Long-term octreotide treatment prevents vascular hyporeactivity in portal-hypertensive rats

Abstract

Chronically portal-hypertensive rats show in vitroNatural somatostatin and its long-acting analogue vascular hyporeactivity in large part mediated by the octreotide 8 are increasingly used as vasoconstrictive endothelium-derived vasodilator nitric oxide. We tested agents in the treatment of variceal hemorrhages. 9-11 whether long-term octreotide treatment (15 mg/kg sub-Additionally, long-term octreotide treatment has recutaneously in 5% D/W, 8-hourly) corrects the in vitro cently been shown to prevent the development of the vascular hyporeactivity. Increases in perfusion pres-hyperdynamic circulation and sodium retention in presures (Dmm Hg) to potassium chloride (30-300 mmol/L) hepatic portal-hypertensive rats. 12 of in vitro perfused superior mesenteric arterial vascu-The mechanism or mechanisms of the vasopressor lar beds of partial portal vein-ligated (PVL) rats were action of natural somatostatin and octreotide are still significantly (P õ .05) higher in octreotide (n Å 9) comunclear. Because both peptides do not directly interact pared with placebo (n Å 10, 5% D/W) treated animals.Octreotide significantly (P õ .05) increased mean arte-with vascular smooth muscle cells, 13 as hypothesized rial pressure compared with placebo, the values being beforehand because of their rapid onset of action, 14 129 { 3 and 117 { 4 mm Hg, respectively. Furthermore, their vasoactivity seems to be caused by indirect mecha significant (P õ .001) correlation was observed be-anisms. tween in vitro vascular reactivity and mean arterialWe explored (1) whether long-term octreotide treatpressure. Incubation of separate vascular beds (n Å 7 ment may prevent the in vitro vascular hyporeactivity for both PVL and sham-operated rats) with octreotide in superior mesenteric arterial vascular beds of prehe-(10 06 mol/L) did not enhance pressure responses to 125 patic portal-hypertensive rats to the receptor-indepenmmol/L potassium chloride, and failed to increase perfudent vasopressor potassium chloride, and, if this is the sion pressures in preconstricted vessel preparations (n case, (2) whether octreotide might directly interact Å 6), excluding a direct inhibitory effect on NO. In summary, long-term octreotide treatment prevents in vitro with the secretion of the endothelium-dependent vasovascular hyporeactivity in prehepatic portal-hyperten-dilator NO. Systemic vasodilatation 1 and in vitro vascular hypo-linsdorf, Switzerland) with a weight of 285 { 7 g were used reactivity 2-5 are features of animal models of chronic (no significant differences between compared groups). In all portal hypertension. This in vitro vascular hyporeactiv-experiments, the authors adhered to the local guiding princiity of superior mesenteric arterial vascular beds seems ples for the care and use of animals. to be caused by an increased secretion of the endothe- Received October 19, 1994; accepted December 11, 1995. In Vitro Perfusion Preparation C. C. Sieber is the recipient of a SCORE career development grant of the Swiss National Foundation (3200-042547.94)...

Effects of a long-acting formulation of octreotide on renal function and renal sodium handling in cirrhotic patients with portal hypertension: A randomized, double-blind, controlled trial

“…22,35,36 The mechanism is not well defined, but a direct action of octreotide on vascular smooth muscle tone in splanchnic resistance vessels of portal hypertensive rats seems unlikely. 37,38 Also, a direct inhibitory effect of octrotide on nitric oxide secretion in the splanchnic vascular epithelium has been ruled out. 37 However, the experimental studies on the effects of octreotide on vascular reactivity have all been performed on splanchnic vessels, and a direct effect of octreotide in other areas of the vasculature has indeed been suggested by a recent study in cirrhotic patients.…”

“…37,38 Also, a direct inhibitory effect of octrotide on nitric oxide secretion in the splanchnic vascular epithelium has been ruled out. 37 However, the experimental studies on the effects of octreotide on vascular reactivity have all been performed on splanchnic vessels, and a direct effect of octreotide in other areas of the vasculature has indeed been suggested by a recent study in cirrhotic patients. 10 In addition, the experimental studies indicate that an inhibitory effect of octreotide on renin-aldosterone secretion as well as normalization of arginin-vasopressin may be responsible for the beneficial effects on sodium excretion.…”

Acute effects of the oral administration of midodrine, an α-adrenergic agonist, on renal hemodynamics and renal function in cirrhotic patients with ascites

“…Thus, a different and more complex therapeutic strategy has recently been proposed in these patients to potentiate the effects of vasoconstrictors on the splanchnic vascular bed, such as a long-term administration of the drug (i.e., terlipressin) 30 and its combined use with albumin solution 31 or with an inhibitor of endogenous vasodilators. As far as the potential effectiveness of inhibitors of endogenous vasodilators is concerned, it should be underscored that experimental data showed that octreotide, 32 an inhibitor of glucagon release, as well as nitric oxide inhibition may reverse the arterial hyporeactivity in portal hypertensive rats. 33,34 In particular, nitric oxide inhibition was shown to reverse both the in vitro hyporeactivity to ␣-adrenergic agents in portal hypertensive rats 33 and the hyperdynamic circulation and renal sodium and water retention in vivo in rats with cirrhosis and ascites.…”

Antifibrotic and Hemodynamic Effects of the Early and Chronic Administration of Octreotide in Two Models of Liver Fibrosis in Rats

“…This has been well demonstrated with glucagon, 4 and also with NO. 40 Moreover, it has been demonstrated that octreotide may inhibit the release of tumor necrosis factor ␣, 20 another NO synthase inductor.…”