The acidic
protein chromogranin A (CgA) is the precursor of several regulatory
peptides generated by specific proteolytic processes. Human recombinant CgA NH(2)-terminal fragment STA-CgA(1-78) (hrSTA-CgA(1-78)), containing
vasostatin-1 (CgA(1-76)) domain, exerts a negative inotropic effect and counteracts the beta-
adrenergic positive inotropic effect on the rat heart. We hypothesized an involvement of
nitric oxide (NO)-dependent pathway in both cardiodepression and cardioprotection by hrSTA-CgA(1-78). We also hypothesized an involvement of
adenosine A(1) receptor and
protein kinase C (PKC) in cardioprotection by hrSTA-CgA(1-78). Therefore, we evaluated whether 1) the cardioinhibition mediated by hrSTA-
CgA(1-78) involves the G(i/o)
proteins/NO-dependent signal transduction cascade, 2) hrSTA-
CgA(1-78) induces ischemic preconditioning-like protective effects on the myocardium, and 3) inhibition of
NO synthase (NOS),
adenosine A(1) receptor, or PKC affects hrSTA-
CgA(1-78) protection. Using the isolated rat heart, we found that the reduction of left ventricular pressure (LVP), rate-pressure product, and maximal values of the first derivative of LVP elicited by hrSTA-
CgA(1-78) at 33 nM is abolished by blocking G(i/o)
proteins with
pertussis toxin, scavenging NO with
hemoglobin, and blocking NOS activity with N(G)-monomethyl-
l-arginine or N(5)-(iminoethyl)-l-
ornithine,
soluble guanylate cyclase with 1H-[1,2,4]
oxadiazole-[4,4-a]quinoxalin-1-one, and
protein kinase (PKG) with
KT5823. Data suggest the involvement of the G(i/o)
proteins/NO-cGMP-PKG pathway in the hrSTA-
CgA(1-78)-dependent cardioinhibition. When given before 30 min of
ischemia, hrSTA-
CgA(1-78) significantly reduced the size of the
infarct from 64 +/- 4 to 32 +/- 3% of the left ventricular mass. This protective effect was abolished by either NOS inhibition or PKC blockade and was attenuated, but not suppressed, by the blockade of A(1) receptors. These results suggest that hrSTA-
CgA(1-78) activity triggers two different pathways: one of these pathways is mediated by A(1) receptors, and the other is mediated by NO release. As with repeated brief preconditioning
ischemia, hrSTA-
CgA(1-78) may be considered a stimulus strong enough to trigger both pathways, which may converge on PKC.