THE EFFECT OF KETOTIFEN ON NITRIC-OXIDE SYNTHASE ACTIVITY

1 We studied the effect of ketotifen, a second generation H-1-receptor antagonist on nitric oxide synthase (NOS) activity in colonic mucosa and in renal tissues, and on rat renal haemodynamics in vivo. 2 Ketoti fen (100 mu g ml(-1)) increased human colonic NOS activity from 3.7 +/ - 0.6 to 14.5 +/- 1.3 nmol g(-1) min(-1) (P<0.005, ANOVA). In rat rena l cortical and medullary tissues ketotifen increased NOS activity by 5 5% and 86%, respectively (P<0.001). The stimulation of NOS activity wa s attenuated by NADPH deletion and by the addition of N-omega nitro-L- arginine methyl ester (L-NAME) or aminoguanidine, but not by [Ca2+] de privation. NOS activity was unaffected by two other H-1-antagonists, d iphenhydramine and astemizole, or by the structurally related cyprohep tadine. Renal cortical NOS activity was also significantly stimulated 90 min after intravenous administration of ketotifen to anaesthetized rats. 3 Ketotifen administration to anaesthetized rats induced modest declines in blood pressure and reduced total renal, cortical and outer medullary vascular resistance. This is in contrast to diphenhydramine , which did not induce renal vasodilatation. 4 We conclude that ketoti fen stimulates NOS activity by mechanisms other than I-Ii-receptor ant agonism. The association of this effect with therapeutic characteristi cs of ketotifen and the clinical implications of these findings are ye t to be defined.