G. I. Russell

REVERSIBLE HYPERTENSION AND HYPOTHYROIDISM

Six patients with hypothyroidism and hypertension whose blood pressure fell to normal when treated with thyroxine (172.7.2/112.2.1 to 140.3.2/84.1.6 mmHg, P<0.001) are described. Plasma renin activity (1.76±0.63 ng angiotensin I.ml−1.h−1) was low before treatment. Hypertension with low plasma renin is consistent with sodium retention. Hypertension in the hypothyroid patient only requires further evaluation if it persists after adequate treatment with thyroxine.

Reversal of experimental renovascular hypertension

The aim of this review is to examine the pathophysiological mechanisms that are involved in the reversal of experimental renovascular hypertension, concentrating on observations made in the two-kidney, one clip model in the rat. The haemodynamic changes and alterations in sodium balance are described. The contribution of well established vasoactive systems such as the renin-angiotensin and symphathetic nervous system are discussed

Chemical renal medullectomy. Effect on urinary prostaglandin E2 and plasma renin in response to variations in sodium intake and in relation to blood pressure.

We have studied the possible vasodepressor role of the renal medulla by chemical medullectomy. Bromoethylamine hydrobromide (200 mg/kg) was injected to induce selective renal medullary necrosis in rats. The acute effects on sodium balance and long-term effects on blood pressure, plasma renin concentration (PRC) and urinary prostaglandin E2 (PGE2) were studied and compared with saline injected controls. There was an immediate and sustained increase in urine volume of low osmolality. Direct blood pressure in conscious free-moving animals was higher at 2 and 10 weeks after injection in medullary-damaged rats, although this was only significant at 10 weeks (136 +/- 3.3 vs 118 +/- 4.5 mm Hg, p less than 0.01). An initial negative sodium balance returned to normal by 7 days and rats with established medullary damage tolerated a wide range of sodium intakes. Although there was no evidence of sodium retention on the normal diet, with very high sodium loads some sodium retention was apparent since PRC was suppressed and body weight increased. Plasma creatinine and creatinine clearance were normal. PRC in rats with medullary damage was unchanged on normal diet and rose to similar levels as in control rats on low sodium intake. Urinary PGE2 was markedly reduced (148 +/- 54 vs 536 +/- 71 ng/day, p less than 0.01) in medullary damaged rats, consistent with the renal medulla being the major source of urinary PGE2. High salt intake increased urinary PGE2 in normal and proportionally in medullary damaged rats, whereas on a low sodium intake, urinary PGE2 was not different from that on the normal diet in either group.(ABSTRACT TRUNCATED AT 250 WORDS)

Baroreceptor-heart rate reflex function before and after surgical reversal of two-kidney, one-clip hypertension in the rat.

Baroreflex function was studied in conscious early phase (less than 6 weeks) two-kidney, one-clip hypertensive rats before and 24 hours after surgical reversal of hypertension by removal of the constricting renal artery clip or after pharmacological reduction of blood pressure by an infusion of hydralazine or captopril. A normotensive sham-clipped group was included. Another group of two-kidney, one-clip rats was studied 3 weeks after unclipping. Baroreflex sensitivity, as assessed by the steady-state method using a graded phenylephrine infusion, mean arterial pressure, and heart rate were measured preoperatively and at 24 hours postoperatively. Two-kidney, one-clip rats were significantly hypertensive preoperatively compared with control (mean arterial pressure, 183 +/- 4 vs. 106 +/- 2 mm Hg, p less than 0.001), heart rate was similar (420 +/- 9 vs. 401 +/- 9 beats/min, p greater than 0.05), and baroreflex sensitivity was significantly reduced (0.76 +/- 0.07 vs. 1.50 +/- 0.20 msec/mm Hg; p less than 0.001). There was a minimal change in heart rate despite the fall in mean arterial pressure in all hypertensive groups, indicating resetting of the baroreflexes. At 24 hours after the operation, baroreflex sensitivity was unchanged in all groups compared with the preoperative value. By 3 weeks, baroreflex sensitivity was significantly greater than in the hypertensive two-kidney, one-clip rats before the operation and 24 hours after they were unclipped, but not compared with normotensive sham-clipped rats. Thus, although resetting occurs within 24 hours, whatever the method of blood pressure reduction, baroreflex sensitivity remains impaired at this time.(ABSTRACT TRUNCATED AT 250 WORDS)

Responsiveness to pressor agents in experimental renovascular and steroid hypertension. Effects of converting enzyme inhibitor and nephrectomy.

To assess changes in responsireness to pressor agents in experimental hypertension, we examined pressor dose-response curves to graded doses of angiotensin II (All) and norepinephrine (NE) in anesthetized normal rats and rats with eariy (< 6 weeks) or chronic (> 4 months) two-kidney one clip renovascular hypertension and deoxycorticosterone (DOC) salt hypertension. Occupancy of receptors by endogenous AH was reduced by converting enzyme inhibition with captopril or bilateral nephrectomy. Rats with DOC-salt hypertension were significantly more responsive to AH than normal rats or rats with renovascular hypertension (p < 0.05). Captopril administration had no effect upon AH responsiveness in DOC-salt hypertension, but enhanced the responses of normal rats and rats with renovascular hypertension, so that there were no significant differences in the All dose-response curves after captopril. Bilateral nephrectomy also eliminated the differences between the responsiveness of DOC-salt and other groups, although responsiveness after bilateral nephrectomy was lower than that after captopril. Captopril administration to nephrectomized animals had no effect upon responsiveness. It is concluded that receptor occupancy by endogenous AH is the major factor that alters pressor responsiveness to AH in normal and experimental hypertensive rats. Duration of hypertension seemed to play no role. By contrast, norepinephrine responsiveness was not significantly different between the experimental groups. However, captopril treatment increased the slope of the dose response curves in intact but not nephrectomized groups. This increased sensitivity appears to be due to inhibition of the renin-angiotensin system, since it was also produced by saralasin infusion, but not by bradykinin infusion. The reninangiotensin system therefore appears to be important in modulating pressor responses to norepinephrine in the intact animal, and this interaction differs from the effect that has been demonstrated in isolated tissues. (Hypertension 4: 238–244, 1982)

REVERSAL OF RENOVASCULAR HYPERTENSION

1. The fall in blood pressure observed in both early and chronic phase Goldblatt 2‐kidney 1‐clip hypertension produced by removing or unclipping the ischaemic kidney is due to a profound fall in peripheral resistance.

Renal Vasodepressor Mechanism: Characterization by Chemical Medullectomy

The features of hypertension produced in the rat by chemical medullectomy with 2-bromoethylamine hydrobromide are described. This procedure partially prevents the fall in blood pressure that occurs when the constriction is removed from the renal artery of rats with two-kidney one-clip Goldblatt hypertension. In normal rats, chemical medullectomy causes a moderate but consistent blood pressure elevation that is dose related and associated with elevation of peripheral resistance; the venous side of the circulation is normal. The hypertension is not associated with sodium retention or with activation of the renin angiotensin system. Although vasopressin levels are elevated, the rise is only modest, and blood pressure is not reduced by a vascular AVP antagonist. It is concluded that chemical medullectomy removes the source of a humoral substance that has been shown by other workers to carry out a vasodepressor role. The chemical medullectomy model therefore offers new insights into the renomedullary vasodepressor system.

Failure of Naloxone to Influence Surgical Reversal of Two-Kidney, One-Clip Hypertension in the Rat

The rapid fall in blood pressure after removal of the constricting clip in two-kidney one-clip (2K-1C) hypertension in the rat is not fully explained by inhibition of the renin-angiotensin system or change in sodium balance. It has been postulated that compounds released in the renal venous effluent following unclipping of 2K-1C rats have a central opiate-like action and endogenous opioids are recognized to have profound hypotensive properties. To investigate this, we removed the clip from, or performed a sham operation in, early phase (<6 weeks) 2K-1C hypertensive rats during an infusion of naloxone, an opioid antagonist, or vehicle alone. The infusion of naloxone did not affect the pattern of blood pressure fall in either undipped or sham-operated rats. Both naloxone-treated and control groups were similarly normotensive at 24 hr postoperation, the MAP being significantly lower than in the sham-operated groups, which regained previously hypertensive levels. Heart rate was unchanged 24 hr postoperatively in all groups. Morphine-induced bradycardia and hypotension were significantly reduced by naloxone infusion. Thus, naloxone infusion had no effect on blood pressure or heart rate in either the sham-operated or the undipped groups, indicating that endogenous opioids do not have a major role in the reversal of renovascular hypertension under these circumstances.

Vascular capacitance in rats subjected to chemical renal medullectomy.

Selective renal medullary destruction is produced in rats by a single injection of 2-bromoethylamine hydrobromide. The object of these studies was to investigate whether destruction of the renal medulla in normal rats would alter vascular capacitance. Conscious bromoethylamine-treated rats (n = 15) were compared with control saline-injected rats (n = 12). Mean circulatory filling pressure was measured during a brief circulatory arrest caused by inflation of a right atrial balloon. Blood volume was determined from plasma volume (iodine-125-labeled albumin) and hematocrit. Mean circulatory filling pressure was measured at resting blood volume and after rapid blood volume changes. Vascular compliance was derived from the mean circulatory filling pressure-blood volume curve. The bromoethylamine-treated rats were significantly hypertensive compared with control rats (mean arterial pressure 133 +/- 2 and 114 +/- 3 mm Hg, respectively, p less than 0.001) and had a significant tachycardia (475 +/- 8 and 443 +/- 10 beats/min, respectively, p = 0.02). Blood volume, plasma volume, hematocrit, and sodium excretion were no different. There was no significant difference in mean circulatory filling pressure (6.5 +/- 0.2 and 6.8 +/- 0.2 mm Hg, respectively, p = 0.4) or vascular compliance (3.64 +/- 0.20 and 3.53 +/- 0.12 ml/kg/mm Hg, respectively, p = 0.7). The position of the vascular pressure-volume curve was unchanged indicating no change in vascular capacity. This would suggest that the destruction of renal medullary vasodepressor mechanisms does not result in alterations in vascular capacitance.

Effect of sodium, deoxycorticosterone and duration of hypertension on pressor responses in rats

1. Enhanced pressor responsiveness to angiotensin II and noradrenaline has been demonstrated in the hypertension that follows deoxycorticosterone (DOC) and salt administration in the rat. The present studies were carried out to assess the importance of factors common to both pressor agents and those specific to individual agents such as receptor availability.