VASOSTATINS, COMPRISING THE N-TERMINAL DOMAIN OF CHROMOGRANIN-A, SUPPRESS TENSION IN ISOLATED HUMAN BLOOD-VESSEL SEGMENTS

Chromogranin A (CGA) belongs to a family of highly acidic proteins which are co-stored and co-released with the catecholamines from the mammalian adrenal gland and occur in nmolar concentrations in the human circulation. A vascular function for the adrenomedullary released and circulating CGA has yet to be established. The present study reports on the novel vasoinhibitory effect of the N-terminal domain of the adrenomedullary CGA in isolated segments of the human internal thoracic artery (ITA) and saphenous vein (SV). The collective term vasostatin(s) refers to N-terminal fragments (CGA1-76 and CGA1-113) of apparent molecular weights 7 to 22 kD, to indicate their vascular inhibitory effects. The sustained contractions evoked by the potent vasoconstrictor peptide, endothelin-1 (ET-1) were suppressed when ITA and SV segments were preincubated for 15 min with vasostatins (72 nM). The vasoinhibitory effects were not dependent on an intact endothelium and suppression of the response to 35 nM ET-1 was approximately 77% and approximately 40% in endothelium-denuded ITA and SV segments, respectively. In endothelium-denuded SV segments the vasostatins suppressed the maximal sustained tension response but not the potency for ET-1, indicating that the vasostatin effect did not involve interference with ET-1 binding to its vascular receptor. Preincubation of endothelium-denuded SV segments with nifedipine (1 muM) inhibited the sustained response to ET-1 greater-than-or-equal-to 10 nM by 50%. By the same protocol a 20 to 40% suppression of the contraction evoked by ET-1 greater-than-or-equal-to 10 nM was obtained in segments preincubated with vasostatins (72 nM), suggesting that inhibition of Ca2+ channel opening might indirectly contribute to the effect of vasostatins on the sustained response to ET-1. The mechanisms for these inhibitory effects of vasostatins on the sustained ET-1 contractions in human blood vessels remain to be elucidated.