The somatostatin analogue octreotide protects against ethanol-induced microcirculatory stasis and elevated vascular permeability in rat gastric mucosa.
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 (IC50 = 5 x 10(-10) mol/l), in contrast to 5-(L)-citrullin-octreotide (IC50 = 3 x 10(-6) mol/l). This was in good agreement with the inhibition of growth hormone release from rat anterior pituitary cells (octreotide: IC50 = 1.2 x 10(-10) mol/l; 5-(L)-citrullin-octreotide: IC50 = 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 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 microcirculatory stasis and elevated 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 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.(ABSTRACT TRUNCATED AT 250 WORDS)
Kusterer
K
K
Johann Wolfgang Goethe-University, Department of Endocrinology, Frankfurt am Main, Germany.
Buchheit
K H
KH
Schade
A
A
Bruns
C
C
Neuberger
C
C
Engel
G
G
Usadel
K H
KH
D000818:Animals; D002199:Capillary Permeability / Q000187:drug effects; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005753:Gastric Mucosa / Q000098:blood supply* / Q000187:drug effects*; D006471:Gastrointestinal Hemorrhage / Q000139:chemically induced / Q000517:prevention & control; D013006:Growth Hormone / Q000378:metabolism; D008297:Male; D008833:Microcirculation / Q000187:drug effects; D015282:Octreotide / Q000494:pharmacology*; D010902:Pituitary Gland / Q000187:drug effects / Q000378:metabolism; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects
D000431:Ethanol; D013006:Growth Hormone; D015282:Octreotide