ACTH-induced Hypertension In Sheep Research Articles

Adrenocorticotrophin-Induced Hypertension in Kats

Adrenocorticotrophin (ACTH) administration raises blood pressure in humans, sheep, and the rat. ACTH hypertension can be reproduced in sheep by combined infusion of aldosterone, 17 alpha-OH-progesterone, and 17 alpha,20 alpha-OH-progesterone, and in humans by cortisol. In the rat, ACTH hypertension is probably due to corticosterone. Progesterone treatment can prevent ACTH-induced hypertension in sheep. This study examined the ability of progesterone to antagonize the onset and development of ACTH-induced hypertension in Sprague-Dawley rats (n = 44). We also investigated the relationship of plasma digoxin-like substances (DLS) to ACTH hypertension. ACTH (0.5 mg/kg/day) significantly increased blood pressure (+24 +/- 5 mm Hg, P < .001) in association with an increase of water intake, urine output, and plasma sodium concentration, and a decrease of body weight and plasma potassium concentration. ACTH increased plasma DLS (+132 +/- 18 pg/mL, P < .01), and there was a positive correlation between DLS and blood pressure (r = 0.68, n = 22, P < .001). Progesterone (50 mg/kg/day) did not block the development of ACTH-induced hypertension in the rat. Although progesterone prevented the ACTH-induced rise in plasma sodium and glucose concentration, it did not prevent the decrease in plasma potassium concentration. The failure of progesterone to prevent ACTH-induced hypertension in the rat argues against a common "hypertensinogenic" mechanism for ACTH hypertension in sheep and rat. DLS may play a role in ACTH-induced hypertension in the rat.

Studies on spirolactone steroid antagonists in ACTH-induced hypertension in sheep

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.

Rapid haemodynamic response to adrenocorticotrophin and the role of peripheral resistance in adrenocorticotrophin-induced hypertension 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.

Ritanserin and serotonergic mechanisms in blood pressure and fluid regulation in sheep.

1. In previous studies, exogenous serotonin (5-HT), administered intravenously, caused dose-related increases in mean arterial pressure and heart rate in conscious sheep. The 5-HT2 antagonist ketanserin (0.1 mg/kg per h, i.v.) was shown to lower blood pressure in the conscious sheep primarily through antagonism of alpha-adrenoceptors. 2. A newer 5-HT2 antagonist, ritanserin, is a more selective antagonist in vivo, as it attenuated or abolished pressor responses to exogenous 5-HT, but not to phenylephrine. 3. When infused alone, ritanserin (0.1 mg/kg per h, i.v.) failed to produce a decrease in blood pressure, suggesting that 5-HT antagonistic properties are not sufficient by themselves to lower blood pressure. 4. Ritanserin displayed a different metabolic profile to ketanserin, with a markedly decreased water intake. The mechanism of this effect is unresolved, but may imply a permissive role for 5-HT in the modulation of drinking responses in the sheep. 5. Ritanserin did not modify ACTH-induced hypertension in sheep.

Prostacyclin infusion does not prevent ACTH-induced hypertension in sheep

The present experiments examine the hemodynamic effects of an intravenous infusion of prostacyclin on the development of ACTH-induced hypertension in conscious sheep. Prostacyclin was infused at either 0.01 μg/min − for 9 days or 0.25 μg/kg min −1 for 4 days. At 0.01 μg/kg minprostacyclin had no effect on blood pressure in normotensive sheep or on the development of ACTH hypertension. Infusion at 0.25 μg/kg min −1 increased heart rate, cardiac output and plasma renin concentration and decreased stroke volume and peripheral resistance in normotensive sheep. Despite these effects it did not prevent development of ACTH-induced hypertension. It is unlikely on the basis of these results that glucocorticoid-induced inhibition of vasodepressor prostacyclin and resulting increase in pressor responsiveness to circulating agonists is the primary cause of ACTH induced hypertension in sheep.

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 effects of increasing extracellular potassium concentration in ACTH-induced hypertension in sheep.

1. ACTH administration (20 microgram day-1 kg-1) to sheep produces hypertension associated with a raised cardiac output and hypokalaemia. 2. The aim of the present experiments was to detail the haemodynamic changes associated with restoration of the extracellular potassium concentration in sheep with ACTH-induced hypertension. 3. After 7 days of ACTH treatment potassium chloride (10 mmol/h) was infused for 3 days to restore plasma [K+] to the pre-ACTH value. 4. ACTH reduced plasma [K+] from 4.4 +/- 0.1 to 3.2 +/- 0.2 mmol/l but 3 days of potassium chloride infusion returned plasma [K+] to 4.3 +/- 0.2 mmol/l. 5. ACTH increased mean arterial pressure from 67 +/- 2 to 88 +/- 1 mmHg in the first 7 days and it remained elevated during potassium chloride infusion (91 +/- 5 mmHg on day 10). 6. Cardiac output rose with 7 days ACTH treatment from 4.9 +/- 0.2 to 6.0 +/- 0.6 l/min but fell progressively with potassium chloride infusion to 4.9 +/- 0.3 l/min on day 10. 7. These studies suggest that potassium status or extracellular [K+] may play a role in determining the haemodynamic profile associated with steroid-induced hypertension.

Effect of ACTH administration on the haemodynamic response to arginine-vasopressin in sheep.

1. Blood pressure, heart rate and cardiac output were studies in intace conscious sheep during AVP infusion at 0.1, 0.25, 0.5 and 1.0 microgram/min for 30 minutes to determine whether pressor responsiveness to AVP was altered in ACTH-induced hypertension. 2. Prior to ACTH treatment, AVP produced rises in blood pressure associated with a fall in heart rate and cardiac output. 3. During ACTH treatment, pressor responsiveness to AVP and decrease in cardiac output were unchanged, but reflex bradycardia was reduced. 4. ACTH-induced hypertension in sheep is not associated with enhanced pressor responsiveness to AVP.

Haemodynamics of Acth-Induced Hypertension in Sheep

1. Administration of adrenocorticotropic hormone (ACTH) to sheep produced increases in mean arterial pressure within 24 h associated with an increase in cardiac output and cardiac rate. Both cardiac output and blood pressure remained elevated over the 5 days of ACTH treatment. 2. Administration of ACTH during beta-adrenoreceptor blockade resulted in an increase in blood pressure without changes in cardiac output at 24 h. 3. Administration of a combined steroid infusion over 5 days produced increases in cardiac output identical with the effects of ACTH but with a substantially smaller effect on blood pressure. 4. These data suggest that the observed changes in cardiac output produced by ACTH treatment may be associated with high blood concentrations of adrenocortical steroids rather than being necessary for the development of the hypertension.