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.     

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.     

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.     

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.     

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.     

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.     

THE EFFECT OF THE ''HYPERTENSINOGENIC STEROID, 9α-FLUORO-CORTISOL ON BLOOD PRESSURE IN SHEEP WITH ACTH-INDUCED HYPERTENSION

The effect of treatment with 9 alpha-fluorocortisol (9 alpha FF), a steroid which causes hypertension in sheep, was examined in sheep with ACTH-induced hypertension. ACTH treatment alone increased mean arterial pressure (MAP), plasma Na concentration, water intake and urine volume and decreased plasma K concentration. 9 alpha FF 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. As 9 alpha FF did not cause a further increment in blood pressure in sheep with ACTH-induced hypertension it is possible that both ACTH and 9 alpha FF may produce hypertension by similar mechanisms.     

DEHYDROEPIANDROSTERONE DOES NOT PREVENT ADRENOCORTICOTROPHIN-INDUCED HYPERTENSION IN CONSCIOUS RATS

1. We tested the hypothesis that dehydroepiandrosterone (DHEA), which prevents dexamethasone-induced hypertension in rats, may block adrenocorticotrophin (ACTH) hypertension, which has been presumed due to corticosterone excess. The blood pressure and metabolic effects of DHEA (18 mg/kg per day) were examined in sham and ACTH-treated (0.5 mg/kg per day) conscious Sprague-Dawley rats (n= 20). 2. ACTH but not sham injection increased blood pressure, water intake and urine output and decreased bodyweight. 3. DHEA administration for 10 days did not alter blood pressure or metabolic effects in either sham or ACTH-treated rats. 4. DHEA, which is known to block dexamethasone-induced hypertension, did not modify ACTH-induced hypertension in the rat. This suggests either that ACTH-induced hypertension is not simply a consequence of glucocorticoid activity or that the action of DHEA in dexamethasone hypertension is not through blocking the glucocorticoid receptor.     

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.     

EFFECT OF SODIUM DEPLETION ON PRESSOR RESPONSIVENESS IN ACTH-INDUCED HYPERTENSION IN MAN

1. Pressor responsiveness to angiotensin II (AII) and phenylephrine (PHE) was measured before and after 5 days of ACTH (1 mg i.m. daily) in six normal men maintained on low sodium diet (15 mmol daily). 2. ACTH caused a significant increase in systolic blood pressure of 9 mmHg. 3. There was no change in pressor responsiveness to AII with ACTH. 4. ACTH increased pressor responsiveness to PHE for both systolic and diastolic blood pressure, with a fall in the threshold for response from 0.9 to 0.6 micrograms/kg per min. 5. Increased pressor sensitivity to catecholamines during ACTH administration in man is not sodium-dependent.     

ADRENOCORTICAL STEROID REQUIREMENTS FOR INITIATION OF ACTH-DEPENDENT HYPERTENSION IN SHEEP

1. Previous studies demonstrated that the combined infusion of cortisol (F), aldosterone (ALDO), deoxycorticosterone (DOC), corticosterone (B), 11-deoxycortisol (S), 17 alpha-hydroxyprogesterone (17 alpha OHP) and 17 alpha, 20 alpha- dihydroxy-4-pregnane-3-one (17 alpha 20 alpha OHP), 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, 17 alpha OHP and 17 alpha 20 alpha OHP together, increased MAP by 19 mmHg, similar to both complete steroid cocktail (+25 mmHg) or ACTH administration (+21 mmHg). Infusion of F, 17 alpha OHP and 17 alpha 20 alpha OHP increased MAP by +7 mmHg. Infusion of ALDO, 17 alpha OHP and 17 alpha 20 alpha OHP 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, 17 alpha OHP and 17 alpha 20 alpha OHP 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 micrograms/h) was substituted for cortisol, giving a total of 10 micrograms/h aldosterone. High dose ALDO (10 micrograms/h), 17 alpha OHP and 17 alpha 20 alpha OHP 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 micrograms/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, 17 alpha OHP and 17 alpha 20 alpha OHP. Therefore, the putative 'hypertensinogenic' receptor may be multivalent with binding sites for F, ALDO and 17 alpha 20 alpha OHP, 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.     

ROLE OF NITRIC OXIDE IN THE DEVELOPMENT OF CORTICOTROPIN-INDUCED HYPERTENSION IN SHEEP

1. The possibility that altered synthesis of vascular nitric oxide (NO) plays a role in the development of corticotropin-induced hypertension in sheep was examined by determining the effect of concomitant infusion of L-arginine, a precursor of NO, on the development of the hypertension. 2. Corticotropin (5 μg/kg per h) infused over 2 days increased mean arterial pressure (MAP) from 83 ± 4 to 99 ± 4 mmHg in five conscious sheep. Concomitant infusion of L-arginine (60 mg/kg per h) did not alter this response; infusion of L-arginine alone had no effect on blood pressure. 3. The dose of L-arginine (60 mg/kg per h) used blocked the rise in MAP (+16 mmHg) in response to a 5 h infusion of N-nitro-L-arginine (1 mg/kg per h). 4. These findings suggest that disruption of NO synthesis does not play a role in the development of corticotropin hypertension in sheep.     

LONG-TERM INCREASES IN RENAL SYMPATHETIC NERVE ACTIVITY AND HYPERTENSION

1. Essential hypertensive patients have been characterized by increased sympathetic nerve activity, increased peripheral vascular tone, decreased plasma volume and normal cardiac output when compared with normotensive subjects. Bilateral renal denervation reduces the magnitude or delays the onset of the blood pressure response in numerous models of experimental hypertension regardless of the aetiology of the elevation in arterial pressure. 2. Using a servocontrolled intrarenal infusion system, we have elevated intrarenal noradrenaline concentration via intermittent renal artery infusion without decreasing renal blood flow as a method of simulating selective elevation of renal sympathetic outflow. 3. Chronic intrarenal adrenergic stimulation increased arterial pressure within 24 h and this hypertension persisted for 28 consecutive days. The elevated arterial pressure was not associated with sustained increases in plasma renin activity, aldosterone, circulating catecholamines, arginine vasopressin or significant renal vasoconstriction. Urinary sodium excretion was chronically elevated and the dogs remained in negative sodium balance for the duration of the intrarenal noradrenaline infusion. 4. After 2 weeks of elevated intrarenal neurotransmitter coupled with hypertension, renal vascular reactivity to further adrenergic stimulation was significantly increased because the hypertension was maintained during continual reductions in the daily dosage of neurotransmitter allowed to be infused by the servocontroller. After only 28 days of noradrenaline infusion, renal vascular hypertrophy developed in vessels from 150–300 μm. 5. We conclude that selective and intermittent increases in intrarenal adrenergic neurotransmitter are sufficient to elicit chronic hypertension in the absence of volume expansion. This intrarenal neuroadrenergic hypertension is closely associated with the haemodynamic parameters which characterize a major subset of human essential hypertensives.     

ROLE OF THE SYMPATHETIC NERVOUS SYSTEM IN THE ONSET OF HYPERTENSION IN THE RAT: THE EFFECT OF 6-OH-DOPAMINE

1. The effect of chemical sympathectomy with 6-OH-dopamine (6-OHDA) on the onset of adrenocorticotrophin (ACTH)-induced hypertension was examined in Sprague-Dawley rats (n = 23). 2. 6-OHDA injection produced a fall in systolic blood pressure (SBP) from 100 +/- 5 mmHg control to 74 +/- 4 mmHg post-6-OHDA Treatment Day 1 (P less than 0.001), but did not alter food or water intake, urine volume or electrolyte excretion. 3. Compared with sham injection, ACTH-treated rats showed an increase in blood pressure (sham: 98 +/- 7 mmHg; ACTH: 123 +/- 9 mmHg on Treatment Day 10; P less than 0.01), loss of bodyweight, and increases in water intake and urine volume. 4. The magnitude of the blood pressure rise on ACTH was greater in 6-OHDA-treated rats than in intact control rats. Metabolic changes were similar. 5. Chemical sympathectomy with 6-OHDA did not delay or block the onset of ACTH hypertension in the rat.     

FAILURE OF NEOMYCIN TO MODIFY ACTH INDUCED HYPERTENSION IN SHEEP

Studies in rats have shown that neomycin administration attenuates certain types of adrenocortical steroid dependent hypertension, including ACTH hypertension. The effects of oral neomycin on ACTH induced hypertension were examined in conscious sheep. Neomycin has no effect on the blood pressure or metabolic responses to ACTH in sheep.     

THE HAEMODYNAMIC EFFECTS OF CYCLOSPORIN A IN SHEEP

SUMMARY
1. 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.     

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.     

EFFECTS OF β-ADRENOCEPTOR BLOCKADE ON PROSTACYCLIN MEDIATED RENIN RELEASE IN SHEEP

1. The effect of prostacyclin (PGI₂) infusion on plasma renin concentration (PRC) was examined before and after propranolol treatment in sheep. 2. Increasing doses of prostacyclin (0.05, 0.1 or 0.3 μg/kg per min) produced dose dependent increases in PRC. 3. There was a significantly lower PRC response after propranolol at 0.3 μg/kg per min only.     

LACK OF PRESSOR RESPONSE TO INTRACEREBROVENTRICULAR INFUSION OF ALDOSTERONE IN SHEEP

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 micrograms/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 micrograms/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.     

POINT OF VIEW: WHY HYPERTENSION IS OVERDIAGNOSED AND OVERTREATED IN 1987

1. The decision whether arterial blood pressure (BP) is elevated or normal is usually based on inadequate data: few readings in the presence of great variability of BP; levels higher in the presence of the doctor; and diastolic BP often higher sitting and standing than lying. 2. Assessments of response and of the need for increases in drug dosage are also based on insufficient data. 3. Increased morbidity and mortality from stroke and heart attack, and incomplete correction with treatment have been interpreted as suggesting further benefit from aggressive reduction of BP to 'normal' in all patients. 4. The emergence of powerful drugs with few side-effects, and the promise of lowering office BP to 'normal' as monotherapy, has removed the hesitation to treat 'mild' hypertension. 5. Attempts to lower sitting office diastolic BP to 'normal' have led to increasing drug dosage, dose-related, drug-specific side-effects, and lethargy due to hypotension. 6. Newer self-measurement BP units can be used easily by most patients, cost less than five visits to the doctor and provide a cheap method of obtaining sufficient data on which to base informed management decisions. Supported by normal echocardiographic left ventricular mass, normal 'home BP' (including lying diastolic) permits many mild hypertensives to remain off medications. 7. Non-drug therapy avoids or reduces long-term drug therapy, with its side-effects.