Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery

Alterations after prolonged hypoxia in the rat

Philip W. Shaul, Bernard Kinane, Melody A. Farrar, L. Maximilian Buja, Ronald R. Magness

Research output: Contribution to journalArticle

58 Citations (Scopus)

Abstract

Prostacyclin is a critical mediator of structure and function in the pulmonary circulation, causing both the inhibition of vascular smooth muscle growth and vasodilatation via the stimulation of adenylate cyclase. To examine the potential role of alterations in prostacyclin production or mechanism of action in chronic hypoxic pulmonary hypertension, we determined the effects of prolonged (7 d) in vivo hypoxia on in vitro prostacyclin synthesis and mediation of adenylate cyclase activity in rat main pulmonary arteries. In control arteries prostacyclin production exceeded that of prostaglandin (PG) E2 by 25-fold, with 42% originating from the endothelium. Studies utilizing indomethacin revealed that endogenous prostaglandins mediate at least 69% of basal adenylate cyclase activity. Prostacyclin-stimulated enzyme activity was enhanced by exogenous GTP, indicating that this is a receptor-mediated process involving G protein amplification. Comparable dose-related responses to prostacyclin and PGE2 suggest that these agents may activate a common receptor. After 7 d of in vivo hypoxia there was a 2.7-fold increase in in vitro prostacyclin production, with equivalent increases in synthesis in the endothelium and vascular smooth muscle. However, despite this increase there was no change in basal adenylate cyclase activity, and this was associated with attenuated sensitivity of the enzyme to prostacyclin stimulation. Concomitant diminution of the response to betaadrenergic stimulation, with previously-demonstrated beta receptor downregulation and unaltered postreceptor-mediated activity, suggests that the blunted response to prostacyclin is due to receptor downregulation. Parallel studies of the thoracic aorta indicated that these changes are specific to the pulmonary artery. It is postulated that attenuation of the response of adenylate cyclase to prostacyclin may contribute to the structural changes and hypertension observed in the pulmonary vasculature of the rat with chronic hypoxia.

Original languageEnglish (US)
Pages (from-to)447-455
Number of pages9
JournalJournal of Clinical Investigation
Volume88
Issue number2
StatePublished - Aug 1991

Fingerprint

Epoprostenol
Adenylyl Cyclases
Pulmonary Artery
Vascular Smooth Muscle
Dinoprostone
Endothelium
Down-Regulation
Hypoxia
Pulmonary Circulation
Enzymes
Guanosine Triphosphate
Thoracic Aorta
GTP-Binding Proteins
Pulmonary Hypertension
Vasodilation
Indomethacin
Prostaglandins
Arteries
Hypertension
Lung

Keywords

  • Aorta
  • Cyclic AMP
  • G proteins
  • Hypertension
  • Prostaglandin E

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery : Alterations after prolonged hypoxia in the rat. / Shaul, Philip W.; Kinane, Bernard; Farrar, Melody A.; Buja, L. Maximilian; Magness, Ronald R.

In: Journal of Clinical Investigation, Vol. 88, No. 2, 08.1991, p. 447-455.

Research output: Contribution to journalArticle

Shaul, Philip W. ; Kinane, Bernard ; Farrar, Melody A. ; Buja, L. Maximilian ; Magness, Ronald R. / Prostacyclin production and mediation of adenylate cyclase activity in the pulmonary artery : Alterations after prolonged hypoxia in the rat. In: Journal of Clinical Investigation. 1991 ; Vol. 88, No. 2. pp. 447-455.
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