William F. Graham

[DES-ASP1] angiotensin II in the sheep: Blood levels and its effect on plasma renin concentration

Abstract The present study describes an improved method for measuring angiotensin III in arterial blood. This was accomplished by SE-sephadex column to separate angiotensin II from angiotensin III prior to radioimmunoassay. The arterial concentration of angiotensin III measured before and after 24 to 48 hours sodium depletion by acute cannulation of parotid gland was 12.4 ± 1.7 fmol/ml (SEM, n=7) and 49.8 ± 10.3 fmol/ml (SEM, n=7) respectively. The arterial concentration of Val 4 -angiotensin III obtained from continuous infusion of Val 4 -angiotensin III at rates of 24 and 48 nmol/h in sodium deficient sheep were 245 ± 32.5 fmol/ml (n=6) and 330 ± 11.4 fmol/ ml (n=7) respectively. The clearance rate of exogenous Val 4 -angiotensin III in sodium deficient sheep after correction for endogenous level was calculated to be 140 ± 13.6 L/h (SEM, n=13). This was in the same order as Ile 5 -angiotensin II and Ile 4 -angiotensin III reported earlier in sodium replete sheep. Prolonged intravenous infusion of Val 4 -angiotensin III at a rate of 48 nmol/h in sodium- deficient sheep suppressed plasma renin concentration to the same extent as equimolar infusions of angiotensin II. This suggests that angiotensin III may inhibit renin secretion by a similar mechanism to angiotensin II.

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.

EFFECT OF ACTH ADMINISTRATION ON THE HAEMODYNAMIC RESPONSE TO ARGININE-VASOPRESSIN IN SHEEP

1. Blood pressure, heart rate and cardiac output were studied in intact conscious sheep during AVP infusion at 0.1, 0.25, 0.5 and 10 μg/min for 30 minutes to determine whether pressor responsiveness to AVP was altered in ACTH‐induced hypertension.

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.

EFFECTS OF ACUTE VERSUS CHRONIC DELETION OF ARTERIAL BARORECEPTOR INPUT ON THE CARDIOVASCULAR RESPONSES TO EXERCISE IN THE RABBIT

1. These experiments were designed to confirm that at the onset of treadmill exercise in rabbits the tonic reflex depressor effects of input to the central nervous system from arterial baroreceptors is abolished, thus contributing to the rise of systemic arterial pressure (SAP) and heart rate (HR).

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.

ACTH hypertension modifies the haemodynamic effects of prostacyclin infusions in sheep.

1. The haemodynamic effects of short‐term prostacyclin infusions (0.05‐0 50 /μg/kg per min) were investigated in conscious adult sheep.