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.     

HAEMODYNAMIC EFFECTS OF LONG-TERM ENDOTHELIN INFUSION IN CONSCIOUS SHEEP

1. Synthetic human endothelin-1 was infused intravenously at 15 micrograms/h for 24 h to examine its cardiovascular actions in five conscious sheep. 2. Endothelin produced a maximum increase in mean arterial pressure (MAP) of +8 mmHg at 8 h, with an increase in calculated total peripheral resistance (CTPR) of +2.6 mmHg/L per min, whilst cardiac output (CO) was unchanged. At 24 h MAP was not significantly elevated, however CTPR had increased by +2.8 mmHg/L per min and CO had decreased by 0.9 L/min. 3. This study shows that long-term administration of endothelin produces sustained arterial vasoconstriction in sheep.     

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.     

ACUTE HAEMODYNAMIC RESPONSES TO UNILATERAL RENAL ARTERY STENOSIS IN CONSCIOUS DOGS

The acute responses to renal artery stenosis were studied in chronically instrumented, unanaesthetized dogs. Stenosis of one renal artery produced a rise in arterial pressure and a fall in total peripheral conductance, but no change in cardiac output. The resistance to blood flow of the stenotic kidney 1 h after stenosis was 25% greater than before stenosis. This rise in resistance was due to the resistance of the renal artery stenosis itself. Blood flow to the contralateral kidney fell by 13% (s.e.m. = 3) at 1 h and resistance rose by 39% (s.e.m. = 5). Plasma renin activity was elevated approximately 10 fold. Calculations of changes in peripheral conductances following stenosis showed that the stenotic kidney was responsible for 14% of the fall in total peripheral conductance at 1 h, and the contralateral kidney for 18%. Thus acute renal artery stenosis produced a prompt rise in arterial pressure due to reduced peripheral conductance, of which the two kidneys (stenotic and contralateral) were responsible for one-third.     

RAPID HAEMODYNAMIC RESPONSES TO ATRIAL NATRIURETIC FACTOR (99–126) IN CONSCIOUS SHEEP

1. Haemodynamic effects of 20 micrograms and 100 micrograms injection of atrial natriuretic factor 99-126 (ANF) were studied in conscious sheep. 2. ANF injection rapidly decreased blood pressure associated with a fall in total peripheral resistance, increased heart rate and cardiac output. These parameters returned to normal within 5 min of injection. 3. This study shows that ANF has an initial vasodilatory action to decrease blood pressure, which is different from the hypotensive mechanism seen with short-term infusion (60 min) of ANF in sheep.     

ACUTE HAEMODYNAMIC AND HORMONAL EFFECTS OF ORAL DOXAZOSIN IN NORMAL SUBJECTS

Haemodynamic and hormonal effects of doxazosin, a long-acting alpha 1-adrenoceptor antagonist (2 mg) were compared with placebo in six normal men. Doxazosin at 2 mg produced lower supine systolic blood pressure and plasma cortisol concentration than control at 4 h only, but these changes were not sustained. Both supine and standing pulse rate were increased by active drug after 6 h. In this acute study doxazosin did not affect plasma renin or aldosterone concentrations.     

WHOLE BODY AND RENAL NORADRENALINE RELEASE DURING ACUTE INFUSION OF ENDOTHELIN-1 IN CONSCIOUS SHEEP

1. The present study investigated in conscious sheep the response of the sympathetic nervous system to a systemic infusion of 20 nmol/h endothelin-1 (ET-l), using a tritiated-noradrenaline (NA) tracer dilution technique. 2. Mean arterial pressure increased from 79 ±3 mmHg to a maximal level of 102± 12 mmHg by 30 min of ET-1 infusion. 3. Total and renal NA kinetics were measured during this time. Total NA spillover was not affected by infusion of ET-1. In contrast, renal NA spillover decreased from a control level of 81 ± 5 to 30 ± 14ng/min (P<0.01) after 20 min and to 27 ± 7ng/min (P<0.01) after 30 min of ET-1 infusion. 4. The present findings are consistent with the proposal that a direct vasoconstrictor action of ET-1 results in a paroreflex mediated reduction in renal sympathetic vasoconstrictor activity.     

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.     

MODERATE SODIUM RESTRICTION AND POTASSIUM SUPPLEMENTATION IN ESSENTIAL HYPERTENSION

Continuous 24 h arterial blood pressure and vasoactive hormones were measured in twelve patients with essential hypertension after 4 weeks on a control sodium intake (180 mmol/day) and after similar periods of sodium restriction (80 mmol/day) and potassium supplementation (200 mmol/day). Sodium restriction was associated with variable blood pressure changes in individual patients and a small reduction in 24 h mean pressure of 4/3 mmHg. The greatest fall in blood pressure with sodium restriction was seen in those patients with the least rise in renin. Potassium supplementation was associated with variable individual blood pressure changes and a trivial reduction in mean 24 h pressures (0.1/0.8 mmHg). Mean 24 h plasma aldosterone concentration was significantly higher during sodium restricted and potassium-supplemented diets, compared to control levels, but other vasoactive hormones were unchanged.     

VERAPAMIL-INDUCED SECRETION OF ACTIVE AND INACTIVE RENIN IN CONSCIOUS SHEEP

1. Regulation of plasma active and inactive renin was investigated using conscious sheep with indwelling artery, vein and bladder catheters. Control and experimental studies were carried out in the same animals on different days. 2. The calcium antagonist drug verapamil was given as an initial bolus injection (0.5 mg/kg) followed by a continuous infusion (0.1 mg/kg per h) over a 2.5 h period. 3. Plasma active and inactive renin changed in parallel. Both were significantly increased within 15 min of the initial drug dose and both attained a peak increase after 45 min. Thereafter, the two forms of renin returned to basal levels despite continued infusion of the drug. 4. Effective renal plasma flow (C_PAH) was also transiently increased by verapamil and followed a similar time course to changes in plasma active and inactive renin concentration. Arterial blood pressure, however, remained suppressed by verapamil for the duration of the study. 5. Verapamil did not alter urine flow or sodium and potassium excretion rates. 6. These results are discussed in relation to the possible link between intrarenal haemodynamics and renin secretion in conscious and in anaesthetized animals and also in relation to the concept that variation in the relative amounts of active and inactive renin secreted in differing physiological situations represents a mechanism for regulating the renin-angiotensin system.     

AN ANALYSIS OF THE HAEMODYNAMIC EFFECTS OF TOLBUTAMIDE IN CONSCIOUS DOGS

1. In conscious chronically instrumented dogs, tolbutamide (5-45 mg/kg) induced significant dose-related increases in mean arterial pressure and left ventricular end-diastolic pressure. 2. Cardiac output was decreased while heart rate, d(LVP)/dt, and regional myocardial performance at the left ventricle were not significantly affected. Computed total peripheral resistance was increased. 3. Pretreatment with the alpha-antagonist phentolamine (1-1.5 mg/kg) abolished the pressor response. Furthermore, the pressor response to norepinephrine (0.1 microgram/kg) was enhanced by pretreatment with tolbutamide (45 mg/kg). 4. In an isolated tissue preparation using ring segments of canine femoral arteries, neither tolbutamide nor its major hepatic metabolites (carboxytolbutamide, p-toluene-sulfonamide and p-toluene-sulfonylurea) caused any smooth muscle contraction. However, pretreatment of these tissues with 10(-4), 10(-3), or 10(-2) mol/l tolbutamide potentiated the contractile response to norepinephrine by up to 19% and to phenylephrine by up to 8%. 5. It was concluded that the pressor effect of tolbutamide arises by potentiating the alpha-adrenoceptor mediated vasoconstrictor action of circulating endogenous catecholamines.     

HAEMODYNAMIC AND RENAL EFFECTS OF A NOVEL PROSTAGLANDIN ANALOGUE (L644, 122 (+ISOMER)) IN SHEEP

1. Merino-cross ewes were given an intravenous injection of a prostaglandin analogue, (+)-4-(3-[3-[2-(1-hydroxycyclohexyl)ethyl]-4-oxo-2-thiazolidinyl]- propyl) benzoic acid, at doses of 0.01, 0.05 and 0.10 mg/kg, on separate days, to determine renal and haemodynamic responses. 2. Peripheral vasodilatory effects, indicated by increases in heart rate and cardiac output, and falls in total peripheral resistance, peaked at 20 min at the two highest doses. By 60 min most values had returned to pre-injection levels. There were no changes in mean arterial pressure. 3. At the highest dose of 0.10 mg/kg there was a fall in glomerular filtration rate, renal blood flow and effective renal plasma flow within 20 min. Urinary sodium and potassium excretion also fell with all three doses tested. 4. Plasma renin concentration increased at the 0.05 and 0.10 mg/kg doses and was still elevated at 60 min. 5. The results of this study in the sheep contrast with others in the dog, where renal blood flow is increased and the rat, where blood pressure is increased, and indicate a species specificity in regard to the analogue's actions.     

DELAYED RECOVERY FROM NG-NITRO-L-ARGININE IN THE CONSCIOUS SHEEP

1. In the chronic, awake, instrumented sheep model NG-nitro-L-arginine (NOLA) an inhibitor of nitric oxide synthesis, injected at a dose of 40 mg/kg, produced a significant increase in systolic blood pressure (from 110 +/- 6 to 145 +/- 8 mmHg after 5 min) which persisted for at least 1 h but returned to baseline after 24 h. 2. When NOLA was repeated 1 and 4 days after the first injection, the blood pressure response was significantly attenuated, and at 1 day was no greater than the response to an equivalent volume of saline. The blood pressure response returned to the initial response with an 8 day interval between injections. 3. There was no significant blood pressure response to 100 mL of saline before the NOLA injection; however, 1 and 4 days after NOLA there was a significant rise in blood pressure.     

EFFECT OF ACUTE ADMINISTRATION OF PRAZOSIN ON BLOOD PRESSURE, HEART RATE AND PLASMA RENIN LEVEL IN THE CONSCIOUS NORMOTENSIVE RAT

This study investigated whether the specific alpha-antagonist, prazosin, stimulated basal plasma renin levels and heart rate. Furthermore the beta-adrenergic nervous system was also investigated to ascertain whether it was involved in this effect. Prazosin (0.1 or 1 mg/kg) was injected subcutaneously (s.c.) to conscious normotensive rats, either alone or in combination with the beta-adrenoceptor antagonist, DL-propranolol (1 or 3 mg/kg). Rats bore chronically implanted dorsal aorta cannula for measurement of blood pressure and heart rate and blood sampling for renin determinations. Acute administration of prazosin (1 mg/kg, s.c.) produced a fall in mean arterial pressure accompanied by renin release and tachycardia. A tenfold lower dose of prazosin did not alter blood pressure or heart rate but did stimulate renin release. Acute administration of DL-propranolol, (1 or 3 mg/kg, s.c.) produced falls in blood pressure and heart rate but did not affect plasma renin level. Combinations of prazosin with propranolol gave falls in blood pressure similar to those predicted on the basis of a simple addition of the effects of the two drugs given separately. Prazosin-induced tachycardia and renin release were attenuated by propranolol. It appears that prazosin produces renin release and tachycardia via stimulation of the beta-adrenergic adrenoceptor.     

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.     

EFFECTS OF DIETARY SODIUM RESTRICTION AND FISH OIL SUPPLEMENTS ON BLOOD PRESSURE IN THE ELDERLY

1. The effects on blood pressure of dietary fish oil, sodium restriction and a combination of both strategies were examined in a short-term dietary intervention study of 50 healthy elderly subjects (average age 67 years) with mean initial systolic and diastolic blood pressures of 133 and 77 mmHg, respectively. 2. Subjects were allocated to one of four treatment groups: fish oil with normal sodium, fish oil with low sodium, sunflower oil with normal sodium and sunflower oil with low sodium for 4 weeks. They then crossed over to the alternative sodium treatment for a further 4 weeks whilst remaining on the same oil. 3. The combination of fish oil supplementation with dietary sodium restriction caused significant reductions of blood pressure in the first 4 weeks: systolic blood pressure (SBP) fell by 8.9 mmHg, mean arterial pressure (MAP) by 7.4 mmHg and diastolic blood pressure (DBP) by 6.0 mmHg. 4. Fish oil enhanced the effect of sodium restriction on blood pressure. In the crossover protocol, a change in sodium excretion of 92 mmol/day was accompanied by changes of 6.4, 3.3 and 2.2 mmHg for SBP, MAP and DBP, respectively, in the subjects taking fish oil. However in those taking sunflower oil, blood pressure did not change significantly. 5. The results indicate beneficial interactive effect of dietary fish oil and sodium intake on blood pressure.     

EFFECT OF ACTH ADMINISTRATION ON THE HAEMODYNAMIC RESPONSE TO ARGININE-VASOPRESSIN IN SHEEP

1. Blood pressure, heart rate and cardiac output were studied in intact conscious sheep during AVP infusion at 0.1, 0.25, 0.5 and 10 μg/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.     

DIHYDROCYCLOSPORIN D IN SHEEP: HAEMODYNAMIC AND RENAL EFFECTS

1. This study was designed to test the haemodynamic and renal effects in sheep of dihydrocyclosporin D (dCyD), an immunosuppressant agent derived from the fungus Tolypocladium inflatum Gams. 2. dCyD was infused for 5 days at 12 mg/kg per day. Mean arterial pressure (MAP) was elevated after 24 h, but thereafter returned to control levels. Heart rate was significantly elevated throughout the infusion and was still high 24 h postinfusion. Cardiac output rose after 5 days, but total peripheral resistance was unchanged during the infusion. 3. Glomerular filtration rate, renal blood flow and effective renal plasma flow remained unchanged, although urine sodium excretion rose for the first 48 h. 4. Infusion of the castor oil-based vehicle for cyclosporin, Cremaphore EL, for 5 days in four sheep did not produce any sustained changes in any of the parameters measured.     

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.     

HAEMORRHAGE-INDUCED SECRETION OF ACTIVE AND INACTIVE RENIN IN CONSCIOUS AND PENTOBARBITONE-ANAESTHETIZED SHEEP

The response of plasma levels of active and inactive renin to haemorrhage was investigated in sheep with indwelling artery and vein catheters. In conscious animals, loss of 10% of estimated blood volume over a 5 min period increased plasma active renin by a mean of 59%, a surprisingly small change. Plasma inactive renin also increased, but only by 86%. Maximum increases in both forms of renin occurred within 1 h of the haemorrhage. The effects of an equivalent blood loss were investigated in pentobarbitone-anaesthetized sheep maintained in an upright posture using padded slings. Anaesthesia per se had no effect on plasma active or inactive renin. In anaesthetized sheep, 3 h after haemorrhage, plasma active renin had increased by 403% and inactive renin by 299% above control values, but a plateau (maximum) response was not reached during this time. In both conscious and anaesthetized animals the haemorrhage-induced increases in active and inactive renin occurred in parallel. It appears that haemorrhage of this intensity is a comparatively mild stimulus to increase plasma renin concentration in conscious sheep but is much more effective in anaesthetized animals. This may be linked to anaesthetic-induced increases in prostaglandin synthesis within the kidney.