Coronary vascular and endothelial reactivity changes in transgenic mice overexpressing atrial natriuretic factor. Ku, David D., Lingling Guo, Jun Dai, Cory G. Acuff, and Mark E. Steinhelper. Department of Pharmacology and Toxicology, Vascular Biology and Hypertension Program of the Division of Cardiovascular Disease, Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294
APStracts 3:0219H, 1996.
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 constituitively 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 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 which permits an effective and reproducible evaluation of coronary endothelial and vascular function. Both left main and right coronary arteries (resting luminal diameter of 70-90 [mu]m) were isolated, pressurized and changes in luminal diameter were determined by videomicroscopy. The coronary pressure-luminal diameter relationship was not significantly different between the TTR-ANF transgenic and nontransgenic littermates. Relaxation of coronaries to 0.1-100 nM ANF was significantly reduced in the transgenic (Emax=43+/- 10%, M+/-SE of 11 vessels) as compared to the 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 the transgenic mice (Emax=46+/-10%, n=12) compared to the nontransgenic (Emax=85+/-5%, n=14). In contrast, the dose-dependent vasoconstriction to endothelin-1, KCl and the thromboxane mimetic, U46619, 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 down-regulation and/or desensitization. Endothelium-dependent relaxation was also significantly depressed in the transgenic mouse coronary arteries, but smooth muscle- specific dilation and constriction were not affected. The present findings are consistent with previous studies of the TTR-ANF transgenic mice showing that ANF regulates arterial blood pressure and vascular function. 

Received 29 March 1996; accepted in final form 6 May 1996.
APS Manuscript Number H298-6.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 June 96