The somatostatin analogue octreotide protects against ethanol-induced microcirculatory stasis and elevated vascular permeability in rat gastric mucosa

Abstract

Somatostatin 14 and various derivatives protect rat gastric mucosa against ethanol-induced lesions. Their mechanism of action is unknown. We investigated the effect of two somatostatin derivatives, octreotide and 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 microcirculatory mechanisms behind the gastroprotective effect. Radioligand studies revealed a high affinity of octreotide for the somatostatin receptor (IC 50 = 5 × 10 −10 mol/l), in contrast to 5-( l)-citrullin-octreotide (IC 50 = 3 × 10 −6 mol/l). This was in good agreement with the inhibition of growth hormone release from rat anterior pituitary cells (octreotide: IC 50 = 1.2 × 10 −10 mol/l; 5-( l)-citrullin-octreotide: IC 50 = 3 × 10 −6 mol/l. Intragastric administration of ethanol to rats resulted in lesions of the gastric mucosa affecting 18.9 ± 3.1% of the 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)-citrullin-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 mic increase in microvascular permeability, measured by the extravasation of the tracer fluorescein-isothiocyanate-dextran (molecular weight 150 000). Pretreatment with octreotide (0.1 ng/kg s.c.) prevented stasis and reduced capillary permeability significantly. 5-( l)-citrullin-octreotide had no effect on ethanol-induced microcirculatory stasis and elevated vascular permeability in rat gastric mucosa. In summary, very low doses of octreotide have a benefical effect on ethanol-induced hemorrhagic lessions, microcirculatory stasis and increased capillary permeability. This effect is most likely mediated by somatostatin receptors.