Peptidase activity as a determinant of agonist potencies in some smooth muscle preparations.
The influence of degradation by peptidases on concentration-response relationships for peptide agonists of the tachykinin and bombesin-like families was investigated. The combined presence of three peptidase inhibitors, phosphoramidon (1 microM), captopril (1 microM) and bestatin (100 microM), had no significant effect on the onset rates or peak contractile responses to these peptides in the rat urinary bladder and guinea-pig taenia caeci preparations, or on their peak potentiation of the contractile response to field-stimulation in the guinea-pig vas deferens preparation. However, rates of offset of the response to tachykinins were markedly prolonged in tissues treated with peptidase inhibitors. In experiments designed to estimate clearance of applied peptide from the organ bath, there was an initial rate of loss with the guinea-pig vas deferens and taenia caeci which, measured over the first 5 min, had a half-time of 2-3 min which was then prolonged to 6-8 min in the presence of peptidase inhibitors. These results show that although peptide breakdown can be demonstrated in these systems, it seems not to be an important determinant of relative pharmacological activity measured in terms of peak response.
Smooth Muscle Regulatory Research Unit, King's College London, U.K.
J M
JM
Hall
A J
AJ
Fox
I K
IK
Morton
D000818:Animals; D002432:Cecum / Q000187:drug effects; D004558:Electric Stimulation; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D009130:Muscle, Smooth / Q000187:drug effects / Q000201:enzymology*; D010447:Peptide Hydrolases / Q000378:metabolism*; D010455:Peptides / Q000378:metabolism; D011480:Protease Inhibitors / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains; D013373:Substance P / Q000494:pharmacology; D001743:Urinary Bladder / Q000187:drug effects; D014649:Vas Deferens / Q000187:drug effects
D010455:Peptides; D011480:Protease Inhibitors; D013373:Substance P; D010447:Peptide Hydrolases