Effects of ritanserin, a selective and specific S2-serotonergic antagonist, on portal pressure and splanchnic hemodynamics in portal hypertensive rats

Serotonergic mechanisms have recently been implicated in the pathogenesis of portal hypertension; this suggests that blockade of serotonin S2 receptors may be a new approach for the pharmacological therapy of portal hypertension. This study was aimed at investigating the effects of ritanserin, a selective S2-serotonergic antagonist, in portal-hypertensive rats whose condition was due to partial portal vein ligation. The animals were randomized under double-blind conditions into two groups: the first received ritanserin (0.7 mg/kg body wt, intravenously), and the second received the same volume of placebo (isotonic saline solution). The hemodynamic studies were performed using radiolabeled microspheres 60 min after drug administration. Ritanserin administration significantly reduced portal pressure (from 11.8 +/- 0.8 mm Hg to 9.4 +/- 0.6 mm Hg; p less than 0.05). This was associated with lower portocollateral resistance (1.8 +/- 0.2 mm Hg/ml/min 100 gm in the ritanserin group vs. 2.3 +/- 0.2 mm Hg/ml/min 100 gm in rats receiving placebo; not significant), but we saw no changes in portal-vein inflow (5.5 +/- 0.7 ml/min 100 gm vs. 5.4 +/- 0.5 ml/min 100 gm), mean arterial pressure (95.9 +/- 3.5 mm Hg vs. 94.0 +/- 4.0 mm Hg) and cardiac index (31.9 +/- 3.5 ml/min 100 gm vs. 28.5 +/- 2.6 ml/min 100 gm). Hepatic arterial and kidney blood flows were not modified by ritanserin. In summary, our results demonstrate that ritanserin infusion decreases portal pressure without causing systemic hemodynamic changes. This effect is probably due to a decrease in portocollateral resistance in portal-hypertensive rats. These results provide further for a role of serotonin in the pathogenesis of portal hypertension.     

Hyperdynamic circulation in a chronic murine schistosomiasis model of portal hypertension

Chronic murine schistosomiasis is a natural disease model of portal hypertension closely mimicking the clinical and histological features of human hepatic schistosomiasis. We studied the splanchnic and systemic hemodynamics in the murine model of schistosomiasis by radioactive microsphere technique. Mice infected with 60 cercariae of Schistosoma mansoni (n = 8) were studied hemodynamically 11 wk after the infection and were compared with age-matched healthy controls (n = 11). Mean portal venous inflow in the infected mice (3.82 +/- 0.32 ml/min) was 61% higher than in the healthy animals (2.37 +/- 0.25 ml/min; p less than 0.01). A twofold increase in hepatic arterial flow was also seen in mice with schistosomiasis (0.47 +/- 0.14 ml/min) as compared with controls (0.16 +/- 0.03 ml/min; p less than 0.05), whereas splanchnic arteriolar resistance (60.91 +/- 7.64 vs. 101.21 +/- 11.06 mm Hg.min.ml-1.gm; p less than 0.05) and peripheral vascular resistance (112.05 +/- 14.05 vs 254.53 +/- 29.86 mm Hg.min.ml-1.gm; p less than 0.01) were reduced. There was a significant increase in cardiac index (752 +/- 99 vs. 453 +/- 55 ml.min-1.kg body weight-1; p less than 0.05) and reduction in mean arterial pressure (81.37 +/- 3.09 vs. 101.45 +/- 5.85 mm Hg; p less than 0.05) in the infected animals compared with controls. These observations clearly demonstrate the existence of a hyperdynamic circulatory state in this model of portal hypertension.     

Evidence for normal nitric oxide-mediated vasodilator tone in conscious rats with cirrhosis.

Because it has been hypothesized that the hyperkinetic circulation in portal hypertension is the result of increased synthesis of nitric oxide, we compared the hemodynamic effects of nitric oxide synthesis--specific agonist (L-arginine) and antagonist between normal and cirrhotic conscious rats. The dose-response curves showed that L-arginine significantly decreased arterial pressure and increased heart rate. These changes started at the 200 mg/kg dose and were similar in both groups of rats. In both groups of rats NG-monomethyl-L-arginine (25 mg/kg) significantly decreased cardiac output by 35%. In cirrhotic rats, NG-monomethyl-L-arginine decreased portal pressure from 15.3 +/- 0.9 mm Hg to 13.6 +/- 0.7 mm Hg and portal tributary blood flow from 7.8 +/- 0.7 ml.min-1.100 gm-1 to 5.9 +/- 0.7 ml.min-1.100 gm-1; it significantly increased portal territory vascular resistance from 950 +/- 108 dyn.sec.cm-5.100 gm-1 x 10(3) to 1,579 +/- 258 dyn.sec.cm-5.100 gm-1 x 10(3). In normal rats, portal tributary blood flow decreased similarly, by 27%, and portal territory vascular resistance increased by 55%. In neither group was hepatic arterial blood flow altered. Before and after NG-monomethyl-L-arginine administration, arterial cyclic GMP concentrations were not significantly different between normal and cirrhotic rats. In conclusion, this study shows evidence of a normal role for nitric oxide-mediated vasodilatation in rats with cirrhosis and that inhibition of nitric oxide synthesis reduces portal hypertension. These results did not support the hypothesis that nitric oxide synthesis is increased in cirrhosis.     

Lipoic acid prevents development of the hyperdynamic circulation in anesthetized rats with biliary cirrhosis

Chronic bile duct ligation is associated with the development of oxidant injury, biliary cirrhosis, portal hypertension, and a hyperdynamic circulation. We have previously demonstrated that the hyperdynamic circulation in the partial portal vein-ligated rat can be prevented by the administration of N-acetylcysteine. To extend these findings, we have examined the effect of lipoic acid, a thiol-containing antioxidant, on hemodynamics, oxidative stress, and nitric oxide (NO) production in bile duct-ligated (BDL) cirrhotic rats. Lipoic acid was given continuously in drinking water to normal and BDL rats; control rats received ordinary drinking water, and animals were studied at 24 days following surgery. Lipoic acid prevented the development of the hyperdynamic circulation (cardiac index [CI]: 15.7 +/- 2.0 vs. 29.5 +/- 2.1 mL x min-1 x 100 g-1; P <. 05) and significantly attenuated the rise in portal pressure (PP) (12.7 +/- 0.8 vs. 15.2 +/- 0.5 mm Hg; P <.05). Hepatic nitric oxide synthase (NOS) activity and plasma nitrite/nitrate concentration increased significantly following bile duct ligation, and both of these were prevented by lipoic acid. Lipoic acid had no effect on the biochemical or histological parameters of liver function in the cirrhotic group. We conclude that lipoic acid prevents the development of the hyperdynamic circulation in the rat model of biliary cirrhosis, and that this is associated with decreased synthesis of NO.     

Gallbladder emptying stimuli in obese and normal-weight subjects.

Gallbladder stasis may be an important factor in the pathogenesis of cholesterol-gallstone formation in some individuals. We investigated gallbladder function in a group of nondieting, gallstone-free, healthy subjects with normal (22 +/- 1 kg/m2) and high (36 +/- 1 kg/m2) body mass indexes. Fasting gallbladder volume (28.2 +/- 4.4 ml) and residual volume after maximal emptying (8.4 +/- 2.3 ml) in high-body-mass index subjects were not significantly different from those of normal-body-mass index subjects (20.5 +/- 2.5 ml and 4.2 +/- 1.3 ml, respectively). The percentage of gallbladder emptying (71% +/- 5%) and the rate of gallbladder emptying (-1.9 +/- 0.3 x 10(-2) min-1) in high-body-mass index subjects in response to a maximal emptying stimulus was similar to the percentage of emptying (78% +/- 6%) and rate of emptying (-2.3 +/- 0.6 x 10(-2) min-1) in normal-body-mass index subjects. A liquid meal containing less than 1 gm fat, 14 gm protein and 6 gm carbohydrate resulted in both a decreased rate of gallbladder emptying and an increased residual gallbladder emptying and an increased residual gallbladder volume in both groups. The addition of 10 or 20 gm (but not 4 gm) of fat to the liquid meal restored gallbladder emptying to the maximal-stimulus level. These results demonstrate that gallbladder emptying in response to a single liquid meal stimulus is not altered in obesity and that dose-response relationships to fat are similar in obese and normal-weight individuals.(ABSTRACT TRUNCATED AT 250 WORDS)     

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)     

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)     

Abnormal cardiovascular response to exercise in young asymptomatic diabetic patients with retinopathy

Heart rate, blood pressure, and left ventricular ejection fraction (LVEF) were measured by means of Au 195 m first-pass angiocardiography, during maximal supine bicycle exercise in 20 young asymptomatic patients with insulin-dependent diabetes (IDD) (10 retinopathic and 10 uncomplicated) and in 10 control subjects. Five patients with retinopathic IDD also had mild subclinical autonomic neuropathy. Exercise capacity was diminished, although not significantly, in patients with retinopathic IDD. Heart rate and LVEF were similar in all groups at rest and at submaximal exercise. At peak exercise patients with retinopathic IDD had significantly lower heart rate (134 +/- 4 bpm) and LVEF (62.9 +/- 3.7%) than those with umcomplicated IDD (158 +/- 8 bpm and 76.6 +/- 2.4%, respectively) and control subjects (152 +/- 6 bpm and 73.5 +/- 1.9%, respectively). LVEF increased vs baseline in all control subjects and patients with uncomplicated IDD, but in only three with retinopathic IDD. Leg muscle blood flow (MBF) was also evaluated at rest and during exercise by 133Xe washout. Exercise MBF was significantly lower in patients with retinopathic IDD (40.5 +/- 2.23 ml X min-1 X 100 gm-1) than in control subjects (49.9 +/- 1.87 ml X min-1 X 100 gm-1) and in those with uncomplicated IDD (49.0 +/- 1.87 ml X min-1 X 100 gm-1). Diffuse microangiopathy, alone or in combination with neuropathy, might be responsible for the impairment of cardiovascular function in diabetes.     

Vasodilatation and sodium retention in prehepatic portal hypertension.

Sodium retention and peripheral vasodilatation are common consequences of portal hypertension secondary to cirrhosis. Although peripheral vasodilatation has been extensively documented in prehepatic portal hypertension, it is not known whether sodium retention is also a feature of this entity. The aim of this study in portal vein-constricted rats was to evaluate (a) whether sodium retention is a feature of prehepatic portal hypertension and (b) if sodium retention is present in this model, what its temporal relationship with peripheral vasodilatation might be. It was proposed that an understanding of the temporal interplay between peripheral vasodilatation and sodium retention could shed light on the current theories of sodium retention in portal hypertension. Rats were studied 1, 2, 3, and 4 days after partial portal vein ligation (n = 80) or sham operation (n = 63). Sodium retention was evaluated by changes in the size of the sodium space measured by the volume of distribution of 22Na. Systemic vascular resistance was calculated from mean arterial pressure (measured by arterial catheterization) and cardiac index (measured by thermodilution). A decrease in systemic vascular resistance was already observed on day 1 after constriction of the portal vein (4.2 +/- 0.2 vs. 5.2 +/- 6.1 mm Hg.min.mL-1.100 g; P less than 0.01). However, an expansion of the sodium space, which indicates sodium retention, was not observed until day 2 after induction of portal hypertension (37.1 +/- 0.8 vs. 32.6 +/- 0.7 mL.100 g-1; P less than 0.01). Therefore, sodium retention should be considered along with peripheral vasodilatation among the characteristic features of prehepatic portal hypertension. Because the reduction in systemic vascular resistance preceded the expansion of the sodium space by at least 24 hours, the finding of this study indicates that sodium retention follows peripheral vasodilatation.     

Increased total vascular capacity in conscious cirrhotic rats.

The purpose of the present study was to determine the role of the systemic venous circulation in the hemodynamic alterations of the cirrhotic disease. Cardiac output (thermodilution; n = 8), mean circulatory filling pressure (balloon technique; n = 6), and blood volume (Evans blue dye; n = 7) were investigated in a rat model of liver cirrhosis without ascites induced by a 12-week individualized CCl4/phenobarbital treatment. Compared with control rats, conscious cirrhotic rats showed a hyperdynamic circulation characterized by normotension, high cardiac output (51 +/- 4.8 vs. 28.6 +/- 1.3 mL.min-1.100 g-1; P less than 0.01), and expanded blood volume (6.5 +/- 0.15 vs. 5.4 +/- 0.22 mL.100 g-1; P less than 0.05). There were no significant differences between control and cirrhotic rats in mean circulatory filling pressure (6.40 +/- 0.27 vs. 5.99 +/- 0.22 mm Hg, respectively) or in the pressure gradient for venous return (6.17 +/- 0.19 vs. 5.8 +/- 0.21 mm Hg, respectively). To further examine the venous tone, effective vascular compliance was estimated with the vascular filling-blood volume relationship by measuring the vascular filling before and after rapid changes in volume (+/- 8 mL.kg-1). Compliance was similar in both control and cirrhotic rats (3.15 +/- 0.26 and 3.41 +/- 0.21 mL.mm Hg-1), but the vascular filling-total blood volume relationship of the cirrhotic rats was displaced toward the volume axis. In conclusion, the increase in blood volume without changes in mean circulatory filling pressure (or venous tone) of the cirrhotic rats indicates a situation with venodilation and elevated total venous capacity; this is likely to be an important mechanism that could explain the hyperdynamic circulation of the cirrhotic disease.     

Hemodynamic mechanisms of emerging portal hypertension caused by schistosomiasis in the hamster

A hamster model of schistosomiasis has provided the first opportunity to sequentially examine the early phases of the development of portal hypertension in a natural model of chronic liver disease. Groups of hamsters were infected with 50 cercariae of Schistosoma mansoni and underwent hemodynamic evaluation at intervals of 5, 8, 12 and 20 wk after infection. A progressive rise in intrahepatic resistance (from 4.0 +/- 0.4 to 8.4 +/- 1.0 mm Hg min.ml-1.gm liver weight [p less than 0.01]) appeared to play a major role in the initial stages of evolving portal hypertension. A gradual decline in portal blood flow (from 2.1 +/- 0.3 to 1.3 +/- 0.1 ml.min-1.gm-1 liver weight [p less than 0.01]) was only partially compensated for by an increase in hepatic arterial flow. Accordingly, by week 20, total hepatic blood flow decreased 23%. Liver weight that increased markedly between 5 and 12 wk after infection, as a result of the acute accumulation of obstructing granulomas, stabilized between wk 12 and 20, while a gradual but progressive rise in hepatic collagen content was seen. Portal pressure increased 75% during the study period. Chronic examination of this natural model should help define the pathogenesis of the complications of portal hypertension and contribute to the basis for effective intervention in this disease process.     

Effects of calcitonin gene-related peptide on cardiac contractility, coronary hemodynamics and myocardial energetics in idiopathic dilated cardiomyopathy.

This study was performed to examine the effects of calcitonin gene-related peptide on cardiac function and coronary circulation in patients with heart failure. Synthetic human calcitonin gene-related peptide was infused in the left main coronary artery of 9 patients undergoing cardiac catheterization at different doses corresponding to incremental infusion rates of 15, 50, 150 and 600 pmol.min-1. No hemodynamic change was observed in response to administration of the 2 lowest doses. The 2 highest doses induced an increase in cardiac index and a decrease in systemic arterial pressure. The infusion of 600 pmol.min-1 resulted in a decrease of mean systemic arterial pressure (86.8 +/- 6.5 to 71.8 +/- 4.9 mm Hg; p less than 0.01), and an increase in both cardiac index (2.1 +/- 0.1 to 3.1 +/- 0.17 liters.min-1.m-2; p less than 0.01) and heart rate (87 +/- 3.7 to 101 +/- 6.1 beats.min-1; p less than 0.01). These hemodynamic changes were associated with a significant increase in plasma norepinephrine and epinephrine concentrations. Peak positive first derivative of left ventricular pressure did not change at any infusion rate. Left ventricular end-diastolic pressure decreased at the 2 highest doses associated with a decrease in plasma atrial natriuretic factor concentration (730 +/- 140 to 436 +/- 115 pg.ml-1; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Ursodeoxycholic acid limits liver histologic alterations and portal hypertension induced by bile duct ligation in the rat.

Chronic administration of ursodeoxycholic acid (UDCA) has recently been suggested as a potential treatment for cholestatic liver disease. The purpose of this study was to examine the effects of chronic oral administration of UDCA on the histological, biochemical, and hemodynamic abnormalities induced by bile duct ligation in the rat. Fifty-one rats with ligation-section of the common bile duct were randomly and blindly assigned to receive UDCA (25 mg/kg each day) or placebo by gavage for 4 weeks. At the end of the treatment period, morphometric analysis showed that in rats treated with UDCA, hepatocyte and sinusoidal volume fractions were significantly higher than in rats receiving placebo [41.9 +/- 3.2% vs. 28.1 +/- 1.8%, (mean +/- SE) and 7.4 +/- 0.1% vs. 4.3 +/- 0.3%, respectively], whereas bile duct volume fraction (reflecting bile ductular proliferation) and connective tissue fraction were significantly lower in rats treated with UDCA than in rats receiving placebo (14.2 +/- 1.5% vs. 20.0 +/- 1.0% and 35.4 +/- 2.4% vs. 47.6 +/- 1.7%, respectively). Serum aminotransferase and alkaline phosphatase activities, and total serum bile acids and individual bile acid concentrations were not significantly different between the two groups. Portal pressure (12.7 +/- 0.5 mm Hg vs. 17.1 +/- 0.5 mm Hg), portal tributary blood flow (5.7 +/- 0.4 vs. 9.3 +/- 0.4 mL.min-1.100 g-1 body weight), and cardiac index (41.1 +/- 1.8 vs. 50.6 +/- 1.4 mL.min-1.100 g-1 body weight) were significantly lower in UDCA-treated rats than in placebo-treated animals. In portal vein stenosed rats, chronic administration of UDCA had no hemodynamic effects, a finding that suggests UDCA has no direct vasoactive effect on splanchnic circulation. It is concluded that in rats with bile duct ligation UDCA limits the severity of liver disease and consequently of portal hypertension and hyperkinetic circulation.     

The effect of liver transplantation on circulating levels of estradiol and progesterone in male patients: parallelism with hepatopulmonary syndrome and systemic hyperdynamic circulation improvement

The correction of hepatopulmonary syndrome (HPS) after liver transplantation (LT) remains controversial. The aims of our study were to: 1) analyze whether LT reverses HPS; 2) note any relationship between HPS and the systemic hemodynamic disturbance; and 3) note changes in circulating sex hormones and the possible association with pulmonary and systemic hemodynamic changes. Systemic hemodynamic parameters, cardiac output and systemic vascular resistance (SVR), sex hormones, and intrapulmonary vasodilatation assessed by contrast transesophageal echocardiography, and gas exchange abnormalities were investigated in 19 patients with advanced cirrhosis prior to and 6 months (176.8+/-30 days) after LT. LT was followed by a marked reduction in cardiac output (6.6+/-1.7 vs 3.5+/-0.5 l/min; p<0.001) and SVR (1039+/-460 vs 1978+/-294 dyn x sec x cm(-5); p<0.005). Before LT, circulating estradiol and progesterone levels were invariably elevated (66+/-22 pg/ml and 1.8+/-1.1 ng/ml, respectively, normal values <31 pg/ml and 0.35 ng/ml, respectively), and dropped after LT (28+/-12 pg/ml p<0.001 and 0.38+/-0.2 ng/ml; p<0.001, respectively). Seventeen of 19 patients had intrapulmonary vasodilatation and increased alveolar-arterial oxygen difference, thereby fulfilling diagnostic criteria for HPS. Patients with HPS presented higher cardiac output (p<0.05), lower SVR (p<0.01), and higher progesterone and estradiol levels than patients without HPS (p<0.05). LT produced normalization of intrapulmonary vasodilatation in all patients. LT normalized hyperdynamic circulation and is a useful therapeutic option in patients with HPS. Normalization of sex hormone levels after LT suggests that they could play a pathogenic role in the development of HPS.     

Left ventricular dynamics and plasma catecholamines during isometric exercise in patients following cardiac transplantation

Haemodynamics and plasma catecholamine responses to isometric exercise were evaluated invasively in 11 orthotopic heart transplant recipients and seven control subjects. Differences in haemodynamic responses between the two groups were already apparent after one min of handgrip at 30% of maximal voluntary contraction, and very pronounced at the end of the fourth minute. At this point transplanted patients showed smaller increments in heart rate (4.8 +/- 3.2 vs 20.4 +/- 14.1 beats.min-1, P less than 0.001), mean arterial pressure (13.7 +/- 7.2 vs 31.5 +/- 12.2 mmHg, P less than 0.001) and cardiac index (0.51 +/- 0.22 vs 1.02 +/- 0.53 L.min-1.m-2, P less than 0.01), whereas left ventricular end-diastolic pressure increased to a greater extent (8.8 +/- 4.9 vs 2.2 +/- 1.8 mmHg, P less than 0.01). Stroke volume index increased similarly (3.8 +/- 1.8 vs 2.0 +/- 3.5 ml beat-1.m-2, NS) and systemic vascular resistance remained unchanged in both groups. The slopes of the left ventricular function curves (ratio of change in left ventricular work to change in left ventricular end-diastolic pressure) indicated depressed left ventricular function in the transplanted patients. The two groups showed similar increments in mixed venous plasma norepinephrine and epinephrine indicating normal sympathoadrenal activation in the transplanted patients. In conclusion, transplanted hearts respond to handgrip with attenuated increases in heart rate, cardiac output and arterial pressure and by increasing left ventricular filling pressure, suggesting a poor contractile reserve probably due to denervation. Circulating catecholamines, especially epinephrine, probably contribute to the cardiac responses to isometric exercise.     

The molecules: mechanisms of arterial vasodilatation observed in the splanchnic and systemic circulation in portal hypertension

A hyperdynamic splanchnic and systemic circulation is typical of cirrhotic patients and has been observed in all experimental forms of portal hypertension. The hyperdynamic circulation is most likely initiated by arterial vasodilatation, leading to central hypovolemia, sodium retention, and an increased intravascular volume. Arterial vasodilatation is regulated by a complex interplay of various vasodilator molecules and factors that influence the production of those vasodilator molecules. Nitric oxide (NO) has been recognized as the most important vasodilator molecule that mediates the excessive arterial vasodilatation observed in portal hypertension. The aims of this review are (1) to categorize NO synthase isoforms involved in NO overproduction; (2) to explain the mechanisms of endothelial NO synthase up-regulation; and (3) to summarize other molecules involved in the arterial vasodilatation.     

Alterations in intestinal permeability and blood flow in a new model of mesenteric ischemia.

Disturbances in intestinal circulation for even short periods of time can produce mucosal injury, translocation of gut bacteria, and multiple organ failure. We recently reported a model of intestinal ischemia that included occlusion of the superior mesenteric artery (SMA) and interruption of collateral arcades from the right colic and jejunal arteries for 20 min. This present study was designed to characterize further our model of intestinal ischemia by quantitatively assessing changes in intestinal permeability (plasma to luminal clearance of 51Cr-labeled EDTA) and intestinal blood flow (IBF) (microspheres). A total of 89 rats were included for study; mean arterial blood pressure and acid-base balance were not significantly altered by intestinal ischemia or reperfusion. Baseline measurements of 51Cr-labeled EDTA were not significantly different among the experimental animals, and clearance did not change throughout the experimental period in the sham-ischemic group (N = 14). Clearance of 51Cr-labeled EDTA at the end of 20 min of intestinal ischemia (0.194 +/- 0.057 ml/min/100 gm, N = 17) was significantly greater than that measured at control (0.079 +/- 0.006 ml/min/100 gm, P less than 0.05). In addition, clearance measurements during reperfusion (20 min, 0.362 +/- 0.051; 60 min, 0.267 +/- 0.084 ml/min/gm) were significantly higher than those measured at the end of ischemia. Baseline IBF was similar in all rats (N = 42); SMA occlusion reduced IBF by 99% from baseline (from 1.4 +/- 0.27 to 0.014 +/- 0.001 ml/min/gm, N = 20). Removal of the SMA clip returned intestinal perfusion to baseline values (1.72 +/- 0.51 ml/min/g).(ABSTRACT TRUNCATED AT 250 WORDS)     

Clinical pharmacology of enalapril in hypertension with chronic renal failure

The effects of a single oral dose of enalapril (20 mg) on blood pressure (BP), heart rate (HR) plasma renin activity (PRA) aldosterone (PA), converting enzyme inhibition (CEI) and enalaprilat (E, active metabolite) were investigated during 96 h in 3 groups of 5 hypertensive patients with (1) normal renal function (creatinine clearance: Clcr greater than 80 ml.min-1); (2) moderate chronic renal failure: 80 greater than or equal to Clcr greater than 30 ml.min-1; (3) severe chronic renal failure: 30 greater than or equal to Clcr greater than 10 ml.min-1. Results are as follows (mean +/- SEM): (Table: see text) CEmax: maximal plasma concentration; TEmax: delay corresponding to CEmax; TE 1/2: plasma elimination half-life; AUCE: area under plasma level versus time curve. a: p less than 0.01; b: p less than 0.001; versus (1). In the 3 groups, CEI reached 87-94% as early as the 3rd h; however, at 96 h, CE1 was higher in (3) than in (1) and (2): 77.6 +/- 3.3% versus 6.0 +/- 1.6 and 17.7 +/- 4.8 (p less than 0.001 respectively). In (3). PRA increased at the 1st h and remained elevated: at 96 h, delta PRA was + 3.0 +/- 2.9 ng.ml-1 -.h-1 in (3) versus + 0.10 +/- 0.06 and + 0.25 +/- 0.17 ng.ml-1.h-1 .n (1) and (2) [(3) versus (1): p less than 0.01]; delta PA was lower in (3): -4.56 +/- 2.01 ng. 100 ml-1 versus -0.54 +/- 0.31 and -2.50 +/- 0.38 ng. 100 ml-1 [(3) versus (1): p less than 0.05].(ABSTRACT TRUNCATED AT 250 WORDS)     

Comparison of differences in the hemodynamic response to passive postural stress in healthy subjects greater than 70 years and less than 30 years of age

To test the hypothesis that age-related increases in arterial pressure alter the cardiovascular response to physiologic stress, 9 healthy elderly volunteers (74 +/- 2 years) and 7 young subjects (27 +/- 3 years) were subjected to a standard 60 degrees upright tilt. Cardiac volumes were measured with patients in the supine position and 5 minutes after they assumed an upright posture using radionuclide ventriculography, while heart rate, blood pressure and forearm cutaneous flow were recorded continuously and simultaneously. Only the expected age-related increase in mean arterial pressure (young subjects, 79 +/- 1 mm Hg; elderly subjects, 99 +/- 3 mm Hg; p less than 0.001) distinguished the 2 groups at baseline. However, during upright tilt, elderly subjects had significant decreases in stroke volume (supine [108 +/- 9 ml] vs upright [78 +/- 9 ml]; p less than 0.01) and cardiac index (supine [3.4 +/- 0.2 liters/min/m2] vs upright [2.8 +/- 0.2 liters/min/m2]; p less than 0.05) because of an inability to reduce end-systolic volume (supine, 44 +/- 6 ml; upright, 51 +/- 7 ml); however, mean arterial pressure was maintained through an increase in peripheral resistance. In contrast, the young relied solely on cardiac adaptations to postural stress by decreasing end-systolic volume (supine, 62 +/- 5 ml; upright, 39 +/- 5 ml; p less than 0.01) and increasing heart rate (57 +/- 2 min-1 to 71 +/- 3 min-1, p less than 0.01), whereby cardiac output and mean arterial pressure were maintained during tilt.(ABSTRACT TRUNCATED AT 250 WORDS)     

How Does Glibenclamide Lower Plasma Glucose Concentration in Patients with Type 2 Diabetes?

Twelve patients with Type 2 diabetes and uncontrolled hyperglycaemia, never before treated with anti-diabetic drugs, were studied before and after several months of glibenclamide therapy. Fasting plasma glucose fell significantly (p less than 0.01) from 12.5 +/- 1.1 (mean +/- SE) to 8.3 +/- 0.4 mmol l-1 with glibenclamide therapy, as did glycosylated haemoglobin (from 12.0 +/- 0.9 to 8.4 +/- 0.7%). The improvement in blood glucose control was accompanied by an increase in postprandial plasma insulin concentration measured hourly from 0800 to 1600 h (p less than 0.001). Over the same period, plasma NEFA and lactate levels were significantly (p less than 0.001) lower after treatment with glibenclamide. Mean (+/- SE) insulin-mediated glucose metabolic clearance rate was evaluated during glucose clamp studies, and was significantly higher (p less than 0.001) after glibenclamide therapy at steady-state insulin levels of approximately 10 mU l-1 (53 +/- 3 vs 38 +/- 2 ml-2 min-1) and approximately 70 mU l-1 (78 +/- 9 vs 55 +/- 6 ml m-2 min-1). Hepatic glucose production was also lower following glibenclamide treatment at both the lower (56 +/- 5 vs 68 +/- 5 mg m-2 min-1) and higher 22 +/- 4 vs 32 +/- 6 mg m-2 min-1) insulin levels.(ABSTRACT TRUNCATED AT 250 WORDS)