Effect of the diuretic, 1,4-dimorpholino-7-phenylpyrido[3,4-d]-pyridazine (DS-511) and its derivatives on ADH-cyclic AMP system in rat renal medullary slices.
The effect of the diuretics, 1,4-dimorpholino-7-phenylpyrido[3,4-d]pyridazine (DS-511) and its 4'-hydroxy derivative [DS-511(4'-OH)] on the ADH-cyclic AMP system was studied in slices of rat renal medulla. These compounds alone did not affect the basal level of cyclic AMP in the slices. Preincubation with 10(-6) mol DS-511 or 10(-7) to 10(-5) mol DS-511-(4'-OH) in the presence of theophylline, inhibited arginine vasopressin stimulated formation of cyclic AMP, but after washing the slices the formation was restored. Etacrynic acid required higher concentrations such as 10(-5) and 10(4-) mol to cause inhibition. No effect was observed with furosemide and hydrochlorothiazide in concentrations up to 10(-4) mol. DS-511(4'-OH) at concentrations higher than 10(-6) mol inhibited the activity of cyclic AMP-phosphodiesterase in the medullary homogenate. These results suggest the water diuretic action of DS-511 is partly mediated by its inhibition of the ADH-cyclic AMP system.
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000378:metabolism; D000818:Animals; D001127:Arginine Vasopressin / Q000494:pharmacology; D000242:Cyclic AMP / Q000378:metabolism*; D004232:Diuretics / Q000494:pharmacology*; D066298:In Vitro Techniques; D007672:Kidney Cortex / Q000187:drug effects; D007679:Kidney Medulla / Q000187:drug effects / Q000378:metabolism*; D008297:Male; D009025:Morpholines / Q000494:pharmacology; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D013806:Theophylline / Q000494:pharmacology; D013997:Time Factors; D014667:Vasopressins / Q000494:pharmacology*
D004232:Diuretics; D009025:Morpholines; D011724:Pyridazines; D014667:Vasopressins; D001127:Arginine Vasopressin; D013806:Theophylline; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases