Atrial natriuretic peptide suppresses renal vasoconstriction induced by angiotensin II and norepinephrine in dogs.

Atrial natriuretic peptide (ANP, 10 and 50 ng/kg per min), infused into the renal artery, suppressed decreases in renal blood flow induced by intrarenal arterial injection of angiotensin II (Ang II, 25-100 ng) and norepinephrine (NE, 0.25-1 microgram) in anesthetized dogs. Sodium nitroprusside (SNP, 0.1-5.0 micrograms/kg per min) slightly attenuated the blood flow response to Ang II but not the response to NE. 8-Bromo cyclic GMP (8bcGMP, 0.5-25 micrograms/kg per min) did not suppress the blood flow response to Ang II. Although at a high dose ANP attenuated the blood flow response to Bay K 8644 (1-4 micrograms), nifedipine pretreatment (20 micrograms/kg plus 1 microgram/kg per min i.v.) did not affect the inhibitory effect of ANP on the NE-induced response. The vaso-inhibitory effects of ANP therefore could not be related exclusively to stimulation of cGMP production or inhibition of voltage-dependent Ca2+ channels.     

INTRACEREBROVENTRICULAR ANP(1–28) HAS NO OBVIOUS EFFECTS ON RENAL BLOOD FLOW AND FUNCTION IN CONSCIOUS SHEEP

1. The study examines whether intracerebroventricular (ICV) infusion of atrial natriuretic peptide (human ANP, 1–28) influences renal electrolyte and water excretion, vasopressin release, renal and femoral blood flows in conscious ewes. The blood flow was measured by chronically implanted ultrasonic flow probes. 2. ICV infusion of ANP(1–28) at 25 pmol/min for 60 min did not affect renal Na and K excretion or plasma vasopressin levels. In two out of six animals a mild water diuresis developed at about 50 min post-infusion. 3. The plasma osmolality, Na, K and protein concentrations did not change during the experiments. 4. The renal and femoral arterial blood flows were not influenced by 30 min ICV infusions of ANP(1–28) at 25 and 85 pmol/min. 5. It is concluded that human ANP(1–28) has no, or negligible, effects on renal function, femoral and renal blood flow when given ICV in amounts obviously elevating cerebrospinal fluid levels far above normal.     

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.     

Amplification by atrial natriuretic peptide of the haemodynamic and renal responses to an acute volumic stress in the rat

1. The purpose of the present study was to test the effects of synthetic atrial natriuretic peptide (ANP) on renal haemodynamics and excretory capacities of salt and water in the rat during an 'acute volumic stress', which was induced by brisk disturbances of the circulatory volume. 2. To this end, 29 anaesthetized male Wistar rats were rapidly injected with 1 mL of 0.85% NaCl, repeated twice at 60 s intervals. The injectates contained no ANP (n = 5) or 1 x 0.25 (n = 6), 3 x 0.25 (n = 6), 1 x 2.5 (n = 6) or 3 x 2.5 micrograms (n = 6) ANP, added to the first injectate only (1 x) or to each injectate (3 x). Renal blood flow (RBF) was continuously measured with an electromagnetic flow transducer. 3. Renal blood flow increased transiently (approximately 30 s) by approximately 13% (P < 0.05) during each injection of saline without ANP. Addition of 0.25 or 2.5 micrograms ANP to the first injectate enhanced RBF by 21 and 35%, respectively (both P < 0.05), but did not modify the time sequence. Furthermore, addition of 0.25 microgram ANP to the second and third injectate produced an almost similar change in RBF at the end of each injection (delta RBF = 20 and 17%, respectively). In contrast, the addition of 2.5 micrograms ANP to the second and third injectate did not produce the same changes in RBF observed at the end of the first injection. The amplitude of the change in RBF was then similar to the increase in RBF induced by 1 mL saline without ANP. Mean arterial pressure (MAP) did not change significantly during repeated injections of saline alone or with addition of 0.25 microgram ANP to the first injectate. However, MAP decreased significantly (by 5, 9 and 9 mmHg) after the injection of 3 x 0.25, 1 x 2.5 or 3 x 2.5 micrograms ANP, respectively. 4. Sodium excretion was rapidly increased from 2.600 +/- 0.654 to 9.330 +/- 1.322 mumol/min after injection of 3 x 1 mL of 0.85% NaCl (P < 0.05). Thereafter, sodium excretion remained enhanced throughout the experiment, so that 70% of the sodium load injected was recovered at the end of the experiment. Atrial natriuretic peptide added to the injectates further elevated the maximal responses in diuresis and natriuresis induced by saline injections without ANP (P < 0.001). A maximal effect was observed after the addition of 2.5 micrograms ANP to the first saline solution. When the amount of sodium excreted was calculated by integrating the areas under the curve of the natriuretic responses, a relationship was established as a function of the amount of ANP added to the saline solutions. It was characterized by a threshold in the presence of 2.5 micrograms ANP added to the first injectate when the integration period was limited to 4 min 30 s and 14 min 30 s after starting the first injection of the varying test solutions. When the integration period was extended until the end of the experiment (2 h), the amount of sodium excreted in each group was further enhanced, especially after injection of 3 x 1 mL of 0.85% NaCl without ANP or with 1 x 0.25 and 3 x 0.25 microgram ANP. Differences in sodium excretion between groups were attenuated (P < 0.054, ANOVA). 5. In conclusion, our results demonstrate differential effects of synthetic ANP on renal vascular reactivity and excretory capacity. These effects were superimposed on changes induced by acute volumic stress. In particular, effects of saline injections on renal vascular compliance were amplified in the presence of ANP added in varying amounts to the injectates. This amplification was limited to 2.5 micrograms ANP.     

Atrial natriuretic peptides: Reproducibility of renal effects and response of liver blood flow

Summary To assess the variability of the response to exogenous atrial natriuretic peptide (ANP), it was infused at the rate of 1 µg/min for 2 h in 6 salt-loaded normal volunteers under controlled conditions on 2 occasions at an interval of 1 week. The effect on solute excretion and the haemodynamic and endocrine actions were highly reproducible. The constant ANP infusion caused a delayed and prolonged excretion of sodium, chloride and calcium, no change in potassium or phosphate excretion or in glomerular filtration rate but a marked decrease in renal plasma flow. Blood pressure, heart rate and the plasma levels of angiotensin II, aldosterone, arginine vasopressin and plasma renin activity were unaltered. The effect of a 2-h infusion of ANP 0.5 µg/min or its vehicle on apparent hepatic blood flow (HBF) was also studied in 14 normal volunteers by measuring the indocyanine green clearance. A 21% decrease in HBF was observed in subjects who received the ANP infusion (p<0.01 vs vehicle). Thus, ANP infused at a dose that did not lower blood pressure decreased both renal and liver blood flow in normotensive volunteers. The renal and endocrine responses to ANP were reproducible over a 1-week interval.     

EFFECTS OF ATRIAL NATRIURETIC PEPTIDE ON PHENYLEPHRINE-INDUCED RENIN RELEASE IN DOGS

1. The effect of atrial natriuretic peptide (ANP) on alpha-adrenoceptor agonist-induced renin release was examined in the de-ennervated kidney of the anaesthetized dog pretreated with propranolol (1 mg/kg, intravenous). 2. Phenylephrine (50 ng/kg per min) infused into the renal artery increased the renal secretion rate of renin (RSR) without affecting systemic blood pressure or renal blood flow. 3. Although basal RSR was unaffected, the phenylephrine-induced increase in RSR was abolished during intrarenal arterial infusion of ANP (10 ng/kg per min). 4. The results suggests that exogenously administered ANP could suppress alpha-adrenoceptor-mediated renin release in the dog.     

Effects of the selective neutral endopeptidase inhibitor, retrothiorphan, on renal function and blood pressure in conscious normotensive Wistar and hypertensive DOCA-salt rats.

Atrial natriuretic peptide (ANP) is degraded by neutral endopeptidase (NEP) mainly in the proximal tubule of the kidneys. We studied the effects of retrothiorphan, a potent and highly specific NEP inhibitor on renal function and blood pressure (BP). A 25-mg/kg bolus injection (group bolus), or bolus injection plus infusion 25 mg/kg + 25 mg/kg/h (group infusion), was given to conscious normotensive Wistar and hypertensive DOCA-salt rats. Bolus and infusion produced increases in diuresis (110 +/- 15 vs. 103 +/- 15 vs. 42 +/- 9 microliters/min) and natriuresis (10.6 +/- 3.0 vs. 7.0 +/- 1.0 vs. 5.4 +/- 1.0 mumol/min) in normotensive rats, with a maximum change at 30 min. Change in kaliuresis was not significant. These renal effects were associated with nonsignificant increases in urinary cyclic GMP and ANP. Arterial pressure and heart rate (HR) were not affected. Bolus or infusion of retrothiorphan also induced increases in diuresis (92 +/- 16 vs. 124 +/- 13 vs. 38 +/- 6 microliters/min) and natriuresis (10.3 +/- 2.0 vs. 12.5 +/- 1.0 vs. 5.0 +/- 1.0 mumol/min) in DOCA-salt hypertensive rats, with a maximum change at 30 min. The changes in diuresis and natriuresis induced by retrothiorphan were correlated with a significant increase in urinary cyclic GMP excretion (r = 0.89, p < 0.001 and r = 0.91, p < 0.001). Urinary ANP did not change in controls but significantly increased in the treated rats; urinary immunoreactive bradykinin (BK) also tended to increase. Plasma ANP and hematocrit did not change after retrothiorphan, but plasma cyclic GMP increased significantly after infusion. Only infusion caused a decrease in arterial pressure in DOCA-salt rats (-20 mm Hg at 120 min). Renal clearance studies in DOCA-salt rats showed that retrothiorphan has a transient effect on renal hemodynamics, with increases in glomerular filtration and renal blood flow (RBF) and a decrease in renal vascular resistance (RVR). Its renal action was also tubular, with an increase in fractional sodium excretion. We also compared the effects of retrothiorphan in normotensive Brown-Norway kininogen-deficient rats (BN-Kat) and DOCA-salt hypertensive kininogen-deficient rats. The NEP inhibitor induced increases in diuresis and natriuresis in both groups, with increased urinary cyclic GMP. Urinary immunoreactive BK did not change significantly in normotensive or DOCA-salt hypertensive kininogen-deficient rats.(ABSTRACT TRUNCATED AT 400 WORDS)     

Hemodynamic, renal, and hormonal effects of 8-Br-cyclic GMP in conscious dogs with and without congestive heart failure

In conscious dogs, we examined the hypothesis that the effects of atrial natriuretic peptide (ANP) are mediated by cyclic GMP and tested whether stimulation of the intracellular pathway beyond the ANP receptor level still exerts ANP-like effects during tolerance to ANP in heart failure. We studied the hemodynamic, renal, and hormonal effects of the cyclic GMP analogue 8-bromo-cyclic GMP (8-Br-cyclic GMP) in conscious dogs before and after induction of congestive heart failure by right ventricular pacing. In healthy dogs, 8-Br-cyclic GMP (1-100 micrograms/kg/min) dose-dependently decreased mean arterial pressure (MAP -19% by 100 micrograms/kg/min) and total peripheral resistance (TPR -22%) with no change in cardiac output (CO) and right atrial pressure, increased urine flow (UF 52%), and sodium excretion (UNaV 135%). Plasma renin (62%) and norepinephrine (NE 24%) were increased. In dogs with heart failure, 8-Br-cyclic GMP induced a similar arteriolar dilation (MAP -16%, TPR -23%) with no change in CO and preload. However, the effects on renal excretory function were abolished or markedly attenuated (UF -4%, UNaV 7%). Plasma renin (163%) and aldosterone (40%) were increased. Our findings support the hypothesis that the renal effects of ANP are mediated by cyclic GMP in vivo. The attenuation of renal effects of 8-Br-cyclic GMP in heart failure does not prove but is in agreement with the hypothesis that an intracellular defect beyond cyclic GMP production might be involved in the tolerance to ANP in heart failure.     

Differential renal responses to atrial natriuretic peptide in two-kidney, one clip goldblatt hypertensive rats

Bilateral renal clearance experiments were performed to examine the effects of synthetic rat atrial natriuretic peptide (ANP, atriopeptin II) on the arterial blood pressure (BP) and individual kidney function in anesthetized 2-kidney, 1 clip Goldblatt hypertensive rats (n = 14) and normotensive rats (n = 15). Bolus administration of graded doses of ANP from 2.5 to 10 micrograms/kg produced dose-related reductions in BP in hypertensive and normotensive rats. Despite profound reductions in BP, there were significant increases in glomerular filtration rate, urine flow, absolute and fractional excretion rates of sodium and potassium, osmolar clearance, and free water clearance in the nonclipped kidney, whereas no significant changes in these renal indices occurred in the clipped kidney. The enhanced renal responses were dose-dependent. The normal kidney responded to ANP with similar magnitude. When ANP was infused intravenously (0.3 microgram/kg.min i.v.) during 2 h, BP maximally reduced by 36 +/- 2 mm Hg (24 +/- 1%) in the hypertensive group and by 27 +/- 2 mm Hg (22 +/- 2%) in the control group. Again, there were distinct renal responses between the two kidneys of hypertensive rats. These results indicate that ANP effectively reduces BP and preferentially increases the excretory function of the nonclipped kidney without compromising the function of the clipped kidney in this hypertensive model.     

Effects of adenosine on adrenergically induced renal vasoconstriction in dogs

The role of exogenous and endogenous adenosine in the neural control of renal blood flow was studied in anesthetized dogs. The plasma norepinephrine (NE) concentration was measured by high-performance liquid chromatography and the renal NE secretion rate was calculated. Renal nerve stimulation (1-3 Hz) reduced renal blood flow and increased NE secretion rate. The intrarenal arterial injection of NE (0.3-1.0 micrograms) also reduced renal blood flow. Infusion of adenosine (10-100 micrograms/min) into the renal artery attenuated the increase in NE secretion rate induced by renal nerve stimulation, but the nerve stimulation-induced decrease in renal blood flow was unaffected. On the other hand, adenosine potentiated the NE-induced renal blood flow response. Similar results were obtained with an adenosine potentiator, dipyridamole (1-10 micrograms/min). An adenosine receptor blocker, theophylline (0.3-1.0 mg/min), potentiated the NE secretion rate response induced by nerve stimulation, without any change in the renal blood flow response. The NE-induced renal blood flow response was attenuated by theophylline. These results suggest that adenosine inhibits neural NE release and enhances vasoconstriction in the dog kidney during sympathetic stimulation under in vivo conditions. These post- and presynaptic mechanisms may thus be activated by endogenous adenosine.     

Central administration of kisspeptin-lO inhibits natriuresis and diuresis induced by blood volume expansion in anesthetized male rats

Aim:

To investigate the possible role of hypothalamic kisspeptin in the regulation of body fluid metabolism and maintenance of internal homeostasis.

Methods:

Natriuresis and diuresis were induced by blood volume expansion (VE) in anesthetized male rats and kisspeptin-10 was intracerebroventricularly (icv) administered. Radioimmunoassay (RIA) was used to measure the plasma arginine vasopressin (AVP) and atrial natriuretic peptide (ANP) concentrations during the VE. The mediation of the renal sympathetic nerve was also investigated in rats with bilateral renal sympathetic denervation.

Results:

The increased urine flow and sodium excretion induced by VE were significantly inhibited by icv injection of 5 nmol kisspeptin-10 (P<0.05), which peaked 20 min after the decrease in VE. The mean arterial blood pressure and heart rate did not change during the experiment. Plasma AVP concentrations were significantly increased 20 min after icv injection of 5 nmol kisspeptin-10 during VE (P<0.05), while pretreatment with 5 nmol kisspeptin-10 did not significantly change plasma ANP concentrations. Furthermore, pretreatment with 5 nmol kisspeptin-10 could significantly inhibit VE-induced natriuresis and diuresis in renal sympathetic denervated rats (P<0.05).

Conclusion:

Central administration of kisspeptin-10 inhibited VE-induced natriuresis and diuresis. This effect was likely mediated by increasing AVP release independent of plasma ANP concentration and renal sympathetic nerve activity.     

Thiorphan, an inhibitor of endopeptidase 24.11, potentiates the natriuretic activity of atrial natriuretic peptide

To evaluate the role of endopeptidase 24.11 in metabolism of atrial natriuretic peptide (ANP) in vivo, we examined the effect of thiorphan, an inhibitor of this enzyme, on plasma ANP concentrations and the cardiovascular and renal actions of ANP(99-126). Thiorphan alone produced a modest increase in urinary sodium excretion in anesthetized rats; however, urine flow, arterial pressure, and basal plasma ANP concentrations were unchanged. When administered during an infusion of ANP(99-126) (330 ng/kg/min i.v.), thiorphan increased the plasma concentration of ANP and enhanced the diuretic and natriuretic activity of this hormone. The effects on urine flow and urinary sodium excretion were most pronounced immediately after the inhibitor was administered and later diminished in magnitude. Thiorphan did not alter the depressor activity of exogenous ANP(99-126). These data suggest that endopeptidase 24.11 participates in metabolism of ANP(99-126) and that thiorphan potentiates the renal actions of this hormone by inhibiting its degradation.     

Effects of midodrine on blood flow in dog vascular beds

Effects of alpha-(2,5-dimethoxyphenyl)-beta-glycinamide-ethanol hydrochloride (midodrine, ST-1085) on blood flow in different vascular beds were examined in anesthetized dogs. Intravenously administered midodrine at doses of 0.3 and 0.6 mg/kg induced a transient increase followed by a long-lasting decrease in femoral arterial blood flow. Renal arterial blood flow exhibited an initial decrease followed by returning toward the control level, and thereafter decreased again. Vertebral, common carotid, superior mesenteric and coronary arterial blood flow, and cardiac output gradually decreased. Midodrine did not have any effects on cerebral tissue blood flow. The changes were more remarkable at a dose of 0.6 mg/kg than at 0.3 mg/kg. Each arterial blood flow change was statistically analyzed 20, 30 and 60 min after the administration of 0.6 mg/kg of midodrine. The decrease of coronary arterial blood flow by the treatment with midodrine was significantly smaller than those of superior mesenteric and femoral arterial blood flow at 20 and 30 min after midodrine administration. The decrease of renal arterial blood flow was significantly smaller than those of superior mesenteric arterial blood flow at 20 and 30 min, and femoral arterial blood flow at 20, 30 and 60 min after the administration. The decrease of vertebral arterial blood flow was also smaller than that of femoral arterial blood flow at 20, 30 and 60 min after the administration.     

Bioactivity of natriuretic peptide coinfusions; no evidence for unique effects of BNP in conscious sheep

Few studies have addressed the possibility that brain natriuretic peptide (BNP) possesses a profile of bioactivity that is distinct from that of atrial natriuretic peptide (ANP). Accordingly, we assessed the biologic actions of BNP in the setting of maximal or near-maximal ANP-induced biologic activity. Background ANP infusions (7.5 pmol/kg/min) administered on all study days, increased plasma ANP (approximately 120 pM) and cyclic guanosine monophosphate (GMP) levels (approximately 40 nM), and induced significant decreases in arterial pressure and cardiac output associated with increased heart rate, hematocrit, diuresis, and natriuresis. Increasing the dose twofold after 1 h (experiment 1, n = 5) showed no enhancement of these actions despite a further twofold increase in plasma ANP and cyclic GMP (both p values <0.001). Addition of low-dose BNP (2 pmol/kg/min) after 1 h background infusion (experiment 2, n = 8), increased plasma BNP levels (30 pM, p < 0.001) but caused no significant effects on the hemodynamic, renal, or hormonal indices measured. In conclusion, in the setting of maximal hemodynamic, renal, and endocrine responses to high-dose background infusions of ANP, coinfusion of BNP exhibits no enhancement of, or additional, biologic activity. This study provides no evidence for unique short-term biologic actions of ANP and BNP.     

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.     

Action of the competitive angiotensin II antagonist saralasin during the initial phase of glycerol-induced acute renal failure of the rat

Summary The effects of the competitive angiotensin II antagonist saralasin (1-sarcosine-8-alanine-5-isoleucine-angiotensin II) on renal function in healthy rats and in rats with myohemoglobinuric acute renal failure were studied. Acute renal failure was induced by an intramuscular injection of 50% glycerol (10 ml ·kg^–1). Functional impairment of the glycerol treated animals consisted in a decrease of renal blood flow (electromagnetic flowmeter) and GFR and in an increase of urine volume and arterial blood pressure.In healthy rats saralasin (6 g·kg^–1·min^–1 i.v.) had no renal effects by itself but antagonized the angiotensin II (200 ng·kg^–1·min i.v.) induced fall of renal blood flow and GFR and the increase of arterial blood pressure. Given to glycerol treated animals saralasin did not induce any change of arterial blood pressure, renal blood flow, GFR or the urinary excretion of fluid and sodium.Supported by Deutsche Forschungsgemeinschaft     

Renal effects of a new member of adrenomedullin family, adrenomedullin2, in rats

A new member of the adrenomedullin family, adrenomedullin2, was identified in mammals. The effects of adrenomedullin2 on renal hemodynamics and urine formation were examined in rats. Intrarenal arterial infusion of adrenomedullin2 at rates of 30, 100 and 300 pmol/kg/min decreased blood pressure and increased heart rate in a dose-dependent fashion. Adrenomedullin2 infusion at 100 pmol/kg/min significantly increased renal blood flow and urine flow. At the higher infusion rate (300 pmol/kg/min), adrenomedullin2 significantly decreased urine flow. Continuous intrarenal infusion of adrenomedullin2 at 100 pmol/kg/min significantly increased renal blood flow from 6.7+/-0.5 to 8.8+/-0.5 ml/min and decreased renal vascular resistance from 16+/-1 to 11+/-1 mm Hg min/ml. Urine flow was significantly increased from 21.5+/-4.9 to 36.2+/-8.5 microl/min and urinary excretion of sodium was increased from 2.3+/-0.9 to 4.9+/-1.4 microEq/min. Blood pressure, heart rate and glomerular filtration rate did not change. Infusion of a similar dose of adrenomedullin also increased renal blood flow (6.8+/-0.4-8.8+/-0.6 ml/min), urine flow (25.4+/-3.2-42.8+/-9.4 microl/min) and urinary excretion of sodium (2.8+/-0.6-6.5+/-1.2 microEq/min), decreased renal vascular resistance (15+/-1-11+/-1 mm Hg min/ml) and did not alter glomerular filtration rate. Thus, the renal actions induced by adrenomedullin2 were similar to those of adrenomedullin. These data suggest that adrenomedullin2 may play an important role in the regulation of renal hemodynamics and urine formation.     

CHRONIC INTRARENAL INFUSION OF LOW-DOSE ANGIOTENSIN II IN DOGS INCREASES ARTERIAL PRESSURE WITHOUT IMPAIRMENT OF RENAL FUNCTION

1. To determine whether chronic angiotensin II (AngII) infusion into the renal artery, at a dose which increases systemic arterial pressure, reduces glomerular filtration rate (GFR) and renal blood flow, AngII was infused at 0.5 ng/kg per min into the renal artery or intravenously in chronically instrumented dogs for 1 month. 2. Mean arterial pressure (MAP) rose significantly (P < 0.05) during the infusion of AngII into the renal artery (+7 ± 2 nunHg on days 26-30). There were no significant changes in GFR or renal blood flow. When the same dose of AngII was infused intravenously, MAP did not change significantly (?2 ± 2mmHg) and there were no significant changes in GFR or in renal blood flow. 3. We conclude that AngII infused into the renal artery for 1 month, at a dose which was initially subpressor, causes a rise in arterial pressure that is not associated with impairment of renal function.     

RENAL EXTRACTION OF ATRIAL NATRIURETIC PEPTIDE IN UNILATERAL RENAL ARTERY STENOSIS

1. Elevated peripheral atrial natriuretic peptide (ANP) levels were observed in 12 patients with unilateral renal artery stenosis (U-RAS). 2. Renal extraction of ANP was higher across the affected than the unaffected kidney in U-RAS, provided the glomerular filtration rate in the affected kidney was not severely reduced (> 12 mL/min). As ANP is a high clearance compound, reduced flow on the affected side may result in increased renal extraction of ANP. 3. When glomerular filtration rate (GFR) in the affected kidney was severely reduced (<12 mL/min), renal extraction of ANP was also reduced, possibly contributing to increased circulating ANP levels in this subgroup. 4. Overall, renal extraction of ANP was inversely correlated to peripheral ANP levels in patients with U-RAS. This might be explained by progressive sodium retention as GFR falls leading to volume expansion and increased ANP secretion.     

BLUNTED NATRIURETIC RESPONSE TO ENDOGENOUS ATRIAL NATRIURETIC PEPTIDE DURING RAPID CARDIAC PACING IN ANAESTHETIZED DOGS

1. We investigated whether diuresis and natriuresis induced by endogenous atrial natriuretic peptide (ANP) were blunted during rapid cardiac pacing. 2. Changes in plasma ANP, renal function and haemody-namics during rapid cardiac pacing were studied in anaesthetized closed-chest dogs. Dogs were paced via the right ventricle at a rate of 200 b.p.m. (moderate pacing) or 250 b.p.m. (severe pacing) for 180 min. 3. The maximal increases in plasma ANP and urinary excretion of cGMP during severe pacing were four- and three-fold higher, respectively, than those during moderate pacing. Despite the higher concentration of plasma ANP, the maximal increases in urine volume, urinary excretion of sodium and fractional excretion of sodium during severe pacing were similar to those during moderate pacing. Mean arterial pressure and renal vascular resistance were decreased only by severe pacing. The increase in total peripheral resistance during severe pacing was significantly smaller than that during moderate pacing. However, the glomerular filtration rate was kept at basal levels by both moderate and severe pacing. 4. These results suggest that there are certain mechanisms that counteract renal tubular sodium reabsorption induced by endogenous ANP under conditions of severe pacing. The suppression occurs at tubular sites but not at glomerular sites. One of the possibilities for the suppression is the decrease in renal perfusion pressure accompanied by decreases in peritubular capillary hydrostatic pressure.