Role of renal medullary heme oxygenase in the regulation of pressure natriuresis and arterial blood pressure

Recent studies have demonstrated that inhibition of renal medullary heme oxygenase (HO) activity and carbon monoxide (CO) significantly decreases renal medullary blood flow and sodium excretion. Given the crucial role of renal medullary blood flow in the control of pressure natriuresis, the present study was designed to determine whether renal medullary HO activity and resulting CO production participate in the regulation of pressure natriuresis and thereby the long-term control of arterial blood pressure. In anesthetized Sprague-Dawley rats, increases in renal perfusion pressure induced significant elevations of CO concentrations in the renal medulla. Renal medullary infusion of chromium mesoporphyrin (CrMP), an inhibitor of HO activity, remarkably inhibited HO activity and the renal perfusion pressure-dependent increases in CO levels in the renal medulla and significantly blunted pressure natriuresis. In conscious Sprague-Dawley rats, continuous infusion of CrMP into the renal medulla significantly increased mean arterial pressure (129+/-2.5 mm Hg in CrMP group versus 118+/-1.6 mm Hg in vehicle group) when animals were fed a normal salt diet (1% NaCl). After rats were switched to a high-salt diet (8% NaCl) for 10 days, CrMP-treated animals exhibited further increases in mean arterial pressure compared with CrMP-treated animals that were kept on normal salt diet (152+/-4.1 versus 130+/-4.2 mm Hg). These results suggest that renal medullary HO activity plays a crucial role in the control of pressure natriuresis and arterial blood pressure and that impairment of this HO/CO-mediated antihypertensive mechanism in the renal medulla may result in the development of hypertension.     

Effects of low-dose epinephrine infusion on cardiovascular and renal responses to water immersion in humans

Elevated plasma epinephrine concentrations may impair blood pressure homeostasis and renal sodium and volume excretion in response to central hypervolemia. We studied the effects of a low-dose epinephrine infusion (12 ng/kg/min) on cardiovascular and renal responses to a thermoneutral head-out water immersion in eleven healthy men.Responses to water immersion without epinephrine were characterized by significant suppression of plasma renin activity (PRA), plasma aldosterone concentration, and renal norepinephrine excretion, and an augmentation of natriuresis and diuresis. Epinephrine infusion, which raised mean plasma epinephrine concentration 4.3-fold, slightly increased plasma norepinephrine and renal norepinephrine excretion, markedly stimulated PRA (+66.7%), but decreased plasma aldosterone (−11.7%), and augmented renal sodium and volume excretion. Despite the presence of the epinephrine infusion, water immersion continued both to suppress PRA and aldosterone, and to increase natriuresis and diuresis in a qualitatively similar pattern. During all conditions blood pressure and heart rate remained unchanged.It is concluded that physiologic responses to central hypervolemia are not impaired at stress levels of circulating epinephrine. During epinephrine infusion, despite a concomitant increase in plasma norepinephrine and a stimulation of PRA, blood pressure remained constant in response to water immersion due to an augmentation of natriuresis and diuresis.     

Renal sympathetic neuroeffector function in renovascular and angiotensin II-dependent hypertension in rabbits

We tested the hypotheses that the gains of specific renal sympathetic neuroeffector mechanisms are altered in secondary hypertension and that the nature of these alterations depends on the precise experimental setting of the kidney. Rabbits were sham operated, or made comparably hypertensive (mean arterial pressure increased 17% to 24%) by clipping the left or right renal artery or by chronic infusion of angiotensin II (20 to 50 ng kg(-1) min(-1) SC). Four to 6 weeks later, under pentobarbital anesthesia, the left renal nerves were sectioned and electrically stimulated at low (0 to 2 Hz) and high (4 to 8 Hz) frequencies. Neurally evoked reductions in total renal blood flow, cortical perfusion, urine flow, and sodium excretion and increases in renal norepinephrine spillover were not significantly greater in kidneys of hypertensive rabbits than normotensive controls. Neurally evoked increases in renal renin release and the slope of the relationship between renin release and norepinephrine spillover were less in kidneys of hypertensive rabbits than normotensive controls. Low-frequency renal nerve stimulation reduced medullary perfusion, which was negatively correlated with renal norepinephrine spillover in kidneys from all 3 groups of hypertensive rabbits but not normotensive controls. Two-hertz stimulation reduced medullary perfusion by 19% in hypertensive rabbits but not in normotensive rabbits. Thus, of all of the renal sympathetic neuroeffector mechanisms studied, only neural control of medullary perfusion was enhanced in these models of secondary hypertension. This effect appears to be mediated postjunctionally, not through enhanced neural norepinephrine release, and may contribute to the development and/or maintenance of hypertension in these models.     

Preservation of renal function by angiotensin during chronic adrenergic stimulation

The purpose of the present study was to determine the role of angiotensin II (Ang II) in mediating renal responses to chronic intrarenal norepinephrine infusion. Norepinephrine was continuously infused for 5 days into the renal artery of unilaterally nephrectomized dogs at progressively higher daily infusion rates: 0.05, 0.10, 0.20, 0.30, and 0.40 micrograms/kg/min. In three additional groups of dogs, norepinephrine infusion was repeated during chronic intravenous captopril administration to fix plasma Ang II concentration at 1) low levels (no Ang II infused), 2) high levels in the renal circulation (Ang II infused intrarenally at a rate of 1 ng/kg/min), and 3) high levels in the systemic circulation (Ang II infused intravenously at a rate of 5 ng/kg/min). In the control group of animals with intact renin-angiotensin systems, there were progressive increments in mean arterial pressure (from 96 +/- 4 to 141 +/- 6 mm Hg) and plasma renin activity (from 0.4 +/- 0.1 to 10.9 +/- 4.5 ng angiotensin I/ml/hr) and concomitant reductions in glomerular filtration rate and renal plasma flow to approximately 40% of control during the 5-day norepinephrine infusion period. In marked contrast, when captopril was infused chronically without Ang II, mean arterial pressure was 20-25 mm Hg less than that under control conditions, and the renal hemodynamic effects of norepinephrine were greatly exaggerated; by day 3 of norepinephrine infusion, both glomerular filtration rate (16 +/- 2% of control) and renal plasma flow (12 +/- 4% of control) were considerably lower than values in control animals (86 +/- 4% and 80 +/- 8% of control, respectively). Similarly, when a high level of Ang II was localized in the renal circulation during captopril administration, mean arterial pressure was depressed, and again there were pronounced renal responses to norepinephrine. Conversely, when Ang II was infused intravenously during captopril administration, mean arterial pressure was not reduced, and the glomerular filtration rate and renal plasma flow responses to norepinephrine were similar to those that occurred under control conditions. These findings indicate that the renin-angiotensin system prevents exaggerated renal vascular responses to chronic norepinephrine stimulation by preserving renal perfusion pressure.     

Hypotensive and natriuretic actions of adrenomedullin in subjects with chronic renal impairment

Plasma levels of adrenomedullin are increased in chronic renal failure. The significance of this finding is uncertain, because the biological effects of adrenomedullin in renal impairment are unknown. Therefore, we studied the effects of adrenomedullin infusion in subjects with chronic renal impairment. Eight males with IgA nephropathy and plasma creatinine of 0.19+/-0.03 mmol/L (mean+/-SEM) were studied in a vehicle-controlled crossover design. Each subject was studied twice; subjects were administered either adrenomedullin at a low dose and then a high dose (2.9 and 5.8 pmol/kg per minute, respectively, for 2 hours each) or a 4-hour vehicle control (Hemaccel), in random order, on day 4 of controlled metabolic diets. Adrenomedullin infusion achieved plasma adrenomedullin concentrations in the pathophysiological range after the low (31.2+/-5.1 pmol/L) and high (47.4+/-4.3 pmol/L) dose, and plasma cAMP was increased. Compared with vehicle control, high-dose adrenomedullin increased peak heart rate (+21.7+/-3.3 bpm, P<0.01) and cardiac output (+2.9+/-0.2 L/min, P<0.01) and lowered both systolic and diastolic blood pressures by >10 mm Hg (P<0.05). Plasma renin activity, angiotensin II, and norepinephrine increased by up to 50% above baseline levels (P<0.05 for all), whereas aldosterone and epinephrine were unchanged. Urinary volume and sodium excretion increased significantly (P<0.05) with low-dose adrenomedullin, whereas creatinine clearance was stable, and proteinuria tended to decrease. In subjects with chronic renal impairment due to IgA nephropathy, adrenomedullin infusion lowered blood pressure, stimulated sympathetic activity and renin release, and caused diuresis and natriuresis. Adrenomedullin may have a role in modulating blood pressure and kidney function in renal disease.     

Impaired renorenal reflexes in spontaneously hypertensive rats

In normotensive Sprague-Dawley rats stimulation of renal mechanoreceptors and chemoreceptors by increasing ureteral pressure and retrograde ureteropelvic perfusion with 0.9 M NaCl results in a contralateral inhibitory renorenal reflex response with contralateral diuresis and natriuresis. Since efferent renal nerve activity is increased in spontaneously hypertensive rats (SHR) and renal denervation delays the onset of hypertension in SHR in association with increased diuresis and natriuresis, the present study was undertaken to examine whether renorenal reflexes were altered in SHR compared with normotensive Wistar-Kyoto rats (WKY). In WKY mean arterial pressure was 113 +/- 2 mm Hg and remained unchanged during renal mechanoreceptor and chemoreceptor stimulation. Increasing ureteral pressure 35 mm Hg increased ipsilateral afferent renal nerve activity 4.5 +/- 1.7 resets/min, decreased contralateral efferent renal nerve activity 3.2 +/- 0.8 resets/min, and increased contralateral urine flow rate 33 +/- 4% and urinary sodium excretion 49 +/- 8%. Similarly, retrograde ureteropelvic perfusion with 0.9 M NaCl increased ipsilateral afferent renal nerve activity 2.5 +/- 0.6 resets/min, decreased contralateral efferent renal nerve activity 2.4 +/- 1.1 resets/min, and increased contralateral urine flow rate 39 +/- 5% and urinary sodium excretion 38 +/- 8%. Stimulating renal mechanoreceptors and chemoreceptors to the same extent in SHR failed to increase ipsilateral afferent renal nerve activity, decrease contralateral efferent renal nerve activity, and produce a contralateral diuresis and natriuresis. It is concluded that renorenal reflexes are impaired in SHR. Failure of ipsilateral afferent renal nerve activity to increase during renal mechanoreceptor and chemoreceptor stimulation indicates a peripheral defect at the level of the renal sensory receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Inhibition of cyclooxygenase-2 in the rat renal medulla leads to sodium-sensitive hypertension

Cyclooxygenase-2 expression in the renal medulla is regulated by dietary salt intake. The present study was performed to determine the influence of chronic inhibition of medullary cyclooxygenase-2 on arterial blood pressure in conscious Sprague-Dawley rats maintained on a high-salt (4% NaCl) or a low-salt (0.4% NaCl) diet. Rats were uninephrectomized and instrumented with femoral arterial and femoral vein or renal medullary interstitial catheters. Each rat received a continuous medullary or intravenous infusion of saline (0.5 mL per hour) for 3 control days, followed by infusion of the cyclooxygenase-2 inhibitor NS-398 (10 mg/kg per day) for 5 days. Medullary interstitial infusion of NS-398 significantly increased mean arterial pressure in the 4% NaCl group from 126+/-2 to 146+/-2 mm Hg (n=6) but did not alter blood pressure in the 0.4% NaCl group (n=6). Intravenous infusion of NS-398 to rats on the 4.0% NaCl diet also failed to alter mean arterial pressure (n=5). To test the blood pressure effect of a mechanistically different inhibitor of cyclooxygenase-2, an antisense oligonucleotide against cyclooxygenase-2 (18-mer; 8 nmol per hour) was infused into the renal medulla of rats maintained on a high-salt diet. Administration of the antisense oligonucleotide reduced cyclooxygenase-2 immunoreactive protein by 36% and significantly increased mean arterial pressure from 127+/-2 to 147+/-2 mm Hg (n=6). Renal medullary interstitial infusion of a scrambled oligonucleotide did not alter arterial pressure (n=5). These results demonstrate the importance of cyclooxygenase-2 in the renal medulla in maintaining blood pressure during high-salt intake.     

Comparative renal effects of intravenous administration of fenoldopam mesylate and sodium nitroprusside in patients with severe hypertension

We studied the renal effects of intravenous administration of fenoldopam mesylate, a dopamine-1 agonist, vs sodium nitroprusside following acute reduction of blood pressure (BP) in 11 patients with severe hypertension (supine BP, 168/124 to 252/135 mm Hg). Following randomization (open-label), timed urinary and plasma samples for clearance of urea and creatinine and excretion of sodium, potassium, and calcium were obtained as well as plasma renin activity for a two-hour collection prior to infusion, during a two-hour period of BP control (supine diastolic BP, 95 to 110 mm Hg), and following two hours off the drugs. Mean arterial pressure was lowered similarly with the two drugs (-22% on fenoldopam vs -20% on nitroprusside; P = NS), and neither plasma renin activity nor plasma aldosterone concentration were changed by either drug. However, patients receiving fenoldopam had significant increases in urinary flow and excretion of sodium, potassium, and calcium, whereas patients receiving nitroprusside had no changes in these parameters. Patients receiving fenoldopam had a net fluid balance of -334 mL from the end of baseline to the end of the treatment period, while the nitroprusside group had a positive balance of 382 mL. Thus, these findings show that acute BP reduction with fenoldopam is associated with both a diuresis and natriuresis in severely hypertensive patients while lowering BP with nitroprusside does not predictably alter renal function and causes a moderate expansion in volume.     

Captopril modifies the hemodynamic and neuroendocrine responses to sodium nitroprusside in hypertensive patients

To determine if clinically effective doses of the antihypertensive agent captopril affected the neuronal release of norepinephrine or baroreflex sensitivity, changes in plasma norepinephrine concentration and heart rate were related to the changes in mean arterial pressure seen during the intravenous infusion of stepwise incremental doses of sodium nitroprusside before and during captopril treatment in eight hypertensive men with normal or low plasma renin activity. At all times, significant linear correlations were found between the decrease in mean arterial pressure and the dose of sodium nitroprusside, the increase in heart rate and the decrease in mean arterial pressure, and the increase in plasma norepinephrine concentration and the decrease in mean arterial pressure. When the subjects were treated with captopril (25 mg t.i.d.) for 2 to 4 weeks, supine mean arterial pressure decreased from 130 to 114 mm Hg (-12%; p less than 0.05), heart rate did not change, supine and upright plasma renin activity increased, while supine plasma norepinephrine and epinephrine concentration decreased slightly. Therapy with captopril (25 mg t.i.d.) increased baroreflex sensitivity, as assessed by the slope of the regression line relating the increase in heart rate to the decrease in mean arterial pressure, and increased the responsiveness of the sympathetic nervous system, as assessed by the slope of the regression line relating the increase in plasma norepinephrine concentration to the decrease in mean arterial pressure. These increases were accompanied by a decrease in the slope of the regression line relating the decrease in mean arterial pressure to the dose of sodium nitroprusside and thus were associated with a decreased sensitivity to the vasodepressor effects of sodium nitroprusside.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal medullary blood flow and salt load in Lyon hypertensive rats

The present work studied renal medullary blood flow (MBF) and its response to salt load in Lyon hypertensive (LH) rats to understand the mechanisms underlying the abnormal renal sodium excretion exhibited by LH rats. Experiments were conducted in uninephrectomized, anesthetized, and volume-expanded 15-week-old male LH and their normotensive (LL) controls. Under standard diet, LH rats exhibited a blunted pressure diuresis and natriuresis associated with an absence of pressure-induced increase in MBF compared to LL rats. One week of salt load (2% NaCl as drinking water) induced a significant increase in blood pressure (BP) in LH (+11 mm Hg) than in LL (+6 mm Hg) rats associated with a decrease in MBF in LH rats only (from 182 +/- 25 to 122 +/- 20 perfusion units, P < .001). Finally, despite the salt load-induced increase in pressure natriuresis, it remained significantly lower in LH than in LL rats. The results show an alteration in MBF regulation in LH rats and suggest that this abnormality may be involved in their blunted pressure natriuresis and their enhanced salt sensitivity.     

Intrarenal beta-receptor and renal baroreceptor interaction in the control of the renin response to transient reduction of the renal perfusion pressure in man

We have examined the mechanisms mediating the release of renin elicited in man by reduction of renal perfusion pressure. Fifteen patients with essential hypertension and six normotensive subjects were investigated during diagnostic renal arteriography. Renal neural receptors were inhibited by propranolol (10 mg i.v.) and activated by a standard cold pressor test. Vascular receptors were stimulated by unilateral reduction of renal perfusion pressure by 50%, using a balloon-tipped catheter. The stimulus caused release of renin. In hypertensives, arterial plasma renin increased by 44, 69 and 73% of control at 5, 15 and 30 min, respectively. Adrenergic activation by cold raised the arterial and the renal venous renin by approximately 50% of control and caused a fourfold rise when it was combined with the arterial obstruction. Following propranolol the renin response to reduction of the renal perfusion pressure was delayed and reduced, and cold stimulation, both alone and in combination with arterial obstruction, failed to stimulate renin release. Findings were qualitatively and quantitatively similar in the normotensive group. This study supports the hypothesis that the renin response to reduction of renal perfusion pressure in man results from an interaction of adrenergic and vascular receptors. It cannot be stated whether the former are synergistic or supplementary to the latter, even though adrenergic activation by cold stimulation provides evidence that a synergism between the two may exist.     

Blood pressure-dependent inhibition of Renin secretion requires A1 adenosine receptors

Renal perfusion pressure (RPP) regulates renin release with a reduction of RPP stimulating and an elevation inhibiting renin secretion. The precise sensing and effector mechanisms by which changes in arterial pressure are linked to the exocytosis of renin are not well-defined. The present experiments were designed to study the potential role of adenosine as a mediator of this renal baroreceptor mechanism. In isolated perfused mouse kidneys a stepwise reduction of RPP from 90 mm Hg to 65 and 40 mm Hg stimulated renin secretion rates (RSR) 1.4-fold and 3.6-fold, whereas stepwise elevations of RPP from 90 mm Hg to 115 and 140 mm Hg suppressed RSR to 64% or 40% of baseline. Inactivation of A1 adenosine receptors by either pharmacological blockade (DPCPX 1 micromol/L) or genetic deletion (A1AR(-/-) mice) did not modify the stimulation of renin release by a low RPP, but completely prevented the suppression of renin secretion by higher perfusion pressures. In vivo, the induction of arterial hypertension by either acute (single subcutaneous injection) or chronic (osmotic minipump for 72 hours) application of phenylephrine significantly reduced plasma renin concentration (PRC) in wild-type mice to approximately 40% of control, whereas it did not significantly affect PRC in A1AR(-/-) mice. Together these data demonstrate that A1 adenosine receptors are indispensable for the inhibition of renin secretion by an increase in blood pressure, suggesting that formation and action of adenosine is responsible for baroreceptor-mediated inhibition of renin release. In contrast, the stimulation of the renin system by a low blood pressure appears to follow different pathways.     

Modulation of the natriuretic response to atrial natriuretic peptide by alterations in peritubular Starling forces in the rat

The mechanisms underlying the natriuretic response to infusions of atrial natriuretic peptide (ANP) remain incompletely defined. By acting as renal vasodilators, atrial peptides may serve to alter peritubular capillary physical forces and favor a decrease in tubule solute reabsorption. Therefore, we studied the effects of known modifiers of intrarenal Starling forces on the natriuresis induced by infusion of intravenous hANP [4-28] (0.5 microgram/kg/min) in anesthetized, euvolemic Munich-Wistar rats. In the first series of studies, infusion of ANP resulted in a significant natriuresis, diuresis, and increase in inulin clearance and in a slight fall in systemic arterial pressure, as compared to vehicle infusion. Subsequent elevation of renal perfusion pressure by superimposition of angiotensin II infusion (0.1-0.2 microgram/kg/min i.v.) on continued ANP infusion resulted in marked further enhancement of natriuresis, independent of changes in glomerular filtration rate (GFR). In the second set of experiments, in which oncotic pressure in the postglomerular capillaries was elevated by hyperoncotic exchange transfusion, administration of ANP did not result in natriuresis, even though GFR increased by the same magnitude as that seen in isooncotic animals given ANP. These observations are consistent with the view that peritubular capillary hydraulic and oncotic pressures modulate the natriuretic and diuretic effects of ANP.     

Cationic amino acid transport in the renal medulla and blood pressure regulation

Previous studies have indicated that NO synthesis in isolated inner medullary collecting duct cells is reduced by cationic amino acids that compete with L-arginine for cellular uptake. In the present study, we investigated the effects of chronic renal medullary infusion of cationic amino acids on renal NO concentration and mean arterial pressure (MAP) in Sprague-Dawley rats. Renal medullary infusion of L-ornithine (50 microg/kg per min) or L-lysine (50 microg/kg per min) markedly decreased NO in the medulla (vehicle, 124 +/- 11 nmol/L; L-ornithine, 45 +/- 4 nmol/L; L-lysine, 42 +/- 6 nmol/L) and increased MAP (vehicle, 111 +/- 7 mm Hg; L-ornithine, 143 +/- 6 mm Hg; L-lysine, 148 +/- 3 mm Hg) after 5 days of infusion. In contrast, intravenous infusion of the same dose of L-ornithine or L-lysine for 5 days increased plasma concentration to levels similar to those observed with intramedullary infusion but did not change NO in the medulla or alter MAP. Furthermore, the NO-suppressing and hypertensive effects of medullary interstitial infusion of L-ornithine (50 microg/kg per min) were attenuated by simultaneous infusion of L-arginine (500 microg/kg per min; NO, 97 +/- 10 nmol/L; MAP, 124 +/- 3 mm Hg). A 5-day infusion of an antisense oligonucleotide against CAT-1 (18-mer, 8.3 nmol/h) significantly decreased CAT-1 protein in the medulla, decreased NO in the medulla (scrambled oligo, 124 +/- 10 nmol/L; antisense oligo, 67 +/- 11 nmol/L), and increased MAP (scrambled oligo, 113 +/- 2 mm Hg; antisense oligo, 130 +/- 2 mm Hg). These results suggest that uptake of L-arginine by cationic amino acid transport systems in the renal medulla plays an important role in the regulation of medullary NO and MAP in rats.     

Effects on regional renal blood flow when unclipping a two-kidney, one-clip hypertensive Wistar rat during renal nerve stimulation.

Blood pressure (BP) is rapidly normalized when removing the obstruction from the renal artery of a two-kidney, one-clip renovascular hypertensive rat (unclipping). This study tested whether efferent renal nerve stimulation (ERNS) of the unclipped kidney affects this drop in BP or the associated changes in diuresis-natriuresis and regional renal blood flow. Three groups of anesthetized renovascular hypertensive Wistar rats were studied: 1) W(C) (time control); 2) W(UC) (unclipped after 30 min); and 3) W(UC+NS) (unclipped after 30 min, with ERNS at 5 Hz for 2 h). Renal excretion and regional hemodynamics (laser Doppler) were monitored in the unclipped kidney. Medullary and cortical blood perfusion increased by 84% and 95%, respectively, in W(UC) 30 min after unclipping (P < .001) but only with 8% and 9%, respectively, in W(UC+NS) (P = NS). Unclipping induced a marked increase in diuresis-natriuresis that was largely unaffected by ERNS. In W(UC) and W(UC+NS) BP returned to normotensive levels within 4 h. However, during the first 30 min, average BP decreased significantly less in W(UC+NS) (9%, 20 mm Hg) than in W(UC) (16%, 35 mm Hg) (P < .05). ERNS at 5 Hz effectively prevented the increase in medullary blood perfusion but did not affect the fall in blood pressure or the pressure diuretic/natriuretic response seen after unclipping. The results suggest that both the reduction in BP and the pressure-induced increase in diuresis/natriuresis seen when unclipping the 2K,1C renovascular hypertensive rat occurs largely independently of ERNS and an increase in medullary blood perfusion.     

Cardiovascular, renal, and endocrine response to atrial natriuretic peptide in angiotensin II mediated hypertension

Studies done in vitro have demonstrated that atrial natriuretic peptide (ANP) antagonizes angiotensin II-mediated contraction of vascular smooth muscle. The present studies were designed to examine the in vivo actions of ANP in acute angiotensin II-mediated hypertension. The cardiovascular, renal, and hormonal effects of intravenous ANP were evaluated in anesthetized normotensive (n = 6) and hypertensive (n = 6) dogs. In both groups, ANP (3.0 micrograms/kg bolus, 0.3 micrograms/kg/min continuous infusion) reduced arterial pressure and cardiac output without changing systemic vascular resistance. ANP specifically reduced renal vascular resistance and increased sodium excretion. The natriuresis observed was greater in hypertensive than in normotensive dogs. This occurred without a significant change in glomerular filtration rate or aldosterone. The ANP-mediated reduction in arterial pressure was associated with an increase in circulating arginine vasopressin and catecholamines but not in renin. These studies demonstrate that ANP-mediated hypotension results from a reduction in cardiac output without changing systemic vascular resistance, ANP acts as a specific renal vasodilator, ANP-mediated natriuresis can occur without alteration in glomerular filtration rate or aldosterone, and ANP specifically inhibits the release of renin without inhibiting the release of other circulating vasoconstrictors.     

Hypotensive effect of chronic intrarenal infusion of acetylcholine during angiotensin hypertension

We examined the role of the pressure natriuresis phenomenon in long-term arterial pressure control. Uninephrectomized dogs were housed in metabolic cages and made hypertensive with a continuous background intravenous infusion of angiotensin II (AngII, 12 ng/kg/min). To increase the ability of the kidney to excrete salt and water, we infused acetylcholine (ACH, 2.0 micrograms/kg/min), a potent natriuretic agen, directly into the renal artery. In four dogs, ACH decreased mean arterial pressure (MAP) from 144 +/- 5 mm Hg to 113 +/- 3 mm Hg. Sodium excretion increased by about 60% on the first day of infusion and then returned rapidly toward the control value. On cessation of the ACH infusion, there was a transient but marked sodium retention, and the hypertension returned. A control infusion of ACH intravenously rather than into the renal artery in the same four dogs did not affect MAP or sodium excretion during AngII hypertension.     

The systemic beta-adrenergic pathway to renin secretion: relationships with the renal prostaglandin system

The relationship between renin release evoked by circulating beta-agonists and the renal prostaglandin (PG) system is incompletely defined. Thus, we evaluated systemic and renal hemodynamic responses to iv (0.5 micrograms/kg X min) and intrarenal arterial (0.6 micrograms/kg X min) infusions of the beta1-agonist prenalterol (PNL) in four separate groups of anesthetized dogs. Consecutive iv PNL infusions (n = 6) resulted in a reversible decrease in mean arterial pressure (130 to 117 mm Hg; P less than 0.05) and increases in cardiac output (3.93 to 4.90 liters/min; P less than 0.001), PRA (1.96 to 5.12 ng/ml X h; P less than 0.01), and 6-keto-PGF 1 alpha levels (190 to 482 pg/ml; P less than 0.01). The glomerular filtration rate and renal blood flow were modestly, but not significantly, decreased by the PNL infusions. In a second group of dogs, the infusion of the PG synthesis inhibitor indomethacin (IN; 10 mg/kg, iv; n = 7) before the second PNL infusion blunted PG increases but did not significantly modify the systemic or renal hemodynamic responses to PNL. The magnitude of the PRA and renin secretory rate (RSR) increases post-IN administration was similar to control values, but the absolute levels achieved were not as great as before IN infusion. To assess the role of the renal baroreceptor pathway to renin release after PNL, a suprarenal clamp was used to maintain a constant renal perfusion pressure during PNL infusion in a third group of dogs. In this group (n = 5), both PRA and RSR (from innervated and denervated kidneys) increased after PNL infusion, although IN again diminished the maximum PRA and RSR responses observed. Finally, the unilateral intrarenal arterial infusion of PNL in the last group of dogs did not alter PRA, RSR, or renal hemodynamics. These results demonstrate that renin release elicited by a circulating beta-agonist functions independently of PG synthesis, and that the pathway operates via an extrarenal mechanism.     

Renal effects in cirrhotic patients with avid sodium retention of atrial natriuretic factor injection during norepinephrine infusion.

The administration of atrial natriuretic factor to patients with cirrhosis, and avid sodium retention causes marked hypotension and blunted kidney responses. To evaluate whether the unresponsiveness of the kidney is caused by a fall in mean blood pressure below a critical value for the renal blood perfusion pressure (80 mm Hg), we studied nine such patients and compared the effects of synthetic atrial natriuretic factor alone (1 micrograms/kg as a bolus) with those of an atrial natriuretic factor combination with infused norepinephrine titrated to raise baseline blood pressure by 15 to 20 mm Hg (182 to 625 ng/kg/min). The administration of atrial natriuretic factor during norepinephrine infusion caused a fall in mean blood pressure to values not less than 80 mm Hg in eight of nine patients, with a slight natriuresis (greater than 5 mumol/min) in five patients but no changes in the other four. The mean urinary sodium output was markedly lower than that previously observed after atrial natriuretic factor injection into normal subjects and into cirrhotic patients without avid sodium retention. Unlike sodium excretion, urine flow rate and free water clearance (which were not affected by atrial natriuretic factor alone) were markedly improved by the coadministration of norepinephrine and atrial natriuretic factor. In four additional patients we studied the urinary electrolyte excretion during a low-dose infusion of atrial natriuretic factor (20 ng/kg/min) to which an infusion of norepinephrine titrated to maintain blood pressure over 80 mm Hg was added. In only one of these four patients urinary sodium output consistently increased during atrial natriuretic factor infusion, and the output increased even more when norepinephrine was added.(ABSTRACT TRUNCATED AT 250 WORDS)