Notes: 1. Studies in the rat and the dog have shown that infusion of aldosterone for several weeks into the cerebral ventricles (ICV) can produce hypertension at doses that do not have an effect when infused systemically. We have previously shown that a high physiological dose of aldosterone infused intravenously at 10 μg/h in sheep produces an increase in blood pressure of 7 mmHg within 2 days.2. In this paper we report the effects of ICV infusion of aldosterone at 2 μg/h for 6 days in conscious sheep.3. Neither blood pressure nor heart rate were altered, and there were no consistent changes in any of the metabolic parameters measured.4. These results do not support a role for central effects of aldosterone in the hypertension produced by systemic infusion of the steroid in sheep.

Notes: 1. Studies in sheep have led to the concept of a ‘hypertensinogenic’ (HT) steroid hormone activity, whereby the blood pressure (BP) raising effects of adrenocortical steroids can be separated from their in vivo glucocorticoid (GC) or mineralocorticoid (MC) activities.2. The three main lines of evidence are as follows: (i) BP raising effects of ACTH cannot be reproduced by appropriate rates of infusion of steroids with GC and MC activities; (ii) certain steroids e.g. 9α-fluorocortisol can increase BP at rates of infusion below threshold for in vivo GC or MC actions and for many steroids there is no correlation between GC, MC and HT effects; (iii) demonstration of differential antagonism of HT, MC and GC effects.3. Studies in man show that the BP effects of ACTH are due to cortisol (F) at levels which have both MC and GC activity. However, BP effects of ACTH cannot be blocked by MC and GC antagonists.4. Although complete separation of in vivo GC, MC and HT activities has not been possible in man, our own studies show a degree of dissociation. Taken together, these data suggest that steroids may raise BP by a HT mechanism distinct from classical in vivo MC or GC activities in man as well as 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. 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. To investigate a role for peptides derived from the precursor molecule pro- opiomelanocortin (POMC) on the control of aldosterone secretion (ASR), α-, β-, γ1, and γ2-melanocyte stimulating hormone (MSH), corticotropin-like intermediate lobe peptide (CLIP) or β-endorphin were infused into the adrenal arterial supply of sheep with an adrenal cervical autotransplant.2. None of the peptides had any significant effect on aldosterone secretion rate in Na replete, unstressed, conscious animals. In contrast, ACTH-stimulated ASR approximately twofold.3. POMC-derived peptides other than ACTH appear to have little or no effect on the short-term control of aldosterone secretion in vivo, although a role in control and modulation of adrenal function over the longer term cannot be discounted.

Notes: 1. In conscious ewes pregnancy was associated with a significantly increased heart rate and cardiac output, while mean arterial pressure (MAP) and stroke volume were unchanged.2. The present study examines the effect of arginine vasopressin (AVP) infused at 0.3, 1, 3.0, and 10 μg/h, into water-loaded and sodium-depleted ewes, either non-pregnant or during the last third of gestation.3. In the water-loaded state, MAP rose significantly at the lowest rate of infusion in both pregnant and non-pregnant ewes. Bradycardia occurred first at 0.3 μg/h in the pregnant ewes but not until 3.0 μg/h in the non-pregnant animals.4. In sodium deficiency there was no increase in MAP at any rate of infusion in either group. Bradycardia occurred in both groups at 1 μg/h.5. This study shows that the pressor effects of AVP are unchanged by pregnancy. However, pregnant ewes are more sensitive to AVP-induced bradycardia when the ewes are water-loaded.

Notes: 1. Merino-cross ewes were given an intravenous injection of a prostaglandin analogue, (+)-4-{3-[3-[2-(1 -hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]-propyl} benzoic acid, at doses of 0.01,0.05 and 0.10 mg/kg, on separate days, to determine renal and haemodynamic responses.2. Peripheral vasodilatory effects, indicated by increases in heart rate and cardiac output, and falls in total peripheral resistance, peaked at 20 min at the two highest doses. By 60 min most values had returned to pre-injection levels. There were no changes in mean arterial pressure.3. At the highest dose of 0.10 mg/kg there was a fall in glomerular filtration rate, renal blood flow and effective renal plasma flow within 20 min. Urinary sodium and potassium excretion also fell with all three doses tested.4. Plasma renin concentration increased at the 0.05 and 0.10 mg/kg doses and was still elevated at 60 min.5. The results of this study in the sheep contrast with others in the dog, where renal blood flow is increased and the rat, where blood pressure is increased, and indicate a species specificity in regard to the analogue's actions.

Notes: 1. Adrenocorticotrophin (ACTH), given as long-acting Synacthen depot (Ciba-Geigy), at 1000 μg/day, in divided doses 12 hourly, is known to increase blood pressure in man.2. Fifty μg/day of short-acting Synacthen given intravenously produced a rise in blood pressure and may be a threshold dose.3. Twelve hourly intramuscular injections of short-acting Synacthen over the dose range 100–400 μg/day was not sufficient to raise blood pressure.

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. 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.