THE SOMATOSTATIN ANALOG OCTREOTIDE PROTECTS AGAINST ETHANOL-INDUCED MICROCIRCULATORY STASIS AND ELEVATED VASCULAR-PERMEABILITY IN RAT GASTRIC-MUCOSA

Somatostatin 14 and various derivatives protect rat gastric mucosa aga inst ethanol-induced lesions. Their mechanism of action is unknown. We investigated the effect of two somatostatin derivatives, octreotide a nd 5-(L)-citrullin-octreotide, on ethanol-induced hemorrhagic lesions, microcirculatory stasis and elevated vascular permeability in the rat stomach, with the goal to elucitate the pharmacological and microcirc ulatory mechanisms behind the gastroprotective effect. Radioligand stu dies revealed a high affinity of octreotide for the somatostatin recep tor (IC50 = 5 X 10(-10) mol/l), in contrast to 5-(L)-citrullin-octreot ide (IC50 = 3 x 10(-6) mol/l). This was in good agreement with the inh ibition of growth hormone release from rat anterior pituitary cells (o ctreotide: IC50 = 1.2 X 10(-10) mol/l; 5-(L)-citrullin-octreotide: IC5 0 = 3 x 10(-6) mol/l). Intragastric administration of ethanol to rats resulted in lesions of the gastric mucosa affecting 18.9 +/- 3.1% of t he area of the glandular stomach. Octreotide reduced the area to 6.4 /- 1.7% (P < 0.05). The dose-response curve was bell-shaped. 5-(L)-cit rullin-octreotide was totally devoid of any protective activity (dose range: 0.1 ng/kg to 0.1 mg/kg). We further investigated the effect of the two peptides on ethanol-induced microcirculatory stasis and elevat ed vascular permeability. Ethanol in a concentration of 50% induced an increase in microvascular permeability, measured by the extravasation of the tracer fluorescein-isothiocyanate-dextran (molecular weight 15 0000). Pretreatment with octreotide (0.1 ng/kg s.c.) prevented stasis and reduced capillary permeability significantly. 5-(L)-citrullin-octr eotide had no effect on ethanol-induced microcirculatory stasis and el evated vascular permeability in rat gastric mucosa. In summary, very l ow doses of octreotide have a benefical effect on ethanol-induced hemo rrhagic lesions, microcirculatory stasis and increased capillary perme ability. This effect is most likely mediated by somatostatin receptors .