Campbell D. Spence

THE HAEMODYNAMIC EFFECTS OF CYCLOSPORIN A IN SHEEP

SUMMARY

Rapid haemodynamic response to adrenocorticotrophin and the role of peripheral resistance in adrenocorticotrophin-induced hypertension in conscious sheep*

The haemodynamic effects associated with the onset of hypertension induced by infusion of adrenocorticotrophin (ACTH) were investigated in sheep. Analysis of haemodynamic data collected over 24 h by a computer-based monitoring system revealed that mean arterial pressure (MAP) was significantly increased after 4 h. Cardiac output was significantly raised after 1 h. The increased cardiac output was initially offset by a fall in calculated total peripheral resistance (CTPR) and MAP did not begin to rise until CTPR had returned to control values. This suggested that the return of CTPR to control values was essential for the development of hypertension. The development of ACTH-induced hypertension was prevented by both nisoldipine, a calcium channel blocker, and minoxidil, a vascular smooth muscle relaxant. Nisoldipine administration was also found to reverse established ACTH hypertension. A greater fall in MAP and CTPR occurred in the onset and established phase of ACTH hypertension sheep compared with normotensive controls. These results indicate that constriction of the peripheral vasculature is essential for the onset and maintenance of ACTH-induced hypertension in the sheep, and that the vasoconstriction does not involve a specific Ca21+-dependent mechanism because minoxidil was as effective as nisoldipine in abolishing the pressor response to ACTH. The onset of ACTH-induced hypertension in sheep is characterized by very rapid haemodynamic changes with an increase in cardiac output and a relative increase in CTPR after an initial peripheral vasodilatation.

ADRENOCORTICAL STEROID REQUIREMENTS FOR INITIATION OF ACTH‐DEPENDENT HYPERTENSION IN SHEEP

1. Previous studies demonstrated that the combined infusion of cortisol (F), aldosterone (ALDO), deoxycorticosterone (DOC), corticosterone (B), 11‐deoxycortisol (S), 17α‐hydroxyprogesterone (17αOHP) and 17α, 20α‐dihydroxy‐4‐pregnane‐3‐one (17α20αOHP), at rates equivalent to their production during adrenocorticotrophic hormone (ACTH) treatment, reproduced the pressor and metabolic responses to ACTH administration in sheep.

DIGOXIN ENHANCES THE PRESSOR RESPONSE TO ALDOSTERONE ADMINISTRATION IN CONSCIOUS SHEEP

1. This study examined the hypothesis that inhibition of Na, K ATPase with digoxin would enhance the pressor response to aldosterone infusion in conscious sheep.

Blood pressure and metabolic effects of 18-OXO-cortisol in sheep

18-Oxo-cortisol (18-oxo-F) has been isolated from the urine of subjects with primary aldosteronism. This study examines the pressor, mineralocorticoid and glucocorticoid effects of 18-oxo-F in conscious sheep--a well studied species for the assessment of the pressor effect of steroid hormones. 18-oxo-F (24 mg/day i.v. for 5 days, n = 3) increased mean arterial pressure MAP (64 +/- 2 mmHg control and 75 +/- 6 mmHg on day 5 P less than 0.001). There was no change in heart rate. Plasma [K+] decreased from a control of 4.3 +/- 0.1 mmol/l control to 2.9 +/- 0.3 mmol/l on day 5 (P less than 0.001). Urinary Na+ excretion decreased on the first infusion day (233 +/- 18 mmol/day control and 124 +/- 20 mmol/day on infusion day 1 P less than 0.001). Urinary K+ excretion was reduced on days 1, 4 and 5 of the infusion. Thus in sheep, 18-oxo-F increased blood pressure associated with in vivo evidence of mineralocorticoid activity.

THE INFLUENCE OF A HIGH K INTAKE ON THE HYPERTENSIVE EFFECT OF ACTH AND DOC IN SHEEP

1. The effect of 5 days administration of ACTH or DOC, was examined before and after chronic potassium (K) loading in sheep.

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.

CENTRALLY MEDIATED INCREASED SYMPATHETIC ACTIVITY IS NOT IMPORTANT IN THE GENESIS OF ACTH‐INDUCED HYPERTENSION IN SHEEP

1. Adrenocorticotrophin (ACTH) administration to sheep produces a rapid adrenally dependent hypertension which is maximal after 3 days and associated with increased cardiac output (CO) and heart rate (HR), while calculated total peripheral resistance remains unchanged.

Metabolic and Blood Pressure Effects of 6α-Methylprednisolone in the Conscious Sheep

Methylprednlsolone has been reported to be produce hypertension in the rat but to have no effect on blood pressure in the dog. In this study, methylprednlsolone infused to conscious sheep for up to 10 days at either 20 μg/kg/hr or 100 μg/kg/hr, failed to induce a hypertensive response. Metabolic effects characteristic of glucocorticoid activity, such as increased water intake and urine volume, were observed in all animals. No consistent decrease in plasma potassium concentration was observed with either rate of infusion, indicating a lack of in-vivo mlneralocortlcoid activity. In the conscious sheep, like the dog, methylprednlsolone exhibits only glucocorticoid activity and does not increase blood pressure.

The Anti-Hypertensive Effect of Potassium Loading in Experimental Hypertension: A Comparison of Sheep with Other Species

The anti-hypertensive effect of potassium (K) loading in human essential hypertension and several types of experimental hypertension is well established. However, the mechanism of the anti-hypertensive effect is not understood. The natriuretic effect of a high K intake has lead many to conclude that the blood pressure lowering effect of K may be mediated through enhanced sodium (Na) excretion leading to negative Na status. Review of the literature suggests that the anti-hypertensive effect of K loading, at least in sheep, can not be explained simply by changes in Na excretion.