Differential regulation of beta(2)-adrenoceptor-mediated inotropic and lusitropic response by PDE3 and PDE4 in failing and non-failing rat cardiac ventricle

作者：Afzal Faraz; Aronsen Jan Magnus; Moltzau Lise Roman; Sjaastad Ivar; Levy Finn Olav; Skomedal Tor; Osnes Jan Bjorn; Qvigstad Eirik^*

来源：British Journal of Pharmacology, 2011, 162(1): 54-71.

DOI：10.1111/j.1476-5381.2010.00890.x

• phosphodiesterase
• beta(1)-adrenoceptor
• beta(2)-adrenoceptor
• heart failure
• inotropic response
• lusitropic response

BACKGROUND AND PURPOSE
beta-Adrenoceptors play a major role in regulating myocardial function through cAMP-dependent pathways. Different phosphodiesterases (PDEs) regulate intracellular cAMP-pools and thereby contribute to the compartmentalization of cAMP-dependent effects. We explored the involvement of PDEs in limiting the beta(2) adrenoceptor-mediated positive inotropic (PIR) and lusitropic (LR) responses in sham-operated (Sham) and failing rat hearts.
EXPERIMENTAL APPROACH
Extensive myocardial infarctions were induced by coronary artery ligation in Wistar rats. Rats developing heart failure were studied 6 weeks after surgery. Contractility was measured in left ventricular strips from failing and Sham hearts. cAMP was quantified by RIA.
KEY RESULTS
In ventricular strips, stimulation of beta(2)-adrenoceptors with (-)-adrenaline (300 nM CGP20712A present) exerted a small PIR and LR. In Sham hearts, beta(2)-adrenoceptor-mediated as well as beta(1)-adrenoceptor-mediated PIR and LR were increased by selective inhibition of either PDE3 (1 mu M cilostamide) or PDE4 (10 mu M rolipram). In failing rat hearts, PDE3 inhibition enhanced PIR and LR to both beta(1)- and beta(2)-adrenoceptor stimulation while PDE4 inhibition had no effect on these responses despite a significant increase in cAMP levels. Combined PDE3/4 inhibition further enhanced the PIR and LR of beta(2)- and beta(1)-adrenoceptor activation both in Sham and failing hearts, compared with PDE3 inhibition alone. PDE4 enzyme activity was reduced in failing hearts.
CONCLUSIONS AND IMPLICATIONS
Both PDE3 and PDE4 attenuated beta(2)- and beta(1)-adrenoceptor-mediated contractile responses in Sham hearts. In failing hearts, these responses are attenuated solely by PDE3 and thus even selective PDE3 inhibitors may provide a profound enhancement of beta-adrenoceptor-mediated responses in heart failure.

• 出版日期2011-1