Timothy J. Humphery

Adrenocortical steroid hormones in production of hypertension in sheep

In the conscious sheep the contribution of physiological and pharmacological levels of the two major classes of adrenal steroid hormones “glucocorticoids” and “mineralocorticoids” in the production of hypertension have been examined using the model of ACTH induced hypertension, an adrenally dependent steroid hypertension which can be reproduced by infusion over 5 days of a combination of cortisol (5 mg/h), corticosterone (0.5mg/h), 11-deoxycortisol (1 mg/h), DOC (25 mg/h), aldosterone (3μg/h), 17α-hydroxyprogesterone (1 mg/h) and 17α,20α-dihydroxyprogesterone (500 μg/h) at rates to produce blood levels seen with ACTH treatment. Hypertension cannot be reproduced by infusion of any of these steroids individually at these rates. Omission of 17α-hydroxyprogesterone and 17α,20α-dihyroxyprogesterone from the infusion results in similar metabolic effects to ACTH but only small increases in blood pressure. These studies together with in vitro and in vivo assessment of the lack of “mineralocorticoid” and “glucocorticoid” activity of 17α-hydroxyprogesterone and 17α,20α-dihydroxy-progesterone have led us to postulate a new class of steroid action—hypertensinogenic steroids. Infusion of 9α-fluorocortisol (9α-FF) at 0.2 mg/day increases blood pressure without the associated metabolic effects seen at higher dose (0.63 or 2 mg/day). Based on in vitro renal receptor affinity of 9α-FF for “mineralocorticoid” and “glucocorticoid” receptors, doses of aldosterone and cortisol approx. equivalent to either 0.63 or 2 mg/day of 9α-FF reproduce the metabolic effects of 9α-FF but have only a small effect on blood pressure. These data suggest that the hypertensive effects of adrenal steroid hormones are not simply related to their “mineralocorticoid” or “glucocorticoid” activity and support our proposal of a further class of steroid hormone action.

Prostaglandin synthesis inhibition with indomethacin in ACTH-induced hypertension.

The short- and long-term effects of indomethacin administration were examined in normotensive and ACTH-induced hypertensive conscious sheep. Indomethacin, 1 mg/kg/h for 60 min, caused a transient rise in mean arterial pressure (MAP) and calculated total peripheral resistance (CTPR) and a fall in cardiac output in normotensive sheep. In sheep with ACTH hypertension, these haemodynamic effects were prolonged. Indomethacin infusion at 3 mg/kg/day for 3 days had no observable haemodynamic or metabolic effects. Concomitant infusion of ACTH increased MAP and CTPR. These studies suggest prostaglandins play only a minor role in regulation of blood pressure in normal conscious sheep, but modulate the blood pressure rise in ACTH hypertension in sheep.

The effect of ACTH on the blood clearance rate of aldosterone, cortisol, 17α-hydroxyprogesterone and 17α,20α-dihydroxy-4-pregnen-3-one in the sheep

Abstract The blood clearance rate (BCR) of aldosterone, cortisol, 17α-hydroxyprogesterone (17αOHP) and 17α,20α-dihydroxy-4-pregnen-3-one (17α20αOHP) has been measured in conscious sheep prior to and after 5 or 6 days ACTH treatment. ACTH increased the BCR of cortisol but did not change the BCR of the other three steroids. 17αOHP had a BCR greater than liver blood flow suggesting extra-hepatic metabolism. In vivo conversion of 17αOHP to 17α20αOHP by ovine red cells has been shown to be a significant site of this metabolism. It is suggested that this conversion of 17αOHP to 17α20αOHP may be important in the expression of the “hypertensinogenic” effect of 17αOHP.

IN‐VIVO MODIFICATION OF ANGIOTENSIN 11 PRESSOR RESPONSIVENESS IN SHEEP BY INDOMETHACIN

1. Sodium (Na) depletion, due to uncompensated loss of parotid saliva, reduces the pressor responsiveness to angiotensin II (AII) in intact conscious sheep.

HAEMODYNAMIC CHANGES IN ACTH-INDUCED HYPERTENSION IN SHEEP

1. ACTH (20 μg/kg per day) produced an elevation in blood pressure associated with an increase in cardiac output in conscious sheep, due in the first 72 h to a rise in heart rate. Stroke volume did not rise until the fourth day of ACTH treatment.

Changes in the relationship between cerebrospinal fluid and blood composition produced by ACTH treatment in conscious sheep.

Abstract It has been proposed that an increase in CSF osmolality could be involved in the genesis of hypertension by activation of central nervous system receptors involved in cardiovascular regulation. ACTH induced hypertension in the sheep is an adrenally dependent model of steroid induced hypertension. This study reports the effect of ACTH administration (20 g/kg/day) for 5 days on the composition of cerebrospinal fluid (CSF) and blood (plasma) in conscious sheep. ACTH increased CSF and plasma osmolality within 24 h associated with parallel increases in both blood and CSF glucose concentrations and plasma and CSF sodium concentration. Plasma potassium fell within 24 h, but CSF potassium did not change over the 5 days of ACTH treatment. Neither calcium nor magnesium changed in either plasma or CSF. CSF phosphate increased and plasma phosphate decreased. CSF and plasma bicarbonate were elevated with ACTH. Plasma chloride decreased after 5 days of ACTH treatment but was not associated with a change in CSF. The relevance of the measured changes in CSF osmolality and composition to the mechanisms involved in the production of ACTH-induced hypertension will be subject of further experimentation.

Effect of ACTH and Adrenal Corticosteroids on Renal Function in Sheep

The effects of administration of ACTH and the major ovine adrenal steroids on renal function in conscious sheep were examined. Glomerular filtration rate and effective renal plasma flow increased with

EFFECT OF POSTASSIUM, ANGIOTENSIN II AND ACTH ON BLOOD ALDOSTERONE AND CORTISOL IN SHEEP ON DIFFERENT DIETARY POTASSIUM AND SODIUM INTAKES

1. The short term aldosterone response to manipulations of potassium (K), angiotensin II (AII) and ACTH were examined in sheep on a variety of chronic electrolyte regimes.

EFFECT OF ADRENOCORTICAL STEROIDS AND THEIR STRUCTURAL ANALOGUES ON BLOOD PRESSURE IN SHEEP

1. A model of adrenocortical steroid‐induced hypertension based on the effects of ACTH administration has been developed in sheep. The present studies examine the effects of a number of different steroid hormones on blood pressure to investigate their structure‐activity relationships.

DIURETIC AND HAEMODYNAMIC EFFECTS OF MK 447 IN NORMOTENSIVE AND HYPERTENSIVE SHEEP

1. The short term effects of the novel diuretic MK 447 were examined in both normotensive and hypertensive (ACTH treated) conscious sheep.