Endothelin A receptors mediate relaxation of guinea pig internal anal sphincter through cGMP pathway.
BACKGROUND
Endothelin (ET) modulates motility of the internal anal sphincter through unclear receptor subtypes.


METHODS
We measured relaxation of guinea pig internal anal sphincter strips caused by ET-related peptides and binding of (125)I-ET-1 to cell membranes prepared from the internal anal sphincter muscle. Visualization of (125)I-ET-1 binding sites in tissue was performed by autoradiography.


RESULTS
In the guinea pig internal anal sphincter, ET-1 caused a marked relaxation insensitive to tetrodotoxin, atropine, or omega-conotoxin GVIA. ET-2 was as potent as ET-1. ET-3 caused a mild relaxation. The relative potencies for ETs to cause relaxation were ET-1 = ET-2 > ET-3. The ET-1-induced relaxation was inhibited by BQ-123, an ET(A) antagonist, but not by BQ-788, an ET(B) antagonist. These indicate that ET(A) receptors mediate the relaxation. The relaxant response of ET-1 was attenuated by LY 83583, KT 5823, Rp-8CPT-cGMPS, tetraethyl ammonium, 4-aminopyridine and N(omega)-nitro-L-arginine, but not significantly affected by N(G)-nitro-L-arginine methyl ester, N(G)-methyl-L-arginine, charybdotoxin, apamin, KT 5720, and Rp-cAMPS. These suggest the involvement of cyclic guanosine 3',5'-cyclic monophosphate (cGMP), and potassium channels. Autoradiography localized (125)I-ET-1 binding to the internal anal sphincter. Binding of (125)I-ET-1 to the cell membranes prepared from the internal anal sphincter revealed the presence of two subtypes of ET receptors, ET(A) and ET(B) receptors.


CONCLUSIONS
Taken together, these results demonstrate that ET(A) receptors mediate relaxation of guinea pig internal anal sphincter through the cGMP pathway.
Huang
S-C
SC
Department of Internal Medicine, Buddhist Tzu Chi General Hospital, Hualien and Tzu Chi University, Hualien, Taiwan. shihchehuang@hotmail.com
D001003:Anal Canal / Q000187:drug effects / Q000502:physiology*; D000818:Animals; D001345:Autoradiography; D006152:Cyclic GMP / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D019333:Endothelin-2 / Q000494:pharmacology; D019334:Endothelin-3 / Q000494:pharmacology; D006168:Guinea Pigs; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D009126:Muscle Relaxation / Q000187:drug effects / Q000502:physiology*; D009130:Muscle, Smooth / Q000378:metabolism*; D044022:Receptor, Endothelin A / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D019332:Endothelin-1; D019333:Endothelin-2; D019334:Endothelin-3; D044022:Receptor, Endothelin A; D006152:Cyclic GMP