cyclic-gmp and Ascites

Pulmonary arterial hypertension is characterized by high pulmonary blood pressure, vascular remodeling and right ventricular hypertrophy. In the present study, we investigated whether genistein would prevent the development of low temperature-induced pulmonary hypertension in broilers. Hemodynamic parameters, vascular remodeling, the expression of endothelial nitric oxide and endothelin-1 content in lung tissue were evaluated. The results demonstrated that genistein significantly reduced pulmonary arterial hypertension and suppressed pulmonary arterial vascular remodeling without affecting broilers' performance. The beneficial effects appeared to be mediated by restoring endothelial function especially endothelial nitric oxide and endothelin-1, two critical vasoactive molecules that associated with the development of hypertension. Genistein supplementation might be a potential therapeutic strategy for the treatment of pulmonary hypertension.

Topics: Animals; Ascites; Chickens; Cold Temperature; Cyclic GMP; Dose-Response Relationship, Drug; Endothelin-1; Endothelium, Vascular; Genistein; Hemodynamics; Hypertension, Pulmonary; Lung; Male; Neovascularization, Pathologic; Nitric Oxide Synthase Type III; Pericardial Effusion; Phytoestrogens; Poultry Diseases; Weight Gain

In the present study, we tested the hypothesis that inhibition of renal phosphodiesterase type 5 (PDE5) in patients with liver cirrhosis and ascites increases sodium excretion. The effect of sildenafil citrate was studied in a randomized double-blind. placebo-controlled crossover study. Diuretics were withdrawn, and a fixed sodium diet (100 mmol/day) was given to the patients for 5 days before both study days. After a 60-min basal period, eight patients received either oral sildenafil (50 mg) or placebo. Glomerular filtration rate (GFR) and renal blood flow (RBF) were determined by 99mTc-diethylenetriamine-pentaacetate and (131)I-hippuran clearances. In human nephrectomy specimens, PDE5 mRNA was expressed at similar levels in the cortex (n = 6) and inner medulla (n = 4). Histochemical staining showed PDE5 immunoreactivity in collecting ducts and vascular smooth muscle. At baseline, cirrhotic patients exhibited elevated plasma concentrations of ANP, renin, ANG II, and aldosterone that did not differ on the 2 study days. Basal sodium excretion was similar at the 2 study days (median 17 and 18 mmol, respectively), and patients were in positive sodium balance. Sildenafil increased heart rate, plasma renin activity, plasma ANG II, and aldosterone concentrations significantly after 60 min. Plasma cGMP concentration was increased after 120 and 180 min, and urinary sodium excretion and mean arterial blood pressure were decreased significantly at 120 and 180 min. Plasma ANP concentration, GFR, and RBF did not change after sildenafil. In patients with ascites and cirrhosis, inhibition of PDE5 did not promote natriuresis but led to increased plasma levels of the renin-angiotensin-aldosterone system.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Adult; Animals; Ascites; Blood Pressure; Cross-Over Studies; Cyclic GMP; Cyclic Nucleotide Phosphodiesterases, Type 5; Female; Gene Expression Regulation, Enzymologic; Hormones; Humans; Hypertension, Renal; Kidney Medulla; Liver Cirrhosis; Male; Middle Aged; Phosphodiesterase Inhibitors; Piperazines; Potassium; Purines; Rats; Sildenafil Citrate; Sodium; Sodium Chloride, Dietary; Sulfones; Water

This study reports the effects of a short-term (60 min) low-dose (20 ng x kg(-1) x min(-1)) infusion of synthetic urodilatin (URO) in patients with liver cirrhosis. URO is a natriuretic peptide. A total of 15 cirrhotic patients with ascites and nine without ascites participated in a randomized, double-blind, placebo-controlled study in a crossover design. Renal hemodynamics were estimated by a clearance technique using radioactive tracers, and tubular handling of sodium was evaluated by the lithium clearance method. The renal effects of URO were characterized by a significant increase in urine sodium excretion rate (UNa) and urine flow rate (V) in the cirrhotic patients without ascites (UNa: 173%; V: 94%) and with ascites (UNa: 219%, P < 0.01; V: 42%, P < 0.01) when compared with placebo infusions. Fractional excretion of sodium increased significantly, indicating a tubular effect of URO on sodium handling. Filtration fraction, lithium clearance (a marker of end-proximal fluid delivery), and fractional excretion of lithium increased, fractional proximal tubular sodium reabsorption decreased, and absolute proximal tubular sodium reabsorption remained unchanged, suggesting increased delivery of isotonic fluid from the proximal tubule during URO infusion. In addition, a significant decrease in fractional distal tubular sodium reabsorption contributed to the natriuresis. In conclusion, URO improved sodium and urine output in cirrhotic patients with and without ascites by enhancing fluid delivery from the proximal tubules in addition to inhibiting fractional sodium reabsorption in the distal nephron.

Topics: Adult; Ascites; Atrial Natriuretic Factor; Cyclic GMP; Diuretics; Dizziness; Double-Blind Method; Female; Glomerular Filtration Rate; Humans; Infusions, Intravenous; Kidney Tubules; Lithium; Liver Cirrhosis; Male; Middle Aged; Natriuresis; Peptide Fragments; Renal Plasma Flow, Effective; Renin-Angiotensin System; Second Messenger Systems

Patients with cirrhosis and ascites have high plasma levels of atrial natriuretic peptide (ANP). Pharmacological doses of this hormone usually worsen systemic hemodynamics of cirrhotic patients. We assessed whether ANP influences cardiovascular homeostasis and renal function in patients with compensated cirrhosis at plasma levels comparable to those observed in patients with cirrhosis and ascites.. Radionuclide angiocardiography was performed in eight compensated cirrhotic patients during placebo (three periods of 15 min each) and ANP infusion (2, 4, and 6 pmol/kg.min for 15 min each), together with appropriate blood and urine sampling, to evaluate left ventricular diastolic, systolic, and stroke volume, heart rate, cardiac output, arterial pressure, peripheral vascular resistance, creatinine clearance, urinary sodium excretion, plasma renin activity, plasma aldosterone, norepinephrine and hematocrit.. The infusion increased plasma ANP up to levels (52.03 +/- 2.29 pmol/L) comparable with those observed in 35 patients with ascites (46.42 +/- 1.57 pmol/ L). This increment was associated with significant reductions in left ventricular end diastolic volume, stroke volume, cardiac index (from 3.7 +/- 0.7 to 3.1 +/- 0.5 L/min.m2, p < 0.05) and mean arterial pressure (from 96.7 +/- 6.5 to 88.5 +/- 9.5 mmHg, p < 0.05), while heart rate and hematocrit significantly increased. Peripheral vascular resistance did not change. These hemodynamic effects occurred despite significant increases in plasma renin activity and norepinephrine. ANP also induced increases in creatinine clearance, urinary sodium excretion, and fractional sodium excretion.. Low-dose ANP affected cardiovascular homeostasis and renal sodium handling in compensated cirrhosis, suggesting that this hormone may be involved in the pathophysiology of systemic hemodynamic and renal functional abnormalities of cirrhosis.

Topics: Aldosterone; Analysis of Variance; Ascites; Atrial Natriuretic Factor; Creatinine; Cyclic GMP; Female; Hematocrit; Hemodynamics; Humans; Hypertension, Portal; Infusions, Intravenous; Kidney; Kidney Function Tests; Liver Cirrhosis; Middle Aged; Natriuresis; Norepinephrine; Renin

Cyclic GMP (cGMP) concentration is increased in plasma of patients with liver cirrhosis. Three possible mechanisms may contribute: increased cGMP synthesis by soluble (activated by nitric oxide), or particulate (activated by atrial natriuretic peptide (ANP)) guanylate cyclase or increased release from cells.. The aim of this work was to analyze the possible contributors to increased plasma cGMP and to assess whether changes in the parameters of the system vary with the degree of liver disease (Child Pugh score) or by the presence of ascites.. We measured cGMP in plasma and lymphocytes, soluble guanylate cyclase activation by nitric oxide in lymphocytes, nitrates and nitrites and ANPs (activator of particulate guanylate cyclase) in plasma. We analyzed the correlation between changes in different parameters to discern which parameters contribute to increased plasma cGMP.. The plasma content of nitrates+nitrites, ANP and cGMP are increased. Activation of soluble guanylate cyclase by nitric oxide is increased in patients while basal cGMP in lymphocytes is decreased.. Both increased ANP and increased activation of soluble guanylate cyclase by nitric oxide contribute to increased plasma cGMP in patients. The concentrations of ANP and cGMP in plasma increase with the degree of disease and are higher in patients with ascites.

Topics: Adult; Aged; Ascites; Atrial Natriuretic Factor; Cells, Cultured; Cyclic GMP; Guanylate Cyclase; Humans; Liver Cirrhosis; Lymphocytes; Male; Middle Aged; Nitrates; Nitric Oxide; Nitrites; Penicillamine

A possible defect of guanosine 3'-5'-cyclic monophosphate (cGMP) content in the renal tissue caused by an increased activity of cGMP phosphodiesterase (PDE) has, so far, not been evaluated in the pathogenesis of renal resistance to endogenous natriuretic peptides (ENP) in cirrhosis with ascites. To test this hypothesis the activity of cGMP-PDE and the concentration of cGMP were evaluated in vitro in the renal tissue of 10 control rats and 10 cirrhotic rats with ascites before and after the intravenous (IV) administration of Zaprinast (Sigma, St. Louis, MO), a specific cGMP-PDE inhibitor (30 microgram/kg/min). Moreover, the effects of the intravenous administration of Zaprinast (15 microgram/kg/min and 30 microgram/kg/min) on renal plasma flow (RPF), glomerular filtration rate (GFR), and urinary sodium excretion (U(Na)V) were evaluated in 10 conscious control rats and 10 conscious cirrhotic rats with ascites. The effects of Zaprinast on plasma renin activity (PRA) was also evaluated in 10 control rats and in 10 cirrhotic rats with ascites. Finally, the effect of Zaprinast on RPF, GFR, and U(Na)V were evaluated in 10 cirrhotic rats after the IV administration of the ENP-receptor antagonist, HS-142-1. The renal content of cGMP was reduced in cirrhotic rats because of increased activity of cGMP-PDE. Zaprinast inhibited cGMP-PDE activity and increased the renal content of cGMP in these animals. The inhibition of cGMP-PDE was associated with an increase in RPF, GFR, and U(Na)V and a reduction in PRA. HS-142-1 prevented any renal effect of Zaprinast in cirrhotic rats. In conclusion, an increased activity of the cGMP-PDE in renal tissue contributes to the renal resistance to ENP in cirrhosis with ascites.

Topics: 3',5'-Cyclic-GMP Phosphodiesterases; Animals; Ascites; Cyclic GMP; Hemodynamics; Kidney; Liver Cirrhosis, Experimental; Male; Phosphodiesterase Inhibitors; Polysaccharides; Purinones; Rats; Rats, Wistar; Renin-Angiotensin System

Cirrhosis is typically associated with a hyperdynamic circulation consisting of low blood pressure, low systemic vascular resistance (SVR), and high cardiac output. We have recently reported that nonspecific inhibition of nitric oxide synthase (NOS) with nitro-L-arginine methyl ester reverses the hyperdynamic circulation in rats with advanced liver cirrhosis induced by carbon tetrachloride (CCl(4)). Although an important role for endothelial NOS (eNOS) is documented in cirrhosis, the role of neuronal NOS (nNOS) has not been investigated. The present study was carried out to specifically investigate the role of nNOS during liver cirrhosis. Specifically, physiological, biochemical, and molecular approaches were employed to evaluate the contribution of nNOS to the cirrhosis-related hyperdynamic circulation in CCl(4)-induced cirrhotic rats with ascites. Cirrhotic animals had a significant increase in water and sodium retention. In the aorta from cirrhotic animals, both nNOS protein expression and cGMP concentration were significantly elevated compared with control. Treatment of cirrhotic rats for 7 days with the specific nNOS inhibitor 7-nitroindazole (7-NI) normalized the low SVR and mean arterial pressure, elevated cardiac index, and reversed the positive sodium balance. Increased plasma arginine vasopressin concentrations in the cirrhotic animals were also repressed with 7-NI in association with diminished water retention. The circulatory changes were associated with a reduction in aortic nNOS expression and cGMP. However, 7-NI treatment did not restore renal function in cirrhotic rats (creatinine clearance: 0.76 +/- 0.03 ml. min(-1). 100 g body wt(-1) in cirrhotic rats vs. 0.79 +/- 0.05 ml. min(-1). 100 g body wt(-1) in cirrhotic rats+7-NI; P NS. ). Taken together, these results indicate that nNOS-derived NO contributes to the development of the hyperdynamic circulation and fluid retention in cirrhosis.

Topics: Animals; Arginine Vasopressin; Ascites; Blotting, Western; Cyclic GMP; Enzyme Inhibitors; Hemodynamics; Indazoles; Kidney; Kidney Function Tests; Liver Cirrhosis, Experimental; Male; Nitric Oxide Synthase; Nitric Oxide Synthase Type I; Osmolar Concentration; Rats; Rats, Sprague-Dawley; Sodium; Vasodilation

Normalization of the increased vascular nitric oxide (NO) generation with low doses of NG-nitro-L-arginine methyl ester (L-NAME) corrects the hemodynamic abnormalities of cirrhotic rats with ascites. We have undertaken this study to investigate the effect of the normalization of vascular NO production, as estimated by aortic cyclic guanosine monophosphate (cGMP) concentration and endothelial nitric oxide synthase (eNOS) protein expression in the aorta and mesenteric artery, on sodium and water excretion. Rats with carbon tetrachloride-induced cirrhosis and ascites were investigated using balance studies. The cirrhotic rats were separated into two groups, one receiving 0.5 mg/kg per day of L-NAME (CIR-NAME) during 7 d, whereas the other group (CIR) was administrated the same volume of vehicle. Two other groups of rats were used as controls, one group treated with L-NAME and another group receiving the same volume of vehicle. Sodium and water excretion was measured on days 0 and 7. On day 8, blood samples were collected for electrolyte and hormone measurements, and aorta and mesenteric arteries were harvested for cGMP determination and nitric oxide synthase (NOS) immunoblotting. Aortic cGMP and eNOS protein expression in the aorta and mesenteric artery were increased in CIR as compared with CIR-NAME. Both cirrhotic groups had a similar decrease in sodium excretion on day 0 (0.7 versus 0.6 mmol per day, NS) and a positive sodium balance (+0.9 versus +1.2 mmol per day, NS). On day 7, CIR-NAME rats had an increase in sodium excretion as compared with the CIR rats (sodium excretion: 2.4 versus 0.7 mmol per day, P < 0.001) and a negative sodium balance (-0.5 versus +0.8 mmol per day, P < 0.001). The excretion of a water load was also increased after L-NAME administration (from 28+/-5% to 65+/-7, P < 0.05). Plasma renin activity, aldosterone and arginine vasopressin were also significantly decreased in the CIR-NAME, as compared with the CIR rats. The results thus indicate that normalization of aortic cGMP and eNOS protein expression in vascular tissue is associated with increased sodium and water excretion in cirrhotic rats with ascites.

Topics: Aldosterone; Animals; Aorta; Arginine Vasopressin; Ascites; Atrial Natriuretic Factor; Body Water; Cyclic GMP; Enzyme Inhibitors; Kidney; Liver Cirrhosis, Experimental; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Renin; Sodium

Nitric oxide (NO) is postulated to play a role in the pathogenesis of arterial vasodilation in chronic portal hypertension. This present study investigates the relationship between systemic hemodynamics and the vascular production of NO, as estimated by measuring cyclic guanosine monophosphate (cGMP) in aortic tissue in two models of chronic portal hypertension in the rat: the partial portal vein ligation (PVL) model and CCl4-induced cirrhosis. NOS was also examined by Western blotting in aortic and mesenteric vessels. Sham-operated rats and rats given phenobarbital were used as controls. PVL rats and rats with cirrhosis and ascites showed a typical pattern of a hyperdynamic circulatory state, when compared with their respective controls: mean arterial pressure; PVL: 113 +/- 2 versus 124 +/- 2, P < .01 and cirrhotics: 103 +/- 5 versus 130 +/- 4 mm Hg, P < .01. Cardiac index; PVL: 32 +/- 2 versus 26 +/- 1, P < .01 and cirrhotics: 51 +/- 3 versus 30 +/- 1 mL . min-1 . 100 gm-1, P < .0001. Systemic vascular resistance; PVL: 3.7 +/- 0.1 versus 4.9 +/- 0.2, P < .01 and cirrhotics: 2.1 +/- 0.2 versus 4.4 +/- 0.2 mm Hg . min-1 100 g-1, P < .0001. Aortic cGMP was markedly increased in cirrhotic rats with ascites (728 +/- 83 fmol/ mg protein) as compared with phenobarbital-treated controls (244 +/- 31 fmol/mg, P < .001). This increase was abolished by chronic administration of N(omega)-nitro-L-arginine methyl ester. By contrast, PVL rats had an aortic cGMP concentration similar to sham-operated controls (282 +/- 16 fmol/mg vs. 274 +/- 33 fmol/mg, P = not significant) and significantly lower than that found in cirrhotic rats with ascites. Expression of cirrhotic aortic endothelial nitric oxide synthase (eNOS) was increased but PVL aortic eNOS did not differ from that of controls, whereas the mesenteric eNOS was increased in both PVL and cirrhotic rats as compared with the controls. These results suggest that vascular NO production is higher in cirrhotic rats than in PVL rats. This increased production may contribute to the more marked abnormalities in systemic hemodynamics seen in experimental cirrhosis as compared with PVL.

Topics: Animals; Aorta; Ascites; Carbon Tetrachloride; Cyclic GMP; Hemodynamics; Hypertension, Portal; Ligation; Liver Cirrhosis, Experimental; Male; Nitric Oxide; Nitric Oxide Synthase; Portal Vein; Rats; Rats, Sprague-Dawley; Vasodilation

To elucidate and to try to reverse the antinatriuretic mechanisms in liver cirrhosis, atrial natriuretic peptide (ANP) was given as a pharmacological bolus dose (2 micrograms per kg body weight) to 14 cirrhotic patients, and as a control to 14 healthy subjects. The nine patients with ascites had baseline values of glomerular filtration rate (GFR), effective renal plasma flow (ERPF) and blood pressure (BP) similar to controls. Their distal tubular fractional reabsorption of sodium (DFRNa), estimated by the lithium clearance technique, was higher than in controls, and so were plasma values of aldosterone (564 vs. 119 pmol l-1 medians), endothelin (1.23 vs. 0.63 pmol l-1), ANP (7.5 vs. 3.6 pmol l-1) and cyclic GMP (8.8 vs. 4.6 nmol l-1); p < 0.01 for all. The five patients without ascites had higher GFR and ERPF, and lower plasma angiotensin II than controls. After ANP injection, similar plasma levels of ANP and cyclic GMP were reached in all groups. Urinary sodium excretion rate increased in controls (0.23 to 0.52 mmol min-1, p < 0.01), while GFR increased (108 to 117 ml min-1, p < 0.05), and DFRNa decreased (93 to 89%, p < 0.01). In cirrhotics with ascites sodium excretion was unaltered (0.12 to 0.11 mmol min-1), and so was GFR (84 to 83 ml min-1). Proximal tubular fractional reabsorption of sodium increased after 90 min, whereas DFRNa decreased immediately (97 to 96%, p < 0.01) though less markedly than in controls. Sodium excretion increased in four of five patients without ascites (0.23 to 0.27 mmol min-1, medians). In patients with ascites, endothelin in plasma decreased after ANP (p < 0.05). Plasma levels of angiotensin II, aldosterone and vasopressin were unchanged in all groups. In conclusion, although hyper-reabsorption of sodium occurred in the distal rather than the proximal part of the nephron in cirrhotic patients with ascites, ANP had no natriuretic effect. This was most probably due primarily to the lack of increase of GFR and blunted inhibition of DFRNa, attributed to high aldosterone. The effect of ANP in suppressing the high endothelin did not seem to improve sodium excretion.

Topics: Adult; Aged; Aldosterone; Angiotensin II; Arginine Vasopressin; Ascites; Atrial Natriuretic Factor; Cyclic GMP; Dinoprostone; Endothelins; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Kidney; Liver Cirrhosis; Male; Middle Aged; Renal Plasma Flow, Effective; Sodium; Urination

Cirrhotic patients with ascites refractory to diuretics also have blunted response to marked elevations of plasma atrial natriuretic factor levels alone or to moderate intravascular volume expansion by head-out water immersion. However, these patients usually undergo natriuresis after peritoneovenous shunting. To dissect the factors responsible for this response, we studied the effects on separate days of moderate intravascular volume expansion and highly elevated plasma atrial natriuretic factor levels (head-out water immersion and atrial natriuretic factor infusion) or marked volume expansion and moderate plasma atrial natriuretic factor level elevation (head-out water immersion and albumin infusion) in 13 alcoholic cirrhotic patients with massive ascites. Three of these patients, who responded to initial head-out water immersion with a negative sodium balance, served as controls. Unresponsiveness to head-out water immersion was confirmed in the remaining 10 patients on both days on the basis of blunted natriuretic response (urinary sodium excretion < 0.8 mmol/hr after 2 hr). In contrast, these 10 refractory patients were able to achieve negative sodium balance with both combinations. Mean urinary sodium excretion increased from a baseline level of 0.13 +/- 0.10 mmol/hr to a peak level of 2.29 +/- 0.61 mmol/hr after head-out water immersion and atrial natriuretic factor infusion and from 0.10 +/- 0.3 mmol/hr to 1.61 +/- 0.62 mmol/hr after head-out water immersion and albumin infusion. Both maneuvers were associated with suppression of plasma renin activity and serum aldosterone levels. With head-out water immersion and atrial natriuretic factor infusion, we noted a significant increase in 5' cyclic GMP levels, a second messenger of atrial natriuretic factor, indicating possible activation of atrial natriuretic factor receptors at the inner medullary collecting ducts. In contrast, with head-out water immersion and albumin infusion no such increase in levels occurred, indicating that the increase in urinary sodium excretion was mainly due to increased delivery of sodium to the cortical distal nephron, as indicated by a disproportionate increase in urinary potassium excretion. In conclusion, massive (as opposed to moderate) volume expansion or greatly elevated levels of plasma atrial natriuretic factor associated with moderate volume expansion can improve blunted atrial natriuretic factor responsiveness in cirrhotic patients with refractory ascites. This a

Topics: Adult; Aged; Aldosterone; Ascites; Atrial Natriuretic Factor; Creatinine; Cyclic GMP; Female; Hematocrit; Humans; Immersion; Kidney Function Tests; Liver Cirrhosis; Male; Middle Aged; Potassium; Renin; Sodium; Time Factors; Urea

60% of chronic caval dogs with ascites did not respond to atrial natriuretic peptide (ANP) (75 ng.kg-1.min-1) with a natriuresis (TIVC-NR; delta UNaV = 2 +/- 0.8 mu eq/min) whereas the remaining 40% responded normally (TIVC-R; delta UNaV = 216 +/- 50 mu eq/min). Since proximal tubule neutral endopeptidase 24:11 (NEP) destroys most of intrarenal luminal ANP and kinins, we attempted to convert TIVC-NR into TIVC-R by providing NEP inhibition with SQ 28603 at 30 mg/kg. This potent and specific NEP inhibitor produced a natriuresis when administered alone to nine TIVC-NR dogs (delta UNaV = 67 +/- 2 mu eq/min) and permitted a natriuresis in the presence of ANP (delta UNaV = 97 +/- 18 mu eq/min). A natriuretic response to ANP could also be induced in TIVC-NR dogs by providing renal arterial bradykinin or intravenous captopril, a kininase inhibitor. Urodilatin, a natriuretic peptide not destroyed by intrarenal NEP was without effect in TIVC-NR dogs but increased UNaV when given to TIVC-R and normal dogs. Providing bradykinin to TIVC-NR now permitted an increment in delta UNaV (62 mu eq/min) when urodilatin was reinfused. TIVC-R dogs could be converted into TIVC-NR by pretreating with a specific bradykinin antagonist before infusing ANP. We conclude that TIVC-NR dogs are deficient in intrarenal kinins but are converted to responding dogs after NEP inhibition because of increased kinin delivery to the inner medullary collecting duct.

Topics: Alanine; Animals; Ascites; Atrial Natriuretic Factor; Chronic Disease; Cyclic GMP; Dogs; Female; Kidney Tubules; Kinins; Male; Neprilysin; Protease Inhibitors; Receptors, Bradykinin; Receptors, Neurotransmitter; Sodium

Chronic caval dogs with ascites were identified as being natriuretic "responders" or "nonresponders" (delta UNaV less than 20 microequiv./min) following an infusion of atrial natriuretic peptide (ANP) (100 ng.kg-1.min-1). To learn more about the factors modulating tubular resistance to ANP, we attempted to convert responders into nonresponders and vice versa by manipulating the physiological environment. To responding dogs, we readministered ANP in the presence of noradrenaline (n = 5), angiotensin (n = 5), indomethacin (n = 4), and adenosine receptor blockage with theophylline (n = 4), and with purposeful reduction of blood pressure (n = 5). To nonresponding dogs, we readministered the ANP in the face of alpha-adrenergic blockade (n = 4), saralasin (n = 4), dipyridamole to block adenosine cellular uptake (n = 5), and elevation of blood pressure (n = 4). In no case were we able to alter the initial natriuretic response to ANP. Binding parameters of ANP receptors in suspensions of renal papillary cells were equivalent in responding caval dogs (n = 6), nonresponding dogs (n = 7), and normal controls (n = 7), as was cGMP generation. We conclude that the tubular resistance to ANP in caval dogs unresponsive to this natriuretic peptide is not due to antagonism from catecholamines or angiotensin but may be due to a post-cGMP problem in signal transduction, or a reduction in the delivery of ANP to the distal nephron.

Topics: Animals; Ascites; Atrial Natriuretic Factor; Cells, Cultured; Cyclic GMP; Dogs; Drug Resistance; Female; Hemodynamics; Kidney; Male; Natriuresis; Vena Cava, Inferior

Plasma concentrations of atrial natriuretic factor (ANF) and cyclic 3',5'-guanosine monophosphate (cGMP) were measured in 11 cirrhotic patients with ascites, 11 cirrhotic patients without ascites and 15 control subjects. The following were determined in 15 of the cirrhotic patients and in all the control subjects: blood volume (BV) and furosemide-induced changes in BV, plasma values of ANF, cGMP, angiotensin II (AII), aldosterone (Aldo), arginine vasopressin (AVP) and urinary excretion rates of cGMP, prostaglandin E2 (PGE2), water and sodium. Basal plasma levels of ANF and cGMP were higher in patients with cirrhosis than in controls, but were the same in both groups of cirrhotics (ANF: cirrhosis with ascites 12.7, without ascites 13.4, and in controls 5.8 pmol l-1 (medians); cGMP: 7.7, 7.4 and 4.3 nmol l-1, respectively). BV was less reduced after furosemide in the cirrhotic patients (6.0%) than in the healthy subjects (10.1%), but basal BV did not differ. Urinary sodium excretion rates after furosemide were significantly lower in the cirrhotic patients than in the controls. PGE2 excretion rate increased after furosemide in the cirrhotic patients (0.29 to 0.66 pmol min-1; P less than 0.01) but not in the controls (0.31 to 0.38 pmol min-1). After furosemide ANF and cGMP decreased slightly in both groups whereas AII and Aldo increased; AVP increased in the controls, but not in the cirrhotic patients. In conclusion, plasma values of ANF and cGMP are increased in liver cirrhosis both with and without ascites. This and the elevated PGE2 excretion after furosemide may be compensatory phenomena in order to facilitate renal sodium excretion.

Topics: Adult; Aged; Ascites; Atrial Natriuretic Factor; Blood Volume; Cyclic GMP; Dinoprostone; Diuresis; Female; Furosemide; Humans; Liver Cirrhosis; Male; Middle Aged; Natriuresis

To clarify the involvement of atrial natriuretic peptide (ANP) in the pathogenesis of liver cirrhosis, we measured plasma ANP in patients with various stages of cirrhosis and in age-matched normal subjects. Urinary cyclic guanosine monophosphate (cGMP) was also measured as a marker of active biological ANP. In addition, effects of exogenous synthetic human ANP (0.5 micrograms/kg) on renal functions were examined in normal subjects and in cirrhotics without ascites or with mild ascites. Plasma ANP levels were not significantly different among these 3 groups. Urinary cGMP concentrations were significantly higher in both cirrhotics without ascites and cirrhotics with mild ascites, (340 pmol/ml, P less than 0.05 and 496 pmol/ml, P less than 0.01 respectively) than normal subjects (95 pmol/ml). In normal subjects, marked increases in urinary volume (UV), sodium excretion (UNaV), fraction excretion of sodium (FENa) and free water clearance (CH2O) were induced after ANP infusion, and significant recoveries were subsequently observed in these parameters. However, in cirrhotics, the responses to ANP infusion of UV, FENa and CH2O were far less dramatic. The response of UV, UNaV and FENa in cirrhotics with mild ascites was delayed compared to cirrhotics without ascites. These results suggest that the blunted natriuretic responsiveness to ANP is contributory to the pathogenesis of initial sodium retention in cirrhotics.

Topics: Ascites; Atrial Natriuretic Factor; Cyclic GMP; Hormones; Humans; Liver Cirrhosis; Middle Aged; Natriuresis; Urine

Sodium-retaining cirrhotic and chronic caval dogs with ascites show a heterogeneous natriuretic response to atrial natriuretic factor (ANF) infusions such that half will increase their urinary excretion of sodium and half will show no natriuretic response whatsoever. In these studies we have examined several physiological variables that might discriminate between these two experimental populations. We studied 22 caval dogs (11 natriuretic responders, 11 nonresponders) and 19 cirrhotic dogs (9 responders, 10 nonresponders). After an infusion of rat ANP-(1-28), 125 ng.kg-1.min-1, differences in glomerular filtration rate, blood pressure, or urinary excretion of guanosine 3',5'-cyclic monophosphate (cGMP) could not differentiate between the two types of dogs. When the left kidney of nonresponding dogs in both the caval and cirrhotic groups was either denervated or vasodilated with acetylcholine bromide (60-80 micrograms/min), the attenuation of the natriuretic response to ANF was not reversed. Papillary plasma flow (PPF) after ANF infusion was measured by a Lillienfield technique and averaged 36 +/- 4 ml.min-1.100 g-1 in normal dogs, 10.7 +/- 0.7 ml.min-1.100 g-1 in both responding and nonresponding caval dogs, and 48.3 +/- 1.1 ml.min-1.100 g-1 for each group of cirrhotic dogs. We conclude that differences in renal perfusion, PPF, cGMP generation, or the presence of intact renal nerves cannot explain the lack of a post-ANF natriuretic response in half of caval or cirrhotic dogs. Other physiological determinants must explain the heterogeneity of natriuretic response to ANF observed in edematous dogs.

Topics: Animals; Ascites; Atrial Natriuretic Factor; Blood Pressure; Cyclic GMP; Denervation; Dogs; Drug Resistance; Edema; Female; Fibrosis; Kidney; Ligation; Male; Natriuresis; Renal Circulation; Sodium; Vasodilation; Vena Cava, Inferior

We investigated the effect of a continuous infusion (50 micrograms as an initial bolus followed by a maintenance infusion at a rate of 0.1 micrograms/min.kg body wt for 45 min) of synthetic human atrial natriuretic factor (hANF) on renal hemodynamics and the renin-angiotensin-aldosterone system in 15 cirrhotic patients with ascites. Basal hANF levels were higher in cirrhotic patients when compared with normal values. Human atrial natriuretic factor infusion induced a significant decrease in mean blood pressure (from 77.8 +/- 1.1 to 68.6 +/- 1.5 mmHg, p less than 0.001) and a significant increase in heart rate (from 76.4 +/- 2.7 to 89.8 +/- 2.4 beats/min, p less than 0.001) in the patients studied. A remarkable increase in natriuresis (i.e., greater than or equal to 200 muEq/min) was observed in 5 patients (responders), whereas the infusion did not modify sodium excretion (i.e., less than or equal to 20 muEq/min) in 6 patients (nonresponders) and induced an intermediate response in 4 patients. Human atrial natriuretic factor-induced natriuresis was related to changes in renal hemodynamics that occurred during hANF infusion. In responders, the extent of the natriuretic response paralleled the increase of effective renal plasma flow and glomerular filtration rate; in non-responders the absent natriuretic response was associated with an evident reduction of these parameters. The reduction of blood pressure was similar in responders and nonresponders, but in the latter group it was followed by a marked increase of plasma renin activity and heart rate. It is likely that in nonresponders the natriuretic effect of hANF was blunted by the hemodynamic and hormonal changes triggered by the concomitant hANF-induced hypotension. This probably occurs in the presence of a greater reduction of effective arterial blood volume, as suggested by the higher baseline levels of plasma renin activity and the inability to increase free water excretion after a water load observed in nonresponders.

Topics: Adult; Aged; Aldosterone; Ascites; Atrial Natriuretic Factor; Cyclic GMP; Female; Glomerular Filtration Rate; Hemodynamics; Humans; Infusions, Intravenous; Liver Cirrhosis; Male; Middle Aged; Renal Circulation; Renin; Sodium