SUMMARY1. 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.

SUMMARY 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.

This study investigated the anti-mineralocorticoid potency and haemodynamic effects of a series of mineralocorticoid antagonists of the spirolactone type (RU 28318, spironolactone, K-prorenoate, K-canrenoate and canrenone), for their ability to prevent the development of ACTH-induced hypertension in conscious sheep. In vivo bioassay, using aldosterone dependent changes in parotid salivary [Na+]/[K+] of sodium depleted adrenalectomized sheep, showed spironolactone was the most potent anti-mineralocorticoid tested. Infusions of the antagonists at equal doses alone for 4 days demonstrated that none affected mean arterial pressure, except for K-prorenoate which exhibited slight pressor activity. All the antagonists produced a natriuresis. Some of the steroid antagonists of the spirolactone group blocked the development of ACTH hypertension in sheep, spironolactone being the most effective. This study provides additional evidence for an essential mineralocorticoid component in ACTH-induced hypertension.

SUMMARY1. 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.

The haemodynamic effects associated with the onset of hypertension induced by infusion of adrenocorticotrophin (ACTH) were investigated in sheep. Analysis of haemodynamic data collected over 24 h by a computer-based monitoring system revealed that mean arterial pressure (MAP) was significantly increased after 4 h. Cardiac output was significantly raised after 1 h. The increased cardiac output was initially offset by a fall in calculated total peripheral resistance (CTPR) and MAP did not begin to rise until CTPR had returned to control values. This suggested that the return of CTPR to control values was essential for the development of hypertension. The development of ACTH-induced hypertension was prevented by both nisoldipine, a calcium channel blocker, and minoxidil, a vascular smooth muscle relaxant. Nisoldipine administration was also found to reverse established ACTH hypertension. A greater fall in MAP and CTPR occurred in the onset and established phase of ACTH hypertension sheep compared with normotensive controls. These results indicate that constriction of the peripheral vasculature is essential for the onset and maintenance of ACTH-induced hypertension in the sheep, and that the vasoconstriction does not involve a specific Ca21+-dependent mechanism because minoxidil was as effective as nisoldipine in abolishing the pressor response to ACTH. The onset of ACTH-induced hypertension in sheep is characterized by very rapid haemodynamic changes with an increase in cardiac output and a relative increase in CTPR after an initial peripheral vasodilatation.

SUMMARY 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.

1. This study examined the hypothesis that inhibition of Na,K ATPase with digoxin would enhance the pressor response to aldosterone infusion in conscious sheep. 2. While intravenous infusion of digoxin (10 micrograms/kg per day for 5 days) had no effect on blood pressure and aldosterone infusion (6 micrograms/kg per day for 5 days) increased blood pressure by 7 mmHg, combined infusion of digoxin and aldosterone increased blood pressure by 17 mmHg. 3. The metabolic effects of the combined digoxin and aldosterone infusion were similar to those for aldosterone alone, suggesting that digoxin did not enhance the mineralocorticoid action of aldosterone. 4. The results of this study suggest that changes in Na influx (aldosterone-dependent) and efflux (digoxin-dependent) are important in the genesis of aldosterone-induced hypertension.

The anti-hypertensive effect of potassium (K) loading in human essential hypertension and several types of experimental hypertension is well established. However, the mechanism of the anti-hypertensive effect is not understood. The natriuretic effect of a high K intake has lead many to conclude that the blood pressure lowering effect of K may be mediated through enhanced sodium (Na) excretion leading to negative Na status. Review of the literature suggests that the anti-hypertensive effect of K loading, at least in sheep, can not be explained simply by changes in Na excretion.

SUMMARY 1. Repeated observations indicate that ACTH administration causes hypertension. 2. Development of hypertension requires 17α‐hydroxyprogesterone and 17α, 20α‐dihydroxy‐4‐pregnene‐3‐one to be present in association with other steroids. 3. The hypertensinogenic activity of corticosteroids is distinct from their glucocorticoid and mineralocorticoid effects. 4. The location of central and peripheral receptors for this hypertensinogenic activity is not clear. 5. The physiological mechanisms that mediate the response are unknown, though a number of potential mediating effects has been demonstrated. 6. The overall importance of unusual steroids and steroid actions in human essential hypertension still requires elucidation.

The effect of increased potassium (K) intake (800 mmol/day) was investigated in conscious sheep to elucidate the mechanism of the anti-hypertensive effect of K loading. Mean arterial pressure rose (4mm Hg, n = 13, p less than 0.001). Cardiac output (n = 5) increased from 4.4 +/- 0.1 to 6.1 +/- 0.2 1/min (p less than 0.001). Calculated total peripheral resistance fell from 17 +/- 1 to 12 +/- 1 mmHg.min/1 (p less than 0.001). There was no change in plasma volume (n = 5), but extracellular fluid volume (n = 5) increased from 221 +/- 26 to 271 +/- 27 ml/kg (p less than 0.05). Glomerular filtration rate and effective renal plasma flow (n = 5) were unchanged. Plasma K concentration, fluid intake and urine volume increased. Urinary Na excretion increased from 106 +/- 11 to a maximum of 217 +/- 28 mmol/day on day 2 (p less than 0.001), and was decreased on day 7, 44 +/- 13 mmol/day (p less than 0.05). Calculated Na deficit was -268 mmol by day 10, but there was no change in responsiveness to infused angiotensin II, noradrenaline, vasopressin or tyramine. These changes differ from those seen with Na depletion alone in sheep, and are not compatible with the hypothesis that K loading exerts its effects solely by increasing Na excretion.

The study was performed to examine the hypothesis that adrenocorticotrophic hormone (ACTH) induced hypertension in sheep would be enhanced if the blood level of angiotensin II (ANG II), normally suppressed during ACTH administration, was kept at control levels by intravenous infusion of ANG II. Administration of ACTH at 1.0 microgram/kg/day for 6 days produced a half maximum rise in mean arterial pressure, delta 14 mmHg, associated with hypokalaemia and initial urinary sodium retention. A rate of ANG II infusion, (0.9 microgram/kg/day) for 6 days, was contrived to produce a small increase in peripheral resistance and mean arterial pressure, delta 10 mmHg. Pressor responses to concomitant infusion of ACTH and ANG II were additive, delta 25 mmHg. There was no potentiation of ACTH hypertension by ANG II in the sheep.

Previous studies in sheep have provided evidence for a separate "hypertensinogenic" class of adrenocortical steroid activity which is not simply related to their classical mineralocorticoid (MC) and/or glucocorticoid (GC) actions. This study investigated the structure-activity relationships of the effects of structural analogues of prednisolone on mean arterial pressure (MAP), and MC and GC actions in sheep. Infusions of these synthetic GC at 0.6 and 24 mg/day produced variable pressor effects which were dissociated from their MC and GC actions. In other experiments, the minimum adrenocortical steroid requirement to reproduce the onset of ACTH-dependent hypertension was determined. Infusion of cortisol, aldosterone, 17 alpha-hydroxy progesterone and 17 alpha,20 alpha-dihydroxy-4-pregnene-3-one was found to be sufficient to reproduce the hypertensive response to ACTH administration in sheep. A subsequent experiment showed that substitution of cortisol by the more potent synthetic GC, prednisolone had no effect on MAP. Therefore, cortisol appears to exert an essential action in ACTH hypertension which is not dependent on its GC activity. Other studies have found that prednisolone (100 mg/day) antagonized 9 alpha-fluoro-prednisolone (0.6 mg/day) induced hypertension but not its MC effects. The effect of progesterone (500 mg/day) and the progesterone analogues, norethisterone, medroxy-progesterone and 16 alpha-methyl progesterone on ACTH (5 micrograms/kg per day) hypertension was investigated. Progesterone completely blocked the hypertension and MC effects of ACTH infusion, while medroxy-progesterone partially blocked the increase in MAP. These data support our concept of a "hypertensinogenic" class of steroid activity.

18-Oxo-cortisol (18-oxo-F) has been isolated from the urine of subjects with primary aldosteronism. This study examines the pressor, mineralocorticoid and glucocorticoid effects of 18-oxo-F in conscious sheep--a well studied species for the assessment of the pressor effect of steroid hormones. 18-oxo-F (24 mg/day i.v. for 5 days, n = 3) increased mean arterial pressure MAP (64 +/- 2 mmHg control and 75 +/- 6 mmHg on day 5 P less than 0.001). There was no change in heart rate. Plasma [K+] decreased from a control of 4.3 +/- 0.1 mmol/l control to 2.9 +/- 0.3 mmol/l on day 5 (P less than 0.001). Urinary Na+ excretion decreased on the first infusion day (233 +/- 18 mmol/day control and 124 +/- 20 mmol/day on infusion day 1 P less than 0.001). Urinary K+ excretion was reduced on days 1, 4 and 5 of the infusion. Thus in sheep, 18-oxo-F increased blood pressure associated with in vivo evidence of mineralocorticoid activity.

This study investigated the effect of 5 day infusions of 6 alpha and 9 alpha-fluoro and 16 alpha, 17 alpha-acetal analogues of prednisolone on blood pressure in conscious sheep. In vivo mineralocorticoid (MC) and glucocorticoid (GC) activities of these steroids were also measured. Prednisolone (100 mg/d) produced a small increase in mean arterial pressure associated with increased fasting plasma [glucose] and polyuria, but had no MC activity. 9 alpha-fluoro substitution greatly enhanced both the pressor and MC activity of prednisolone. The effect of 9 alpha-fluoro substitution on pressor activity was not affected by beta-methylation at C-16 (betamethasone), but was attenuated by either alpha-hydroxylation or alpha-methylation at C-16 (triamcinolone and dexamethasone, respectively). The effect of 9 alpha-fluoro substitution on MC activity as determined by urinary Na excretion was not altered by a methyl group at C-16 in either alpha or beta configuration but the MC activity was attenuated by an alpha-hydroxyl group at C-16. In contrast, 6 alpha-fluoro substitution had little influence on pressor, MC and GC activities. 16 alpha, 17 alpha-acetonide and 16 alpha, 17 alpha-butylidenedioxy substitution increased the pressor activity of parent compounds, but had no influence on either GC or MC activity. This study demonstrates a dissociation between the pressor effects and the MC and GC activities associated with steroid administration and provides further evidence to support the concept of 'hypertensinogenic' class of steroid activity which can be distinguished from their MC and GC activity.

SUMMARY1. Cyclosporin A (CyA; 12 mg/kg/day) was infused into six conscious sheep over 5 days to examine the haemodynamic effects of the drug in normal animals.2. Mean arterial pressure was increased from 73(1) mmHg to 90(4) mmHg (P < 0.001). There was no change in cardiac output but calculated total peripheral resistance was elevated from 16(1) to 21(2) mmHg min/1 (P < 0.001) on day 4.3. There was no change in plasma [Na], but a fall in plasma [K]. Urinary Na excretion decreased. Glomerular filtration rate, filtration fraction, renal blood flow, renal vascular resistance, body weight, plasma renin and blood aldosterone concentration were unchanged.4. CyA produces an increase in blood pressure in sheep associated with an increase in total peripheral resistance on days 1, 3, and 4, in the absence of changes in renal function. This suggests that CyA hypertension is not simply a consequence of nephrotoxicity.

The roles of the autonomic nervous system, renin-angiotensin system, and arginine vasopressin (AVP) during the onset of ACTH-induced hypertension were investigated in conscious sheep. Autonomic ganglion blockade or combined adrenergic and cholinergic receptor blockade demonstrated that an intact sympathetic nervous system was not essential for the development or maintenance of the hypertension. Autonomic blockade augmented the pressor response to ACTH, indicating that baroreceptor-mediated reflexes normally operate to suppress the degree of hypertension produced by ACTH. Evidence was obtained suggesting that the renin-angiotensin system and AVP may partially contribute to the maintenance of ACTH hypertension in the presence of autonomic blockade. However, the precise mechanism by which ACTH raises arterial pressure remains to be elucidated.

This study investigated the effect of 5 day infusions of two structurally novel synthetic steroids, nivazol and cortivazol on blood pressure and in vivo indices of “glucocorticoid” and “mineralocorticoid” activity. Cortivazol at 24 mg/day raised mean arterial pressure (MAP) by 16 mmHg (P < 0.001). This was associated with increased cardiac rate, and increased fasting plasma [glucose], polyuria and polydipsia a trilogy characteristic of glucocorticoid effect. Cortivazol had no consistent action on plasma [Na] or [K], but caused an initial transient urinary Na retention and raised urinary excretion of Na and K on days 3 and 4 of treatment. Nivazol at 24 mg/day raised MAP 10 mmHg (P < 0.001), but cardiac rate was unchanged. This infusion was also associated with the glucocorticoid effects of increased fasting plasma [glucose] and increased urine volume. Plasma [K] fell from a control of 4.4 ±0.1 to 4.0 + 0.1 mmol/l (P < 0.01) after 5 days of infusion. There was no significant effect of nivazol on urinary Na or K excretion.