Antihypertensive therapy increases tetrahydrobiopterin levels and NO/cGMP signaling in small arteries of angiotensin II-infused hypertensive rats

Kyu Tae Kang, Jennifer C. Sullivan, Frank T. Spradley, Livius V. d'Uscio, Zvonimir S. Katusic, Jennifer S. Pollock

Research output: Contribution to journalArticle

20 Scopus citations

Abstract

We previously reported that small mesenteric arteries from hypertensive rats have increased NOS-derived H2O2 and reduced NO/cGMP signaling. We hypothesized that antihypertensive therapy lowers blood pressure through a tetrahydrobiopterin (BH4)-dependent mechanism restoring NO/cGMP signaling and endothelial NOS (NOS3; eNOS) phosphorylation in small arteries. To test this hypothesis, small mesenteric arteries from normotensive rats (NORM), angiotensin II-infused rats (ANG), ANG rats with triple therapy (reserperine, hydrochlorothiazide, and hydralazine), or ANG rats with oral BH4 therapy were studied. Both triple therapy and oral BH4 therapy attenuated the rise in systolic blood pressure in ANG rats and restored NO/cGMP signaling in small arteries similarly. Triple therapy significantly increased vascular BH4 levels and BH4-to-BH2 ratio similar to ANG rats with BH4 supplementation. Furthermore, triple therapy (but not oral BH4 therapy) significantly increased GTP cyclohydrolase I (GTPCH I) activity in small arteries without a change in expression. NOS3 phosphorylation at Ser1177 was reduced in small arteries from ANG compared with NORM, while NOS3 phosphorylation at Ser633 and Thr495 were similar in ANG and NORM. NOS3 phosphorylation at Ser1177 was restored with triple therapy or oral BH4 in ANG rats. In conclusion, antihypertensive therapy regulates NO/cGMP signaling in small arteries through increasing BH4 levels and NOS3 phosphorylation at Ser1177.

Original languageEnglish (US)
Pages (from-to)H718-H724
JournalAmerican Journal of Physiology - Heart and Circulatory Physiology
Volume300
Issue number3
DOIs
StatePublished - Mar 2011

Keywords

  • Hypertension
  • Nitric oxide synthase
  • Small mesenteric arteries
  • Triple therapy

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine
  • Physiology (medical)

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