Estrogen protects transgenic hypertensive rats by shifting the vasoconstrictor-vasodilator balance of RAS.
In pursuit of the hypothesis that estrogen shifts the vasoconstrictor-vasodilator balance of the renin-angiotensin system, we investigated the cardiovascular responses to administration of angiotensin-(1-7) [ANG-(1-7)] and angiotensin II (ANG II) in female transgenic (mRen2)27-positive [Tg(+)] and -negative [Tg(-)] rats in the presence and absence of 3 wk of estrogen replacement therapy. Fifty-three female Tg(-) and Tg(+) rats were oophorectomized and received either 17 beta-estradiol (1.5 mg/rat s.c. for 3 wk) or vehicle. At the end of 3 wk of estrogen treatment, mean blood pressure was lowered in freely moving chronically cannulated Tg(+) (159 +/- 4 vs. 145 +/- 5 mmHg, P < 0.05) and Tg(-) (119 +/- 4 vs. 108 +/- 2 mmHg, P < 0.05) rats. Moreover, the magnitude of the depressor component of the biphasic response to ANG-(1-7) was significantly enhanced in estrogen-treated Tg(+) rats, whereas the pressor component to ANG-(1-7) was attenuated in both Tg(+) and Tg(-) rats. Estrogen replacement significantly attenuated the pressor response to ANG II in both Tg(+) and Tg(-) rats. In addition, estrogen replacement therapy significantly reduced plasma ANG-converting enzyme activity in association with a reduction in circulating levels of ANG II. Tissue levels (kidney and aorta) of ANG-converting enzyme were also reduced with chronic estrogen replacement therapy. On the other hand, estrogen augmented the levels of plasma ANG-(1-7) in Tg(+) animals. Plasma renin activity was unchanged with estrogen treatment. These findings provide the first evidence demonstrating that estrogen is protective against hypertension, possibly by amplifying the vasodilator contributions of ANG-(1-7), while reducing the formation and vasoconstrictor actions of ANG II.
Brosnihan
K B
KB
Hypertension Center, Bowman Gray School of Medicine, Wake Forest University, Winston-Salem, North Carolina 27157-1032, USA.
Li
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P
Ganten
D
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Ferrario
C M
CM
D000803:Angiotensin I; D000804:Angiotensin II / Q000097:blood / Q000494:pharmacology; D000818:Animals; D030801:Animals, Genetically Modified; D001013:Aorta, Thoracic / Q000201:enzymology; D001794:Blood Pressure / Q000187:drug effects; D004958:Estradiol / Q000627:therapeutic use*; D015914:Estrogen Replacement Therapy; D005260:Female; D006973:Hypertension / Q000188:drug therapy* / Q000235:genetics / Q000503:physiopathology*; D007668:Kidney / Q000201:enzymology; D051379:Mice; D008955:Models, Cardiovascular; D009131:Muscle, Smooth, Vascular / Q000201:enzymology; D010052:Ovariectomy; D010446:Peptide Fragments / Q000494:pharmacology; D007703:Peptidyl-Dipeptidase A / Q000097:blood / Q000378:metabolism; D051381:Rats; D012083:Renin / Q000096:biosynthesis / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000502:physiology*; D014661:Vasoconstriction / Q000502:physiology*; D014664:Vasodilation / Q000502:physiology*
D010446:Peptide Fragments; D000804:Angiotensin II; D004958:Estradiol; D000803:Angiotensin I; D007703:Peptidyl-Dipeptidase A; D012083:Renin; C118790:angiotensin I (1-7)