In vascular smooth muscle cells (SMC), 3’-5’-cyclic adenosine monophosphate (cAMP) is a key mediator that initiates vasodilation. Downstream effectors of cAMP-induced SMC relaxation include large conductance, Ca²⁺-activated, K⁺ channels (BK_Ca) channels. Hydrolysis of cAMP by phosphodiesterases (PDEs) controls its cellular fate.Here, we sought to establish : i) respective contributions of PDE3 and PDE4 families in regulating tone of rat coronary arteries (CA) under various cAMP stimuli; ii) the particular role of BK_Ca channels under these stimuli.

CA were isolated from adult male Wistar rats. Responses to vasodilators were studied on CA rings mounted on a small vessel myograph and contracted with thromboxane analogue U46619. cAMP-PDE activity was measured in CA lysate using a radioenzymatic assay. Contributions of PDE3 and PDE4 were studied using selective inhibitors, namely Ro 20-1724 (Ro, 10μM) and cilostamide (Cil, 1μM). Role of BK_Ca channels was studied using the specific blocker iberiotoxin (IBTX, 100 nM).

Contributions of PDE3 and PDE4 to the total cAMP hydrolysing activity in rat CA were 55±5% and 31±2%, respectively. Addition of Ro or Cil on contracted CA induced relaxations that were strongly blunted in the presence of IBTX. Ro and Cil potentiated relaxant responses to increasing concentrations of cAMP-elevating agents, namely β-adrenergic receptor agonist isoproterenol (ISO) or the forskolin analogue L858051 (L85), a direct activator of cAMP production. IBTX shifted to the right the relaxant response to L85 whereas it reduced maximal response to ISO. Interestingly, IBTX blocked the potentiating effect of Ro on ISO response, but not on L85 response. By contrast, BK_Ca inhibition neither prevented potentiation of ISO nor L85 responses by Cil.

Our data suggest that, in rat CA, the contribution of BK_Ca channels to the relaxant effects of PDE3 and PDE4 inhibition varies depending on the mode of cAMP stimulation.

The author hereby declares no conflict of interest