The effects of [Leu13]
motilin were examined in vivo after its
intravenous administration into anesthetized dogs and in vitro with isolated preparations of canine mesenteric artery. [Leu13]
Motilin (0.1-10 nmol x kg(-1), i.v.) induced both strong and clustered phasic contractions in the gastric antrum and duodenum. At doses of over 1 nmol x kg(-1), [Leu13]
motilin also produced transient decreases in arterial blood pressure, left ventricular pressure, maximum rate of rise of left ventricular pressure, and total peripheral resistance, and an increase in aortic blood flow and heart rate. A selective
motilin antagonist,
GM-109 (Phe-cyclo[Lys-Tyr(3-tBu)-betaAla]
trifluoroacetate), completely abolished the gastric antrum and duodenal motor responses induced by [Leu13]
motilin. In contrast,
hypotension induced by [Leu13]
motilin (1 nmol x kg(-1)) was unchanged in the presence of
GM-109. In isolated mesenteric artery preparations precontracted with
U-46619 (10(-7) M), [Leu13]
motilin (10(-8)-10(-5) M) induced an endothelium-dependent relaxation, and this was inhibited by a pretreatment with
N(omega)-nitro-L-arginine, a competitive inhibitor of
NO synthase (10(-4) M). A high dose (10(-4) M) of
GM-109 slightly decreased [Leu13]
motilin-induced relaxation, and shifted the concentration-response curve of [Leu13]
motilin to the right. However, the pA2 value (4.09) of
GM-109 for [Leu13]
motilin in the present study was conspicuously lower than that previously demonstrated in the rabbit duodenum (7.37). These results suggest that [Leu13]
motilin induces
hypotension via the endothelial NO-dependent relaxation mechanism and not through the receptor type that causes upper gastrointestinal contractions.