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.     

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.     

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.     

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.     

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.     

Prostaglandin synthesis inhibition with indomethacin in ACTH-induced hypertension

The short- and long-term effects of indomethacin administration were examined in normotensive and ACTH-induced hypertensive conscious sheep. Indomethacin, 1 mg/kg/h for 60 min, caused a transient rise in mean arterial pressure (MAP) and calculated total peripheral resistance (CTPR) and a fall in cardiac output in normotensive sheep. In sheep with ACTH hypertension, these haemodynamic effects were prolonged. Indomethacin infusion at 3 mg/kg/day for 3 days had no observable haemodynamic or metabolic effects. Concomitant infusion of ACTH increased MAP and CTPR. These studies suggest prostaglandins play only a minor role in regulation of blood pressure in normal conscious sheep, but modulate the blood pressure rise in ACTH hypertension in sheep.     

HAEMODYNAMIC RESPONSE TO ACTH ADMINISTRATION IN ESSENTIAL HYPERTENSION

1. The haemodynamic and volume response to ACTH administration was investigated in six patients with mild, untreated essential hypertension and two patients with Addison's disease on maintenance steroids. Blood pressure, heart rate and weight were recorded daily. Plasma volume (125I-HSA) and cardiac output (thermo-dilution) were measured during the control period and on the 5th day of ACTH treatment. 2. In the hypertensive subjects, mean arterial pressure rose from 94.3 +/- 2.2 to 105.7 +/- 2.8 mmHg on the 5th day of ACTH administration (P less than 0.02). Plasma volume rose from 29.8 +/- 2.2 to 34 +/- 2.2 ml/kg. Cardiac index increased from 2.85 +/- 0.21 to 3.32 +/- 0.14 l/min per m2 (P less than 0.05). Cardiac output rose from 5.81 +/- 0.69 to 6.72 +/- 0.59 l/min. Calculated total peripheral resistance, heart rate and body weight were unchanged. No such changes were seen in patients with Addison's disease. 3. The haemodynamic characteristics of ACTH in patients with mild untreated essential hypertension are similar to those in the experimental model 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.     

Atropine potentiates the pressor effect of arginine-vasopressin in conscious dogs

The hemodynamic effects of injections of arginine-vasopressin (AVP) at different doses were measured before and after administration of atropine (250 micrograms/kg), propranolol (2 mg/kg), or phenoxybenzamine (5 mg/kg) in conscious dogs. Measurements of arterial pressure derived from a chronic indwelling catheter, and aortic flow derived from an aortic electromagnetic flow probe, were digitized and analyzed by computer to assess mean and pulsatile arterial pressure, cardiac output, total peripheral resistance, heart rate, and other hemodynamic variables. AVP alone moderately increased arterial pressure and decreased cardiac output and heart rate. For doses between 20 and 40 ng/kg, mean arterial pressure increased by 17.4 +/- 1.5 mm Hg. After atropine, the same dose of AVP increased pressure by 51.6 +/- 3.2 mm Hg. The bradycardiac response to AVP was blunted by atropine as was the decrease in cardiac output. The effect of AVP on total peripheral resistance was not affected by atropine. Neither alpha- nor beta-adrenergic blockade enhanced the pressor effect of arginine-vasopressin. Our results indicate that the potentiation of the pressor response to AVP previously reported with total autonomic blockade is largely due to preventing a vagallymediated decrease in cardiac output in conscious dogs.     

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.     

Possible involvement of an impaired baroreflex mechanism but not the renin-angiotensin system and vasopressin in the enhanced pressor responsiveness to physostigmine in spontaneously hypertensive rats

Effects of physostigmine on heart rate, mean arterial pressure (MAP), plasma renin concentration (PRC) and vasopressin (AVP) release were investigated in spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats. Physostigmine (100 micrograms/kg, i.a.) produced a greater and prolonged hypertensive response in the SHR than in the WKY. Heart rate was increased by physostigmine in SHR rats while it was unchanged in the WKY. PRC was unchanged or even slightly decreased in these animals when MAP was increased by physostigmine. An AVP pressor antagonist did not attenuate the pressor and cardiac effects of physostigmine in these animals. These data indicate that an impaired baroreflex mechanism or a different mode of sympathetic neuronal activation by physostigmine through the central mechanism appears to be contributory, at least in part, to the enhanced pressor responsiveness in the SHR. The renin-angiotensin system and AVP do not appear to be involved in the enhanced pressor responsiveness to physostigmine in SHR rats.     

PRESSOR RESPONSIVENESS IN STEROID-INDUCED HYPERTENSION IN MAN

Pressor responsiveness to angiotensin II (AII) and phenylephrine (PE) was examined before and after 5 days of ACTH (1 mg, i.m., daily) or hydrocortisone (200 mg, orally, daily) in six normotensive men. Pulse pressure was higher prior to PE than AII infusion, presumably due to feeding. Systolic blood pressure (SBP) was increased by both ACTH and hydrocortisone treatment, but more by ACTH. There were no significant changes in AII pressor responsiveness with either ACTH or hydrocortisone. ACTH increased pressor responsiveness to PE at 1.35 and 2 micrograms/kg per min, and hydrocortisone at 0.6-2 micrograms/kg per min, with falls in pulse rate at 0.3-0.9 micrograms/kg per min. Changes in pressor responsiveness do not explain ACTH hypertension.     

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.     

CARDIOVASCULAR ACTIONS OF HUMAN ENDOTHELIN IN CONSCIOUS SHEEP

1. Synthetic human endothelin was injected intravenously over the range 1.5-50 micrograms to examine its cardiovascular actions in conscious sheep. 2. Mean arterial pressure increased by 9-21 mmHg within 30-120 s over the range 5-50 micrograms 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.     

Cyclosporin A and pressor responsiveness in sheep

Pressor response to graded infusion of angiotensin II, noradrenaline, arginine-vasopressin, and serotonin and blood pressure change following indomethacin, an inhibitor of cyclooxygenase, were examined in conscious sheep, before and during the development of cyclosporin A-induced hypertension. Cyclosporin caused an increase in mean blood pressure from 68 +/- 2 to 82 +/- 3 mm Hg (p less than 0.001) and in heart rate from 67 +/- 4 to 91 +/- 4 beats/min (p less than 0.001). Pressor and heart rate responses to all substances tested were not changed by cyclosporin treatment suggesting that changes in pressor responsiveness are unlikely to be involved in the development of cyclosporin hypertension in sheep.     

Hemodynamic effects of antagonists of the vasoconstrictor action of vasopressin in conscious dogs

Two antagonists of the pressor action of arginine-vasopressin (AVP) were studied in conscious, normally hydrated dogs: 1-deaminopenicillamine-4-valine-8-D-arginine-vasopressin, or dPVDAVP, and 1-(beta-mercapto-beta, beta-cyclopentamethylene propionic acid)2-(O-methyl)tyrosine arginine-vasopressin, or d(CH2)5Tyr(Me)AVP. We first examined the hemodynamic effects of these antagonists when given alone. The infusion of dPVDAVP, 200 ng/kg/min, increased cardiac output (measured with an aortic electromagnetic flowmeter) by 23% and heart rate by 27%, leaving arterial pressure unchanged. Most of the change in cardiac output reflected a large increase in skeletal muscle blood flow, as determined by radioactive microspheres. The injection of d(CH2)5Tyr(Me)AVP, 10 micrograms/kg, had little effect on cardiac output, arterial pressure, and heart rate. We then examined the ability of the two antagonists to block the hemodynamic responses to injections of AVP. In the absence of the antagonists, AVP induced dose-related increases in mean arterial pressure and total peripheral resistance, as well as decreases in heart rate and cardiac output. The antagonist dPVDAVP shifted the dose-response curves to the right without changing their slope. On the contrary, the hemodynamic response to AVP was strikingly modified following blockade with d(CH2)5Tyr(Me)AVP. Cardiac output and heart rate increased, whereas total peripheral resistance decreased, for doses of AVP between 25 and 400 ng/kg. It is concluded that some antagonists of the pressor action of vasopressin may influence hemodynamics of conscious dogs by effects other than competitive antagonism at the level of vascular receptors.     

Effects of atrial natriuretic factor on pressor responsiveness to angiotensin II, norepinephrine, and vasopressin in conscious sheep.

The effects of pretreatment with atrial natriuretic factor (ANF) on the pressor responsiveness to injections of angiotensin II (ANGII), arginine vasopressin (AVP), and norepinephrine (NE), as well as the effect of pretreatment with ANGII on the hypotensive responses to ANF injection were studied in conscious sheep. The hemodynamic effects of ANF infusion (100 micrograms/h for 60 min) were also examined in animals pretreated with the angiotensin-converting enzyme (ACE) inhibitor, captopril. Infusion of ANF attenuated the pressor responsiveness to exogenous AII and NE, but caused no significant change in the blood pressure increases produced by vasopressin. In contrast, infusion of AII had no effect on the immediate hypotensive response to ANF injection. Infusion of ANF for 60 min produced similar hemodynamic actions in sheep during ACE inhibition as compared with the responses observed in normal sheep, although the reduction in cardiac output and increase in calculated total peripheral resistance was attenuated. Infusion of captopril increased plasma concentration of renin (PRC), and infusion of ANF produced no further change in PRC. In conclusion, the short-term cardiovascular responses to ANF infusion in conscious sheep are not mediated solely by inhibition of the renin-angiotensin system. However, ANF attenuates the pressor actions of pharmacologic doses of exogenous ANGII and NE. In contrast, the vasodepressor response to exogenous ANF injection was not altered in animals receiving ANGII infusion. This study suggests that ANF may be important in regulating the effects of endogenous vasoconstrictor hormones on blood pressure (BP).     

Role of nitric oxide in adrenocorticotrophin-induced hypertension: L-arginine effects reversed by N-nitro-L-arginine

1. L-arginine prevents adrenocorticotrophin (ACTH)-induced hypertension in the rat. To confirm that this effect is mediated through the nitric oxide (NO) system, we examined whether N-nitro-L-arginine (NOLA) could reverse the L-arginine-induced blockade of ACTH-induced hypertension. 2. Blood pressure and metabolic parameters were examined in sham-, ACTH-, L-arginine + sham-, NOLA + sham-, ACTH + L-arginine- and ACTH + L-arginine + NOLA-treated Sprague-Dawley rats (n = 40). 3. Adrenocorticotrophin treatment increased systolic blood pressure (SBP), water intake and urine output and decreased bodyweight. N-Nitro-L-arginine alone increased SBP without affecting metabolic variables. L-Arginine alone did not affect blood pressure. The SBP was lower in L-arginine + ACTH- than ACTH-treated rats (P < 0.001), but was higher following ACTH + L-arginine + NOLA than ACTH + L-arginine (P < 0.05). 4. N-Nitro-L-arginine reversed the blood pressure-lowering effect of L-arginine in ACTH-induced hypertension in the rat, supporting the notion that NO plays a role in the hypertension.     

DIURETIC AND HAEMODYNAMIC EFFECTS OF MK 447 IN NORMOTENSIVE AND HYPERTENSIVE SHEEP

The short term effects of the novel diuretic MK 447 were examined in both normotensive and hypertensive (ACTH treated) conscious sheep. The drug had profound diuretic, natriuretic and kaliuretic effects in both groups. Plasma sodium was unchanged but plasma potassium fell and haematocrit increased. Plasma renin concentration increased with MK 447 in the normotensive but not the hypertensive sheep. In the normotensive sheep cardiac output fell, peripheral resistance increased and blood pressure was unchanged. In the hypertensive ACTH treated sheep cardiac output and blood pressure fell but resistance was unchanged.     

Effect of the calcium antagonist nilvadipine on haemodynamics at rest and during cold stimulation in essential hypertension

Summary The immediate haemodynamic effects of the calcium antagonist nilvadipine have been studied in ten patients with established mild essential hypertension.Nilvadipine 4 mg p.o. reduced both the systolic and diastolic blood pressures within 60 min, associated with a fall in total peripheral resistance and an increase in heart rate and cardiac index. The peak of blood pressure and total peripheral resistance reached during a cold pressor test were reduced by nilvadipine, but it did not affect the haemodynamic responsiveness to cold stimulation.Plasma renin activity was unaltered and the plasma noradrenaline concentration was increased only slightly.Thus, nilvadipine lowered blood pressure at rest and during cold stimulation as a result of arteriolar dilatation. The hypotensive effect at rest was associated with a reflex increase in heart rate and cardiac index.