Dipyridamole-induced C-type natriuretic peptide mRNA overexpression in minipig with pacing-induced left ventricular dysfunction.

Purpose: Molecular, neurohormonal, and haemodynamic changes occur in the setting of left ventricular dysfunction (LVD) of ischemic or non-ischemic origin. Re- cently it was demonstrated that dipyridamole (DP), a phosphodiesterase inhibitor able to increase the intracellular levels of cAMP and cGMP, restores ischaemic tissue blood flow stimulating angiogenesis through a protein kinase A-dependent eNOS pathway. C-type natriuretic peptide (CNP), a potent regulator of vascular tone, is expected to mimic the migration-stimulatory effect of NO via a cGMP dependent mechanism. Aim of this study was to assess the role of concomitant treatment with DP on CNP levels in blood and myocardial tissue of minipigs with pacing-induced LVD. Methods: LVD was induced by pacing at 200 bpm in the right ventricular (RV) apex of minipigs undergoing concomitant DP therapy (5 mg/kg p.o.) (DP+, n=4) or placebo (DP-, n=4). Four sham operated minipigs (C-SHAM) were used as controls. All animals underwent a 2D EchoDoppler examination immediately after single chamber pace-maker implantation and after 4-weeks of RV tachycardic pacing. Animals were sacrificed after 4 weeks pacing and cardiac tissue collected in each minipig from 6 regions of the LV wall. In LVD animals blood samples were also drawn at baseline and after 4 weeks pacing and CNP plasma levels were determined by radioimmunoassay. CNP, natriuretic peptide receptor (NPR)- B, NPR-C and BNP cardiac mRNA expression were evaluated by Real Time-PCR in all animals. Results: After 4 weeks of pacing, LV fractional shortening (LVFS) was markedly reduced in DP- and to a lower extent in DP+ (DP-:21.5±2%, DP+:31.4±4%) as compared to baseline (DP-:38.0±3%, DP+:40.3±1.4%, p<0.0001, p=0.03 re- spectively). LVFS was unchanged in C-SHAM (43±3% vs 44±2%). CNP gene ex- pression resulted lower in DP- (0.13±0.03) with respect to C-SHAM (0.51±0.1) and DP+ (0.43±0.2) as well as NPR-B (C-SHAM: 0.42±0.06, DP-:0.32±0.06, DP+:0.63±0.1) (p=0.011 DP- vs DP+). NPR-C mRNA expression was signifi- cantly (p<0.001) lower both in DP-(0.33±0.06) and DP+ (0.45±0.07) with re- spect to C-SHAM (1.2±0.2). As expected, the mRNA expression BNP levels were higher in LVD as compared to C-SHAM. CNP plasma levels resulted higher in DP+ compared to DP- (22.0±7.1, 15.8±3.8 pg/ml, respectively, p=0.37). Conclusion: These data suggest that DP may serve as a preconditioning agent to increase the protective CNP-mediated endocrine response in LVD. This re- sponse, mediated by its specific receptor NPR-B, may open new insights on molecular targets for treatment of LVD.