RENAL RESPONSES TO ANGIOTENSIN II IN CONSCIOUS DOGS: EFFECTS OF ASPIRIN AND INDOMETHACIN

1. Angiotensin II was infused into the renal artery of unanaesthetized dogs at 0.4 and 2.0 ng/kg per min for 40 min each. 2. Indomethacin (3 mg/kg, and 1 mg/kg per h infusion i.v.) accentuated the angiotensin II-induced falls in glomerular filtration rate, renal blood flow and urine flow rate. Indomethacin did not alter the effects of angiotensin II on Na+ or K+ excretions. 3. Aspirin (35 mg/kg p.o. 2.5 h and 0.5 h prior to experiment) did not significantly change the renal effects of angiotensin II. 4. Both aspirin and indomethacin accentuated renal vasoconstriction during briefer (5 min) angiotensin II infusion. 5. Thus indomethacin and aspirin had markedly different effects on the actions of angiotensin II in the kidney. This suggests that at least one of these drugs has actions which affect angiotensin II-mediated vasoconstriction other than via cyclooxygenase inhibition.     

RENAL RESPONSES TO SLIGHT ELEVATIONS OF RENAL ARTERIAL PLASMA ANGIOTENSIN II CONCENTRATION IN DOGS

1. Angiotensin II was infused into the renal artery of intact kidneys of slightly volume expanded anaesthetized dogs at rates of 125, 250, 500, and 1000 pg/kg body weight per min, resulting in elevations of the calculated renal arterial plasma angiotensin II concentration of 16·9 (s.e.m. = 2·1), 35·0 (s.e.m. = 4·3), 73·3 (s.e.m. = 8·8), and 159·8 (s.e.m. = 20·4) pg/ml. 2. Angiotensin II caused significant dose-dependent decreases of renal blood flow and of renal plasma flow of -4·1% (s.e.m. = 1·5, P(0·05) at the lowest and of -19·6% (s.e.m. = 1·4, P(0·001) at the highest rate of infusion. Glomerular filtration rate remained essentially unchanged at the two lower infusion levels and decreased by -6·7% (s.e.m. = 2·2, P(0·05) and -8·3% (s.e.m. = 2·5, P(0·05) at the higher rates of infusion. Filtration fraction thus increased by +6·3% (s.e.m. = 2·4, P(0·05) at the lowest and by +14·2% (s.e.m. = 3·6, P(0·01) at the highest rate of infusion. 3. Urine volume decreased by -7·7% (s.e.m. = 0·8, P(0·001) at the lowest and by -35·2% (s.e.m. = 4·8, P(0·001) at the highest rate of infusion, while the study showed similar dose-dependent decreases for urinary sodium and potassium excretion and for the fraction of filtered sodium excreted.     

SYSTEMIC AND REGIONAL HAEMODYNAMIC RESPONSES TO ISOPRENALINE IN CONSCIOUS RENAL HYPERTENSIVE RABBITS

1. Using the electromagnetic flow probe and the radioactive microsphere technique, systemic and regional haemodynamic variables were measured in conscious normotensive and hypertensive rabbits. The rabbits were made hypertensive by unilateral nephrectomy combined with cellophane-wrapping of the remaining kidney and systemic and regional haemodynamic effects of isoprenaline infusions (0.5 μg-kg^?1 .min^?1) were compared in the two groups of animals. 2. Isoprenaline evoked increases in heart rate and cardiac index while the total peripheral resistance decreased. In the hypertensive rabbits the effects were similar, except for a significantly more pronounced decrease in blood pressure. 3. Isoprenaline increased the fraction of the cardiac output delivered to the heart, skin and fat, at the expense of the fractions to the brain, stomach, small intestine, pancreas, liver and kidney(s) in both normotensive and hypertensive animals. Local peripheral resistance was decreased, most prominently, in the heart, skin, skeletal muscle and fat. 4. In the normotensive rabbits pretreatment with propranolol (4 mg.kg^?1 infused in 1 h) effectively blocked the cardiovascular responses following isoprenaline infusion. 5. Since the systemic and regional haemodynamic effects of isoprenaline were not less (if anything, slightly more) in the hypertensive than in the normotensive rabbits, our results provide no evidence for subsensitivity of β-adrenoceptors as a contributory factor in the development of hypertension in this model.     

COMPARISON OF INITIAL RESPONSES TO RENAL ARTERY STENOSIS IN PENTOBARBITONE–ANAESTHETIZED AND CONSCIOUS DOGS

1. Trained chronically-instrumented dogs were subjected to renal artery stenosis twice. A 50 mmHg stenosis pressure gradient was established while the dogs were conscious or anaesthetized with pentobarbitone and prepared for renal surgery. 2. Prior to stenosis, the anaesthetized dogs had significantly higher mean arterial pressure, renal vascular resistance and plasma renin activity than when they were conscious. 3. Twenty-four hours after stenosis, when all dogs were fully conscious, significant elevations in mean arterial pressure and plasma renin activity were seen only in the dogs anaesthetized for stenosis production. Creatinine clearance over this period was also markedly less than after renal artery stenosis of conscious animals. 4. It seems likely that more severe renal artery stenosis is required to produce a given pressure gradient in anaesthetized dogs than in the conscious dogs.     

PROSTAGLANDINS DO NOT MEDIATE RENIN RELEASE DURING SEVERE REDUCTION OF RENAL BLOOD FLOW IN CONSCIOUS DOGS

1. Renal blood flow was reduced by about 80% for 90 min in chronically instrumented conscious dogs following aspirin, indomethacin or no pretreatment. 2. There were no significant differences between the rises in plasma renin activity in the three groups of dogs (+ 7.9, s.e.m. = 1.4; +8.1, s.e.m. = 1.5; and +7.5, s.e.m. = 1.8 ng/ml per h, respectively) or in mean arterial pressure (36.0, s.e.m. = 5.6; 38.6, s.e.m. =2.6, or 35.4, s.e.m. =4.7 mmHg; respectively). 3. These results strongly suggest that prostaglandins do not mediate renin release during severe reduction of renal blood flow in conscious dogs.     

EFFECTS OF FIVE NON-STEROIDAL ANTI-INFLAMMATORY DRUGS ON THE RENAL AND SYSTEMIC RESPONSES TO ARACHIDONATE IN CONSCIOUS DOGS

1. The effects of five different non-steroidal anti-inflammatory drugs (NSAID) on the renal blood flow responses to arachidonate were compared. 2. Arachidonate (5-200 micrograms/kg) injected into the renal arteries of conscious dogs caused dose-related renal vasodilatation with no systemic effects. 3. Aspirin (35 mg/kg), phenylbutazone (12 mg/kg) and ibuprofen (25 mg/kg) all markedly reduced arachidonate-induced renal vasodilatation. 4. In contrast, neither indomethacin (3 mg/kg) or its related drug sulindac sulphide (6 mg/kg) significantly reduced arachidonate-induced renal vasodilatation. 5. All NSAID abolished the hypotensive response to intravenous injection of arachidonate (10 mg). 6. Thus, indomethacin and sulindac did not block the effects of renal artery injections of arachidonate but did abolish the systemic effects. Aspirin, phenylbutazone and ibuprofen greatly reduced responses to both renal artery and intravenous arachidonate. 7. Indomethacin and aspirin both reduced the production of prostaglandin E2 and 6-keto-PGF1 alpha by dog renal cortical microsomes in vitro. 8. Thus, indomethacin and sulindac had different effects to other NSAID on arachidonate-induced renal vasodilatation. The results are compatible with the hypothesis that some sites of prostaglandin production in the kidneys of conscious dogs may be relatively resistant to inhibition by indomethacin and sulindac.     

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.     

SYSTEMIC AND REGIONAL HAEMODYNAMICS IN EXPERIMENTAL RENAL HYPERTENSION IN CONSCIOUS RABBITS

1. The radioactive microsphere method was used to measure the distribution of cardiac output, regional flows and resistances in conscious normotensive and hypertensive rabbits implanted with an electromagnetic flow probe on the ascending aorta or pulmonary artery. Hypertension was induced by wrapping one kidney with cellophane and removing the other, and studies were performed about 5 weeks later. 2. Heart rate, stroke volume, cardiac output and total renal mass were reduced in the hypertensive animals, while the weight of, and the cardiac output distribution to left ventricle and the remaining kidney were increased. 3. In renal hypertensive rabbits, the weight normalized regional blood flow was diminished in a number of tissues, including the kidney, and, except for some organs in the splanchnic area (stomach, small intestine, mesentery and pancreas) and the fat, there was a rather uniform increase in tissue vascular resistance.     

RENAL AUTOTRANSPLANTS IN SHEEP: INVESTIGATION OF RENAL FUNCTION AND RENOVASCULAR HYPERTENSION

1. A novel surgical preparation of sheep with a cervical renal autotransplant has been developed. 2. Glomerular filtration rate and effective renal plasma flow were 25.1 ± 1.0 ml/min and 208 ± 10 ml/min respectively (n= 26). 3. The responses to water load and deprivation, to AVP injection, to Na depletion and intravenous hypertonic saline load show the kidneys responded in an appropriate physiological manner. 4. Constriction of the carotid-renal artery to reduce mean renal arterial pressure to 23 ± 4 mmHg (n= 4) resulted in an increase in systemic mean arterial pressure from 70 ± 4 mmHg to 75 ± 4 mmHg within 5 min. Systemic blood pressure further increased to 110 ± 7 mmHg with 2 h of constriction, when renal arterial pressure had increased to 45 ± 2 mmHg.     

THE EFFECTS OF MECLOFENAMATE ON RENAL AND PERIPHERAL VASCULAR BEDS IN CONSCIOUS RABBITS

1. Meclofenamate caused a dose-dependent increase in renovascular resistance in conscious rabbits. 2. This effect was greatest in inner cortical zones at the highest dose (6 mg/kg) but at the lowest dose (0-75 mg/kg) vascular resistance in the outer cortex was preferentially increased. 3. In contrast, meclofenamate increased cerebral perfusion and the proportion of cardiac output received by the testis. No effect was demonstrated on other organs studied. 4. The results suggest a local vasodilator influence of renal prostaglandins in normal conscious rabbits.     

EFFECT OF RENAL AND ADRENAL DENERVATION ON THE RENIN RESPONSE TO SLOW HAEMORRHAGE IN DOGS

SUMMARY 1. The effect on plasma renin activity of moderate slow haemorrhage (7.5 ml. kg⁻¹. h⁻¹ for 2 h) was studied in intact dogs and in dogs whose adrenals and kidneys had been denervated surgically.
2. In dogs with intact renal and adrenal nerves, plasma renin activity rose during haemorrhage without any accompanying change in systemic blood pressure, but with marked decreases in renal function, an increased filtration fraction and an increased haematocrit. The latter effects can be attributed to sympathetic stimulation evoked by haemorrhage.
3. In dogs with denervated kidneys and adrenals, haemorrhage did not result in a significant elevation of plasma renin activity until the 2 h collection period, at which time mean systemic blood pressure had fallen 32 mmHg. Renal function changes were less marked and neither filtration fraction nor haematocrit rose, suggesting the absence of sympathetic stimulation.
4. It concluded that the sympathetic nervous system plays an important role in the renin response to slow haemorrhage until such time as blood pressure falls sufficiently to activate a second stimulatory mechanism, perhaps a renal baro-receptor.     

PROSTAGLANDINS AND SYSTOLIC BLOOD PRESSURE, BUT NOT ANGIOTENSIN II, INDEPENDENTLY AFFECT ATRIAL NATRIURETIC PEPTIDE LEVELS IN MAN

1. Two hours after a single dose of indomethacin (INDO), plasma renin activity (PRA) and atrial natriuretic peptide (ANP) levels decreased, which is consistent with an effect of lowering prostaglandins (PG). 2. After 48 h of INDO, PRA remained low but ANP had increased, which is consistent with the known effect of prostaglandin inhibitors to cause sodium retention, with a resulting volume expansion. 3. Infusions of angiotension II (AII), which raises diastolic blood pressure (BP) 20 mmHg or more, consistently raised ANP levels. The ANP response to AII infusion was reduced 48 h after INDO, which is consistent with an important role for PG in AII-stimulated ANP release. 4. After PG were blocked with INDO, the stimulating effect of AII on ANP at doses that increased diastolic BP less than 20 mmHg was insignificant, whereas before INDO it was significant. 5. In dose-response studies, INDO increased the systolic BP response but decreased the ANP response to AII, which is consistent with a direct effect of PG on ANP that is independent of systolic BP. 6. Prostaglandins and BP are important in the ANP response to AII infusion in normal subjects, but AII itself appears to have little direct effect on ANP.     

REGIONAL DISTRIBUTION OF THE CARDIAC OUTPUT AND RENAL RESPONSES TO ATRIAL ATRIURETIC PEPTIDE INFUSION IN RABBITS WITH CONGESTIVE HEART FAILURE

1. A biventricular, low-output congestive cardiomyopathy was induced in 19 rabbits by administering adriamycin (16 mg/kg). The effects of alpha-rat atrial natriuretic peptide (ANP) infused at 0.1, 0.2 and 0.4 micrograms/kg per min, were then examined in terms of (i) central haemodynamics (ii) regional blood flow (iii) renal function and (iv) plasma norepinephrine and plasma renin. 2. In this dose range, ANP produced progressive and significant falls in stroke volume, cardiac output and mean arterial pressure, owing to a fall in venous return. The heart rate response to this was blunted. 3. Using radiolabelled microspheres, significant falls in the perfusion of cutaneous, gastrointestinal and musculoskeletal tissues were observed, due to reduced vascular conductances in these beds. These changes were accompanied by activation of the sympathetic nervous system as evidenced by a progressive rise in plasma norepinephrine. A significant increase in plasma renin was only observed with the highest infusion of ANP. 4. Renal blood flow was maintained in the face of a falling mean arterial pressure and cardiac output, but diuretic and natriuretic effects were absent. 5. It was concluded that the dominant influence of ANP infusion in this model of heart failure appeared to be a reduction in cardiac preload with detrimental overall haemodynamic consequences.     

RENAL DENERVATION POTENTIATES THE NATRIURETIC AND DIURETIC EFFECTS OF ATRIAL NATRIURETIC PEPTIDE IN ANAESTHETIZED RABBITS

1. The role of the renal nerves in modulating the action of atrial natriuretic peptide (ANP) in the kidney was studied by comparing the responses to ANP in innervated and surgically denervated kidneys in anaesthetized rabbits. 2. A low dose of ANP (0.05 μg/kg per min, i.v.) was used to minimize the confounding effects of systemic hypotension. 3. The natriuretic and diuretic responses to ANP were significantly greater in denervated kidneys than in kidneys with intact innervation. Sodium excretion from denervated kidneys rose by 7.49 ± 3.11 μmol/min in response to ANP (-55%, P<0.05) compared to 0.84 ± 0.59 μmol/min (-28%, NS) in innervated kidneys. Urine flow increased markedly in denervated kidneys by 73.2 ± 29.9 μmol/min (-60%, P<0.05) but not in innervated kidneys. 4. Fractional sodium excretion increased significantly in denervated kidneys in response to ANP (median 2.3% to median 3.0%, P<0.05). 5. Renal blood flow, glomerular filtration rate (GFR) and glomerular capillary pressure were unchanged in response to ANP in either denervated or innervated kidneys. Pre-glomerular vascular resistance fell in denervated kidneys during ANP infusion. 6. The natriuresis and diuresis observed in the denervated kidneys, due to an increased fractional excretion of sodium without increases in GFR or glomerular capillary pressure, is consistent with effects of ANP on tubular reabsorption of sodium. 7. Thus, ANP produced a natriuresis and diuresis at a low dose in denervated but not in innervated kidneys. This indicates that reflex activation of renal nerves may antagonize the renal effects of ANP.     

RENIN RESPONSE TO GRADED HAEMORRHAGE IN CONSCIOUS RATS

1. A haemorrhage volume/plasma renin activity (PRA) response relationship was established for five levels of acute haemorrhage ranging from 1.5 to 15 ml/kg in conscious rats. In addition, the effects of chronic indomethacin and/or acute propranolol administration on the PRA response to 5 and 10 ml/kg haemorrhage was assessed. 2. Mean arterial pressure decreased in a haemorrhage volume dependent manner which was not significantly altered by indomethacin and/or propranolol. 3. Haemorrhage volumes of 1.5 and 3.0 ml/kg did not significantly alter PRA. At haemorrhage volumes of 5.0 ml/kg and higher, PRA increased in a volume-dependent manner. Propranolol decreased basal PRA levels but had little effect on the response to haemorrhage. Indomethacin had no effect on basal PRA, but attenuated the response to haemorrhage somewhat. When propranolol and indomethacin were combined, the PRA response to haemorrhage was significantly attenuated. 4. The conscious cannulated rat model exhibits predictable and reproducible renin responses to haemorrhage and is an excellent model for studying the control of renin secretion.     

ANGIOTENSIN II-INDUCED CONTRACTION OF MESANGIAL CELLS IN ACUTE RENAL ARTERY STENOSIS IN DOGS

1. Renal artery stenosis was induced in anaesthetized dogs, and the kidney rapidly fixed after 30 min. 2. Electron microscopy revealed marked folding of the paramesangial basement membrane in stenotic kidneys (n = 7). The extent of this folding was significantly less in dogs treated with captopril (n = 6). 3. It is suggested that this folding reflects angiotensin II-induced contraction of the mesangial cells, which may help maintain glomerular filtration rate following stenosis.     

ROLE OF THE AUTONOMIC NERVOUS SYSTEM IN THE ACUTE RESPONSES TO RENAL ARTERY PRESSURE REDUCTION IN CONSCIOUS DOGS

1. Plasma renin and arterial pressure responses to acute renal artery pressure reduction were compared in intact dogs and ‘autonomically-blocked’ dogs subjected to adrenalectomy, chronic guanethidine treatment and acute vagal block (methscopolamine). 2. Following reduction of renal artery pressure plasma renin activity and concentration rose more in the autonomically blocked dogs than in the intact dogs. When renal artery pressure was held at 30 mmHg for 1 h, plasma renin activity rose by 19-1 ng/ml per h (range 11-6-28-7) in autonomically blocked dogs and 3-65 ng/ml per h (range 1-54-5-89) in intact dogs. When renal artery pressure was held at 60 mmHg plasma renin activity rose 3-28 ng/ml per h (range 2-4-4-7) and 1-90 ng/ml per h (range 1-30-3-56), respectively. 3. Arterial blood pressure also rose more in autonomically blocked dogs in accord with the greater rise in plasma renin activity. The relationships between the increases in arterial pressure and plasma renin were closely similar in the two groups. 4. We conclude that the relase of renin and increase in arterial blood pressure in response to renal artery stenosis is normally inhibited by arterial baroreflexes.     

EFFECT OF ANGIOTENSIN-CONVERTING ENZYME INHIBITION ON RENAL NOREPINEPHRINE SPILLOVER RATE AND BAROREFLEX RESPONSES IN CONSCIOUS RABBITS

1. To evaluate the effects of angiotensin-converting enzyme (ACE) inhibition on sympathetic nerve activity, renal and total norepinephrine (NE) spillover rates were examined under control conditions and during enalaprilat infusion at rest and in response to sodium nitroprusside (SNP)-induced hypotension. 2. Resting renal and total NE spillover rate during enalaprilat infusion were similar to control values. 3. During SNP infusion at 10 μg/kg per min, renal NE spillover rate increased by 26% in enalaprilat-treated group and by 39% in controls, in response to falls in mean arterial pressure (MAP) of 25 and 19% respectively. 4. During sympathetic stimulation induced by SNP, total NE spillover rate was significantly increased in both groups, but the 50% (s.e.m. = 12) increase in the enalaprilat-treated group was less (P<0.05) than the 97% (s.e.m. = 16) change observed in controls. 5. Enalaprilat treatment resulted in a higher renal to total NE spillover ratio (P<0.05). The ratio fell in parallel in both groups during SNP-induced hypotension. 6. This study indicates that the sympathetic nervous system interacts dynamically with the renin-angiotensin system during hypotensive stimulation but this occurs predominantly at sites other than the kidney.     

CROMAKALIM SUPPRESSES HYPERTONIC SALINE-INDUCED RENAL VASOCONSTRICTION IN ANAESTHETIZED DOGS

1. Intrarenal arterial infusion of hypertonic saline (HS) transiently increased and then gradually reduced renal blood flow (RBF) in anaesthetized dogs. Glomerular filtration rate (GFR) but not filtration fraction decreased at the end of the infusion. 2. In the presence of a potassium channel opener cromakalim (0.3 μg/kg per min), HS infusion failed to reduce RBF; the initial increase in RBF was maintained throughout the infusion. Since cromakalim also prevented the decrease in GFR, HS infusion lowered filtration fraction. 3. The results suggest that cromakalim inhibits both pre-and postglomerular vasoconstriction induced by HS infusion.