Bradykinin contribution to renal blood flow effect of angiotensin converting enzyme inhibitor in the conscious sodium-restricted dog

We examined the relative contribution of renin-angiotensin system blockade and bradykinin potentiation to the renal hemodynamic effect of the angiotensin converting enzyme inhibitor enalaprilat in sodium-deprived dogs. Six conscious dogs instrumented for monitoring of blood pressure (BP) and renal blood flow (RBF) were employed in five groups of experiments. In group 1, enalaprilat alone was administered, and it decreased BP by -24 +/- 3 mm Hg and increased RBF by 135 +/- 15 ml/min. During a constant intravenous infusion of saralasin (group 2), enalaprilat decreased BP by -7 +/- 3 mm Hg and increased RBF by 84 +/- 7 ml/min (delta BP and delta RBF, p less than 0.01 vs. group 1 by analysis of variance). During a constant intrarenal arterial infusion of saralasin (group 3), the respective changes in BP and RBF after enalaprilat were -10 +/- 3 mm Hg and 69 +/- 12 ml/min, and these results did not differ from those of group 2. The infusion of saralasin intravenously or intrarenal arterially decreased BP slightly and increased RBF. In the presence of an intravenous infusion of a specific bradykinin antagonist, D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Phe-Thi-Arg.TFA (B5630) (group 4), enalaprilat decreased BP by -28 +/- 4 mm Hg and increased RBF by 82 +/- 24 ml/min (delta RBF, p less than 0.01 vs. group 1).(ABSTRACT TRUNCATED AT 250 WORDS)     

A comparison of synthetic rat and human atrial natriuretic factor in conscious dogs

The renal and hypotensive responses to intravenous infusions of 10, 50, 100, and 200 pmol/kg/min of synthetic rat atrial natriuretic factor (Arg101-Arg-Ser-Ser-Cys-Phe-Gly-Gly-Arg-Ile110-Asp-Arg-Ile-G ly-Ala-Gln-Ser-Gly -Leu-Gly120-Cys-Asn-Ser-Phe-Arg-Tyr; disulfide bond between cysteines) were compared with those produced by synthetic human atrial natriuretic factor (Met110) in five conscious dogs. Increasing doses of rat or human atrial natriuretic factor lowered mean arterial pressure in a dose-related manner. At 200 pmol/kg/min, the maximally effective dose for both peptides, mean arterial pressure was reduced from 116 +/- 4 to 96 +/- 5 mm Hg and from 117 +/- 5 to 100 +/- 3 mm Hg (p less than 0.01), respectively. Neither peptide affected heart rate. Fractional sodium excretion increased from 0.69 +/- 0.22 to 3.95 +/- 1.23% and from 0.69 +/- 0.16 to 4.62 +/- 0.72% during infusions of 200 pmol/kg/min of rat and human atrial natriuretic factor, respectively. Urine volume and fractional chloride excretion rose during infusions of rat or human atrial natriuretic factor in a manner that resembled the elevation in sodium excretion. The stimulation of fractional potassium excretion by both rat and human peptides was more variable and not as clearly dose-dependent. Glomerular filtration rate was enhanced by both rat and human atrial natriuretic factor, while neither peptide significantly changed renal plasma flow.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Renal insensitivity to atrial natriuretic peptide in patients with cirrhosis and ascites. Effect of increasing systemic arterial pressure.

The IV infusion of pharmacological doses (0.05 microgram.kg-1.min-1) of atrial natriuretic peptide to 16 patients with cirrhosis and ascites induced a significant increase in sodium excretion (65 +/- 23 to 517 +/- 231 mu Eq/min), urine volume (10.7 +/- 2.3 to 15.7 +/- 3.7 mL/min), and glomerular filtration rate (89 +/- 4 to 110 +/- 4 mL/min) in only 5 patients (responders). No significant changes in these parameters (15 +/- 6 to 11 +/- 4 mu Eq/min, 5.5 +/- 1.0 to 4.2 +/- 1.1 mL/min, and 81 +/- 5 to 79 +/- 6 mL/min, respectively) were observed in the remaining patients (nonresponders). Compared with responders, nonresponders had significantly lower baseline sodium excretion (P less than 0.02), urine flow (P less than 0.05), free water clearance (2.5 +/- 0.9 vs. 6.9 +/- 2.1 mL/min; P less than 0.05), and mean arterial pressure (82 +/- 3 vs. 96 +/- 2 mm Hg; P less than 0.01) and significantly higher plasma renin activity (16.3 +/- 4.9 vs. 1.8 +/- 0.2 ng.mL-1.h-1; P less than 0.05) and aldosterone level (99 +/- 24 vs. 13 +/- 2 ng/dL; P less than 0.05). Atrial natriuretic peptide produced a similar reduction of arterial pressure in both groups. To investigate whether the blunted natriuretic response to atrial natriuretic peptide in nonresponders was caused by their lower arterial pressure, atrial natriuretic peptide was infused in 7 of these patients after increasing their arterial pressure to the levels of responders with nonrepinephrine. The increase in arterial pressure (from 81 +/- 5 to 95 +/- 5 mm Hg), which was not associated with significant changes in plasma renin activity and aldosterone concentration, did not reverse the blunted renal response to atrial natriuretic peptide in any of these patients. These results indicate that cirrhotic patients with blunted renal response to atrial natriuretic peptide are characterized by low arterial pressure, marked overactivity of the renin-aldosterone system, and severe sodium and water retention. Correction of hypotension without increasing effective blood volume does not restore renal insensitivity to atrial natriuretic peptide.     

Captopril restores hemodynamic responsiveness to atrial natriuretic peptide in rats with heart failure

Atrial natriuretic peptide levels are elevated in heart failure. However, the hemodynamic responses to exogenous atrial natriuretic peptide infusion in heart failure are blunted. To determine if captopril can restore hemodynamic responsiveness to atrial natriuretic peptide infusion in rats with heart failure, studies were performed in a rat model of heart failure after coronary artery ligation. Rats with heart failure received either captopril (2 g/l drinking water) or placebo for 4 weeks and then were treated with an infusion of atrial natriuretic peptide (0.3 microgram/kg/min). Captopril treatment alone improved hemodynamics. Left ventricular end-diastolic pressure, mean aortic pressure, and mean circulatory filling pressure decreased from 22 +/- 2 to 14 +/- 1, from 106 +/- 4 to 76 +/- 3, and from 10.5 +/- 0.6 to 8.8 +/- 0.4 mm Hg, respectively. Heart rate, right atrial pressure, and hematocrit were unchanged. Total blood volume decreased from 66.0 +/- 1.0 to 60.0 +/- 1.0 ml/kg; venous compliance increased from 2.1 +/- 0.1 to 2.7 +/- 0.1 ml/kg/mm Hg. Atrial natriuretic peptide alone had minimal hemodynamic effects on rats with heart failure. There was no change in right atrial pressure, mean aortic pressure, left ventricular end-diastolic pressure, mean circulatory filling pressure, and total blood volume. However, atrial natriuretic peptide infusion increased venous compliance from 2.1 +/- 0.1 to 2.4 +/- 0.1 ml/kg/mm Hg. Heart rate and hematocrit increased from 323 +/- 5 to 359 +/- 8 beats/min and from 48 +/- 1% to 51 +/- 1%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic and renal effects of atrial natriuretic peptide in congestive heart failure

The hemodynamic and renal effects of anaritide (human atrial natriuretic peptide 102-126), a synthetic analog of atrial natriuretic peptide, were evaluated in 35 patients with chronic New York Heart Association class II to IV heart failure. There were 32 men and 3 women, aged 33 to 75 (mean +/- standard error of the mean 56 +/- 2) years. In the first phase of the study, right-sided heart catheterization was performed, and anaritide was administered as 1-hour infusions. The rate of the infusion varied among patients from 0.03 to 0.3 micrograms/kg/min. In response to anaritide, there were decreases in mean systemic arterial (94 +/- 2 to 87 +/- 2 mm Hg), right atrial (10 +/- 1 to 8 +/- 1 mm Hg), mean pulmonary arterial (33 +/- 2 to 28 +/- 2 mm Hg) and pulmonary artery wedge (22 +/- 2 to 15 +/- 2 mm Hg) pressures (all p less than 0.05). Cardiac index increased (2.39 +/- 0.15 to 2.62 +/- 0.15 liters/min/m2, p less than 0.05) and heart rate was unchanged. Systemic vascular resistance decreased significantly, but pulmonary vascular resistance was unchanged. There were increases in urine volume (1.6 +/- 0.2 to 2.3 +/- 0.4 ml/min), sodium excretion (47 +/- 13 to 74 +/- 20 muEq/min) and fractional excretion of sodium (0.41 +/- 0.11 to 0.59 +/- 0.14%, all p less than 0.05), while potassium excretion and creatinine clearance did not change. In the second phase of the study, patients received 2-hour infusions of anaritide (0.03 to 0.6 micrograms/kg/min) and placebo with noninvasive monitoring.(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of a new renin inhibitor and enalaprilat in renal hypertensive dogs

The hypotensive efficacy of a potent new renin inhibitor (N alpha-isovaleryl-L-histidyl-L-prolyl-L-phenylalanyl-L-histidyl-ACHPA+ ++-L- phenylalanyl amide) containing (3S,4S)-4-amino-5-cyclohexyl-3-hydroxy pentanoic acid (ACHPA) was compared with the converting enzyme inhibitor (enalaprilat) (MK-422) in conscious one-kidney dogs before and after tightening a renal artery clamp. Dose-response curves to 0.003 to 0.1 mg/kg/min i.v. infusions of the ACHPA-containing renin inhibitory peptide or enalaprilat (0.003-0.1 mg/kg i.v. bolus) were obtained in one-kidney dogs before and 3 days and 14 days after renal artery constriction. The ACHPA-containing renin inhibitory peptide and enalaprilat maximally decreased blood pressure by 10 +/- 2 and 9 +/- 2 mm Hg before constriction and by 12 +/- 2 and 12 +/- 4 mm Hg in dogs treated 14 days after renal artery constriction, respectively. Glomerular filtration rate and effective renal plasma flow were unaltered or slightly improved. In sharp contrast, both compounds elicited significant, dose-related decreases in blood pressure (-26 +/- 4 and -20 +/- 4 mm Hg, respectively), glomerular filtration rate (-21 +/- 3 and -23 +/- 3 ml/min), and renal plasma flow (-45 +/- 14 and -48 +/- 13 ml/min) in dogs examined 3 days after renal artery constriction. These data demonstrate that ACHPA-containing renin inhibitory peptide and enalaprilat are equally effective antihypertensive agents in dogs with renin-dependent renovascular hypertension and lend credence to the contention that the renin-angiotensin system supports renal function in hypertensive states in which renin levels are elevated.     

Modulating effects of atrial natriuretic peptide on vascular permeability and blood pressure by inhibition of cyclic phosphodiesterase GMP in the rat]

Atrial natriuretic peptide lowers arterial pressure and increases hematocrit through reduction in plasma volume caused by a transcapillary shift of plasma fluid and protein toward the interstitium. Cyclic GMP, the second messenger of atrial natriuretic peptide is catabolized by cGMP-phosphodiesterase; therefore we examined the consequences of inhibition of the phosphodiesterase on these responses using the specific cGMP inhibitor M&B 22.948. In anesthetized, bilaterally nephrectomized rats, a 45-min infusion of atrial natriuretic peptide (1 microgram/kg/min) reduced arterial pressure by 7.6 +/- 1.5% and increased hematocrit by 9 +/- 0.6% (both p < 0.01), leading to a calculated decrease in plasma volume of 14.4 +/- 0.9%. Infusion of M&B 22.948 (0.68 mg/kg/min) did not affect hematocrit and lowered arterial pressure by 8.1 +/- 0.5% (p < 0.01), an effect similar to that observed following administration of sodium nitroprusside (10 micrograms/kg/min). Simultaneous infusion of atrial natriuretic peptide and M&B 22.948 had additive arterial pressure lowering effects (-15.9 +/- 1.1%; p < 0.01 vs atrial natriuretic peptide or M&B 22.948 alone), while the increase in hematocrit of 9.4 +/- 0.7% was identical to that seen with atrial natriuretic peptide alone. Thus, M&B 22.948 amplified atrial natriuretic peptide effects on arterial pressure, but not on vascular permeability. These findings indicate differential regulation of atrial natriuretic peptide effects by inhibition of the cGMP-phosphodiesterase.     

Hemodynamic, renal and endocrine effects of atrial natriuretic peptide infusion in severe heart failure

The cardiac release and total body and renal clearances and the hemodynamic, renal and endocrine effects of increasing doses of atrial natriuretic peptide were investigated in 12 patients with severe chronic congestive heart failure. Immunoreactive arterial plasma levels of atrial natriuretic peptide were 10-fold higher than normal and there was no correlation between aortic atrial natriuretic peptide and cardiac filling pressures. The heart released atrial natriuretic peptide into the coronary sinus. The kidney, though a major clearance site, accounted for only 33% of the total body clearance. Administration of 0.3 micrograms/kg per min atrial natriuretic peptide produced significant changes in heart rate (95 +/- 4 to 85 +/- 4 beats/min) and mean arterial (92 +/- 8 to 77 +/- 9 mm Hg), right atrial (13 +/- 3 to 8 +/- 2 mm Hg) and mean pulmonary artery occluded (27 +/- 3 to 14 +/- 3 mm Hg) pressures. Atrial natriuretic peptide increased cardiac index (2.25 +/- 0.18 to 2.83 +/- 0.3 liters/min per m2) and stroke work index (21 +/- 1.5 to 29 +/- 3.4 g/m2), whereas systemic vascular resistance (1,424 +/- 139 to 1,033 +/- 97 dynes.s.cm(-5)) decreased. Infusion of 0.1 microgram/kg per min atrial natriuretic peptide increased urinary flow 128%, fractional excretion of sodium 133% and fractional excretion of potassium 35%. The filtration fraction increased from 29 +/- 2 to 31 +/- 4%. This represented a disproportionate rise in glomerular filtration rate over renal plasma flow. Plasma aldosterone and norepinephrine decreased whereas plasma renin activity remained unchanged. In association with these hemodynamic, excretory and endocrine changes, the urinary excretion of cyclic guanosine monophosphate doubled. Placebo had no effect. These results showed that, despite high circulating levels of atrial natriuretic peptide, administration of this hormone in heart failure is associated with potentially beneficial hemodynamic, renal and endocrine effects.     

Atrial natriuretic peptide decreases circulatory capacitance in areflexic rats

The short-term hemodynamic response to atrial natriuretic peptide appears to be partly mediated by decreased venous return, which could result from increased circulatory capacitance or decreased blood volume. To determine if rat atrial natriuretic peptide 99-126 (0.5 microgram/kg/min IV for 30-70 minutes) dilated capacitance vessels or decreased blood volume, mean circulatory filling pressure (measured during brief circulatory arrest by inflating an intraatrial balloon) and blood volume (51Cr-erythrocytes) were measured in anesthetized rats. Mean circulatory filling pressure, central venous pressure, and blood volume decreased by 0.4 mm Hg, 0.5 mm Hg, and 3.4 ml/kg, respectively. To determine the total circulatory pressure-volume relationship without influence from autonomic reflexes, mean circulatory filling pressure and blood volume were measured in spinal-cord-transected rats before and immediately after infusing or withdrawing 5 ml blood. Atrial natriuretic peptide decreased mean circulatory filling pressure, central venous pressure, and blood volume by 0.9 mm Hg, 1.7 mm Hg, and 8.0 ml/kg, respectively, and displaced the pressure-volume relationship toward the pressure axis by decreasing extrapolated unstressed volume. Similar results were obtained in spinal-cord-transected rats that had initial vascular tone restored to a greater level by norepinephrine infusion. In anephric rats, atrial natriuretic peptide decreased central venous pressure by 0.3 mm Hg and blood volume by 1.6 ml/kg. The results indicate that short-term infusion of atrial natriuretic peptide reduced circulatory capacitance in rats and suggest that this reduction resulted from diminished blood volume due to urinary fluid loss followed by passive vascular recoil and active venoconstriction.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

Hemodynamic effects of infusion versus bolus administration of atrial natriuretic factor

The cardiovascular responses to intravenous bolus administration of several synthetic atrial natriuretic peptides were examined in conscious spontaneously hypertensive rats and compared with the hemodynamic effects of continuous infusions of the peptides. Rats were instrumented with pulsed Doppler flow probes to allow measurement of regional blood flow in the conscious, unrestrained hypertensive rat. Bolus administration of increasing doses (0.036-18 nmol/kg) of atriopeptin II, alpha-rat atrial natriuretic peptide, Wy-47,663, or alpha-human atrial natriuretic peptide caused short-lived, dose-dependent reductions in mean arterial pressure and renal vascular resistance. A marked but transient (10-40 seconds) increase in renal blood flow was observed after administration of the peptides. Mesenteric and hindquarter vasodilation also were observed after bolus injection of high doses of the atrial peptides. Infusion of alpha-rat atrial natriuretic peptide or Wy-47,663 (0.045-1.44 nmol/kg/min) resulted in sustained reductions in mean arterial pressure. The fall in arterial pressure was accompanied by significant reductions in regional blood flow in the renal, mesenteric, and hindquarter vascular beds. Dose-dependent increases in regional vascular resistances were observed in all three vascular beds during the peptide infusions. These data indicate that the hemodynamic responses to synthetic atrial peptides are greatly dependent on the mode of administration of the peptide in conscious spontaneously hypertensive rats. Stable, sustained responses were observed only during infusion steady state conditions.     

Effects of atrial natriuretic factor on the vasoconstrictor actions of the renin-angiotensin system in conscious rats

Previous studies have indicated that the hypotensive effects of atrial natriuretic factor were enhanced in renin-dependent hypertensive rats, suggesting that the atrial peptides may antagonize the vasoconstrictor effects of the renin-angiotensin system. The present study was designed to define further the interaction between atrial natriuretic factor and the renin-angiotensin system by examining the hemodynamic effects of Wy-47,663, a synthetic human atrial natriuretic factor, in conscious normotensive rats, in renin-dependent (aortic-ligated) hypertensive rats, and in rats made hypertensive by chronic infusion of angiotensin II. Changes in renal and mesenteric blood flow were continuously monitored in the rats using pulsed Doppler flow probes chronically implanted in the animals one week prior to testing. Infusion of increasing doses of Wy-47,663 caused dose-dependent reductions in mean arterial pressure in all three groups of rats, but the depressor responses were significantly greater in renal hypertensive and angiotensin II-infused rats. Renal blood flow tended to increase during the infusion of the atrial peptide in the angiotensin II-treated rats, and renal vascular resistance fell significantly (-37 +/- 6%). However, Wy-47,663 significantly reduced renal blood flow in the normotensive and renal hypertensive rats, while renal vascular resistance was increased (29 +/- 6%) and unchanged (3 +/- 9%), respectively. Mesenteric blood flow was reduced significantly, and mesenteric vascular resistance was increased markedly in all three groups of rats during infusion of the atrial peptide. In a separate group of renal hypertensive rats, the hemodynamic effects of complete blockade of the renin-angiotensin system were assessed by injection of an angiotensin II converting enzyme inhibitor (Wy-44,655).(ABSTRACT TRUNCATED AT 250 WORDS)     

Normal TGF responsiveness during chronic treatment with angiotensin-converting enzyme inhibition: role of AT1 receptors

Acute inhibition of angiotensin II formation by angiotensin-converting enzyme inhibition (ACE-I) attenuates tubuloglomerular feedback (TGF) responsiveness. This has been proposed to facilitate sodium excretion, which contributes to the antihypertensive effects of ACE-I. However, in previous experiments in spontaneously hypertensive Fawn-hooded rats, TGF responses were normal during chronic ACE-I treatment. In the present study, we investigated TGF responsiveness during chronic ACE-I treatment in normotensive rats and the involvement of changes in nitric oxide or angiotensin II activity. Maximum TGF responses were assessed in control Sprague-Dawley rats and in rats acutely (acute ACE-I, 3 microgram/min IV) and chronically (chronic ACE-I, 100 mg/L PO 2 to 3 weeks+acute 3 microgram/min enalaprilat IV) treated with ACE-I. In all groups, TGF responses were also assessed during late proximal tubular perfusion with 1 mmol/L nitro-L-arginine. In a last group, the chronic ACE-I treatment was combined with acute ACE-I and high doses of intrarenal losartan (acute 3 microgram/min enalaprilat IV+50 mg/kg losartan). The maximum TGF responses in acutely treated ACE-I rats were strongly attenuated (0.7+/-0.4 mm Hg versus 6.5+/-0.8 mm Hg in control rats, P<0.05). Mean arterial pressure was lower in the chronically treated ACE-I group (107+/-5 mm Hg versus 126+/-5 mm Hg in control rats, P<0.05); however, TGF responses were normal (6. 4+/-0.9 mm Hg). Intraluminal nitro-L-arginine infusion did not influence TGF responses during acute ACE-I (2.3+/-0.4 mm Hg) but enhanced TGF responses during chronic ACE-I to the same extent as in control rats (14.5+/-2.3 versus 16.7+/-1.9 mm Hg, NS). In the rats chronically treated with ACE-I with superimposed acute infusion of losartan or chronically treated with losartan, TGF responses were significantly attenuated (1.8+/-0.8 mm Hg and 2.6+/-0.8 mm Hg, respectively; P:<0.05 versus chronic ACE-I and control). Prolonged administration with ACE-I is associated with normal TGF responses. This phenomenon appears to be mediated by AT1 receptors, because acute treatment with losartan in rats chronically treated with ACE-I and chronic treatment with losartan lead to strong attenuation of TGF responses.     

Pathophysiologic levels of atrial natriuretic factor do not alter reflex sympathetic control: direct evidence from microneurographic studies in humans

To determine if circulating levels of atrial natriuretic factor comparable with those seen in pathophysiologic states alter autonomic control of the circulation, direct recordings of hemodynamic variables and efferent sympathetic nerve activity to muscle (microneurography) were obtained during two separate protocols in a total of 21 normal men (age 25 +/- 1 years). In protocol 1, the responses of 10 men were compared during incremental mechanical unloading of cardiopulmonary baroreceptors with lower body negative pressure versus responses to comparable unloading during infusion of alpha-human atrial natriuretic factor. Lower body negative pressure decreased pulmonary artery diastolic and right atrial pressures, did not alter arterial pressure or heart rate and increased muscle sympathetic nerve activity from 205.2 +/- 36.3 to 438.7 +/- 100.2 units/min (p less than 0.01). Intravenous infusion of atrial natriuretic factor (25 ng/kg per min) increased plasma levels of the hormone from 24 +/- 4 to 322 +/- 34 pg/ml (p less than 0.01, n = 6), produced similar decreases in pulmonary artery diastolic and right atrial pressures, did not alter arterial pressure, increased heart rate and increased sympathetic nerve activity from 233.1 +/- 35.6 to 387.2 +/- 64.9 units/min (p less than 0.05). Thus, during similar hemodynamic perturbations produced by lower body negative pressure or infusion of atrial natriuretic factor at the dose used in this study, these subjects exhibited comparable sympathoexcitatory responses, with a 109 +/- 23% increase in sympathetic activity during lower body negative pressure and a 76 +/- 19% increase during atrial natriuretic factor infusion (p = NS). In protocol 2, the responses of 11 additional men were examined during lower body negative pressure performed before and again during infusion of atrial natriuretic factor (12.5 ng/kg per min). During baseline (prehormone) trials, lower body negative pressure (-14.5 +/- 1.6 mm Hg) decreased central venous pressure, did not change arterial pressure or heart rate and increased sympathetic nerve activity from 215 +/- 47.7 to 372.3 +/- 64.3 units/min (p less than 0.001). Infusion of atrial natriuretic factor increased plasma levels of the hormone from 39 +/- 8 to 313 +/- 18 pg/ml (p less than 0.01, n = 7); central venous pressure was held constant during hormone infusion by intravenous infusion of saline solution.(ABSTRACT TRUNCATED AT 400 WORDS)     

Effects of atrial natriuretic peptide on myocardial contractile and diastolic function in patients with heart failure.

Atrial natriuretic peptide alters left ventricular performance in patients with heart failure. To assess the direct effects of this hormone on myocardial function, its actions were compared with those of the pure vasodilator nitroprusside in 10 patients with heart failure. Simultaneous left ventricular micromanometer pressure and radionuclide volume were obtained during a baseline period, during nitroprusside infusion, during a second baseline period and during atrial natriuretic peptide infusion. The baseline end-systolic pressure-volume relation was generated in nine patients from pressure-volume loops obtained during the two baseline periods and during afterload reduction with nitroprusside. Mean arterial pressure decreased with atrial natriuretic peptide (89 +/- 3 to 80 +/- 2 mm Hg, p less than 0.05) and by a greater amount with nitroprusside (90 +/- 4 to 73 +/- 3 mm Hg, p less than 0.05). Left ventricular end-diastolic pressure also decreased with atrial natriuretic peptide (24 +/- 2 to 16 +/- 3 mm Hg, p less than 0.05) and by a greater amount with nitroprusside (24 +/- 2 to 13 +/- 3 mm Hg, p less than 0.05). Cardiac index increased during infusion of each agent from 2.0 +/- 0.2 to 2.4 +/- 0.2 liters/min per m2 (p less than 0.01). Heart rate increased slightly with nitroprusside but did not change with atrial natriuretic peptide. Peak positive first derivative of left ventricular pressure (dP/dt), ejection fraction and stroke work index were unchanged by either agent. The relation between end-systolic pressure and volume during atrial natriuretic peptide infusion was shifted slightly leftward from the baseline value in four patients, slightly rightward in four and not at all in one patient, indicating no consistent inotropic effect.(ABSTRACT TRUNCATED AT 250 WORDS)     

Atrial natriuretic peptide in patients with diabetes mellitus type I. Effects on systemic and renal hemodynamics and renal excretory function

In the present study the effects of 1 h intravenous infusion of alpha-human atrial natriuretic peptide (24 ng/min/kg) on systemic and renal hemodynamics and on renal excretory function were studied in six insulin-treated and metabolically well-controlled patients with diabetes mellitus (DM) type I and in six healthy control subjects (C). Basal plasma atrial natriuretic peptide (ANP) concentration was 14.6 +/- 2.0 in DM patients and 14.9 +/- 1.3 pmol/L in C and rose similarly in both groups to 87.1 +/- 22.1 and to 86.9 +/- 11.1 pmol/L, respectively, during alpha-hANP infusion (P less than .05). Maximal effects of alpha-hANP occurred between 30 and 60 min after the start of the infusion. Mean arterial pressure (MAP) (83 +/- 5 v 81 +/- 3 mm Hg), heart rate (HR) (63 +/- 2 v 64 +/- 4/min) and total peripheral resistance (TPR) (11 +/- 1 v 10 +/- 1 mm Hg.min/L) remained unaltered in patients with DM. In contrast, in C MAP and TPR decreased from 83 +/- 3 to 77 +/- 2 mm Hg and from 12 +/- 1 to 10 +/- 1 1 mm Hg.min/L, respectively (P less than .05), whereas HR increased from 53 +/- 2 to 59 +/- 3 beats/min (P less than .05). Cardiac output (CO) rose initially by 11% and by 9% in DM and C, respectively. Urine flow increased from 4.1 +/- 0.9 to 11.3 +/- 1.5 mL/min in DM patients and from 3.9 +/- 1.0 to 8.4 +/- 0.8 mL/min in C (P less than .05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Evidence for a renomedullary vasodepressor system in rabbits and dogs

Renal perfusion was increased in anesthetized rabbits and dogs by using an extracorporeal circuit. When left kidney perfusion pressure was raised in rabbits (145-240 mm Hg), arterial pressure fell by 1.34 +/- 0.20 mm Hg/min. Pretreatment of the rabbits with 2-bromoethylamine hydrobromide, which destroyed the renal medulla, abolished the fall in arterial pressure (-0.08 +/- 0.08 mm Hg/min) in response to increased renal perfusion pressure. In dogs (with blockade of autonomic ganglia by pentolinium, converting enzyme inhibition [captopril/enalaprilat], and surgical renal denervation), increasing renal perfusion pressure to 170-220 mm Hg resulted in a fall in arterial pressure by 0.32 +/- 0.03 mm Hg/min (or by 28.9 +/- 3.1 mm Hg over a 90-minute period). Mean arterial pressure did not change significantly in identically prepared dogs not subjected to increased renal perfusion pressure, whereas pretreatment of dogs with bromoethylamine abolished the hypotensive response to increased renal perfusion pressure. Thus, the hypotensive response to increased renal perfusion was dependent on the presence of an intact renal medulla, but hypotension still occurred in the presence of converting enzyme inhibition, autonomic ganglion blockade, and renal denervation. The results provide in vivo evidence in two species that a vasodepressor factor from the renal medulla is released in response to increased renal perfusion.     

Cardiovascular effects of atrial natriuretic factor in anesthetized and conscious dogs

Atrial natriuretic factor lowers blood pressure in normotensive and hypertensive animal models. The present study examined the mechanism of the blood pressure-lowering effect in 10 normotensive dogs. Four awake dogs previously instrumented with electromagnetic flow probes for measurement of cardiac output and catheters for systemic hemodynamic and cardiac dynamic measurements were studied. After a 30-minute control period, a 3 micrograms/kg bolus followed by 0.3 micrograms/min/kg of a 24-residue synthetic atrial natriuretic factor was infused for 30 minutes, followed by a 1-hour recovery period. Mean arterial pressure fell significantly during infusion (control, 125 +/- 4; infusion, 108 +/- 5; recovery, 125 +/- 9 mm Hg; p less than 0.05) and was accompanied by a slight but significant bradycardia (control, 144 +/- 7; infusion, 134 +/- 5; recovery, 145 +/- 7 beats/min; p less than 0.05). Significant reductions in cardiac output (control, 2.66 +/- 0.60; infusion, 2.18 +/- 0.60; recovery, 2.74 +/- 0.60 L/min; p less than 0.05), stroke volume (control, 18.4 +/- 3.9; infusion, 16.0 +/- 4.2; recovery, 19.0 +/- 3.7 ml/beat; p less than 0.05), and maximum increase in rate of change of left ventricular systolic pressure (control, 2475 +/- 200; infusion, 2088 +/- 216; recovery, 2487 +/- 243 mm Hg/sec; p less than 0.05) were also observed during infusion. No significant changes in total peripheral resistance or central venous pressure were noted, although the latter tended to fall during infusion. A similar pattern was observed in six pentobarbital-anesthetized dogs, except that infusion of atrial natriuretic factor did not induce bradycardia.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal interstitial hydrostatic pressure and natriuretic response to high doses of angiotensin II in pregnant rats

BACKGROUND: Administration of high doses of angiotensin II (Ang II) results in natriuretic and diuretic responses that are mediated by increases in renal perfusion pressure (RPP). Elevations in renal interstitial hydrostatic pressure (RIHP) caused by increases in mean arterial pressure (MAP) or RPP are associated with significant increases in urinary sodium excretion (U(Na)V) and urine flow rate (V). In pregnant rats the renin-angiotensin system (RAS) is activated and basal RIHP is reduced. The exact relationship among MAP, RIHP, U(Na)V, and V in response to a high pressor dose of Ang II during normal pregnancy is not known. METHODS: The objective of this study was to evaluate the relationship between MAP and RIHP, and determine the role of RIHP in the natriuretic and diuretic responses to administration of high dose of Ang II in midterm pregnant (MP) and nonpregnant (NP) Sprague-Dawley (SD) rats. RESULTS: Intravenous infusion of Ang II (200 ng/kg/min) significantly increased MAP (DeltaMAP), DeltaU(Na)V, and DeltaV in anesthetized MP and NP rats. The DeltaMAP, DeltaU(Na)V, and DeltaV were 12 +/- 2 mm Hg, 27.9 +/- 2.7 microEq/min, and 197 +/- 23 microL/min for MP rats and were similar (15 +/- 3 mm Hg, 34.1 +/- 4.3 microEq/min, and 242 +/- 34 microL/min, respectively) for NP rats. The RIHP decreased significantly (P < .05) with Ang II infusion in NP (from 6.1 +/- 0.2 to 3.9 +/- 0.4 mm Hg) but not in MP (from 3.3 +/- 0.3 to 4.1 +/- 0.4 mm Hg) groups of rats. Acute renal decapsulation eliminated the change in RIHP mediated by high doses of Ang II infusion in the NP group, but did not affect MAP or the natriuretic and diuretic responses to Ang II in either the MP or NP groups of rats. CONCLUSIONS: The natriuretic and diuretic responses to high doses of Ang II are not mediated by changes in RIHP in pregnant or nonpregnant rats.