Bradykinin acting on B2 receptors contracts colon circular muscle cells by IP3 generation and adenylate cyclase inhibition.
Receptor subtypes and intracellular signaling events involved in bradykinin-evoked contraction of colonic circular muscle are unknown. We studied the roles of inositol trisphosphate (IP3) and cyclic AMP generation and the selectivity for B1 and B2 receptors in guinea pig colon. Bradykinin induced concentration-dependent contraction of circular muscle strips with an EC50 of 2 x 10(-8) M that was inhibited by the B2 antagonist D-Argo-(Hyp3,Thi5,8,D-Phe7)-bradykinin but not the B1 antagonist des-Arg9-[Leu8]bradykinin. The B1 agonist des-Arg9-bradykinin did not evoke contraction or relaxation. Bradykinin induced concentration-dependent shortening of isolated myocytes from circular muscle with an EC50 of 2 x 10(-11) M that was inhibited by the B2 but not the B1 antagonist, confirming the myogenic nature of the bradykinin receptors. Persistence of myocyte contraction in a calcium-free medium with EGTA confirmed the lack of dependence on extracellular calcium. In colon muscle tissue, bradykinin evoked concentration-dependent IP3 generation with an EC50 of 10(-7) M and a maximal level of 58 +/- 17 pmol/mg of protein at 10(-4) M that was inhibited by the B2 but not the B1 antagonist. Bradykinin, acting on B2 receptors, inhibited cyclic AMP formation after forskolin (10(-5) M) with an EC50 of 3 x 10(-8) M and maximal inhibition of 48% at 10(-5) M. In conclusion, bradykinin induces colon muscle contraction via myogenic non-B1 receptors, which are likely of the B2 subtype, with phosphoinositide turnover activation and adenylate cyclase inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
Hasler
W L
WL
Department of Internal Medicine, University of Michigan Medical Center, Ann Arbor, USA.
Kurosawa
S
S
Takahashi
T
T
Feng
H
H
Gaginella
T S
TS
Owyang
C
C
D000067956:Adenylyl Cyclase Inhibitors; D000818:Animals; D001920:Bradykinin / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D000242:Cyclic AMP / Q000096:biosynthesis; D006168:Guinea Pigs; D066298:In Vitro Techniques; D015544:Inositol 1,4,5-Trisphosphate / Q000096:biosynthesis*; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D018002:Receptors, Bradykinin / Q000187:drug effects / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D010738:Type C Phospholipases / Q000502:physiology
D000067956:Adenylyl Cyclase Inhibitors; D018002:Receptors, Bradykinin; D015544:Inositol 1,4,5-Trisphosphate; D000242:Cyclic AMP; D010738:Type C Phospholipases; D001920:Bradykinin