Raimondo Cerini

Circulatory effects of somatostatin analogue in two conscious rat models of portal hypertension.

A somatostatin analogue, a long-acting octapeptide (SMS 201-995), has been reported to decrease portal pressure, but the mechanism is unclear. To elucidate the effects of this drug on both systemic and splanchnic hemodynamics, it was administered in two conscious rat models of portal hypertension. The dose-response curves showed that the somatostatin analogue significantly decreased portal pressure at a lower dose in rats with cirrhosis than in portal vein-stenosed rats. Calculated ED50 values were significantly different among all groups. Intravenous infusion of 8 micrograms/kg body wt.h of somatostatin analogue significantly decreased cardiac output by approximately 20% in both groups of portal hypertensive rats and increased mean arterial pressure by 7%. Accordingly, systemic vascular resistance markedly increased, indicating vasoconstrictor effects of this drug. The somatostatin analogue also significantly decreased portal tributary blood flow by 18% in portal vein-stenosed rats and 27% in cirrhotic rats. In sham-operated rats, somatostatin analogue had no effect on the systemic or splanchnic circulation. This study shows that somatostatin analogue decreases portal pressure principally by reducing portal tributary blood flow. This reduction may be due to either a direct vasoconstrictive effect or diminution in vasoactive hormone release.

Effects of oxygen inhalation on tissue oxygenation in patients with cirrhosis: Evidence for an impaired arterial baroreflex control

In patients with cirrhosis, O2 uptake, i.e., O2 consumption, is abnormally decreased. We administered 50% O2 for 30 min in eight patients with alcoholic cirrhosis to determine whether the subsequent increase in arterial O2 content may correct the low O2 consumption. In addition, we studied in these patients the reflex control of cardiac output and blood pressure by arterial baroreceptors, as O2 inhalation induces a systemic vasoconstriction. Arterial O2 tension, oxyhaemoglobin saturation and arterial O2 content significantly increased as well as systemic vascular resistance and arterial pressure. In contrast, O2 consumption (which was below normal values) under basal conditions, O2 transport, O2 extraction ratio, heart rate, right atrial and pulmonary wedged pressures, cardiac output, hepatic venous pressures, hepatic and azygos blood flows were unaffected by O2 administration. In three patients receiving air, no significant change was observed. Our results show that, in patients with cirrhosis, inhalation of 50% O2 does not correct O2 consumption. We may conclude that reflex control of cardiac output and arterial pressure by arterial baroreceptors is impaired in these patients.

Effects of α1 and β-adrenergic antagonists and 5-hydroxytryptamine receptor antagonist on portal-systemic collateral vascular resistance in conscious rats with portal hypertension

In order to study the acute effects of pharmacological agents on the vascular resistance of portal‐systemic collaterals, a model of total portal vein occlusion with 100% portal‐systemic shunts was developed in the conscious rat. The haemodynamic effects of several vaso‐active substances were evaluated in this model and compared with those obtained after saline administration. Prazosin (0.5 mg), an α1‐adrenergic antagonist, significantly reduced mean arterial pressure by 29%, portal pressure from 13.8 ± 1.0 (mean ± s.e.m.) to 10.1 ± 0.4 mmHg and portal tributary blood flow (radioactive microspheres) from 13.6 ± 2.1 to 11.7 ± 1.2 mL/min. It also decreased portal‐systemic vascular resistance from 95 ± 16 to 73 ± 9 dyn s/cm5 x 103. Propranolol (4 mg), a β‐adrenergic antagonist, significantly reduced mean arterial pressure by 12% and portal pressure from 15.5 ± 1.2 to 13.3 ± 0.9 mmHg while reducing portal tributary blood flow from 14.6 ± 1.5 to 11.0 ± 1.7 mL/min and increasing portal systemic collateral vascular resistance from 88 ± 7 to 103 ± 8 dyn s/cm5 x 103. Ketanserin (0.25 mg/kg), a 5‐hydroxytryptamine receptor antagonist, reduced portal pressure from 15.8 ± 1.0 to 13.3 ± 0.7 mmHg at a dose that did not alter mean arterial pressure or portal tributary blood flow. It achieved this by reducing portal‐systemic collateral vascular resistance from 90 ± 14 to 74 ± 13 dyn s/cm5 x 103. Saline had no significant effect on systemic and splanchnic haemodynamics. This study shows that ketanserin decreases vascular resistance of portal‐systemic collaterals while propranolol increases it. Thus, it is suggested that collateral vascular resistance is accessible to pharmacological manipulation.

Effects of glucagon on systemic and splanchnic circulation in conscious rats with biliary cirrhosis

To elucidate the relationship between the haemodynamic changes and glucagon in cirrhosis, we infused physiologic and supraphysiologic doses of this hormone in conscious rats with portal hypertension due to biliary cirrhosis. Cardiac output and splanchnic organ blood flows were measured by the radioactive microsphere method before and 30 min after glucagon infusion at doses of 2, 5 and 10 ng/min. Serum glucagon increased from a basal level of 92 +/- 17 pg/ml (mean +/- S.E.) to 399 +/- 89, 1151 +/- 136 and 2064 +/- 328 pg/ml, respectively, in sham-operated rats, and from 743 +/- 75 pg/ml to 1497 +/- 197, 1583 +/- 356 and 2957 +/- 649 pg/ml, respectively, in cirrhotic animals at 2, 5 and 10 ng/min doses. In both groups, cardiac output did not change after glucagon infusion at 2 and 5 ng/min doses, suggesting that factors other than glucagon are primarily responsible for the systemic hyperdynamic circulation in cirrhosis. Portal tributary blood flow increased significantly after glucagon infusion in sham-operated rats by 34 and 65% at doses of 5 ng/ml and 10 ng/ml, respectively, and in cirrhotic rats by 29% at a dose of 10 ng/ml. However, portal tributary blood flow did not change after glucagon infusion at the physiologic dose of 2 ng/min. This study shows that glucagon infused at a physiologic dose does not increase splanchnic blood flow, although it increases portal tributary blood flow at supraphysiologic doses. The discrepancy between blood glucagon levels and splanchnic haemodynamic responses suggests that glucagon plays only a minor role and that other factors are primarily responsible for the hyperdynamic state of the splanchnic circulation in rats with biliary cirrhosis.

Model for the study of portal-systemic collateral vascular resistance in the conscious rat

In order to obtain a model for the study of portal-systemic collateral vascular resistance, total portal vein occlusion was performed in rats 48 hr or 3 wk after partial obstruction. Four groups of conscious restrained rats were studied: a) sham-operated, b) partial portal vein ligated, c) 48 hr-total portal vein occluded, and d) 3 wk-total portal vein occluded. In comparison with the sham group, the three portal vein ligated groups had significantly higher cardiac output, portal tributary blood flow, portal pressure (7.7 +/- 0.4 versus 13.5 +/- 0.5, 13.6 +/- 0.8, and 17.7 +/- 1.1 mmHg, mean +/- SE, respectively) and hepatic arterial blood flow (5.8 +/- 0.6 versus 9.5 +/- 0.7, 8.3 +/- 0.5, and 13.9 +/- 1.9 ml/min, respectively). Cardiac output and portal tributary blood flow did not differ between the portal vein ligated groups, but portal pressure and hepatic arterial blood flow were significantly higher in the 3 wk-total portal vein occlusion group. The 3 wk-total portal vein occlusion group showed 99.1 +/- 0.3% shunting, different from the partial (29.7 +/- 16.9%, p less than 0.01) and 48 hr-total portal vein occlusion (46.5 +/- 14.7%, p less than 0.05) groups. Portography confirmed absence of portal-portal collaterals in the 3 wk-total portal vein occlusion group. It is suggested that rats with 3 wk-total portal vein occlusion are useful for the study of acute modifications of portal-systemic collateral circulation, as shunting is total and consistent in this model.