The effect of ketotifen on nitric oxide synthase activity.
1. We studied the effect of ketotifen, a second generation H1-receptor antagonist on nitric oxide synthase (NOS) activity in colonic mucosa and in renal tissues, and on rat renal haemodynamics in vivo. 2. Ketotifen (100 micrograms 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 renal cortical and medullary tissues ketotifen increased NOS activity by 55% and 86%, respectively (P < 0.001). The stimulation of NOS activity was attenuated by NADPH deletion and by the addition of N omega nitro-L-arginine methyl ester (L-NAME) or aminoguanidine, but not by [Ca2+] deprivation. NOS activity was unaffected by two other H1-antagonists, diphenhydramine and astemizole, or by the structurally related cyproheptadine. 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 ketotifen stimulates NOS activity by mechanisms other than H1-receptor antagonism. The association of this effect with therapeutic characteristics of ketotifen and the clinical implications of these findings are yet to be defined.
Heyman
S N
SN
Department of Medicine, Hadassah University Hospital, Mount Scopus, Jerusalem, Israel.
Karmeli
F
F
Brezis
M
M
Rachmilewitz
D
D
D000818:Animals; D003106:Colon / Q000187:drug effects / Q000201:enzymology; D004789:Enzyme Activation; D006801:Humans; D007413:Intestinal Mucosa / Q000187:drug effects / Q000201:enzymology; D007665:Ketotifen / Q000494:pharmacology*; D007668:Kidney / Q000098:blood supply / Q000187:drug effects / Q000201:enzymology; D019001:Nitric Oxide Synthase / Q000378:metabolism*; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects
D019001:Nitric Oxide Synthase; D007665:Ketotifen