AJP - Heart and Circulatory Physiology, Vol 271, Issue 6 2368-H2376, Copyright © 1996 by American Physiological Society

ARTICLES

Coronary vascular and endothelial reactivity changes in transgenic mice overexpressing atrial natriuretic factor

D. D. Ku, L. Guo, J. Dai, C. G. Acuff and M. E. Steinhelper
Department of Pharmacology and Toxicology, University of Alabama at Birmingham 35294, USA.

Recent advances in genetic methods permit the introduction of random and defined mutations into the mouse germ line, producing novel mouse strains, some of which affect the heart and vasculature. A TTR-ANF transgenic strain of mice, which constitutively expresses a fusion gene consisting of the transthyretin promoter and the ANF structural gene, has been shown to result in a lifelong elevation of plasma atrial natriuretic factor (ANF) and a chronically lowered arterial blood pressure. However, no established method for efficient functional analysis of possible alterations in coronary vascular function in mice has been reported. In the present study, we describe an isolated mouse coronary artery preparation that permits an effective and reproducible evaluation of coronary endothelial and vascular function. Both left main and right coronary arteries (resting luminal diam 70-90 microns) were isolated and pressurized, and changes in luminal diameter were determined by videomicroscopy. The coronary pressure-luminal diameter relationship was not significantly different between TTR-ANF transgenic and nontransgenic littermates. Relaxation of coronaries to 0.1-100 nM ANF was significantly reduced in transgenic [maximum effect (Emax) = 43 +/- 10% (mean +/- SE) of 11 vessels] compared with nontransgenic (Emax = 73 +/- 7%, n = 15) mice. Similarly, the relaxant response to an endothelium-dependent dilator, acetylcholine, but not to endothelium-independent dilators sodium nitroprusside and isoproterenol, was significantly decreased in transgenic (Emax = 46 +/- 10%, n = 12) compared with nontransgenic (Emax = 85 +/- 5%, n = 14) mice. In contrast, the dose-dependent vasoconstriction to endothelin-1, KCl and the thromboxane mimetic U-46619 was not significantly different between the two groups. These results indicate that lifelong ANF elevation in mice is associated with a decreased responsiveness of coronary vasorelaxation to ANF, possibly resulting from receptor downregulation and/or desensitization. Endothelium-dependent relaxation was also significantly depressed in transgenic mouse coronary arteries, but smooth muscle-specific dilation and constriction were not affected. The present findings are consistent with previous studies of TTR-ANF transgenic mice showing that ANF regulates arterial blood pressure and vascular function.

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