Differentiation of intestinal smooth muscle relaxation caused by drugs that inhibit phosphodiesterase.
In this study a number of chemically unrelated smooth muscle relaxants were tested: a) for potency of phosphodiesterase (PDE)-inhibition, using guinea pig colon-PDE and rat erythrocyte-PDE, b) for potency and duration of relaxation of the isolated guinea-pig colon, c) for their interaction with NH4Cl and orciprenaline as well as with "high calcium". Compared with the spasmolytic effect inhibition of guinea pig colon-PDE or rat erythrocyte-PDE was strong for papaverine and some other relaxants but was low or virtually absent with verapamil, hexobendine and bencyclane. The spasmolytic effect of some PDE-inhibitors was found diminished by the PDE-activator NH4Cl. Most of these drugs enhanced the relaxant effect of the "cyclase activator" orciprenaline; the latter are designated A-type drugs. Verapamil, bencyclane, hexobendine and M 13 did not show this type of interaction with NH4Cl and orciprenaline; they are designated B-type drugs. With A-type drugs--but not with B-type drugs--a highly significant correlation was observed between potency of relaxation and inhibition of colon-PDE (r = 0.85) as well as rat erythrocyte-PDE (r = 0.77). The spasmolytic action of aminophylline and papaverine (A-type drugs) was not inhibited by elevation of extracellular calcium to 9 mM, whereas relaxation induced by verapamil and hexobendine (B-type drugs) at 1.8 mM calcium was found abolished by 9 mM calcium. It is concluded that A-type drugs relax guinea-pig colon by inhibition of PDE and accumulation of cAMP, and that B-type drugs in all probability act by (a) cAMP-independent mechanism(s).
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors*; D000628:Aminophylline / Q000494:pharmacology; D000643:Ammonium Chloride / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D002217:Carbachol / Q000494:pharmacology; D003106:Colon / Q000187:drug effects; D006168:Guinea Pigs; D006592:Hexobendine / Q000494:pharmacology; D007546:Isoquinolines / Q000494:pharmacology; D009921:Metaproterenol / Q000494:pharmacology; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects* / Q000201:enzymology; D010208:Papaverine / Q000494:pharmacology; D010276:Parasympatholytics / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors; D014700:Verapamil / Q000494:pharmacology
D007546:Isoquinolines; D010276:Parasympatholytics; D010726:Phosphodiesterase Inhibitors; D000643:Ammonium Chloride; D000628:Aminophylline; D009921:Metaproterenol; D002217:Carbachol; D006592:Hexobendine; D014700:Verapamil; D010208:Papaverine; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D002118:Calcium