C-type natriuretic peptide relaxes human coronary artery bypass graft vascular conduits preconstricted by endothelin-1 Kelsall C.J., Chester A.H., Singer D.R.J.*Department of Cardiothoracic Surgery, Heart Science Centre, Harefield Hospital, Middlesex UB9 6JH and *Department of Pharmacology and Clinical Pharmacology, St. George's Hospital Medical School, London.

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Endothelin (ET) is a potent vasoconstrictor implicated in early graft spasm following coronary artery bypass grafting (CABG). We assessed the ability of the endogenous endothelium-derived, nitric oxide independent vasodilator C-type natriuretic peptide (CNP) to reverse prior constriction of vascular conduits commonly used for CABG surgery. We also assessed whether local vascular proteases significantly limit the bio-availability of CNP.

Segments of human saphenous vein (SV), internal mammary artery (IMA) and radial artery (RA) were removed from patients undergoing cardiac surgery (n=34, age 64±2 S.E.), mounted in isolated organ baths and pre-constricted with 10^-7M ET. The ability of increasing concentrations of CNP (with or without aprotinin [APRO], 1000U/ml), to reverse contraction induced by ET was compared with the endothelium-dependent dilator acetylcholine (ACH; 10^-9 to 10^-4M), the endothelium-independent dilator sodium nitroprusside (SNP; 10^-9 to 10^-5M), and papaverine (PAP; 10^-9 to 10^-4M). All drug responses were expressed as a % of constriction by ET, and statistical comparisons made by 2-way repeated measures ANOVA.

Table 1: pD₂ (-log EC₅₀), maximum (%) vasorelaxation, and maximum constriction to ET (mN), in SV, IMA and RA.

Mean ±SEM, N in parentheses. * p<0.05 for PAP vs ACh or SNP for pD₂, t-test.

CNP significantly relaxed ET pre-constriction in all vessels studied (F=17.8, 36.3 and 48.4 respectively; p<0.001). Aprotinin did not significantly affect the CNP concentration response curves in SV (F=0.012, p=0.92), IMA (F=0.79, p=0.42) or RA (F=2.06, p=0.25). ACh relaxed SV weakly, with maximal relaxation at 10^-8M and reconstriction at higher doses. Papaverine completely relaxed all vessels at the highest concentration, but responses were less sensitive than to SNP or ACh.

CNP significantly reverses ET-induced constriction in both arterial and venous conduits routinely used for CABG. Proteolytic breakdown of CNP by local vascular enzymes appears of little importance. CNP may act as an endogenous mediator to limit peri and post-operative spasm following CABG surgery. Strategies to induce CNP release in situ might therefore result in improvement of graft function post-operatively.