Dd. Ku et al., CORONARY VASCULAR AND ENDOTHELIAL REACTIVITY CHANGES IN TRANSGENIC MICE OVEREXPRESSING ATRIAL-NATRIURETIC-FACTOR, American journal of physiology. Heart and circulatory physiology, 40(6), 1996, pp. 2368-2376
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.