Inhibition of cyclic 3′-5′-guanosine monophosphate-specific phosphodiesterase selectively vasodilates the pulmonary circulation in chronically hypoxie rats

Alan H. Cohen, Kimberly Hanson, Ken Morris, Brian Fouty, Ivan F. McMurtry, William Clarke, David M. Rodman

Research output: Contribution to journalArticle

Abstract

While it is known that nitric oxide (NO) is an important modulator of tone in the hypertensive pulmonary circulation, the roles of cyclic 3′-5′-guanosine monophosphate (cGMP) and cGMP-phosphodiesterase (PDE) are uncertain. We found that isolated lung perfusate levels of cGMP were over ninefold elevated in hypertensive vs. normotensive control rats. 98-100% of lung cGMP hydrolytic activity was cGMP-specific PDE5, with no significant decrease in PDE activity in hypertensive lungs, suggesting that the elevation in cGMP was due to accelerated production rather than reduced degradation. In pulmonary hypertensive rat lungs, in vitro, cGMP-PDE inhibition by E4021[1-(6-chloro-4-(3,4-methylbenzyl) amino-quinazolin-2-yl)piperdine-4-carboxylate], increased perfusate cGMP threefold, reduced hypoxic vasoconstriction by 58±2%, and reduced baseline pulmonary artery pressure by 37±5%. In conscious, pulmonary hypertensive rats, intravenous administration of E4021 reduced hypoxic vasoconstriction by 68±8%, pulmonary artery pressure by 12.6±3.7% and total pulmonary resistance by 13.1±6.4%, with no significant effect on cardiac output, systemic pressure, and resistance. Comparison of E4021 to inhaled nitric oxide demonstrated that cGMP-PDE inhibition was as selective and as effective as inhaled NO.

Original languageEnglish (US)
Pages (from-to)172-179
Number of pages8
JournalJournal of Clinical Investigation
Volume97
Issue number1
StatePublished - Jan 1 1996
Externally publishedYes

Keywords

  • Cyclic GMP
  • E4021
  • Endothelial-derived relaxing factor
  • Nitric oxide
  • Zaprinast

ASJC Scopus subject areas

  • Medicine(all)

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