular hypertrophy and that angiotensin II might be important in the development of hypertension in this model, its role in later life being less important.

The relation of arterial pressure and plasma angiotensin II concentration. A change produced by prolonged infusion of angiotensin II in the conscious dog.

Five unrestrained male beagle dogs were given a continuous intravenous infusion for 28 days. First, 0.9% NaCl solution was infused for 7 days, then angiotensin II at 3 ng/kg per min for 14 days, and finally 0.9% NaCl for 7 days. We found that the blood pressure rose gradually in each dog, reaching a peak toward the end of the 14-day infusion of angiotensin IL When angiotensin infusion was stopped, blood pressure fell gradually during 24 hours; the lowest pressure was not reached until 5 days later. To assess the relation between plasma angiotensin II concentration and arterial pressure, dose-response studies were done during the first saline infusion, after 7 and 14 days of angiotensin II infusion, and at the end of the second saline infusion. In these experiments, additional angiotensin II was infused intravenously at 3, 6, and 12 ng/kg per min, each rate for 1 hour. The increase of arterial pressure was then related to concurrent plasma angiotensin II concentration. In all dogs, prolonged infusion of angiotensin shifted the position of this curve upward. Thus, prolonged infusion of angiotensin raised the level of pressure maintained by a given plasma concentration of angiotensin EL Seven days after the angiotensin infusion, the curve had returned to the original position. Plasma aldosterone concentration also increased during all dose-response studies. The slope of the regression curve relating plasma concentrations of angiotensin II and aldosterone was steeper after, but not during, prolonged infusion of angiotensin EL Plasma potassium concentration did not change at any stage. Ore Res 44: 462-458, 1979

Angiotensin II, aldosterone and arterial pressure: a quantitative approach. Arthur C. Corcoran Memorial Lecture.

I AM deeply appreciative of the recognition accorded to me and to my colleagues by my being asked to deliver the A. C. Corcoran Memorial Lecture. I was, unfortunately, never privileged to meet the late Dr. Corcoran, although I was present at the meeting in Paris in 1965 when his death was announced. The manner in which this news was received, and the tributes paid to him at that time, left no doubt of the respect and affection he enjoyed. His scientific achievements stood then, and still stand, without need of an advocate.

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.

Effect of prolonged low-dose angiotensin II infusion on the sensitivity of adrenal cortex in man.

The effect of incremental infusions of isoleucine-5-angiotensin II on blood pressure and plasma aldosterone concentrations was studied in normal man before and after 66 hours of intravenous infusion of angiotensin II at 2 ng kg−1 min−1, sodium and potassium balance being kept roughly constant throughout. Plasma sodium and ACTH concentrations were unaltered, but plasma potassium and magnesium levels and basal plasma cortisol fell slightly after prolonged angiotensin administration. During the prolonged angiotensin infusion plasma renin activity was suppressed, and there was a sustained elevation of arterial pressure and plasma aldosterone concentration. Aldosterone excretion, while clearly increased, showed a regular circadian rhythm, with peak values in the early morning. The angiotensin II-pressor relationship was not significantly changed after the prolonged infusion of angiotensin II, while the angiotensin II-aldosterone dose-response curve was steeper than in the basal state but not identical with that of sodium depletion. No differences were observed in the pressor or aldosterone-stimulant effects of the isoleucine-5 and valine-5 forms of angiotensin II. A trophic effect of angiotensin II on the adrenal cortex may provide a partial explanation for the enhanced response of aldosterone to angiotensin II in sodium depleted man.

Blood pressure and lifespan following brief ACE inhibitor treatment in young spontaneously hypertensive rats.

1. Brief treatment with angiotensin‐converting enzyme (ACE) inhibitors in young spontaneously hypertensive rats (SHR) causes a reduction in blood pressure that persists into maturity. The lifetime effects of such treatment have not been studied.

Microangiopathic Hemolytic Anemia and the Development of the Malignant Phase of Hypertension

Evidence of microangiopathic hemolytic anemia (MHA) was found in 14 of 22 patients with malignant phase hypertension, and in one of these, a patient with proliferative glomerulonephritis, MHA and malignant hypertension developed together during a three-month period of observation. Among 61 rats subjected to unilateral nephrectomy, injected with DOCA, and given 1% saline to drink, 42 developed evidence of MHA. Eighty-four per cent of these also had fibrinoid necrosis and/or plasmatic vasculosis in the remaining kidney at autopsy. Blood pressure rose to 150 mm Hg or more in 72% of these DOCA-injected animals. In 29 control rats subjected to unilateral nephrectomy only, blood pressure rose to 150 mm Hg or more in 21%, MHA developed in 14%, and fibrinoid lesions were found in none. The significance of these observations is discussed in relation to the possibility that MHA is either a consequence of malignant hypertension or a contributory factor in its pathogenesis.

Response of aldosterone and blood pressure to angiotensin II infusion in anephric man. Effect of sodium deprivation.

SUMMARY: Angiotensin II, infused intravenously, increased plasma aldosterone concentration in two of six anephric subjects taking tbeir usaal dietary quantities of sodium. After 3 days of dietary sodium restriction and weight-reducing henodialysis, the aldosterone response to infused angiotensin II in the two previously reactive subjects was enhanced, while the four previously unreacthre subjects also showed a rise n plasma aldosteroae. Before and after sodium depletion the anephric subjects were less responsive than normal sabjects. Even when sodhun-depleted, the aaephrics showed no further rise in plasma aktosterooe when arterial plasma angiotensin II was increased by infusion to concentrations > 50–100 pg/ml, in contrast to sodium-depleted normals who show progressive aldosterone responses with plasma angiotensin II concentrations up to at least 370 pg/ml. Before the infusion of angiotensin II, arterial plasma renin, angiotemin II, and aldosterone were detectable in the anephrics, but were unchanged by dietary sodhim restriction or weight-reducing bcmodialysis. Sodiam depletion caused significant falls in weight, plasma sodium, and blood pressare, bat no changes in plasma potassium or cortisol. Increases in blood pressure in relation to increments of arterial plasma angiotensm II were uaaffected by sodium depletion, as might be expected in the absence of a rise in endogenous angiotensin II.

Renin and Acute Circulatory Renal Failure in the Rabbit

Plasma renin concentration (PRC) was measured in 25 rabbits before and 6, 24, or 72 hours after subcutaneous injection of glycerol. Renal failure and tubular necrosis developed in most animals and PRC rose sixfold to a maximum at 24 hours. Small insignificant changes of PRC were present at 6 and 72 hours. None of these changes was observed in a control group of nine animals killed 24 hours after an injection of saline. The amount of renin extractable from single superficial glomeruli and from renal cortical tissue was reduced after injection of glycerol. In a second study of 11 anesthetized rabbits, renal venous PRC increased on average from 151 to 1810 units/liter following a 4-hour period of renal artery occlusion. Arterial PRC did not change significantly during this time, but the kidneys showed histological changes of acute tubular necrosis. These experiments are compatible with the suggestion that renin is involved in the pathogenesis of acute circulatory renal failure.