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.     

Chronic bile duct ligation in the dog: hemodynamic characterization of a portal hypertensive model

Splanchnic and systemic hemodynamics were measured in six normal dogs and in 18 dogs that had the bile ducts ligated for a period of 8 weeks. In the bile duct-ligated dogs, there was a decrease in arterial pressure (110 +/- 4 mm Hg vs. normal 136 +/- 6 mm Hg; p less than 0.005) and peripheral vascular resistance (4.60 +/- 0.38 vs. 6.28 +/- 0.38 dynes-sec-cm-5; p less than 0.02), and an increase in cardiac index (129 +/- 7 vs. 98 +/- 9 ml per min per kg; p less than 0.05). The splanchnic hemodynamic characteristics in the bile duct-ligated dogs included an increase in portal venous pressure (13.3 +/- 0.6 mm Hg vs. 6.7 +/- 0.5 mm Hg; p less than 001) and wedged hepatic venous pressure (14 +/- 1.2 mm Hg), the development of extensive portal-systemic shunting (49 +/- 10 vs. 0.03 +/- 0.01%; p less than 0.01), and a decrease in portal venous flow (194 +/- 21 ml per min vs. 427 +/- 21 ml per min; p less than 0.001). This study demonstrated that chronic bile duct-ligated dogs develop sinusoidal portal hypertension with extensive portal-systemic shunting and a hyperdynamic systemic circulation. These findings closely resembled hemodynamic abnormalities observed in human cirrhosis and suggest that this model is useful in physiopathological and pharmacological studies of portal hypertension.     

Temporal relationship of peripheral vasodilatation, plasma volume expansion and the hyperdynamic circulatory state in portal-hypertensive rats.

Peripheral vasodilatation and plasma volume expansion are required to generate the hyperdynamic circulatory state observed in portal hypertension. To determine which of these factors is the initial event and to assess their temporal relationship with the development of hyperdynamic circulation, we sequentially measured plasma volume (by 125I-albumin dilution), cardiac index (by thermodilution), mean arterial pressure (by catheterization), superior mesenteric and iliac arterial flows (by Doppler flowmetry) and calculated total and regional peripheral resistances in portal-hypertensive rats. Experimental groups were studied from day 1 through day 4 after partial portal-vein ligation (n = 110) or sham operation (n = 111). Decreased total peripheral resistance was detected within a day of portal-vein ligation (4.18 +/- 0.21 mm Hg.min.ml-1 x 100 gm vs. 5.19 +/- 0.16 mm Hg.min.ml-1 x 100 gm; p less than 0.01). Plasma volume increased significantly on day 2 (4.31 +/- 0.07 ml.100 gm-1 vs. 3.86 +/- 0.04 ml.100 gm-1; p less than 0.05). Cardiac index and regional blood flows increased in parallel with plasma volume elevation. On day 4, maximum values of plasma volume (4.49 +/- 0.08 ml.100 gm-1 vs. 3.73 +/- 0.03 ml.100 gm-1) coincided with fully developed hyperdynamic circulation, as shown by a significant elevation in cardiac index (32.3 +/- 0.6 ml.min-1 x 100 gm-1 vs. 25.5 +/- 1.2 ml.min-1 x 100 gm-1), iliac and mesenteric blood flow. On day 1, vasodilatation was present in the iliac arterial circulation. In contrast, the superior mesenteric artery vascular bed showed vasoconstriction in response to the protal outflow block.(ABSTRACT TRUNCATED AT 250 WORDS)     

Propranolol decreases portal pressure without changing portocollateral resistance in cirrhotic rats

Propranolol decreases portal pressure by reducing portal blood inflow. Studies in rats with prehepatic portal hypertension due to portal vein stenosis (a model with extensive portosystemic shunting) have shown that propranolol increases the portocollateral resistance, which hinders the fall in portal pressure. The present study examined the effects of propranolol on splanchnic and systemic hemodynamics in rats with portal hypertension due to cirrhosis of the liver, a model which is characterized by mild portosystemic shunting. Two groups of rats with CCl4-induced cirrhosis were studied: the propranolol group (n = 8), which received a propranolol infusion of 2 mg per 15 min, and controls (n = 9), which received a placebo (saline) infusion. Hemodynamic measurements were done using radiolabeled microspheres. Propranolol-treated rats had significantly lower cardiac output (-31%) and heart rate (-26%) than controls (p less than 0.001). Hepatic artery flow was not modified by propranolol. Propranolol caused splanchnic vasoconstriction, manifested by increased splanchnic resistance (+57%) and by a significant fall in portal blood inflow (4.8 +/- 0.4 vs. 6.3 +/- 0.5 ml per min.100 gm in controls, p less than 0.05). In contrast with rats with prehepatic portal hypertension, propranolol did not increase portal resistance in cirrhotic rats [2.0 +/- 0.2 vs. 2.0 +/- 0.1 mmHg per ml per min.100 gm body weight (not significant)]. Hence, the fall in portal pressure (-19%) was expected from the decrease in portal inflow (-24%). These results suggest that increased portal resistance in rats with prehepatic portal hypertension may represent an intrinsic effect of propranolol on the portocollateral vessels, since beta-blockade does not modify portal vascular resistance in cirrhosis.     

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.     

Intraportal administration of glyceryl trinitrate or nitroprusside exerts more systemic than intrahepatic effects in anaesthetised cirrhotic rats.

BACKGROUND/AIMS: Increased intrahepatic vascular tone can be pharmacologically manipulated in isolated cirrhotic livers. Intrahepatic endothelial dysfunction may lead to a decreased production of the potent endogenous vasodilator nitric oxide in cirrhotic livers. The aims of the study were to determine whether portal pressure can be lowered in vivo by injecting nitric oxide donors glyceryl trinitrate or nitroprusside directly in the portal vein and whether this is related to a decrease in intrahepatic resistance. METHODS: In anaesthetised CCl4 cirrhotic rats, intraportal doses of glyceryl trinitrate 0.5, 1 or 5 microg/kg/ min or nitroprusside 1, 5 or 10 microg/kg/min did not decrease portal pressure but only arterial pressure. Systemic and splanchnic haemodynamics were measured before and during 15 min intraportal infusion of glyceryl trinitrate 10 microg/kg/min or nitroprusside 20 microg/kg/min. RESULTS: Glyceryl trinitrate decreased portal pressure from 14.0+/-1.1 to 11.8+/-1.4 mm Hg, splanchnic perfusion pressure from 102+/-10 to 74+/-5 mm Hg and portal sinusoidal flow from 2.11+/-0.38 to 1.70+/-0.35 ml/min/g liver (all p<0.05). Nitroprusside did not decrease portal pressure significantly but led to a reduction of the splanchnic perfusion pressure (104+/-9 to 66+/-7 mm Hg) and the portal sinusoidal flow (2.39+/-0.50 to 1.77+/-0.31 ml/min/g liver; all p<0.05). Portal sinusoidal resistance was not altered by either drug. CONCLUSIONS: Intraportal infusion of nitric oxide donors decreased arterial pressure more than portal pressure. Portal sinusoidal resistance remained unaffected, but the liver parenchyma became less perfused with high doses. The systemic effects of nitric oxide donating drugs prevailed.     

Systemic and renal vascular responses to dietary calcium and vitamin D

To assess the consequences of hypercalcemia on systemic and renal hemodynamics, vasoactive hormones, and water and electrolyte excretion in intact, conscious mongrel dogs, measurements in 10 dogs receiving 100 mg/kg calcium gluconate and 10,000 U/kg vitamin D daily for 2 weeks were compared with measurements made in 10 time-control dogs not receiving calcium or vitamin D. Hypercalcemia induced by dietary supplementation with calcium and vitamin D resulted in profoundly reduced glomerular filtration rate (40 vs 78 ml/min in controls; p less than 0.005), estimated renal plasma flow (145 vs 267 ml/min in controls; p less than 0.005), and renal blood flow (254 vs 441 ml/min in controls; p less than 0.005). Renal resistance was significantly increased in the hypercalcemic dogs (0.57 +/- 0.07 vs 0.28 +/- 0.01 mm Hg/ml/min; p less than 0.005). Hypercalcemia also resulted in increased fractional excretion of water (4.8 vs 1.4% in controls; p less than 0.005), sodium (1.4 vs 0.6% in controls; p less than 0.005), calcium (1.7 vs 0.7% in controls; p less than 0.01), and magnesium (10.2 vs 4.1% in controls; p less than 0.005). Systolic blood pressure (160 vs 172 mm Hg in controls; p less than 0.05) and stroke volume were lower (0.024 vs 0.036 L/beat in controls; p less than 0.005) in hypercalcemic dogs, presumably because of the diuresis, while total peripheral resistance was higher (36 vs 31 mm Hg/L/min; p less than 0.05) in controls. Magnesium levels were significantly lower in the experimental group (1.3 vs 1.7 mg/dl in controls; p less than 0.0005). Aldosterone levels, plasma renin activity, and urinary prostaglandin excretion were not significantly affected.(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)     

Heredity and hypertension: impact on metabolic characteristics.

This study was performed to evaluate the possible role of heredity in the clinical characteristics of hypertension. Metabolic, endocrine, and renal measurements were compared in subjects with normal blood pressure who had a family history of hypertension (n = 60) with those of subjects with normal blood pressure who did not have a family history of hypertension (n = 48). The groups were matched for age (mean, 44 +/- 2 years and 45 +/- 2 years) and blood pressure (127 +/- 1/77 +/- 1 mm Hg and 127 +/- 2/77 +/- 1 mm Hg). The following parameters were higher in the patients with a family history of hypertension than in those without. Plasma insulin concentrations (14.1 +/- 1.1 vs 10.8 +/- 1.0 microU/ml; p less than 0.05), insulin-glucose ratio (0.15 +/- 0.01 vs 0.11 +/- 0.010; p less than 0.05), norepinephrine concentrations (315 +/- 24 pg/ml vs 208 +/- 20 pg/ml; p less than 0.01), plasma renin activity (2.1 +/- 0.2 ng Angl/ml/hr vs 1.6 +/- 0.2 ng Angl/ml/hr; p less than 0.02), total cholesterol levels (217 +/- 8 mg/dl vs 197 +/- 0.3 mg/dl; p less than 0.05), creatinine clearance (125 +/- 9 ml/min vs 96 +/- 8 ml/min; p less than 0.01), and albumin excretion rate (3.2 +/- 0.3 micrograms/min vs 2.6 +/- 0.3 micrograms/min; p = 0.1). Moreover, patients with a family history of hypertension had smaller increases in systolic blood pressure during treadmill exercise (55 +/- 3 mm Hg vs 64 +/- 3 mm Hg; p less than 0.03). There were no differences in echocardiographic left ventricular mass index between the groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

Hemodynamic effects of glucagon in portal hypertension

It has been suggested that glucagon contributes to the pathogenesis of portal hypertension by increasing portal blood flow. This study examined this issue by assessing the hemodynamic effects of a pharmacological dose of glucagon (1 mg, intravenously) in patients with cirrhosis and portal hypertension (n = 10) and in subjects without significant liver disease (controls = n = 5). Patients with cirrhosis had much higher glucagon levels than control subjects (875 +/- 167 vs. 186 +/- 25 pg/ml, p less than 0.01) and showed blunted hemodynamic responses after glucagon administration. This occurred despite greater circulating glucagon levels, probably because of a significant prolongation of the plasma half-life of exogenously administered glucagon (4.9 +/- 0.4 vs. 2.7 +/- 0.1 min, p less than 0.1). Control subjects had marked increases in heart rate (+ 19% +/- 4%, p less than 0.01), cardiac index (+ 16% +/- 4%, p = 0.01) and arterial pressure (+ 10% +/- 3%, p less than 0.05), but corresponding changes in patients with cirrhosis (+ 7% +/- 1%, + 6% +/- 1%, and + 6% +/- 2%, respectively) were significantly less pronounced (p = 0.05), and there was a negative correlation between basal glucagon levels and the response of heart rate to glucagon injection (r = -0.804, p less than 0.001). Resistance to the systemic effects of glucagon in cirrhosis may thus be caused by a down-regulation of vascular glucagon receptors. In addition, glucagon administration caused a significant increase in portal pressure (from 18.1 +/- 1.1 to 19.0 +/- 1.2 mm Hg, p less than 0.01), as well as in azygos blood flow (from 0.54 +/- 0.03 to 0.64 +/- 0.04 L/min, + 19% +/- 4%, p less than 0.02), reflecting increased portocollateral blood flow. These findings are consistent with the hypothesis that glucagon is one of the factors contributing to the splanchnic vasodilatation and increased portal pressure of cirrhosis.     

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)     

Octreotide inhibits the meal-induced increases in the portal venous pressure of cirrhotic patients with portal hypertension: a double-blind, placebo-controlled study.

The aim of this study was to determine the effects of the long-acting somatostatin analog, octreotide, on portal venous pressure and collateral blood flow in cirrhotic patients with portal hypertension during fasting and postprandial states. In a double-blind, placebo-controlled study, we investigated the effects of octreotide on the hepatic venous pressures and azygos blood flow of 21 patients before and after a standard liquid meal containing 40 gm of protein in 250 ml. Octreotide significantly reduced azygos blood flow from a mean of 499 +/- 65 ml/min to a mean of 355 +/- 47 ml/min (p < 0.01), but it had no effect on the hepatic venous pressure gradient. The hepatic venous pressure gradient of patients in the placebo group increased significantly, from a fasting mean of 16.4 +/- 1.6 mm Hg to a mean of 20.0 +/- 1.7 mm Hg 30 min after the meal (p < 0.01). In a second protocol hepatic venous pressures were measured in 20 patients at 30-min intervals for 2 hr after ingestion of the mixed meal. Again the placebo group showed a significant increase in the hepatic venous pressure gradient 30 min after the meal (20.4 +/- 1.5 mm Hg vs. 18.2 +/- 1.2 mm Hg; p < 0.05), but the group receiving octreotide showed no significant changes during the 2 hr of observation. We conclude that octreotide significantly reduces azygos blood flow, with little effect on portal venous pressure, and that it appears to inhibit postprandial increases in portal pressure in cirrhotic patients with portal hypertension.     

Hemodynamic effects of octreotide in patients with autonomic neuropathy

BACKGROUND. The somatostatin analogue, ectrootide, is being used to treat postprandial hypotension in patients with autonomic neuropathy. Although the therapeutic effect of the drug is presumably secondary to a splanchnic vasoconstrictor action, its effect on splanchnic hemodynamics has never been characterized in patients with autonomic neuropathy. Moreover, it is unknown whether octreotide acts on other vascular beds in this group of patients or whether it affects cardiac output. We, therefore, measured splanchnic, forearm, and systemic vascular resistance and cardiac output before and after administering octreotide (0.4 microgram/kg s.c.) to patients with idiopathic autonomic neuropathy and diabetic autonomic neuropathy. METHODS AND RESULTS. Splanchnic blood flow was determined from the clearance of indocyanine green in seven patients. We observed that octreotide decreased splanchnic blood flow (from 850 +/- 77 to 664 +/- 48 ml/min, p less than 0.005), increased mean blood pressure (from 97 +/- 6 to 115 +/- 3 mm Hg, p less than 0.005), and increased splanchnic vascular resistance (from 0.118 +/- 0.012 to 0.18 +/- 0.018 mm Hg/ml/min, p less than 0.005). Forearm blood flow was measured by plethysmography in 13 patients. Octreotide increased forearm vascular resistance in patients with idiopathic autonomic neuropathy (n = 8) from 19.1 +/- 1.0 to 27.2 +/- 3.8 mm Hg/ml/min/100 ml forearm volume (p less than 0.01) and from 25.2 +/- 3.9 to 41.0 +/- 6.8 mm Hg/ml/min/100 ml (p less than 0.01) in patients with diabetic autonomic neuropathy (n = 5). Cardiac output was measured by two-dimensional echocardiography. Octreotide administration increased cardiac output in five of six patients with idiopathic autonomic neuropathy (from 4.4 +/- 0.4 to 5.0 +/- 0.5 l/min, p less than 0.02) and five of five patients with diabetic autonomic neuropathy (from 3.8 +/- 0.4 to 5.1 +/- 0.4 l/min, p less than 0.02). Systemic vascular resistance increased in patients with idiopathic autonomic neuropathy from 21.2 +/- 2 to 24.9 +/- 2.6 (p less than 0.05) but did not change in patients with diabetic autonomic neuropathy. CONCLUSION. The pressor effect of octreotide in patients with autonomic neuropathy is associated with increased splanchnic and forearm vascular resistance and with increased cardiac output.     

Acute coronary vasoconstrictive effects of cigarette smoking in coronary heart disease

To investigate the effect of cigarette smoking on the coronary vasculature, coronary sinus flow and myocardial oxygen delivery were measured at rest and during incremental atrial pacing in 10 patients with coronary artery disease. Measurements were then repeated while the patients smoked 2 unfiltered, high-nicotine cigarettes. Although smoking significantly increased the heart rate at rest and double product, coronary sinus flow did not change significantly (141 +/- 32 vs 146 +/- 28 ml/min). At the lowest equivalent pacing rate before and during smoking, the double products were comparable. However, coronary sinus flow was reduced by smoking (146 +/- 28 vs 159 +/- 28 ml/min, p less than 0.01) and coronary vascular resistance was increased (0.96 +/- 0.15 vs 0.83 +/- 0.13 mm Hg ml-1 min, p less than 0.02). The double products were also comparable at the peak pacing rate before and during smoking. Nonetheless, the coronary sinus flow was again lower (167 +/- 23 vs 227 +/- 41 ml/min, p = 0.02) and the coronary vascular resistance was higher (0.77 +/- 0.10 vs 0.63 +/- 0.09 mm Hg ml-1 min, p less than 0.01) during smoking. The transmyocardial arteriovenous oxygen difference was unchanged by smoking; therefore, myocardial oxygen delivery was reduced in proportion to the reductions in coronary sinus flow. Thus, cigarette smoking appears to acutely alter the ability of the coronary vasculature to regulate flow in accordance with the oxygen requirements of the myocardium.     

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.     

Combined dose ratios of dopamine and dobutamine and right ventricular performance after cardiac surgery.

The effect of combined administration of different dose ratios of dobutamine (DB) and dopamine (DA) (DB/DA ratio of 1:1; 1.5:0.5; 2:0; 0.5:1.5; and 0:2), with the added dose kept constant (10 micrograms/kg/min-20 micrograms/kg/min), on right ventricular function (measured by the thermal washout method with the aid of a rapid-response thermistor) was determined in ten patients after cardiac surgery (between 12 and 24 h after surgery). The following values represent the mean +/- SD of DB only and of the DB/DA-equal combination vs DA only. The DB/DA-equal or DB-dominant combination increased the right ventricular ejection fraction vs DA only (0.39 +/- 0.12 [p less than 0.01] and 0.37 +/- 0.11 [p less than 0.05], respectively, vs 0.32 +/- 0.12) and the stroke volume index (43 +/- 12 ml/m2 [p less than 0.01] and 41 +/- 15 ml/m2, respectively, vs 38 +/- 14 ml/m2) and decreased right ventricular end-diastolic pressure (RVEDP) (10 +/- 4 mm Hg [p less than 0.01] and 11 +/- 4 mm Hg [p less than 0.05], respectively, vs 13 +/- 5 mm Hg) and pulmonary capillary wedge pressure (10 +/- 4 mm Hg [p less than 0.01] and 12 +/- 5 mm Hg [p less than 0.05], respectively, vs 14 +/- 6 mm Hg) to the same degree as DB alone. The DB/DA-equal or DB-dominant combination did not induce tachycardia (heart rate, 105 +/- 11 [p less than 0.05] and 95 +/- 14 beats per minute, respectively, vs 90 +/- 17 beats per minute) or have any effect on the right ventricular end-diastolic volume index (RVEDVI) (115 +/- 30 ml/m2 and 117 +/- 33 ml/m2, respectively, vs 127 +/- 42 ml/m2). Moreover, the diastolic parameters of the right ventricle (the ratio of RVEDVI/RVEDP: 15 +/- 8 [p less than 0.05] and 13 +/- 7, ml/mm Hg/m2, respectively, 11 +/- 5 ml/mm Hg/m2) decreased as the ratio of DA increased. This change in the diastolic properties of the right ventricle might have been caused by release of norepinephrine in the myocardium by DA or by improved coronary perfusion with DB. The DB/DA-equal and DB-dominant combinations were superior to DB or DA alone and to the DA-dominant combination in obtaining enhanced right ventricular performance.     

Comparative effects of pacing-induced and flow-limited ischemia on left ventricular function

We compared left ventricular (LV) myocardial blood flow and function accompanying severe demand ischemia (rapid atrial pacing in the presence of critical bilateral coronary stenoses) and supply ischemia (complete bilateral coronary occlusion) of the same ischemic regions in 14 pentobarbital-anesthetized dogs. Pacing-induced ischemia resulted in pronounced reductions in average regional epicardial blood flow (0.8 +/- 0.4 vs. control 1.2 +/- 0.4 [+/- SD] ml/g/min, p less than 0.05) and endocardial blood flow (0.4 +/- 0.1 vs. control 1.3 +/- 0.3 ml/g/min, p less than 0.05). More severe reductions in average regional epicardial and endocardial blood flow were seen after bilateral coronary occlusion (BCO) (0.3 +/- 0.3 and 0.1 +/- 0.1 vs. control 1.3 +/- 0.3 ml/g/min, p less than 0.05, respectively). Hemodynamics of postpacing ischemia (PPi) were consistently characterized by systolic impairment including depressed systolic contractile performance [(+)dP/dtmax 1,281 +/- 442 vs. control 2,173 +/- 775 mm Hg/sec, p less than 0.05], ventricular dilation (left ventricular [LV] end-diastolic dimension [EDD] 47.6 +/- 7.8 vs. control 44.7 +/- 8.6 mm, p less than 0.05), and an increase in LV end-diastolic pressure (EDP) (14.4 +/- 2.8 vs. control 4.2 +/- 2.8 mm Hg, p less than 0.05). Abnormalities in early and late diastolic function with PPi included increased time constant of isovolumic relaxation (78.0 +/- 40.4 vs. control 46.4 +/- 20.5 msec, p less than 0.05) and increased chamber stiffness (1.9 +/- 0.77 vs. control 0.81 +/- 0.55 mm Hg/mm, p less than 0.05), respectively. The LV diastolic pressure-dimension relation, however, shifted upward and to the right in eight of nine animals, whereas an upward shift was observed in only one animal. Thus, in this model of postpacing ischemia, we observed contractile failure and passive changes in diastolic function. Alterations in ventricular function occurred consistently earlier and to a greater extent during BCO than PPi, including higher LVEDP (25.3 +/- 8.1 vs. 14.9 +/- 6.6 mm Hg, p less than 0.05), greater ventricular dilation (delta LVEDD 4.9 +/- 2.5 vs. 3.5 +/- 2.8 mm, p less than 0.05), and reduced minor-axis dimension shortening (3.3 +/- 3.1% vs. 6.5 +/- 3.6%, p less than 0.05). To detect potential qualitative differences in ventricular function between the two types of ischemia, we evaluated hemodynamics at comparable loading conditions (30 seconds to 1 minute of BCO).(ABSTRACT TRUNCATED AT 400 WORDS)     

Response to the Valsalva maneuver after the Fontan procedure for tricuspid valve atresia, single ventricle or pulmonic valve atresia

The Valsalva maneuver was performed during cardiac catheterization in 9 patients who had undergone a Fontan operation (Fontan group) and in 10 control subjects. The Fontan group had higher right atrial (RA) pressure (16 +/- 1 vs 4 +/- 0.5 mm Hg, p less than 0.001), lower cardiac index (2.5 +/- 0.1 vs 3.7 +/- 0.2 liters/min/m2, p less than 0.05), lower stroke index (32 +/- 2 vs 44 +/- 2 ml/beat/m2, p less than 0.05), and higher systemic vascular resistance (31 +/- 1 vs 24 +/- 1 units, p less than 0.05) than the control group. Four patients in the Fontan group had a normal 4-phase Valsalva response, and 5 did not (p less than 0.05). RA pressure was similar in those who responded normally and those who did not (16 +/- 0.5 vs 17 +/- 1 mm Hg), whereas in those who responded normally cardiac index was higher (2.9 +/- 0.2 vs 2.2 +/- 0.1 liters/min/m2, p less than 0.05), stroke index was higher (36 +/- 1 vs 28 +/- 1 ml/beat/m2, p less than 0.05), and systemic vascular resistance was lower (28 +/- 1 vs 31 +/- 1, p less than 0.05). It is concluded that cardiac output is a better predictor of a normal response to the Valsalva maneuver than RA pressure in patients after the Fontan procedure. A normal response to the supine Valsalva maneuver suggests a cardiac index greater than 2.4 liters/min/m2 and stroke index greater than 31 ml/beat/m2.     

Effect of iron deficiency on tissue oxygen delivery in cyanotic congenital heart disease

To test the hypothesis that tissue oxygen delivery would be affected by diminished oxygen stores in cyanotic congenital heart disease, serum ferritin, transferrin saturation, hemoglobin, red cell mean corpuscular volume (MCV), red cell 2,3-diphosphoglycerate (DPG), P50, blood gases, oxygen saturations and systemic oxygen transport were measured in 29 hypoxemic infants and children. For the group, aortic saturation was 81 +/- 9%, PaO2 was 50 +/- 12 mm Hg, hemoglobin 16.2 +/- 2.1 gm/dl and systemic oxygen transport 620 +/- 145 ml/min/m2. P50 was increased above normal values (28.8 +/- 2.3 vs 26.6 +/- 1.1 mm Hg, p less than 0.01), and DPG was 2.35 +/- 0.54 mumol/ml, at the upper limits of normal for this assay. Iron deficiency was present in 8. When patients with P50 greater than or equal to 30 mm Hg and P50 less than 30 mm Hg were compared, iron stores were diminished in the high P50 group: [serum ferritin (19 +/- 8 vs 53 +/- 48 ng/ml, p = 0.0006), transferrin saturation (11 +/- 6 vs 23 +/- 11%, p = 0.003) and MCV (79 +/- 8 vs 86 +/- 4 fl, p = 0.05)]. Hemoglobin, aortic oxygen saturation, PaO2 and systemic oxygen transport were similar in both groups. In children with iron sufficiency, 15 of 21 had MCV greater than 90th percentile for age and sex (p less than 0.001 versus expected distribution). Also, MCV greater than 90th percentile for age and sex had a positive predictive value of 0.88 for iron sufficiency. This study demonstrates that diminished iron stores in cyanotic congenital heart disease are associated with a more right-shifted oxyhemoglobin dissociation curve (increased P50).(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.