Beneficial effect of ultra-low-dose aspirin in platelet activity alterations and haemorrhage observed in experimental portal hypertension.

Ultra-low-dose aspirin has shown a prothrombotic effect in the laser-induced thrombosis model. Several studies of our laboratory have shown a positive effect in rats with two different experimental models of portal hypertension: portal vein ligation, a model with an almost normal liver, and 30 days of bile duct ligation, a model with cirrhosis and presence of ascitis. In both models of portal hypertensive rats, bleeding time was prolonged and thrombi formation, in a laser-induced model of thrombi production, decreased. The hypotheses of the presented studies were that ultra-low-dose aspirin could decrease the bleeding complications in these models and that the mechanism for these effects could act thorough the COX pathway. In different studies, ultra-low dose of aspirin normalized the induced hemorrhage time, thrombi production, and platelet-endothelial cell interaction. The possible beneficial role of these doses of aspirin and mechanism of COX 2 inhibition are discussed.

Role of heme oxygenase/carbon monoxide pathway on the vascular response to noradrenaline in portal hypertensive rats.

1. Portal hypertension (PH), a major syndrome in cirrhosis, producing hyperdynamic splanchnic circulation and hyperaemia. In order to elucidate the contribution of heme oxygenase to the vascular hyporeactivity, we assessed the activity of heme oxygenase-1 (HO-1), measured the in vivo pressure response to noradrenaline (NA) and investigated the effects of blocking the carbon monoxide (CO) and nitric oxide (NO) pathways in a prehepatic model of PH in rats. 2. Portal hypertension was induced by partial portal vein ligation (PPVL). Noradrenaline was injected intravenously. Liver, spleen and mesentery homogenates were prepared for measurement of HO-1 activity and expression. Four groups of rats were used: (i) a sham group; (ii) a PPVL group; (iii) a sham group pretreated with Zn-protoporphyrin IX (ZnPPIX); and (iv) a PPVL group pretreated with ZnPPIX. Each group was studied before and after treatment with the NO synthase inhibitor N(G)-nitro-L-arginine methyl ester (L-NAME). 3. For basal pressures and the pressure response to NA, inhibition of CO and NO pathways by ZnPPIX and L-NAME, respectively, produced an increase in mean arterial pressure (MAP) in sham-operated and in PH rats. Similarly, when both inhibitors were used together in either sham or PPVL rats, a greater increase in MAP was observed. 4. These results, together with the increased HO-1 activity and expression only in the PH group, have led us to suggest that the heme oxygenase/CO pathway is involved in the vascular response to NA in PH rats.

Systemic baroreflex alterations in prehepatic portal hypertensive conscious rats.

In portal hypertensive patients and experimental models, hyperdynamic circulatory disturbances associated to a reduced peripheral resistance and an increased cardiac output appeared. The aim of this research is the study of the baroreflex system behavior partially portal vein ligated-portal hypertensive rats. Sham operated rats (S) (n = 7) and portal hypertensive rats (PH) (n = 9) were used. In anesthetized rats, catheters were introduced into a jugular vein for drug injection and into the ventral tail artery to record blood pressure and heart rate. When rats were conscious and moving freely, a bolus injection of phenylephrine hydrochloride (6 micrograms/kg) was injected in the vein. A sigmoid curve relating systolic blood pressure and heart period was dressed. We analyzed: 1) The gain or sensitivity: the slope of the regression line; 2) The threshold: systolic blood pressure at which the regression begins to be linear. The results were: mean arterial pressure (mmHg): S = 103 +/- 7; PH = 109 +/- 3; gain (ms/mmHg): S = 1.29 +/- 0.10; PH = 0.62 +/- 0.04 (p < 0.001); threshold (mmHg): S = 145 +/- 7; PH = 146 +/- 4. The baroreceptor reflex sensitivity was significantly decreased. No differences appeared in the mean arterial pressure and in the reflex threshold. It is suggested that portal hypertension induces alterations in baroreflex regulation of arterial blood pressure.

Prehepatic portal hypertension in rats modifies norepinephrine metabolism in hypothalamus, medulla oblongata and portal vein.

The present experiments investigated the possible relationship between portal hypertension and norepinephrine metabolism in the central nervous system (hypothalamus and medulla oblongata) and the portal vein in the rat. Group I (72), portal hypertensive, and group II (70) sham-operated animals, were sacrificed day 14, and endogenous norepinephrine content, uptake and release from hypothalamus, medulla oblongata, and portal vein were investigated. In group I our results showed increases in norepinephrine storage (69%; 8.3%) and release (19.7%; 43.8%) and a diminished uptake (42.3%; 27.5%) in the hypothalamus and medulla oblongata, respectively. Portal veins showed a decreased content and uptake (62.5% and 43.5%, respectively) and increased release (25%) compared to group II rats. These results suggest a close relationship between the central nervous system and rat portal hypertension, perhaps related to modifications of central sympathetic activity.