Notes: 1. The effect of captopril on in vitro production of angiotensin I (ANG I), [Val5] -angiotensin II ([Vals]-ANG II) and [Val4]-angiotensin III ([Val5]-ANG-(2–8)) in central venous blood taken from sodium-deficient sheep was studied.2. Captopril enhances in vitro production of ANG I but blocks the in vitro production of [Val5] -ANG II and [Val5] -ANG-(2–8).3. The production of ANG I in blood is faster than that of [Val5]-ANG II and [Val5] -ANG-(2–8).4. The half-life of [Val5]-ANG II and [Val5]-ANG-(2–8) in vitro in blood in the presence of captopril was 10 and 14 min, respectively.5. This in vitro study suggests that the production of [Val5]-ANG II and [Val5] -ANG-(2–8) in blood forms a small part of the total body production of each peptide.

Notes: 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.2. Infusion of the major ovine adrenal steroid hormones (combined steroid infusion of Cortisol, corticosterone, 11-deoxycortisol, aldosterone, deoxycorticosterone) reproduced the metabolic but not the blood pressure effects of ACTH.3. Addition of 17α, 20α-dihydroxyprogesterone and 17α-hydroxyprogester-one, at rates appropriate for conditions of ACTH stimulation, to the combined steroid infusion reproduced both the blood pressure and metabolic effects of ACTH.4. 17α, 20β-Dihydroxyprogesterone, 20β-dihydroxy-11-deoxycortisol and 20β-hydroxycortisol all had additional hypertensive activity when given with combined steroid infusion, but 16α-hydroxyprogesterone, 11β, 17α-dihydroxy-progesterone, 20a-hydroxyprogesterone and 20α-hydroxyprogesterone did not.5. These studies support the concept of a new class of steroid hormone action in blood pressure regulation.

Notes: 1. Sodium (Na) depletion, due to uncompensated loss of parotid saliva, reduces the pressor responsiveness to angiotensin II (AII) in intact conscious sheep.2. Inhibition of prostaglandin synthesis by indomethacin restored All pressor responsiveness in Na-deplete sheep.3. Indomethacin infusion also increased the pressor responsiveness to AII in the Na-replete sheep.4. These findings suggest that in vivo prostaglandins may play a role in modulating the pressor responsiveness to angiotensin II in sheep.

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: SUMMARY 1. The effect of surgical denervation of the adrenal gland on ACTH-induced hypertension in the sheep has been examined. ACTH (80 iu/day) was administered for 5 days to eight sheep before and after bilateral surgical denervation of the adrenal.2. In intact sheep, ACTH-induced hypertension is associated with a significant increase in cardiac output and heart rate. Adrenal denervation obtained by sectioning of the lumbar sympathetic and splanchnic nerves supplying the adrenal gland did not alter the magnitude or time course of the hypertension, or the increase in heart rate.3. Adrenal denervation did not affect the increase in plasma sodium, the fall in plasma potassium, the initial urinary sodium retention, the increase in water turnover or the changes in blood corticosteroids which are seen during ACTH administration to intact sheep. However, in these adrenally denervated sheep ACTH treatment did not significantly change cardiac output.4. This study suggests an important role for a factor or factors from the adrenal cortex in causing ACTH-induced hypertension.

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.