Submitted on April 26, 2006
Accepted on February 9, 2007
Differential Effects of Phosphodiesterase PDE3/PDE4-Specific Inhibitors on Vasoconstriction and cAMP-Dependent Vasorelaxation Following Balloon Angioplasty
Hong Zhao1*, John Quilley2, David C. Montrose1, Swarna Rajagopalan1, Qizhi Guan1, and Carolyn J. Smith1
1 Pharmacology, New York Medical College, Valhalla, United States
2 Pharmacology, New York Medical College, New York, United States
* To whom correspondence should be addressed. E-mail: hong_zhao{at}nymc.edu.
It is known that cAMP and cGMP are important for vasorelaxation and cyclic nucleotide phosphodiesterases (PDEs) regulate their levels. Balloon angioplasty (BAL) is associated with reduced cAMP and cGMP levels and inhibition of PDE3 reduces restenosis. In this study, we found that BAL increased PDE3 activity, which affected vasoreactivity of rat aortic rings 24hr post-BAL; these were compared to intact (INT) and ex vivo endothelium denuded rings (RUB) from sham rats. In BAL and RUB rings, vasorelaxant responses to acetylcholine (ACh) were abolished. The EC50 for phenylephrine (PE) was 1.8-fold less in RUB than in INT or BAL, whereas the maximal contractile effect of PE was greater in BAL than in INT or RUB. PDE3 inhibitors reduced the maximal response to PE by >65% in BAL compared to 10-30% in INT and RUB; the reduction of the maximal response to U46619 was 37% in BAL compared to 8% in INT with no reduction in RUB. PDE4 inhibitors reduced PE-induced tone by <30% in an endothelium-dependent manner. Vasorelaxant responses to agonists that utilize cAMP were greatly impaired in BAL and RUB rings, and inhibition of PDE3 enhanced the vasorelaxant responses in BAL or RUB. Inhibition of PDE4 increased vasorelaxant responses to ISO to a much lesser degree. Thus, PDE3 and PDE4 inhibitors exhibited differential effects on PE-induced tone and vasorelaxant responses to ISO. Inhibition of PDE3 also produced a greater increase in cAMP in BAL than INT or RUB rings. These results suggest that increased PDE3 activity after BAL may promote a vasospastic state and that the reduction in cAMP may, possibly, influence vessel remodeling.
