Restriction of drinking water abrogates splanchnic vasodilation and portal hypertension in portal vein-ligated rats

Portal hypertension is associated with splanchnic vasodilation which is claimed responsible for the maintenance of chronically elevated portal pressure. Vasopressin analogues are used in the treatment of acute variceal bleeding, since they effectively reduce splanchnic blood flow and portal pressure. Dehydration stimulates the release of endogenous vasopressin release. Here we compared the effects of deprivation of drinking water for 18 h with those of vasopressin infusion on mesenteric hemodynamics in portal vein-ligated (PVL) and sham-operated (SHAM) rats. Blood flow in the superior mesenteric artery was measured with the ultrasonic transit time shift technique. Deprivation of drinking water had no hemodynamic effects in SHAM rats, but completely reversed the mesenteric hyperemia and portal hypertension in PVL rats to figures measured in SHAM rats, without altering blood pressure. Similarly, intravenous infusion of low doses of arginine vasopressin (1-10 pmol/min) selectively reduced mesenteric blood flow in PVL rats but had little effect in SHAM rats. These data suggest that control of water balance or aquaretic drugs might have beneficial effects on splanchnic hemodynamics and portal pressure in advanced liver disease, possibly by stimulating endogenous vasopressin release.     

Activation of EP4 receptors prevents endotoxin-induced neutrophil infiltration into the airways and enhances microvascular barrier function

Background and Purpose

Pulmonary vascular dysfunction is a key event in acute lung injury. We recently demonstrated that PGE₂, via activation of E-prostanoid (EP)₄ receptors, strongly enhances microvascular barrier function in vitro. The aim of this study was to investigate the beneficial effects of concomitant EP₄ receptor activation in murine models of acute pulmonary inflammation.

Experimental Approach

Pulmonary inflammation in male BALB/c mice was induced by LPS (20 μg per mouse intranasally) or oleic acid (0.15 μL·g^-1, i.v^.). In-vitro, endothelial barrier function was determined by measuring electrical impedance.

Key Results

PGE₂ activation of EP₄ receptors reduced neutrophil infiltration, pulmonary vascular leakage and TNF-α concentration in bronchoalveolar lavage fluid from LPS-induced pulmonary inflammation. Similarly, pulmonary vascular hyperpermeability induced by oleic acid was counteracted by EP₄ receptor activation. In lung function assays, the EP₄ agonist ONO AE1-329 restored the increased resistance and reduced compliance upon methacholine challenge in mice treated with LPS or oleic acid. In agreement with these findings, EP₄ receptor activation increased the in vitro vascular barrier function of human and mouse pulmonary microvascular endothelial cells and diminished the barrier disruption induced by LPS. The EP₂ agonist ONO AE1-259 likewise reversed LPS-induced lung dysfunction without enhancing vascular barrier function.

Conclusion and Implications

Our results show that activation of the EP₄ receptor strengthens the microvascular barrier function and thereby ameliorates the pathology of acute lung inflammation, including neutrophil infiltration, vascular oedema formation and airway dysfunction. This suggests a potential benefit for EP₄ agonists in acute pulmonary inflammation.     

Effects of COX-1 and COX-2 inhibitors on eicosanoid biosynthesis and the release of substance P from the guinea-pig isolated perfused lung

OBJECTIVE: In the guinea-pig isolated perfused lung, co-administration of bradykinin (BK) and histamine causes the release of pro-inflammatory neuropeptides, an effect that is largely dependent on BK-induced formation of prostaglandins. Since it is known that at least two isoenzymes, cyclooxygenase-1 (COX-1) and cyclooxygenase-2 (COX-2) catalyse the conversion of arachidonic acid to prostaglandins (PGs) and thromboxanes, the present study aimed at investigating the effect of selective COX-1 and COX-2 inhibitors on the evoked release of substance P (SP). MATERIAL AND METHODS: Lungs were vascularly perfused with oxygenated physiological salt solution containing peptidase inhibitors. BK (0.1 microM) and histamine (100 microM) were added to the perfusate for 10 min and 5 min, respectively. The concentrations of 6-keto-PGF1alpha, cysteinyl-leukotriene (LT), and SP were determined in the outflow by radioimmunoassay. RESULTS: In non-stimulated preparations, indomethacin (2 microM) and the selective COX-1 inhibitor SC-560 (0.03-1 microM) reduced basal release of 6-keto-PGF1alpha, without significantly affecting the release of cysteinyl-LT and SP. The selective COX-2 inhibitors NS-398 (1 microM) or DFU (10 microM) had no significant effect on the basal release of eicosanoids or SP. Co-administration of BK and histamine caused a pronounced increase in the concentration of 6-keto-PGF1alpha and cysteinyl-LT, and SP in the effluate. Under these conditions, indomethacin as well as SC-560 reduced the release of 6-keto-PGF1alpha, enhanced cysteinyl-LT release, and attenuated the release of SP. In contrast, the selective COX-2 inhibitors NS 398 and DFU had no significant effect on the stimulated release of eicosanoids or SP. CONCLUSIONS: These results suggest that in the isolated guinea-pig lung, basal prostanoid biosynthesis as well as BK-induced stimulation of prostanoid formation and subsequent facilitation of histamine-induced SP release is primarily mediated by COX-1 without detectable involvement of COX-2.     

Influence of capsaicin-induced denervation on neurogenic and humoral control of arterial pressure

Summary (1) The influence of capsaicin-sensitive afferent neurones on the regulation of blood pressure by reflex noradrenergic responses and by activation of the renin-angiotensin system was investigated in the rat anaesthetized with pentobarbital. (2) Lowering the pressure in the carotid sinus through unilateral carotid occlusion caused a reflex rise in mean systemic blood pressure which was less marked in capsaicin-pretreated rats than in controls, although an equal drop in mean pressure in the carotid sinus region was observed in both groups. Occlusion of the second carotid artery caused an additional increase in mean systemic blood pressure which was identical in the two groups. (3) Pharmacological blockade of the renin-angiotensin-system with captopril induced a more pronounced hypotonia in capsaicin-pretreated than in control rats. Yet, this difference was based on the impaired noradrenergic counterregulation in capsaicin-pretreated rats, because both groups showed identical responses to captopril following guanethidine-induced adrenergic blockade. (4) Plasma renin activity was increased by a factor of 2 following guanethidine treatment of awake animals. It reached levels 5–7 times higher than those observed in awake animals during pentobarbital anaesthesia. This anaesthesia-induced increase in plasma renin activity was not altered by guanethidine pretreatment. There was no difference in plasma renin activity between controls and capsaicin-pretreated rats under all the conditions tested. (5) These results show that the immediate reflex adjustment of blood pressure is impaired in the capsaicin-pretreated rat, possibly because of an impairment of sensors for low perfusion pressure in the carotid sinus. On the other hand, the renin-angiotension-system remains unimpaired after neonatal capsaicin-pretreatment. Send offprint requests to J. Donnerer at the above address