Notes: 1. It has been shown previously that hydrocortisone (F) increases pressor responsiveness in normal subjects. The present study examined the role of vasodilator prostanoids in determining these changes.2. Pressor responsiveness to angiotensin II (AII) (1–8 ng/kg per min) and phenylephrine (PE) (0.3–0.9 μg/kg per min) was examined in six normal men receiving: no treatment (day 1); 100 mg indomethacm p.o. (INDO) in three divided doses over 20 h (day 2); 200 mg F for 5 days, 50 mg 6 hourly p.o. (day 6); F plus 100 mg INDO (day 7).3. Blood pressure, body weight and plasma glucose rose with F and plasma potassium fell. F alone produced significant increases in response to AII at 2 ng/kg per min, for systolic pressure (SBP), diastolic pressure (DBP) and mean arterial pressure (MAP), and at 1 ng/kg per min for DBP. The threshold for SBP, DBP and MAP rises with AII was decreased by F. Responses to PE following F were greater at 0.6 μg/kg per min for SBP, DBP and MAP and the threshold for all parameters fell.4. INDO alone had no significant blood pressure or metabolic effects and no effect on the magnitude of the blood pressure rise with AII, but decreased the threshold dose for effects on MAP. INDO had no effect on the magnitude of the pressure rise with PE, but decreased the threshold dose for effects on SBP.5. INDO did not modify responsiveness or threshold to AII following F. Responsiveness to PE was unchanged and threshold fell for SBP only during INDO.6. These data do not suggest a major role for vasodilator prostanoids in modifying pressor responsiveness in F-treated subjects.

Notes: 1. The effect of renal arterial infusion of synthetic human atrial natriuretic factor (ANF(99–126)) on renal function in the conscious euvolaemic sheep was characterized. ANF (99–126) was infused for 2 h at 5 and 50 μg/h into the renal artery of crossbred Merino ewes with chronically indwelling cannulae inserted in the renal artery. The effect on absolute and fractional excretion of Na, K, Ca, Cl and HCO3, glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and free water clearance (CH2O) were measured.2. Infusion at 50 μg/h produced a fourfold increase in Na and Cl excretion. Ca excretion increased eightfold, while K and HCO3 increased by small amounts. At the lower dose only Na, Cl and Ca excretion increased significantly. The changes in absolute excretion of each ion were closely mirrored by changes in fractional excretion. CH2O became more negative at both levels of infusion. Small changes in GFR were measured at both rates of infusion. No changes in ERPF or renin secretion were observed.3. ANF (99–126) infusion at 50 μg/h for 1 h increased the excretion of Li, such that more than 70% of the change in Na excretion was associated with the changes in Li clearance. Changes in GFR accounted for less than 10% of change in Na excretion.4. Following either long-term (50 μg/h for 6 h) or repeated short-term (20 μg/h for 30 min) infusions of ANF (99–126), the response of Na excretion was not sustained. The mechanisms of the tachyphylaxis remains undetermined.5. ANF (99–126) is a powerful stimulus to the absolute and fractional excretion of Na, K, Ca, Cl and HCO3. The mechanism of action is not known, but appears to be related to changes in tubular function and/or a change in glomerulotubular balance.

Notes: 1. The role of the renin-angiotensin system in the onset of ACTH-induced hypertension was examined in five conscious sheep.2. Captopril infusion alone (15 μg/kg per day) for 2 days produced a small fall in blood pressure.3. After 2 days of captopril ACTH was infused (20 μg/kg per day) for 3 days together with captopril. The blood pressure and electrolyte effects of ACTH administration were not modified by captopril pretreatment.4. These experiments establish that angiotensin II is not important in the onset of ACTH-induced hypertension in sheep.

Notes: 1. The effect of potassium (K) loading for 10 days on bone sodium (Na) and total exchangeable Na in sheep was examined.2. There were no significant changes in Na space or exchangeable Na after K loading.3. Bone Na concentration decreased by approximately 20% after K loading.4. The degree of mobilization of Na from both the non-exchangeable and exchangeable pools in bone is sufficient to account to a large degree for the observed increase in extracellular fluid volume and the net negative sodium balance which is observed during K loading.

Notes: 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.2. Progesterone (500 mg/day) alone, for 5 days, had no effect on blood pressure, but increased urinary Na excretion by 38 ± 10 mmol/day (P 〈 0.05) during the first 24 h.3. Infusion of ACTH (5 μg/kg per day), alone, for 3 days, increased mean arterial pressure by 21 ± 2 mmHg (P 〈 0.001) associated with hypernatraemia, hypokalaemia, urinary Na retention, and increased fasting plasma glucose concentration.4. Progesterone (500 mg/day) concurrently with ACTH blocked the rise in mean arterial pressure and the mineralocorticoid (urinary Na retention) but not the glucocorticoid (increase in plasma glucose concentration) effects associated with ACTH administration.5. Progesterone (500 and 1000 mg/day) failed to reverse the hypertension and hypokalaemia in sheep pretreated for 3 days with ACTH.6. Thus, progesterone blocked the onset but did not affect established ACTH hypertension. The mechanism by which progesterone blocked the development of ACTH hypertension appears to be related to the ability of progesterone to block the essential mineralocorticoid component of the adrenocortical steroids involved in the development of ACTH hypertension.

Notes: 1. Synthetic human endothelin was injected intravenously over the range 1.5–50 μg to examine its cardiovascular actions in conscious sheep.2. Mean arterial pressure increased by 9–21 mmHg within 30–120s over the range 5–50 μg endothelin. The increase in blood pressure was associated with increased calculated total peripheral resistance and a fall in cardiac output and heart rate. Stroke volume was increased.3. Injection of endothelin into ganglion blocked sheep produced vasoconstriction and an increased blood pressure response associated with an attenuation of the effects on cardiac output, heart rate and stroke volume.4. This study suggests that endothelin produces potent arterial vasoconstriction and reflex mediated effects on the heart in conscious sheep.

Notes: 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.2. This study examined which of these adrenocortical steroids were necessary for the initiation of the hypertension produced by these steroids in sheep.3. Infusion of F, ALDO, 17αOHP and 17α20αOHP together, increased MAP by 19 mmHg, similar to both complete steroid cocktail (+25 mmHg) or ACTH administration (+ 21 mmHg). Infusion of F, 17αOHP and 17α20αOHP increased MAP by +7 mmHg. Infusion of ALDO, 17αOHP and 17α20αOHP had no effect on MAP. Thus F and ALDO were essential for the pressor effects of the steroid infusion.4. To determine the role of glucocorticoid activity in the MAP rise, prednisolone, a non-pressor glucocorticoid, was substituted for cortisol. Combined prednisolone, ALDO, 17αOHP and 17α20αOHP infusion did not raise blood pressure. This suggested that the mineralocorticoid component rather than glucocorticoid component of cortisol's activity was involved in the pressor response.5. Aldosterone (7 μg/h) was substituted for cortisol, giving a total of 10 μg/h aldosterone. High dose ALDO (10 μg/h), 17αOHP and 17α20αOHP infusion raised blood pressure by 18 mmHg. Thus, the essential role of cortisol appeared to be due to its occupancy of mineralocorticoid receptors, rather than glucocorticoid receptors.6. Given that ACTH produces a transient initial increase in aldosterone secretion of up to 10 μg/h, it appears that aldosterone and not cortisol is essential for the pressor effects of ACTH.7. Hypertension resulting from the combined steroid infusion in the sheep appears to be produced by a mechanism which involves a complex interaction between ALDO, F, 17αOHP and 17α20αOHP. Therefore, the putative ‘hypertensinogenic’ receptor may be multivalent with binding sites for F, ALDO and 17α20αOHP, or is a site of single interactive receptors for these steroids and that F exerts its permissive action by occupying the same site as ALDO on the hypertensinogenic receptors.

Notes: 1. The effect of treatment with 9α-fluorocortisol (9aFF), a steroid which causes hypertension in sheep, was examined in sheep with ACTH-induced hypertension.2. ACTH treatment alone increased mean arterial pressure (MAP), plasma Na concentration, water intake and urine volume and decreased plasma K concentration.3. 9αFF treatment, for 3 days during continuing ACTH administration, did not change blood pressure but increased heart rate, water intake and urine volume and decreased urinary K excretion.4. As 9αFF did not cause a further increment in blood pressure in sheep with ACTH-induced hypertension it is possible that both ACTH and 9αFF may produce hypertension by similar mechanisms.

Notes: 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.2. This study investigated the proposal that a centrally mediated increase in sympathetic activity is important in the development of ACTH-induced hypertension.3. Concomitant intravenous infusions of either clonidine (60 μg/kg per day) or methyldopa (60 mg/kg per day) with ACTH (5 μg/kg per day) failed to inhibit the increase in mean arterial pressure (MAP) observed with ACTH.4. In a separate experiment clonidine abolished the increase in CO and HR but not the pressor response associated with ACTH administration.5. These results do not support a role for centrally mediated increase in sympathetic activity in the genesis of ACTH-induced hypertension.

Notes: 1. ACTH 1 mg/day for 5 days raises systolic blood pressure (SBP) in normotensive and hypertensive subjects on a fixed electrolyte intake of 100 mmol/day sodium (Na) and potassium (K) (Whitworth et al. 1983).2. The present study examined the effect of Na intake in the high normal range on the haemodynamic and metabolic responses to ACTH.3. ACTH administration on a 200–300 mmol Na intake increased SBP by 35 mmHg (s.e.m. = 11, n= 5) compared with the 22 mmHg (s.e.m. = 4, n= 12) rise seen on a 100 mmol Na intake in our previous study.4. These studies suggest that the effects of adrenocortical steroids on blood pressure in man may be magnified by increasing dietary Na intake.