Improvement of impaired endothelial function by tetrahydrobiopterin in stroke-prone spontaneously hypertensive rats.
To investigate the role of tetrahydrobiopterin (BH4), an essential cofactor of nitric oxide synthase, in endothelial function in a model of genetic hypertension, acetylcholine- and sodium nitroprusside (SNP)-induced vasodilator responses were examined in the absence and presence of BH4 in age-matched adult stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar-Kyoto (WKY) rats. Acetylcholine-induced depressor responses attenuated significantly in SHRSP compared with those in WKY rats. Acetylcholine-induced relaxations in phenylephrine-precontracted aortic rings of SHRSP were also significantly impaired as compared to those of WKY rats, while SNP-induced relaxations were similar between both strains. In SHRSP, intravenous infusion of BH4 (0.12 mg/kg per min for 20 min following a bolus injection of 0.48 mg/kg) significantly improved vasodilator responses to acetylcholine without affecting those to SNP, but in WKY rats BH4 did not influence those to acetylcholine. BH4 infusion itself had no hemodynamic effect in both strains. However, BH4 levels in plasma and thoracic aorta as well as plasma concentrations of nitrite plus nitrate, metabolites of NO, in SHRSP were all significantly greater than those in WKY rats, suggesting the occurrence of compensatory upregulation of NO synthesis in SHRSP. These results demonstrate that the impaired endothelial function in SHRSP cannot be explained simply by the decrease in absolute amount of BH4.
Noguchi
Katsuhiko
K
Department of Pharmacology, School of Medicine, Faculty of Medicine, University of the Ryukyus, Okinawa 903-0215, Japan. noguchi@med.u-ryukyu.ac.jp
Hamadate
Naobumi
N
Matsuzaki
Toshihiro
T
Sakanashi
Mayuko
M
Nakasone
Junko
J
Sakanashi
Makiko
M
Tsutsui
Masato
M
Sakanashi
Matao
M
D000818:Animals; D001012:Aorta, Abdominal / Q000187:drug effects / Q000503:physiopathology*; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism; D001708:Biopterins / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000097:blood / Q000378:metabolism / Q000502:physiology; D019587:Dietary Supplements; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology*; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000235:genetics / Q000503:physiopathology*; D066298:In Vitro Techniques; D007262:Infusions, Intravenous; D008297:Male; D009566:Nitrates / Q000097:blood; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D009573:Nitrites / Q000097:blood; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D013997:Time Factors; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D009566:Nitrates; D009573:Nitrites; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D001708:Biopterins; D019001:Nitric Oxide Synthase; C003402:sapropterin