Amanda F. Reid

Studies on spirolactone steroid antagonists in ACTH-induced hypertension in sheep

This study investigated the anti-mineralocorticoid potency and haemodynamic effects of a series of mineralocorticoid antagonists of the spirolactone type (RU 28318, spironolactone, K-prorenoate, K-canrenoate and canrenone), for their ability to prevent the development of ACTH-induced hypertension in conscious sheep. In vivo bioassay, using aldosterone dependent changes in parotid salivary [Na+]/[K+] of sodium depleted adrenalectomized sheep, showed spironolactone was the most potent anti-mineralocorticoid tested. Infusions of the antagonists at equal doses alone for 4 days demonstrated that none affected mean arterial pressure, except for K-prorenoate which exhibited slight pressor activity. All the antagonists produced a natriuresis. Some of the steroid antagonists of the spirolactone group blocked the development of ACTH hypertension in sheep, spironolactone being the most effective. This study provides additional evidence for an essential mineralocorticoid component in ACTH-induced hypertension.

Haemodynamic effects of long-term endothelin infusion in conscious sheep.

1. Synthetic human endothelin‐1 was infused intravenously at 15 μg/h for 24 h to examine its cardiovascular actions in five conscious sheep.

RECEPTORS AND STEROID‐DEPENDENT HYPERTENSION

1. Repeated observations indicate that ACTH administration causes hypertension.

PROGESTERONE ANTAGONIZES DEVELOPMENT BUT NOT MAINTENANCE OF ACTH‐INDUCED HYPERTENSION IN SHEEP

1. This study investigated the effect of progesterone, which, under certain circumstances, can antagonize both the mineralocorticoid and glucocorticoid activities of steroid hormones, on the development and maintenance of adrenocorticotrophic hormone (ACTH)‐induced hypertension in conscious sheep.

Effect of potassium loading on bone sodium and total exchangeable sodium in sheep.

1. The effect of potassium (K) loading for 10 days on bone sodium (Na) and total exchangeable Na in sheep was examined.

The effect of potassium loading on sodium status and pressor responsiveness in the sheep.

The effect of increased potassium (K) intake (800 mmol/day) was investigated in conscious sheep to elucidate the mechanism of the anti-hypertensive effect of K loading. Mean arterial pressure rose (4mm Hg, n = 13, p less than 0.001). Cardiac output (n = 5) increased from 4.4 +/- 0.1 to 6.1 +/- 0.2 1/min (p less than 0.001). Calculated total peripheral resistance fell from 17 +/- 1 to 12 +/- 1 mmHg.min/1 (p less than 0.001). There was no change in plasma volume (n = 5), but extracellular fluid volume (n = 5) increased from 221 +/- 26 to 271 +/- 27 ml/kg (p less than 0.05). Glomerular filtration rate and effective renal plasma flow (n = 5) were unchanged. Plasma K concentration, fluid intake and urine volume increased. Urinary Na excretion increased from 106 +/- 11 to a maximum of 217 +/- 28 mmol/day on day 2 (p less than 0.001), and was decreased on day 7, 44 +/- 13 mmol/day (p less than 0.05). Calculated Na deficit was -268 mmol by day 10, but there was no change in responsiveness to infused angiotensin II, noradrenaline, vasopressin or tyramine. These changes differ from those seen with Na depletion alone in sheep, and are not compatible with the hypothesis that K loading exerts its effects solely by increasing Na excretion.

Modification of the Haemodynamic Effects of ACTH by Angiotensin II in Sheep

The study was performed to examine the hypothesis that adrenocorticotrophic hormone (ACTH) induced hypertension in sheep would be enhanced if the blood level of angiotensin II (ANG II), normally suppressed during ACTH administration, was kept at control levels by intravenous infusion of ANG II. Administration of ACTH at 1.0 microgram/kg/day for 6 days produced a half maximum rise in mean arterial pressure, delta 14 mmHg, associated with hypokalaemia and initial urinary sodium retention. A rate of ANG II infusion, (0.9 microgram/kg/day) for 6 days, was contrived to produce a small increase in peripheral resistance and mean arterial pressure, delta 10 mmHg. Pressor responses to concomitant infusion of ACTH and ANG II were additive, delta 25 mmHg. There was no potentiation of ACTH hypertension by ANG II in the sheep.