Decreased cGMP level contributes to increased contraction in arteries from hypertensive rats: Role of phosphodiesterase 1

Fernanda R. Giachini, Victor V. Lima, Fernando S. Carneiro, Rita C. Tostes, R. Clinton Webb

Research output: Contribution to journalArticle

29 Scopus citations

Abstract

Recent evidence suggests that angiotensin II (Ang II) upregulates phosphodiesterase (PDE) 1A expression. We hypothesized that Ang II augmented PDE1 activation, decreasing the bioavailability of cyclic guanosine 3′ 5′-monophosphate (cGMP), and contributing to increased vascular contractility. Male Sprague-Dawley rats received mini-osmotic pumps with Ang II (60 ng•min) or saline for 14 days. Phenylephrine (PE)-induced contractions were increased in aorta (Emax168%±8% vs 136%±4%) and small mesenteric arteries (SMA; Emax170%±6% vs 143%±3%) from Ang II-infused rats compared to control. PDE1 inhibition with vinpocetine (10 μmol/L) reduced PE-induced contraction in aortas from Ang II rats (E max94%±12%) but not in controls (154%±7%). Vinpocetine decreased the sensitivity to PE in SMA from Ang II rats compared to vehicle (-log of half maximal effective concentration 5.1±0.1 vs 5.9±0.06), but not in controls (6.0±0.03 vs 6.1±0.04). Sildenafil (10 μmol/L), a PDE5 inhibitor, reduced PE-induced maximal contraction similarly in Ang II and control rats. Arteries were contracted with PE (1 μmol/L), and concentration-dependent relaxation to vinpocetine and sildenafil was evaluated. Aortas from Ang II rats displayed increased relaxation to vinpocetine compared to control (Emax82%±12% vs 445±5%). SMA from Ang II rats showed greater sensitivity during vinpocetine-induced relaxation compared to control (-log of half maximal effective concentration 6.1±0.3 vs 5.3±0.1). No differences in sildenafil-induced relaxation were observed. PDE1A and PDE1C expressions in aorta and PDE1A expression in SMA were increased in Ang II rats. cGMP production, which is decreased in arteries from Ang II rats, was restored after PDE1 blockade. We conclude that PDE1 activation reduces cGMP bioavailability in arteries from Ang II, contributing to increased contractile responsiveness.

Original languageEnglish (US)
Pages (from-to)655-663
Number of pages9
JournalHypertension
Volume57
Issue number3 PART 2
DOIs
StatePublished - Mar 2011

Keywords

  • angiotensin II
  • cGMP
  • hypertension
  • vinpocetine

ASJC Scopus subject areas

  • Internal Medicine

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