Regulation of cardiac response to mechanical loads: interplay between Nitric Oxide and Catestatin

Nitric Oxide (NO) is a well known modulator of cardiac performance both under basal and stimulated (chemically and physically) conditions. In the in vitro working frog heart, the Chromogranin A (CGA)-derived peptide Catestatin (Cts; bovine CGA344-364) exerts a direct cardio-suppressive action through a NOS-NO-cGMP mechanism which requires the functional integrity of the endocardial endothelium (EE) (Mazza et al., 2008). In the present work, we demonstrated that both Cts and NO improve the sensitivity of the frog heart to filling pressure (preload) increases, i.e. Frank-Starling mechanism (length-dependent or heterometric regulation). This effect was abolished by inhibitors of NO synthase (L-NAME), guanylate cyclase (ODQ), protein kinase G (KT5823) and by the functional damage of EE (Triton X-100), indicating an involvement of the EE-NOS-cGMP-PKG pathway. The findings that Cts effect was also abolished by pretreatment with either wortmannin (PI3K inhibitor) or Diltiazem or Thaspigargin (L-type calcium channels and SERCA pumps inhibitors, respectively) were consistent with an EE-NO release through a PI3K-dependent mechanism. Taken together, our data support a putative physiological role of blood-borne or intracardiac Cts in the modulation of the Frank–Starling response of the heart. Cts action is similar to that exerted by NO and can be attributed to the peptide-induced NO release from the EE.