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1 Department of Medicine, University of Cambridge School of Clinical Medicine, Addenbrooke's and Papworth Hospitals, Division of Respiratory Medicine, Cambridge, Cambridgeshire, United Kingdom
* To whom correspondence should be addressed. E-mail: nwm23{at}cam.ac.uk.
Long-term infusion of prostacyclin, or its analogues, is an effective treatment for severe pulmonary arterial hypertension. However, dose escalation is often required to maintain efficacy. The aim of this study was to investigate the mechanisms of prostacyclin receptor desensitization using the prostacyclin analogue, cicaprost, in rat pulmonary
artery smooth muscle cells (PASMCs). Desensitization of the cAMP response occurred to 63nM cicaprost after 6h pre-incubation with agonist (n=11, P<0.05). This desensitization was reversed 12 h after agonist removal (n=3, P<0.05) and resensitization was inhibited by cycloheximide (10µg/ml). Desensitization was heterologous since desensitization to other Gs
-adenylyl cyclase coupled agonists isoproterenol (1µM), adrenomedullin (100nM), or bradykinin (1µM) was also reduced by pre-incubation with cicaprost (n=3, P<0.05). The reduced cAMP response to prolonged cicaprost exposure appeared to be due to inhibition of AC activity since the responses to the direct acting adenylyl cyclase agonist, forskolin, (3µM, n=5, p<0.05) and the selective AC5 activator, NKH 477, were similarly reduced. Expression of AC2 and 5/6 protein levels transiently
decreased after 1 hour cicaprost exposure (n=3, P<0.05 and n=5, P<0.05 respectively). The PKA inhibitor, H89 (1µM), added 1h prior cicaprost pre-incubation (6h, 63nM)
completely reversed cicaprost-induced desensitization, whereas the PKC inhibitor, bisindolylmaleimide (100nM) was only partly effective. Desensitization was not prevented by the Gi inhibitor pertussis toxin. In conclusion, chronic treatment of PASMCs with cicaprost, induced heterologous, reversible desensitization by inhibition of adenylyl cyclase activity. Our data suggest that heterologous Gs desensitization by cicaprost is mediated predominantly by a PKA-inhibitable isoform of adenylyl cyclase, most likely AC5/6.
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