GTP cyclohydrolase 1 inhibition attenuates vasodilation and increases blood pressure in rats.
GTP cyclohydrolase 1 is the rate-limiting enzyme in production of tetrahydrobiopterin, a necessary cofactor for endothelial nitric oxide synthase. We tested the hypothesis that inhibition of tetrahydrobiopterin synthesis impairs endothelium-dependent relaxation and increase blood pressure in rats. 2,4-Diamino-6-hydroxypyrimidine (DAHP), a GTP cyclohydrolase 1 inhibitor, was given in drinking water (approximately 120 mg.kg(-1).day(-1)) to male Sprague-Dawley rats for 3 days. Systolic blood pressures were measured (tail-cuff procedure) for 3 days before and each day during DAHP treatment. Blood pressure was significantly increased after DAHP treatment (122 +/- 2 vs. 154 +/- 3 mmHg before and after DAHP, respectively; P < 0.05). Endothelium-intact aortic segments from pentobarbital sodium-anesthetized rats were isolated and hung in organ chambers for measurement of isometric force generation. Aortas from DAHP-treated rats exhibited a decreased maximal relaxation to ACh compared with controls [% relaxation from phenylephrine (10-7 M)-induced contraction: DAHP 57 +/- 6% vs. control 79 +/- 4%; P < 0.05]. Relaxation responses to A-23187 were also decreased in aortas from DAHP-treated rats compared with controls. Incubation with sepiapterin (10-4 M, 1 h), which produces tetrahydrobiopterin via a salvage pathway, restored relaxation to ACh in aortas from DAHP-treated rats. Superoxide dismutase significantly increased ACh-induced relaxation in aortas from DAHP-treated rats, whereas catalase had no effect. Endothelium-independent relaxation to sodium nitroprusside in aortas from DAHP-treated rats was not different from control rats; however, nitric oxide synthase inhibition increased sensitivity to sodium nitroprusside in aortas from DAHP-treated rats. These results support the hypothesis that GTP cyclohydrolase 1 inhibition decreases relaxation and increases blood pressure in rats.
Mitchell
Brett M
BM
Department of Physiology CL-3162, Medical College of Georgia, 1120 15th Street, Augusta, GA 30912, USA. brettmitchell@hotmail.com
Dorrance
Anne M
AM
Webb
R Clinton
RC
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D004730:Endothelium, Vascular / Q000201:enzymology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000378:metabolism; D007042:Hypoxanthines / Q000494:pharmacology; D008297:Male; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D004791:Enzyme Inhibitors; D007042:Hypoxanthines; D012333:RNA, Messenger; D006136:GTP Cyclohydrolase; C017202:2,4-diaminohypoxanthine