A PHARMACOLOGICAL ANALYSIS OF RECEPTOR SUBTYPES AND THE MECHANISMS MEDIATING THE BIPHASIC RESPONSE INDUCED BY KININS IN THE RAT STOMACH FUNDUS IN-VITRO

Bradykinin (BK), des-Arg(9)-BK (DABK) and related kinins caused biphas ic response (BR) in rat stomach fundus (RSF) precontracted with BaCl2. The B-2 receptor antagonist HOE 140 (3-30 nM) produced parallel right ward shifts of the contractile concentration-response curve (CRC) for BK, yielding a pA(2) value of 9.07 +/- 0.27 and slope of 0.99, but cau sed only discrete rightward shift of the relaxant CRC for BK, leaving the BR CRC to DABK unaffected. The B-1 receptor antagonist des-Arg(9)- NPC 17761 (10 nM to 1 mu M) caused graded rightward shifts of the rela xant (but not the contractile) CRC to DABK, yielding a pA, value of 8. 35 +/- 0.05 and slope of 0.59, but had no effect on BK-induced BR. BK- and DABK- (100 nM) induced relaxation were almost suppressed by apami n (1 mu M) or by nifedipine (1 nM), but were unaffected by nitric oxid e synthase inhibitors, methylene blue, lipo and cyclooxygenase inhibit ors, selective receptor antagonist for histamine (H-1 and H-2), nicoti ne, platelet activating factor, tachykinins (both NK1 and NK2), calcit onin gene-related peptide, vasoactive intestinal peptide and ganglion blocking agent. BK- and DABK-mediated relaxations were reduced in Ca2-free medium plus EGTA, although BK-mediated contraction was more resi stant, Escherichia coli endotoxin treatment (10 mu g/rat), 24 hr befor e, potentiated DABK-induced relaxation, but not contraction, and reduc ed BK-mediated relaxation (P < .05). It is concluded that RSF express both B-1 and B-2 receptors. BK-induced contraction involves activation of B-2 receptors, although DABK-induced relaxation is mediated by B-1 receptors. Both B-1 and B-2 receptors in RSF are constitutive, but LP S treatment caused induction of B-1 and down-regulation of B-2 recepto rs. Finally, kinin-mediated relaxation in RSF are coupled to activatio n of Ca2+ activated K+ channels, and rely on Ca2+ influx via L-type vo ltage-sensitive channels.