CORONARY VASCULAR AND ENDOTHELIAL REACTIVITY CHANGES IN TRANSGENIC MICE OVEREXPRESSING ATRIAL-NATRIURETIC-FACTOR

Recent advances in genetic methods permit the introduction of random a nd defined mutations into the mouse germ line, producing navel mouse s trains, some of which affect the heart and vasculature. A TTR-ANF tran sgenic strain of mice, which constitutively expresses a fusion gene co nsisting of the transthyretin promoter and the ANF structural gene, ha s been shown to result in a lifelong elevation of plasma atrial natriu retic factor (ANF) and a chronically lowered arterial blood pressure. However, no established method for efficient functional analysis of po ssible alterations in coronary vascular function in mice has been repo rted. In the present study, we describe an isolated mouse coronary art ery preparation that permits an effective and reproducible evaluation of coronary endothelial and vascular function. Both left main and righ t coronary arteries (resting luminal diam 70-90 mu m) were isolated aa d pressurized, and changes in luminal diameter were determined by vide omicroscopy. The coronary pressure-luminal diameter relationship was n ot significantly different between TTR-ANF transgenic and nontransgeni c littermates. Relaxation of coronaries to 0.1-100 nM ANF was signific antly reduced in transgenic [maximum effect (E(max)) = 43 +/- 10% (mea n +/- SE) of II vessels] compared with nontransgenic (E(max) = 73 +/- 7%, n = 15) mice. Similarly, the relaxant response to an endothelium-d ependent dilator, acetylcholine, but not to endothelium-independent di lators sodium nitroprusside and isoproterenol, was significantly decre ased in transgenic (E(max) = 46 +/- 10%, n = 12) compared with nontran sgenic (E(max) = 85 +/- 5%, n = 14) mice. In contrast, the dose-depend ent 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 wit h a decreased responsiveness of coronary vasorelaxation to ANF, possib ly resulting from receptor downregulation and/or desensitization. Endo thelium-dependent relaxation was also significantly depressed in trans genic mouse coronary arteries, but smooth muscle-specific dilation and constriction were not affected. The present findings are consistent w ith previous studies of TTR-ANF transgenic mice showing that ANF regul ates arterial blood pressure and vascular function.