EVIDENCE OF AN ADENOSINE-DEPENDENT MECHANISM IN THE HYPOTENSIVE EFFECT OF l-ARGININE IN MAN

1. The hypothesis that endogenous adenosine could play a role in the haemodynamic response to l-arginine is investigated. 2. The study has been divided into two parts. The first part was a single blind, randomized, placebo-controlled study in which L-arginine i.v. infusion (0.07 mmol/kg per min) in five healthy volunteers caused a significant fall in systolic (-14.2%, from 129.0 ± 8.2 to 110.6 ± 8.5 mmHg; F= 62.89, P<0.0l), diastolic (-16%, from 80.0 ± 7.9 to 67.2 ± 7.0 mmHg; F= 18.97, P < 0.0l) and mean (-15.5%, from 96.4 ± 6.7 to 81.4 ± 6.5 mmHg; F= 28.78, P< 0.01) arterial blood pressure, with a concomitant increase of plasma adenosine concentration (from 244.0 ± 32.2 to 637.0 ± 43.4 nmol/L; F= 79.3 P<10.01). Maximal effects were obtained at the end of L-arginine infusion: haemodynamic parameters returned to basal values in about 30 min while adenosine concentrations normalized in about 15 min. Saline infusion had no effect on these parameters. 3. In the second study the effect of L-arginine i.v. infusion on arterial blood pressure, lower limb blood flow and plasma adenosine, before and after theophylline treatment (1000 mg/day for 3 days, p.o.) was examined. In 10 healthy volunteers the i.v. infusion of l-arginine (0.07 mmol/kg per min) was followed by the same haemodynamic changes as reported above and by a Significant increase in lower limb blood flow (+ 36.7%, from 2.18 ± 0.40 to 2.98 ± 0.71mL/min/lOOmL;t = 4.61, P< 0.01). Pretreatment with theophylline, an adenosine-receptor antagonist, did not affect basal values of arterial pressure, lower limb blood flow and adenosine concentration. The pretreatment with theophylline reduced maximal decrease in systolic pressure (- 8.2 vs -15%), in mean pressure (- 9.9 vs -13.7%) and maximal increase in lower limb blood flow (+19 vs + 37%) caused by i.v. infusion of l-arginine (0.07 mmol/kg per rnin). Such a treatment allowed a progressive restoration of basal blood pressure values and of blood flow, during the second half of l-arginine infusion. This observation was confirmed by the analysis of the area under the curves (AUC). A significant difference in AUC values before and after treatment was obtained for systolic pressure (t = 8.25, P< O.Ol), mean pressure (t= 6.67, P<0.0l) and blood flow (t= 2.31, P<0.05). 4. Theophylline study suggested that the endogenous adenosine increase is sufficient to participate at least in part in the haemodynamic changes caused by l-arginine and that it is involved in a secondary response to l-arginine.     

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.     

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.     

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.     

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.     

NITRIC OXIDE INHIBITION DOES NOT PREVENT THE HYPOTENSIVE RESPONSE TO INCREASED RENAL PERFUSION IN RABBITS

1. The involvement of nitric oxide (NO) and platelet activating factor (PAF) in the systemic depressor responses to increased renal perfusion pressure (RPP) were investigated. 2. In anaesthetized rabbits, the left kidney was perfused via an extracorporeal circuit which allowed RPP to be increased from 65 mmHg to 125 mmHg. The response of systemic blood pressure (SBP) to increasing RPP was measured in the same rabbits. 3. One group of rabbits (n = 5) was treated with N^G-nitro-L-arginine (NOLA) to inhibit NO synthase activity (20 mg/kg i.v. bolus). Another group (n= 5), received 250mmol/L NaHCO₃ (4mL/kg bolus) as vehicle treatment. 4. Following an increase in RPP to 125 mmHg, SBP fell at a rate of 0.43 ± 0.06 mmHg/min in the vehicle treated rabbits. After NO synthase inhibition the rate of fall in SBP of 0.34 ± 0.07 mmHg/min was not significantly different from that in the vehicle group (P= 0.3). 5. Blockade of NO synthesis did not alter the renal blood flow, renal vascular resistance changes and pressure-related natriuresis and diuresis responses to increased RPP to 125 mmHg. 6. PAF receptor blockade, using WEB 2086 (0.5 mg/kg plus 0.5 mg/kg/h), did not alter the systemic, renal haemodynamic or urinary responses to increasing renal perfusion pressure to 125 mmHg. 7. These findings indicate that neither NO nor PAF play an important role in the blood pressure lowering activity, intrarenal haemodynamics and urinary excretory responses observed when RPP was increased to a level within the physiological range.     

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.     

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.     

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 AND HORMONAL EFFECTS OF N-NITRO-l-ARGININE, AN INHIBITOR OF NITRIC OXIDE BIOSYNTHESIS, IN SHEEP

1. The haemodynamic and hormonal responses to N-nitro-l-arginine (NOLA), a potent inhibitor of nitric oxide biosynthesis in endothelial cells, were investigated in conscious sheep. 2. Mean arterial blood pressure (MAP), heart rate (HR) and cardiac output by thermodilution (CO) were measured in four oophrectomized ewes. Two other ewes were surgically implanted with aortic electromagnetic flow probes and an indwelling carotid arterial line for monitoring CO and MAP over 40 h. 3. After a control period, NOLA (10 mg/kg) was injected intravenously and MAP, HR and CO monitored and blood samples taken at intervals over the following 24 h. 4. NOLA increased blood pressure within minutes, from 76 ± 4 to a maximum of 99 ± 4 mmHg (P<0.001) at 6 h after injection. It remained elevated 24 h after injection. CO and HR fell but these falls were not sustained longer than 6 h. Calculated total peripheral resistance increased to a maximum of 2 h, but had returned to control levels 24 h after injection. There were no significant changes in plasma concentrations of renin, atrial natriuretic factor, vasopressin, noradrenaline or endothelin during the first hour. 5. NOLA may be a useful tool in understanding the role of the endothelium and nitric oxide in the control of blood pressure.     

DIGOXIN ENHANCES THE PRESSOR RESPONSE TO ALDOSTERONE ADMINISTRATION IN CONSCIOUS SHEEP

1. This study examined the hypothesis that inhibition of Na,K ATPase with digoxin would enhance the pressor response to aldosterone infusion in conscious sheep. 2. While intravenous infusion of digoxin (10 micrograms/kg per day for 5 days) had no effect on blood pressure and aldosterone infusion (6 micrograms/kg per day for 5 days) increased blood pressure by 7 mmHg, combined infusion of digoxin and aldosterone increased blood pressure by 17 mmHg. 3. The metabolic effects of the combined digoxin and aldosterone infusion were similar to those for aldosterone alone, suggesting that digoxin did not enhance the mineralocorticoid action of aldosterone. 4. The results of this study suggest that changes in Na influx (aldosterone-dependent) and efflux (digoxin-dependent) are important in the genesis of aldosterone-induced hypertension.     

COMPARISON OF THE EFFECTS OF OUABAIN AND BRAIN NATRIURETIC PEPTIDE IN SALINE-LOADED SHEEP

1. It has been claimed that ouabain is an endogenous hormone that may be pivotal in the pathogenesis of some forms of hypertension and may exaggerate natriuresis in situations characterized by volume overload. We compared the haemodynamic, renal and endocrine effects of ouabain (at approximately 187 ng/kg per min for 2 h) with those of brain natriuretic peptide (BNP; at 5 pmol/kg per min for 2 h) in nine saline-loaded sheep in a balanced, randomized, single-blind, placebo-controlled crossover study. 2. Brain natriuretic peptide infusion reduced mean arterial pressure whereas ouabain infusion caused no change. Haematocrit rose steadily during BNP infusion but fell during ouabain infusion. Neither ouabain nor BNP affected urine volume, sodium, potassium or creatinine excretion. Mean heart rate declined during the ouabain and placebo infusions, but was not altered during BNP infusion. Endogenous ouabain concentrations were not detectable at baseline or during BNP or placebo infusions, but rose to concentrations of 11 ± 1.3 nmol/L during the ouabain infusion. 3. These results suggest that ouabain is not an endogenous hormone present at physiologically relevant concentrations. Furthermore, ouabain does not cause natriuresis during saline-loading in sheep and is therefore unlikely to be responsible for the exaggerated natriuresis seen in some forms of hypertension.     

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.     

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.     

ENALAPRILAT RESTORES SENSITIVITY OF BAROREFLEX CONTROL OF RENAL AND TOTAL NORADRENALINE SPILLOVER IN HEART FAILURE RABBIT

1. The acute effect of an angiotensin converting enzyme inhibitor (ACEI), enalaprilat, on baroreflex-mediated changes in renal and total NA spillover rate in conscious rabbits with doxorubicin-induced cardiomyopathic congestive heart failure (CHF) were investigated under resting conditions and in response to changes in arterial pressure induced by sodium nitroprusside and phenylephrine infusions. 2. Six saline-treated (N group) and 11 doxorubicin-treated rabbits (1 mg/kg administered i.v. twice weekly) were studied after 4 and 6 weeks treatment. Five CHF rabbits received saline (C group) and six enalaprilat infusion (ACEI group). 3. After 4 weeks of doxorubicin, mean arterial pressure (MAP)-renal noradrenaline (NA) spillover and MAP-total NA spillover curves did not change during enalaprilat infusion. 4. After 6 weeks, the C group showed blunted MAP-renal NA spillover and MAP-total NA spillover curves. In the ACEI group, however, both curves returned toward those seen in the N group (slope of MAP-renal NA curve: from 0.27 to 1.80 ng/min per mmHg, MAP-total NA curve: from 1.61 to 3.59 ng/min per mmHg). 5. Results of this study indicate that enalaprilat enhances baroreflex control of renal and total NA spillover in rabbits with CHF and further support the view that activation of the renin-angiotensin system contributes significantly to the attenuated baroreflex responses in CHF.     

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.     

EFFECTS OF INDOMETHACIN ON STEROID-INDUCED CHANGES IN PRESSOR RESPONSIVENESS IN MAN

1. It has been shown previously that hydrocortisone (F) increases pressor responsiveness in normal subjects. The present study examined the role of vasodilator prostanoids in determining these changes. 2. Pressor responsiveness to angiotensin II (AII) (1-8 ng/kg per min) and phenylephrine (PE) (0.3-0.9 microgram/kg per min) was examined in six normal men receiving: no treatment (day 1); 100 mg indomethacin p.o. (INDO) in three divided doses over 20 h (day 2); 200 mg F for 5 days, 50 mg 6 hourly p.o. (day 6); F plus 100 mg INDO (day 7). 3. Blood pressure, body weight and plasma glucose rose with F and plasma potassium fell. F alone produced significant increases in response to AII at 2 ng/kg per min, for systolic pressure (SBP), diastolic pressure (DBP) and mean arterial pressure (MAP), and at 1 ng/kg per min for DBP. The threshold for SBP, DBP and MAP rises with AII was decreased by F. Responses to PE following F were greater at 0.6 microgram/kg per min for SBP, DBP and MAP and the threshold for all parameters fell. 4. INDO alone had no significant blood pressure or metabolic effects and no effect on the magnitude of the blood pressure rise with AII, but decreased the threshold dose for effects on MAP. INDO had no effect on the magnitude of the pressure rise with PE, but decreased the threshold dose for effects on SBP. 5. INDO did not modify responsiveness or threshold to AII following F. Responsiveness to PE was unchanged and threshold fell for SBP only during INDO.(ABSTRACT TRUNCATED AT 250 WORDS)     

AUTONOMIC BLOCKADE AMPLIFIES CORTISOL-INDUCED HYPERTENSION IN MAN

1. We investigated the role of the autonomic nervous system (ANS) in Cortisol induced hypertension using the technique of total autonomic blockade (AB). 2. Four healthy young males were given 50 mg Cortisol 6 hourly for 6 days. On the day prior to, and the last day of, Cortisol treatment, AB was produced using oral prazosin 1 mg, intravenous clonidine 300 μg, propranolol 0.2 mg/kg and atropine 2 mg. The adequacy of blockade was assessed using the haemodynamic response to Valsalva manoeuvre. 3. Cortisol produced a significant rise in systolic blood pressure (130 ± 2 vs 110 ± 1 mmHg, pre vs post Cortisol; P<0.01). On the final treatment day, AB augmented the increase in diastolic blood pressure (ΔDBP), mean arterial pressure (ΔMAP) and heart rate (ΔHR) compared to the pre-treatment day, ΔDBP: 43 ± 6 vs 17 ± 4 mmHg, post vs pre Cortisol, P<0.005, ΔMAP: 39 ± 4 vs 14 ± 4 mmHg, P<0.001, ΔHR: 45 ± 5 vs 26 ± 4 b.p.m., P<0.05. The change in systolic blood pressure (ΔSBP) was not statistically significant (32 ± 4 vs7 ± 3 mmHg, P= 0.065). 4. These results suggest that the ANS exerts a modulating influence on the hypertensive effect of Cortisol.     

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.     

VASCULAR ACTIONS OF ENDOTHELIN IN THE RABBIT KIDNEY

1. The effect of two doses of endothelin, 10 and 50 ng/kg per min, i.v., on glomerular filtration rate (GFR), tubular stop flow pressure and pre- and post-glomerular vascular resistance have been studied in anaesthetized rabbits. 2. Blood pressure did not change significantly in response to 10 ng/kg per min endothelin or vehicle infusion, but rose steadily during infusion of 50 ng/kg per min endothelin, increasing 11.8 +/- 2.7 mmHg by 90 min of infusion. 3. Glomerular filtration fraction (3H-inulin extraction ratio) rose and remained elevated throughout the endothelin infusion at 50 ng/kg per min. GFR did not change significantly until 70-90 min of the infusion (50 ng/kg per min) when it decreased by about 35%. No significant changes were seen at 10 ng/kg per min endothelin. 4. Sodium excretion rate rose in response to the lower dose, due to an increase in fractional sodium excretion. No changes in sodium excretion were seen at the higher dose of endothelin. 5. Glomerular capillary pressure rose significantly in response to endothelin infusion (50 ng/kg per min). 6. Renal blood flow fell progressively in response to endothelin (50 ng/kg per min), to about one-third of the pre-infusion value. 7. Renal vascular resistance increased progressively with both doses of endothelin, by about 35% at 10 ng/kg per min and about 400% at 50 ng/kg per min after 70-90 min. Preglomerular resistance increased from 1.0 +/- 0.1 to 5.0 +/- 1.9 mmHg/mL per min in response to endothelin 50 ng/kg per min. Postglomerular resistance rose from 1.0 +/- 0.1 to 5.6 +/- 2.17 mmHg/mL per min. 8. Thus endothelin infusion caused progressive renal vasoconstriction with similar magnitude increases in both pre- and postglomerular vessels. The vasoconstriction of the kidney caused by endothelin occurred at a dose which did not effect systemic blood pressure.