THE EFFECT OF RENAL DENERVATION ON ACTH-INDUCED HYPERTENSION IN SHEEP

1. The effect of renal denervation on ACTH-induced hypertension in sheep has been examined. 2. Both intact and renally denervated sheep showed similar rises in blood pressure following ACTH treatment. 3. Following renal denervation, the initial urinary sodium retention and ACTH-withdrawal natriuresis typical of ACTH administration in intact sheep were absent, and the fall in blood pressure was delayed.     

THE EFFECT OF ADRENAL DENERVATION ON ACTH-INDUCED HYPERTENSION IN SHEEP

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.     

DIFFERENTIAL BLOOD PRESSURE AND METABOLIC EFFECTS OF 9α-FLUOROCORTISOL IN MAN

The blood pressure and metabolic effects of 9 alpha-fluorocortisol at 0.15 mg/day and 1.5 mg/day were examined in man. At high dose, systolic pressure and body weight rose, and plasma [K+], urinary sodium excretion and renin concentration fell. At low dose similar metabolic effects were seen but blood pressure was unchanged. 9 alpha-Fluorocortisol has 'mineralocorticoid' effects in man at a dose which does not alter blood pressure. These studies do not provide evidence of a 'hypertensinogenic' class of steroid hormone action in man.     

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. 2. Calculated total peripheral resistance did not change. 3. Intravenous administration of acebutolol prior to and during ACTH administration did not modify the rise in blood pressure, but this was associated with a rise in total peripheral resistance. 4. These studies show that while ACTH-induced hypertension is usually associated with increased cardiac output, rather than total peripheral resistance it still occurs, but is associated with a rise in total peripheral resistance if the rise in cardiac output is prevented by /J-adrenoreceptor blockade.     

EFFECT OF STEROID HORMONES ON BLOOD PRESSURE

1. There is considerable evidence to support the idea that steroid hormones have the potential to increase blood pressure that may not always be via 'classical' mineralocorticoid or glucocorticoid action. 2. Epidemiological studies, together with the evidence from studies in animals, proposed the link between an adverse intra-uterine environment (i.e. undernutrition or excess exposure to glucocorticoids) and the early onset of cardiovascular and metabolic diseases later in life. 3. We tested this by treating pregnant ewes (and foetuses) with excess steroid early in pregnancy. The mean ages at which the prenatal exposure to glucocorticoid (dexamethasone 0.48 mg/h for 48 h) occurred were 22 +/- 0.4 to 29 +/- 0.4 days (prenatal treatment group 1; PTG1) and 59 +/- 2 to 66 +/- 2 days (PTG2), respectively. Basal blood pressures and hormones and the vascular responsiveness to graded doses of angiotensin II and noradrenaline, or to a 5-day adrenocorticotropin hormone treatment (ACTH), in lambs at 4, 10 and 19 months of age were studied. 4. Basal mean arterial pressure in PTG1 group (80 +/- 1 mmHg at 4 months; 83 +/- 1 mmHg at 10 months; and 89 +/- 1 mmHg at 19 months; n = 6) was significantly different (P < 0.05 in all groups) from that in the control group of lambs (74 +/- 2 mmHg at 4 months; 76 +/- 1 mmHg at 10 months; and 81 +/- 1 mmHg at 19 months; n = 7). Prenatal glucocorticoid exposure did not alter vascular responsiveness to noradrenaline, angiotensin II and ACTH in these sheep at any of the ages studied. 5. These results suggest that foetal exposure to maternal dexamethasone during defined developmental stage or 'window' programmes elevated blood pressure, which persists later in life.     

BLOOD PRESSURE AND METABOLIC EFFECTS OF ACTH IN ANEPHRIC SHEEP

1. ACTH (80–100 iu/day) was administered to seven sheep for 3–5 days following bilateral nephrectomy. 2. ACTH treatment produced rises in mean arterial pressure in anephric sheep similar to those observed in intact animals. Following withdrawal of ACTH, blood pressure declined over the following 72 h. 3. ACTH produced a transient fall in plasma potassium in anephric sheep, suggesting an internal redistribution mechanism for this ion. 4. These studies demonstrate that adrenal steroid hormones can modify blood pressure in the absence of the kidney.     

THE EFFECTS OF CALCIUM ANTAGONISTS ON BLOOD PRESSURE AND RESPONSES TO α-ADRENOCEPTOR AGONISTS IN HYPERTENSIVE RABBITS

The effects of the calcium antagonists verapamil and nifedipine on mean arterial blood pressure, heart rate and pressor responses to a range of alpha-adrenoceptor agonists were examined in male normotensive New Zealand white rabbits and in rabbits with perinephritis hypertension. Verapamil and nifedipine caused a greater fall in mean arterial pressure in hypertensive compared to normotensive rabbits both when the fall was expressed as an absolute and as a percentage change. Effects on heart rate were similar in normotensive and hypertensive animals. Pressor responses to phenylephrine were attenuated by nifedipine and verapamil in normotensive and hypertensive rabbits. Pressor responses to alphamethyl noradrenaline were also attenuated by nifedipine, but pressor responses to BHT 920 were not significantly altered by either calcium antagonist in normotensive or hypertensive rabbits at the dose used. Thus the calcium antagonists had a greater effect on alpha 1 - than alpha 2-adrenoceptor mediated responses in both normotensive and hypertensive rabbits. Hypertensive animals showed an increased responsiveness to phenylephrine and alphamethyl noradrenaline but not BHT 920 compared to normotensives. This difference remained after treatment with both the calcium antagonists.     

KETANSERIN DOES NOT PREVENT ACTH-INDUCED HYPERTENSION IN SHEEP

The role of serotonin (5HT) in the pathogenesis of ACTH-induced hypertension in sheep has been examined. The pressor responses to injections of 5HT (0.1-30 micrograms/kg) were similar in normotensive and hypertensive sheep. Prior treatment with the 5HT2 receptor antagonist ketanserin had no effect on the development of hypertension produced by ACTH administration.     

CENTRAL α-ADRENOCEPTORS AND BLOOD PRESSURE REGULATION IN THE RAT

1. Radioligand binding studies using [³H]-prazosin (α₁) and [³H]-yohimbine (α₂) were undertaken to characterize central α-adrenoceptors in regions involved in blood pressure regulation. 2. Both α₁- and α₂-adrenoceptors were identified in the anterior and posterior hypothalamus and dorsal midline area of the caudal medulla oblongata of the rat. 3. The α₁- or α₂-adrenergic pharmacological specificity of the adrenoceptors was similar in each region, although their concentrations were different. 4. The concentration of α₂-adrenoceptors in the anterior hypothalamus was decreased following sino-aortic denervation suggesting that some hypothalamic α₂-adrenoceptors are associated with neurones of the baroreflex arc.     

PROGESTERONE ANTAGONIZES DEVELOPMENT BUT NOT MAINTENANCE OF ACTH-INDUCED HYPERTENSION IN SHEEP

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 less than 0.05) during the first 24 h. 3. Infusion of ACTH (5 micrograms/kg per day), alone, for 3 days, increased arterial pressure by 21 +/- 2 mmHg (P less than 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.     

EFFECT OF POSTASSIUM, ANGIOTENSIN II AND ACTH ON BLOOD ALDOSTERONE AND CORTISOL IN SHEEP ON DIFFERENT DIETARY POTASSIUM AND SODIUM INTAKES

The short term aldosterone response to manipulations of potassium (K), angiotensin II (AII) and ACTH were examined in sheep on a variety of chronic electrolyte regimes. Reduction in Na intake increased blood aldosterone to a greater extent on 100 mmol/day K than a K-free diet. Aldosterone increased in response to AII under conditions of chronic dietary Na restriction, in contrast to acute Na depletion. The effects of K, AII, and ACTH on aldosterone concentrations in sheep on varying intakes of Na and K are similar to that reported for other species.     

CENTRALLY MEDIATED INCREASED SYMPATHETIC ACTIVITY IS NOT IMPORTANT IN THE GENESIS OF ACTH-INDUCED HYPERTENSION IN SHEEP

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 micrograms/kg per day) or methyldopa (60 mg/kg per day) with ACTH (5 micrograms/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.     

THRESHOLD FOR THE EFFECTS OF ACTH ON BLOOD PRESSURE IN SHEEP

The time of onset and dose threshold for ACTH induced hypertension was examined in conscious sheep. ACTH 1 microgram/kg per day significantly raised blood pressure. The maximum rise occurred at 2 micrograms/kg per day. The rise in pressure was significant after 8 h of ACTH infusion.     

THE EFFECT OF EPANOLOL ON INTRA-ARTERIAL AMBULATORY BLOOD PRESSURE AND BARORECEPTOR HEART RATE REFLEX IN ESSENTIAL HYPERTENSION

1. The effect of chronic treatment with epanolol, a new cardioselective beta-adrenoreceptor antagonist with moderate beta 1-selective intrinsic sympathomimetic activity (ISA), on 24 h ambulatory intra-arterial blood pressure (24 h IABP) and the sino-aortic baroreceptor heart rate (SAB/HR) reflex was investigated in six hypertensive subjects. 2. All subjects demonstrated a greater than 10% reduction in mean arterial pressure with atenolol therapy (100 mg once daily) before entering a randomized, double-blind, placebo-controlled, crossover protocol with epanolol (100 mg twice daily for 4 weeks). 3. Epanolol treatment at this dose was not associated with significant reduction in systolic or diastolic 24 h IABP or heart rate. There was no change in SAB/HR reflex set point, sensitivity or latency with epanolol. 4. beta 1-selective ISA may be undesirable in beta-adrenoceptor antagonists used to treat hypertension.     

DEMONSTRATION OF α-ADRENOCEPTOR ANTAGONISM BY THE 5HT2 ANTAGONIST, KETANSERIN (R49945), IN SHEEP

Serotonin causes a dose related (0.1-20 micrograms/kg i.v.) increase in mean arterial blood pressure (MAP) and heart rate in conscious sheep. Ketanserin (0.1 mg/kg per h i.v.) causes a decrease in blood pressure, and an increase in heart rate. In the presence of ketanserin, serotonin induced increases in MAP are attenuated, or abolished, but the increases in heart rate are enhanced. Ketanserin (10 mg/kg per h i.v.) attenuates or abolishes the increase in blood pressure induced by the alpha-adrenoceptor agonist phenylephrine in conscious sheep. When administered in the presence of the alpha-adrenoceptor antagonist prazosin, ketanserin (0.1 mg/kg per h i.v.) fails to induce a further hypotensive response. These data suggest that in the conscious sheep ketanserin exhibits predominantly alpha-adrenoceptor antagonism.     

ANGIOTENSIN CONVERTING ENZYME INHIBITION DOES NOT PREVENT DEVELOPMENT OF ACTH-INDUCED HYPERTENSION IN SHEEP

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

EFFECT OF DIETARY UREA ON BLOOD PRESSURE IN SPONTANEOUSLY HYPERTENSIVE RATS

The feeding of a normal diet containing 13.5% urea (in place of protein in a high protein diet) attenuated the development of severe hypertension and decreased the incidence of stroke in spontaneously hypertensive rats (SHR), when 1% NaCl solution was given to them. The urea not only increased urine volume, but also increased urinary sodium excretion in SHR given 1% NaCl for drinking. Although there was no obvious difference in erythrocyte size between the urea and the control groups, there was a significant inverse correlation between plasma urea level and erythrocyte size. These results suggest that a high protein diet reduced blood pressure partly through the diuretic effect of urea, the common metabolite of various proteins.     

THE EFFECT OF PREGNANCY ON MINERALO- AND GLUCO-CORTICOID SECRETION IN THE SHEEP

1. The peripheral blood concentrations of aldosterone, corticosterone and cortisol were measured during pregnancy in conscious, undisturbed sheep. 2. Aldosterone levels did not change during pregnancy and the mean pregnant value, 1·2 s.d. 1·4 ng/100 ml (n= 12) was not significantly different from the non-pregnant value, 2·1 s.d. 1·7 (n= 16). 3. Cortisol levels likewise were unchanged by pregnancy–non-pregnant values were 0·56 s.d. 0·50 μg/100 mi (n= 12) compared with 0·46 s.d. 0·40 μg/100 ml (n= 16) in pregnant sheep. 4. Sheep of 110–140 days gestation had a 400 mmol greater total exchangeable sodium than non-pregnant sheep. Plasma volume and plasma renin concentration tended to be elevated near to term. 5. Very high aldosterone secretion rates and peripheral blood levels could be produced in pregnant sheep by stress, intravenous ACTH or angiotensin II infusions, and by sodium deficiency. It is suggested that the pregnant sheep may show increased sensitivity in contrast to non-pregnant sheep to these stimuli and the enlarged size of their adrenals may be a contributing factor.     

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. 2. Haemodynamic dose-response curves to prostacyclin were performed before, during and after production of ACTH-induced hypertension. 3. Prior to ACTH administration prostacyclin produced dose-dependent reductions in mean arterial pressure, total peripheral resistance and stroke volume and these were accompanied by increases in heart rate and cardiac output. 4. After 5 days of ACTH-induced hypertension prostacyclin produced similar effects on mean arterial pressure to those seen prior to ACTH but the effects on heart rate, cardiac output, stroke volume and total peripheral resistance were markedly increased. 5. These studies demonstrate that the responsiveness of the circulation to prostacyclin is altered in ACTH-induced hypertension.