Phenylalanine improves dilation and blood pressure in GTP cyclohydrolase inhibition-induced hypertensive rats.
GTP cyclohydrolase (GTPCH), the rate-limiting enzyme in the production of the nitric oxide synthase cofactor tetrahydrobiopterin (BH4), is partly regulated by the GTPCH feedback regulatory protein (GFRP). GFRP can inhibit GTPCH by end-product negative feedback, and L-phenylalanine (L-Phe) reverses this inhibition and increases BH4 biosynthesis in vitro. We hypothesized that L-Phe would increase endothelium-dependent relaxation and decrease blood pressure in rats made hypertensive by GTPCH inhibition. Di-amino-hydroxypyrimidine (DAHP, 10 mmol/L), a known inhibitor of GTPCH, was given with or without L-Phe or D-Phe (2 mmol/L) in the drinking water of rats for 3 days and blood pressure was measured via tail-cuff. Endothelium-intact aortic segments were hung in organ chambers for measurement of isometric force generation. Systolic blood pressure was increased significantly in DAHP-treated rats compared with controls. The addition of L-Phe attenuated the hypertensive effect, whereas D-Phe had no effect. Acetylcholine- and A23187-induced relaxation was decreased in aortas from DAHP-treated rats compared with controls, but was restored in aortas from DAHP+L-Phe-treated rats. Following NOS inhibition, sensitivity to sodium nitroprusside was increased in aortas from DAHP-treated rats, but restored in DAHP+L-Phe-treated rats. These results suggest that L-Phe can reverse GTPCH inhibition in vivo leading to increased vasodilation and decreased blood pressure.
Mitchell
Brett M
BM
Department of Physiology, Medical College of Georgia, Augusta, USA. brettmitchell@hotmail.com
Dorrance
Anne M
AM
Webb
R Clinton
RC
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000633:toxicity; D006136:GTP Cyclohydrolase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006973:Hypertension / Q000188:drug therapy* / Q000201:enzymology* / Q000503:physiopathology; D066298:In Vitro Techniques; D010649:Phenylalanine / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D004791:Enzyme Inhibitors; D010649:Phenylalanine; D006136:GTP Cyclohydrolase