Effect of ethanol on splanchnic hemodynamics in awake and unrestrained rats with portal hypertension

Alcoholic liver disease is frequently accompanied by portal hypertension. We have previously shown that alcohol intake in awake, unrestrained rats is followed by an increase in portal tributary blood flow. In this study, the effect of ethanol on splanchnic hemodynamics in rats with portal hypertension was analyzed. Portal hypertension was induced by partial ligation of the portal vein. This procedure resulted in an increase in portal tributary and hepatic arterial blood flows compared to sham-operated animals. Ethanol (2 gm per kg, oral) increased portal tributary blood flow in both sham-operated and portal vein-ligated rats (sham + water = 37.6 +/- 1.4; sham + ethanol = 63.1 +/- 1.9; p less than 0.01; partial portal vein stenosis + water = 53.2 +/- 3.3; partial portal vein stenosis + ethanol = 69.5 +/- 2.2 ml.kg-1.min-1; p less than 0.01). In sham-operated rats, hepatic artery blood flow was unchanged following ethanol (sham + water = 6.6 +/- 0.7; sham + ethanol = 7.1 +/- 1.0 ml.kg-1.min-1), whereas in portal vein-ligated rats, flow was increased (partial portal vein stenosis + water = 13.7 +/- 1.4; partial portal vein stenosis + ethanol = 19.8 +/- 1.1 ml.kg-1.min-1; p less than 0.025). The adenosine receptor blocker 8-phenyltheophylline suppressed only the ethanol-induced increase in both portal tributary and hepatic artery blood flows in portal vein-ligated rats. The increases in hepatic artery and portal tributary blood flows observed in portal vein-ligated rats without ethanol were not influenced by 8-phenyltheophylline.(ABSTRACT TRUNCATED AT 250 WORDS)     

Altered density of glomerular binding sites for atrial natriuretic factor in bile duct-ligated rats with ascites.

The renal response to atrial natriuretic factor is blunted in cirrhosis with ascites. This might be due to alterations of renal receptors for atrial natriuretic factor. Therefore density and affinity of glomerular atrial natriuretic factor binding sites of bile duct-ligated rats with ascites (n = 10) and of sham-operated controls (n = 10) were determined. Glomerular atrial natriuretic factor binding sites were identified to be of the B-("biologically active") and C-("clearance") receptor type. Discrimination and quantitative determination of B and C receptors for atrial natriuretic factor were achieved by displacement experiments with atrial natriuretic factor(99-126) or des(18-22)atrial natriuretic factor(4-23), an analogue binding to C receptors only. Density of total glomerular atrial natriuretic factor binding sites was significantly increased in bile duct-ligated rats (3,518 +/- 864 vs. 1,648 +/- 358 fmol/mg protein; p less than 0.05). This was due to a significant increase of C-receptor density (3,460 +/- 866 vs. 1,486 +/- 363 fmol/mg protein; p less than 0.05), whereas density of B receptors was not significantly different in bile duct-ligated rats (58 +/- 11 vs. 162 +/- 63 fmol/mg protein). Affinity of atrial natriuretic factor to its glomerular binding sites did not differ significantly between both groups. These data suggest that an altered glomerular atrial natriuretic factor receptor density could be involved in the renal resistance to atrial natriuretic factor in cirrhosis with ascites.     

The role of nitric oxide in the vascular hyporesponsiveness to methoxamine in portal hypertensive rats.

This study examined whether an increased activity of the endothelium-derived relaxing factor, nitric oxide, may account for the hyporesponsiveness to vasoconstrictors in portal hypertension. We performed dose-response curves to methoxamine, an alpha-adrenoceptor agonist, with and without N omega-nitro-L-arginine, a specific inhibitor of nitric oxide synthesis, in experimental portal hypertension. Partial portal vein-ligated or sham-operated rats were pretreated with a continuous intravenous infusion of either N omega-nitro-L-arginine (50 micrograms.kg-1.min-1) or saline. Thirty minutes after starting the infusion of N omega-nitro-L-arginine or saline an infusion of methoxamine (10, 30 and 100 micrograms.kg-1.min-1) was added. Total peripheral resistance was calculated from mean arterial pressure and cardiac index. Repeated measurements of cardiac index were performed by a thermodilution technique. In portal vein-ligated rats pretreated with saline, the increase in total peripheral resistance after methoxamine infusion was significantly less than that of sham-operated rats (0.2 +/- 0.1 vs. 1.0 +/- 0.3, 0.6 +/- 0.1 vs. 1.6 +/- 0.3 and 3.7 +/- 0.5 vs. 6.1 +/- 0.7 mm Hg.ml-1.min.100 gm, p less than 0.05, methoxamine 10, 30 and 100 micrograms.kg-1.min-1, respectively). In the presence of N omega-nitro-L-arginine, the change in total peripheral resistance after methoxamine infusion was similar in both groups (p greater than 0.05). In conclusion, this study demonstrates that a vascular hyporesponsiveness to methoxamine is present in portal vein-ligated rats and that this hyporesponsiveness is reversed by blockade of nitric oxide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Relationships between plasma atrial natriuretic peptide concentrations and hemodynamics and hematocrit in patients with cirrhosis.

We studied the relationships in 29 patients with cirrhosis between pulmonary arterial atrial natriuretic peptide concentrations and the following: systemic and splanchnic hemodynamics, the hematocrit, arterial oxyhemoglobin saturation, oxygen tension and the severity of cirrhosis. Plasma atrial natriuretic peptide concentrations ranged from 21 to 208 pg/ml and averaged 78 +/- 8 pg/ml (mean +/- S.E.M.). Simple regression analysis showed significant correlations between plasma atrial natriuretic peptide concentration and the following: hematocrit, mean pulmonary arterial pressure, wedged hepatic venous pressure, free hepatic venous pressure, pulmonary wedged pressure and serum bilirubin concentrations. No significant correlations were found between plasma atrial natriuretic peptide concentrations and all other hemodynamic values, arterial oxyhemoglobin saturation and oxygen tension. Multiple stepwise regression analysis showed that the hematocrit, mean pulmonary arterial pressure and wedged hepatic venous pressure were significant and independent predictors of pulmonary artery plasma atrial natriuretic peptide concentrations (R2 = 0.69). Partial regression coefficients were -0.74 (p less than 0.001), 0.61 (p less than 0.001) and 0.44 (p less than 0.05) for the hematocrit, the mean pulmonary arterial pressure and the wedged hepatic venous pressure, respectively. In conclusion, in patients with cirrhosis, increased plasma atrial natriuretic peptide concentrations were related to the degree of hemodilution, increased pulmonary arterial pressure and the degree of portal hypertension. Plasma atrial natriuretic peptide concentrations were not influenced by the arterial oxygenation levels.     

Plasma atrial natriuretic peptide and renin-aldosterone in patients with cirrhosis and ascites: basal levels, changes during daily activity and nocturnal diuresis.

Measurements of plasma atrial natriuretic peptide concentrations at 8 AM showed raised levels in 21 patients with cirrhosis and ascites (10.5 +/- 0.8 pmol/L) compared with levels in 10 age-matched controls (4.1 +/- 0.64 pmol/L; p less than 0.0001). In eight patients and 10 controls, atrial natriuretic peptide, plasma renin activity, plasma aldosterone and urinary sodium excretion were measured every 4 hr for 24 hr. Subjects were mobile between 8 AM and 11 PM and supine from 11 PM to 8 AM. In controls, urinary sodium excretion was highest between 4 PM and 11 PM (19.34 +/- 3.74 mumol/min) and lowest between midnight and 8 AM (7.06 +/- 1.23 mumol/min; p less than 0.001). In patients, urinary sodium excretion was 0.63 +/- 0.14 mumol/min between 4 PM and midnight and 1.85 +/- 0.71 mumol/min (p less than 0.08) between midnight and 8 AM. In patients during the day, mean plasma atrial natriuretic peptide concentration did not change despite large individual variation, but large, sustained rises in plasma renin activity and plasma aldosterone were seen. Correlations were noted between atrial natriuretic peptide and urinary sodium excretion between midnight and 8 AM (r = 0.65; p less than 0.02) and 4 PM and midnight (r = 0.54; p less than 0.05) but not between 8 AM and 4 PM. Plasma renin activity dropped from 12.54 +/- 2.49 at midnight to 7.41 +/- 0.88 pmol/hr/ml at 8 AM (p less than 0.05); plasma aldosterone decreased from 1,032 +/- 101 to 798 +/- 56 pmol/L (p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Atrial natriuretic peptide in chronic heart failure in the rat: a correlation with ventricular dysfunction

To assess the relation between atrial natriuretic peptide and ventricular dysfunction, we simultaneously measured both atrial and plasma immunoreactive atrial natriuretic peptide concentrations in rats 4 weeks after myocardial infarction induced by left coronary artery ligation. When compared to controls (n = 39), rats with infarction (n = 16) had markedly elevated plasma immunoreactive atrial natriuretic peptide concentrations (1205.8 +/- 180.9 vs. 126.7 +/- 8.9 pg/ml, p less than 0.001) and reduced immunoreactive atrial natriuretic peptide concentrations in right and left atria (31.4 +/- 4.6 vs. 61.2 +/- 3.2 ng/mg, p less than 0.001; 14.9 +/- 2.2 vs. 32.7 +/- 2.4 ng/mg, p less than 0.001, respectively). Right ventricular weight increased in proportion to infarct size, and both were correlated with plasma immunoreactive atrial natriuretic peptide levels (r = 0.825, p less than 0.001 and r = 0.816, p less than 0.001, respectively). Right atrial immunoreactive atrial natriuretic peptide content was significantly higher than left in both controls and rats with infarction. Both right and left atrial immunoreactive atrial natriuretic peptide concentrations were negatively correlated with both right ventricular weight as well as plasma immunoreactive atrial natriuretic peptide concentrations (right atrium: r = -0.816, p less than 0.001, r = -0.708, p less than 0.01; left atrium: r = -0.687, p less than 0.01, r = -0.644, p less than 0.01, respectively). These results suggest that chronic stimulation of atrial natriuretic peptide release from both atria is associated with increased turnover and depleted stores of atrial natriuretic peptide in atria in proportion to the severity of heart failure. It also suggests that plasma atrial natriuretic peptide levels may be used as a reliable index of cardiac decompensation in chronic heart failure.     

Sequence of morphological and hemodynamic changes of gastric microvessels in portal hypertension.

Changes in gastric microvasculature and blood flow at different phases of portal hypertension were studied in rats 1, 2, 3, 4, and 15 days after induction of portal hypertension or sham operation. Vessel lumen and vessel wall thickness were expressed as a ratio referred to the vessel size. On day 2 after constriction of the portal vein, gastric blood flow was decreased (0.57 +/- 0.06 vs. 0.99 +/- 0.20 mL.min-1.100 g-1; P less than 0.05), and gastric vessels had a distended lumen (0.42 +/- 0.02 vs. 0.28 +/- 0.03; P less than 0.01) and a thin wall (2.11 +/- 0.2 vs. 3.82 +/- 0.4; P less than 0.01). On day 4, the gastric blood flow of portal hypertensive animals was increased (1.15 +/- 0.14 vs. 0.71 +/- 0.07 mL.min-1.100 g-1; P less than 0.05), whereas gastric vessels had a reduced lumen (0.27 +/- 0.02 vs. 0.33 +/- 0.02; P less than 0.01) and a thick wall (4.19 +/- 0.52 vs. 3.16 +/- 0.30; P less than 0.05). By day 15, vessels with the largest lumens (0.45 +/- 0.01 vs. 0.29 +/- 0.01; P less than 0.01) and the thinnest walls (1.78 +/- 0.26 vs. 3.58 +/- 0.62; P less than 0.01) were observed in portal hypertensive animals. In conclusion, the gastric vessels of the 15-day portal vein-ligated rat resemble the structural abnormalities described in human portal hypertensive gastropathy.     

Dietary sodium and inhibition of neutral endopeptidase 24.11 in essential hypertension.

Basal atrial natriuretic peptide levels and the response to exogenous atrial natriuretic peptide are influenced by dietary sodium intake. In view of interest in the therapeutic potential of elevating plasma atrial natriuretic peptide by inhibition of neutral endopeptidase 24.11, we studied the renal and hormonal effects of 200 mg of the oral endopeptidase 24.11 inhibitor candoxatril in eight patients with untreated essential hypertension on high sodium (350 mmol/day) and low sodium (10 mmol/day) diets. With endopeptidase 24.11 inhibition, plasma atrial natriuretic peptide increased more than twofold on low and high sodium diets (p less than 0.05). Plasma N-terminal pro-atrial natriuretic peptide increased on the high sodium intake but was unaffected by candoxatril. Urinary sodium excretion increased threefold on the low sodium and sixfold on the high sodium diet (p less than 0.05). The absolute increase in urinary sodium excretion during the 24 hours after treatment compared with placebo was 18 +/- 8 mmol on the low sodium and 98 +/- 34 mmol on the high sodium diet (p less than 0.05). Plasma renin activity was suppressed by treatment on the low but not on the high sodium diet (p less than 0.05). Blood pressure did not change in the 6 hours after a single dose of candoxatril. These findings show that sodium intake is a major determinant of the response to endopeptidase 24.11 inhibition. The lack of effect on N-terminal pro-atrial natriuretic peptide suggests that candoxatril does not influence cardiac secretion of atrial natriuretic peptide or catabolism of N-terminal pro-atrial natriuretic peptide, and the latter does not appear to play a role in the response to candoxatril.     

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.     

Effect of induced ventricular tachycardia on atrial natriuretic peptide in humans

The effects of induced sustained ventricular tachycardia on the release of plasma-immunoreactive atrial natriuretic peptide were evaluated in 11 adult patients undergoing diagnostic electrophysiologic study. Plasma concentrations of atrial natriuretic peptide withdrawn from the right atrium before and during sustained ventricular tachycardia (mean tachycardia cycle length 320 +/- 68 ms, duration greater than 30 s) were determined by radioimmunoassay. Hemodynamic measurements included phasic femoral artery blood pressure and mean right atrial blood pressure before and during ventricular tachycardia. During ventricular tachycardia, atrial natriuretic peptide increased from 93 +/- 49 pg/ml to 234 +/- 195 pg/ml (p less than 0.05), systolic arterial blood pressure decreased from 120 +/- 16 to 70 +/- 23 mm Hg (p less than 0.001), diastolic arterial blood pressure decreased from 63 +/- 8 to 51 +/- 16 mm Hg (p = NS) and mean right atrial blood pressure increased from 3 +/- 1 to 8 +/- 5 mm Hg (p less than 0.02). In six patients, all hemodynamic variables and the atrial natriuretic peptide were measured during repeated stimulation protocols to investigate the effect of ventricular stimulation for ventricular tachycardia induction on atrial natriuretic factor release. Compared with the values obtained during sinus rhythm, there was no significant increase in atrial natriuretic factor during ventricular stimulation at a cycle length of 600 ms (45 +/- 20 versus 52 +/- 21 pg/ml) or at a cycle length of 400 ms (45 +/- 20 versus 57 +/- 18 pg/ml). No significant linear relation could be found among the changes in mean right atrial pressure, systolic arterial blood pressure and the increase in atrial natriuretic peptide.(ABSTRACT TRUNCATED AT 250 WORDS)     

Acute hemodynamic and hormonal effects of CI-930, a new phosphodiesterase inhibitor, in severe congestive heart failure

The phosphodiesterase inhibitor CI-930 hydrochloride exerts a positive inotropic and vasodilator effect in experimental animals. The acute hemodynamic and hormonal effects of intravenous CI-930 were studied in 9 patients with severe congestive heart failure. At 60 minutes of drug infusion, there was an increase in cardiac index (2.7 +/- 0.9 vs 2.0 +/- 0.7 liters/min/m2, p less than 0.01) and positive dP/dt (1,390 +/- 470 vs 1,100 +/- 300 mm Hg/s, p less than 0.02). Additionally, there were decreases in mean systemic arterial (78 +/- 16 vs 86 +/- 15 mm Hg, p less than 0.01), mean right atrial (5 +/- 3 vs 9 +/- 4 mm Hg, p less than 0.02), mean pulmonary arterial (27 +/- 11 vs 37 +/- 9 mm Hg, p less than 0.01) and LV end-diastolic (19 +/- 8 vs 28 +/- 6 mm Hg, p less than 0.01) pressures. Heart rate did not change (97 +/- 17 vs 97 +/- 22 beats/min). The inotropic response correlated significantly (r = 0.70, p less than 0.05) with the dose of CI-930. Plasma renin activity did not change significantly (from 16 +/- 9 to 23 +/- 15 ng/ml/hour), nor did plasma norepinephrine or arginine vasopressin levels. The plasma atrial natriuretic peptide level decreased (from 153 +/- 97 to 83 +/- 35 pg/ml, p less than 0.02). These findings suggest that intravenous CI-930 hydrochloride is a useful therapeutic agent in congestive heart failure and that its use does not appear to further activate potentially deleterious hormonal systems.     

Responsiveness of plasma atrial natriuretic factor to short-term changes in left atrial hemodynamics after percutaneous balloon mitral valvuloplasty

To assess the effect of short-term alteration of left atrial pressure and volume on the circulating plasma level of atrial natriuretic factor, 11 patients with left atrial hypertension due to mitral stenosis were studied at the time of percutaneous balloon mitral valvuloplasty. Hemodynamic measurements and plasma atrial natriuretic factor levels were obtained before, immediately (5 to 10 min) after and 24 h after valvuloplasty, and echocardiographic left atrial size was determined before and 24 h after valvuloplasty. Immediately after valvuloplasty, left atrial pressure decreased from 28 +/- 2 to 10 +/- 1 mm Hg (p less than 0.0005), mitral pressure gradient decreased from 20 +/- 2 to 7 +/- 1 mm Hg (p less than 0.0005), mitral valve area increased from 0.8 +/- 0.1 to 1.9 +/- 0.2 cm2 (p less than 0.0005) and plasma atrial natriuretic factor level rose from 249 +/- 42 to 348 +/- 50 pg/ml (p less than 0.01). This short-term rise in atrial natriuretic factor level may reflect a transient increase in left atrial pressure associated with balloon occlusion of the mitral valve.(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased blood flow through the portal system in cirrhotic rats

Portal venous pressure is the result of the interplay between portal venous blood flow and the vascular resistance offered to that flow. Whether portal hypertension is maintained only by an increased portal venous resistance or also by an increased blood flow within the portal venous system is still open to speculation. To resolve these differences, splanchnic and systemic hemodynamics were evaluated in cirrhotic rats, induced by CCl4. Blood flow and portal-systemic shunting were measured by radioactive microsphere techniques. All cirrhotic rats had portal hypertension (portal venous pressure 13.5 +/- 1.1 vs. 9.0 +/- 0.5 mmHg, in normal control rats; p less than 0.01), but portal-systemic shunting in cirrhosis (31% +/- 13% vs. 0.2% +/- 0.02%; p less than 0.05) was variable, ranging from 1% to 97%. Portal venous inflow, the total blood flow within the portal system, was increased in cirrhotic rats (5.75 +/- 0.04 vs. 4.52 +/- 0.36 ml/min per 100 g; p less than 0.05). Total splanchnic arterial resistance was reduced in cirrhotic rats (3.3 +/- 0.2 vs. 5.8 +/- 0.5 dyn X s X cm-5 X 10(5); p less than 0.01). Portal venous resistance, however, was not abnormally elevated in cirrhotic rats (4.6 +/- 0.5 vs. 4.7 +/- 0.5 dyn X s X cm-5 X 10(4), p = NS). Splanchnic hemodynamics in cirrhotic rats demonstrate that portal hypertension is maintained, at least in part, by a hyperdynamic portal venous inflow. The hemodynamic data in cirrhotic rats provided evidence that supports the role of an increased portal blood flow in portal hypertension and gives a quantitative definition of splanchnic hemodynamics in intrahepatic portal hypertension.     

Hemodynamic and sympathetic responses to human atrial natriuretic peptide infusion in patients with cirrhosis

To determine the potential usefulness of atrial natriuretic peptide (ANP) in patients with cirrhosis, we examined the effects of the infusion of a low dose of alpha-human ANP (alpha hANP, 25 ng.kg-1.min-1 for 30 min) on renal, splanchnic, systemic hemodynamics and sympathetic outflow in eight patients. Pulmonary arterial plasma ANP concentrations increased from 59 +/- 9 to 328 +/- 41 pg/ml (mean +/- S.E., p less than 0.05). Mean values of glomerular filtration rate and renal plasma flow were not significantly changed. Individual renal plasma flow responses differed from one patient to another. Renal plasma flow increased in two patients, decreased in three and did not change in the other patients. Renal plasma flow changes were correlated with basal renal plasma flow values (r = -0.938, p less than 0.05) but not with arterial pressure changes or renal vein plasma norepinephrine concentration changes. Azygos blood flow increased from 0.43 +/- 0.10 to 0.63 +/- 0.13 l/min (p less than 0.05) and the hepatic-venous pressure gradient decreased from 19.9 +/- 1.5 to 17.5 +/- 2.9 mmHg in post-infusion (p less than 0.05). Mean arterial pressure decreased significantly by 18% and cardiac output by 12%. Systemic vascular resistance and pulmonary arterial plasma norepinephrine concentrations were not significantly modified. Thus, in patients with cirrhosis, alpha hANP appears to have a direct vasodilating action on renal arterioles when basal renal vascular tone is high. In addition, although alpha hANP might exert a portal hypotensive action, alpha hANP induced arterial hypotension as a result of both low cardiac output and a lack of increased sympathetic vascular tone. The arterial hypotensive action may, thus, limit the therapeutic use of low doses of alpha hANP in cirrhotic patients.     

Blunted natriuretic response and low blood pressure after atrial natriuretic factor in early cirrhosis

We compared the natriuretic response to a standard dose of atrial natriuretic factor in nine patients with early cirrhosis (no ascites or edema) with the response in normal subjects displaying a range of baseline sodium excretions due to different sodium intakes (20 mmoles per day, n = 9; 100 mmoles per day, n = 9, and 200 mmoles per day, n = 9). In these normal subjects, sodium output rose, in the same order, from 49 +/- 12 to 177 +/- 26, from 116 +/- 21 to 365 +/- 106 and from 228 +/- 29 to 901 +/- 85 mumoles per min in the first 20 min after 100 micrograms atrial natriuretic factor (human atrial natriuretic factor 99-126). Thus, irrespective of basal excretion, natriuresis rose by at least 2-fold. In the cirrhotic patients, natriuresis rose from 173 +/- 42 to 305 +/- 77 mumoles per min, that is by hardly 1-fold, significantly less than in the normal subjects (p less than 0.01). Renal function studies indicated that atrial natriuretic factor caused less rise in glomerular filtration rate and in fractional sodium excretion. Atrial natriuretic factor induced a fall in blood pressure only in the cirrhotic group, from 130 +/- 4/81 +/- 2 to 108 +/- 4/68 +/- 3 mmHg (p less than 0.001). Plasma atrial natriuretic factor was not low in the cirrhotic patients. Although these data are compatible with a primary disturbance of sodium excretion in early cirrhosis without ascites, such an explanation is complicated by the concomitant drop in blood pressure after atrial natriuretic factor.(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal atrial peptide receptors and natriuresis in two-kidney, one clip hypertension.

It has been suggested that the impaired natriuretic response of the clipped kidney in two-kidney, one clip hypertensive rats is related to downregulation of renal atrial natriuretic peptide receptors. To test this hypothesis, blood volume expansion and atrial peptide binding studies were performed in this model. Infusion of 1% and then 1.5% body weight donor blood (n = 6) caused a progressive increase in plasma immunoreactive atrial natriuretic peptide (107 +/- 26 to 168 +/- 31 to 427 +/- 154 pg/ml, p less than 0.001); the sodium excretion of the nonclipped kidney rose from 230 to 2,200 to 4,000 neq/min (p less than 0.01) but that of the clipped kidney did not rise significantly. There was a highly significant correlation between log cyclic guanosine monophosphate and log sodium excretion by the nonclipped (r2 = 0.749) but not the clipped (r2 = 0.046) kidney. Between clipped and nonclipped kidneys, the association constant (5.26 +/- 0.89 versus 5.17 +/- 0.64 x 10(9)/mol) and apparent binding site density (575 +/- 92 versus 500 +/- 74 fmol/mg protein) for atrial peptide binding in isolated glomeruli did not differ. Assay of atrial peptide-induced cyclic guanosine monophosphate release by isolated glomeruli showed that clipped and nonclipped kidneys were equally responsive. Binding affinity and receptor density did not differ in homogenates prepared from inner medullas of clipped and nonclipped kidneys. These results show that the blunted natriuretic response in clipped kidneys was not associated with any relative decrease in number or function of glomerular or papillary atrial natriuretic peptide receptors.     

Gastric emptying of liquids and solids in the portal hypertensive rat

The effects of portal hypertension on gastric motor function were investigated using the rat staged portal vein ligation model. Gastric emptying of liquids and solids was studied separately following meals labeled with 51Cr or 99Tc by whole stomach scintillation counting. Portal hypertension was consistently established in experimental rats (splenic pulp pressure: mean +/- SEM, portal hypertension versus control, 16.8 +/- 0.7 vs 11.8 +/- 0.7 mm Hg, P less than 0.0001). Although liquids were emptied in an exponential manner and solids in a linear fashion, gastric emptying of both meals was more rapid in the experimental rats. Ten minutes after the liquid meal, more than 50% of the meal had emptied from the stomachs of portal hypertensive rats while only one third of the meal had cleared in the control group (P less than 0.02). Gastric emptying of the solid meal was significantly accelerated in experimental rats at 60 and 120 min (percent meal remaining: portal hypertension versus control, 41.9 +/- 4.0 vs 55.4 +/- 3.5 and 21.5 +/- 4.9 vs 32.6 +/- 4.3, P less than 0.05). Stomachs of portal hypertensive animals were heavier (P less than 0.009) and histologic examination revealed submucosal edema. Thus, a possible mechanism of the disrupted gastric motor function in portal hypertension is decreased gastric wall compliance secondary to edema.     

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 factor in hypertension: bioactivity at normal plasma levels

To ascertain whether small shifts in plasma atrial natriuretic factor (ANF) exerted biological effects in hypertension, we studied the renal, hemodynamic, and hormonal effects of ANF [human ANF-(99-126)] infused at a dose (0.75 pmol/kg/min for 3 hours) that would induce changes in plasma ANF confined to the normal, resting range, in a group of six young men with uncomplicated, mild essential hypertension. During ANF infusions, the patients excreted 11.8 +/- 2.0 mmol (mean +/- SEM) sodium more than during the time-matched placebo phase natriuresis (p less than 0.001, mean increase of 53% above placebo values). Urinary excretion of cyclic guanosine monophosphate rose to more than double (212%, p less than 0.001) placebo values. Plasma renin activity (0.4 +/- 0.05 vs. 0.9 +/- 0.12 nmol/l/hr, p less than 0.0001) and aldosterone concentrations (102 +/- 4 vs. 184 +/- 47 pmol/l, p less than 0.05) were clearly suppressed during administration of ANF. Plasma norepinephrine also fell significantly below placebo values (268 +/- 17 vs. 439 +/- 35 pg/ml, p less than 0.05). Urine volume, the excretion of electrolytes other than sodium, hematocrit, effective renal plasma flow, glomerular filtration rate, and filtration fraction were unaffected by ANF. Similarly, plasma concentrations of epinephrine, arginine vasopressin, adrenocorticotropic hormone, and cortisol were unchanged. Blood pressure and heart rate were unchanged. Minor perturbations in plasma ANF concentrations exert clear biological effects in patients with mild essential hypertension. These data suggest that such minor shifts in plasma ANF are of physiological relevance in mild hypertension and probably contribute to volume homeostasis in this condition.     

Hemodynamic studies in long- and short-term portal hypertensive rats: the relation to systemic glucagon levels

It is not known whether the hyperdynamic state which has been observed in several experimental models and in patients with portal hypertension reflects a temporary phase during the evolution of the portal hypertensive syndrome or is an expression of a permanent steady state. A hemodynamic study was performed in a group of rats with long-standing portal hypertension induced by portal vein constriction performed 6.2 +/- 0.1 months earlier. A group of rats matched by age and weight with short-term (20.7 +/- 0.9 days) portal hypertension and a group of long-term (6.2 +/- 0.1 months) sham-operated rats were used as controls. Cardiac output and regional blood flows were measured using a radioactive microsphere technique. Arterial blood levels of glucagon, a known vasodilator that was implicated in the etiology of the hyperdynamic circulation, were also measured. Portal pressure in long- and short-term portal hypertensive groups (12.3 +/- 0.4 and 13.7 +/- 0.4 mm Hg; not statistically significant) was higher than in the sham group (9.0 +/- 0.3 mm Hg; p less than 0.01). Cardiac output in the long-term portal hypertensive rats was similar to the sham-operated group and lower than in the short-term portal hypertensive group (19.4 +/- 1.0 and 20.6 +/- 1.5 vs. 32.7 +/- 2.0 ml X min-1 X 100 gm body weight-1; p less than 0.01). Portal venous inflow in the long-term portal hypertensive group was also similar to the sham group and lower than in the short-term portal hypertensive group (4.51 +/- 0.36 and 4.58 +/- 0.39 vs. 6.72 +/- 0.48 ml X min-1.(ABSTRACT TRUNCATED AT 250 WORDS)