Although postmenopausal estrogen replacement therapy is known to reduce cardiovascular mortality, the mechanism is not clear yet. Furthermore, the effect of estrogen on vascular tonus is reportedly variable according to the animal models, vascular beds and agonists used.

Bilateral ovariectomies were performed in 12 week-old, 18 spontaneously hypertensive rats (SHR) and 18 normotensive Wistar-Kyoto rats (WKY). Rats were divided into three groups according to the dose of 17β-estradiol (E₂) pellets implanted subcutaneously two weeks after ovariectomy: control (no implantation), low-dose (0.5 mg) and high-dose (5 mg) E₂ replacement group. Two weeks after pellet implantation, organ bath experiments were performed using descending thoracic aortae. For endothelium-dependent relaxation, acetylcholine (10^-9-3×10^-6M) was cumulatively added into the vessels precontracted with 10^-7M norepinephrine (NE). For vasoconstrictor responses, cumulative concentration-contraction curves were constructed in quiescent vessels using NE (10^-9-10^-5M), U46619 (10^-9-3×10^-6M), endothelin-1 (10^-10-10^-7M). In addition, contraction to angiotensin II (10^-7M) was also obtained. Serum 17β-estradiol levels were measured by radioimmunoassay. Blood pressure was measured by tail-cuff method in some SHRs before ovariectomy and after placebo/E₂ replacement.

Endothelium-dependent relaxation to acetylcholine was impaired in WKY treated with 5 mg E₂ (pIC₅₀ ; control vs 5mg E₂ ; 7.75±0.13 vs 7.27±0.16: n=6: p<0.05). No significant effect was noted in SHR. Contraction to angiotensin II was inhibited by low-dose E₂ in WKY and high-dose E₂ in SHR (% of the contraction to 60 mM KCl: WKY: control vs 0.5 mg E₂ ; 39±5 vs 25±2 ; SHR ; control vs 5 mg E₂ ; 34±4 vs 22±2 ; n=6 and p<0.05 in WKY and SHR). In contrast, NE-induced contraction was enhanced by E₂ replacement (both low- and high-dose) in WKY and SHR (WKY: control vs 0.5 mg E₂ vs 5 mg E₂ ; AUC ; 280±24 vs 387±26 vs 374±25: maximal contraction: 137±8 vs 166±8 vs 162±3 ; pD₂ ; 7.63±0.11 vs 8.17±0.13 vs 8.13±0.13 ; SHR ; control vs 0.5 mg EE₂ vs 5 mg EE₂ ; AUC: 265±17 vs 349±16 vs 406±19 ; maximal contraction: 152±6 vs 181±9 vs 203±16 ; pD₂ ; 7.45±0.13 vs 7.91±0.08 vs 8.04±0.04: n=6 and p<0.05 between control and treated groups in WKY and SHR for all parameters). Contraction to U46619 was enhanced by E2 replacement in SHR (control vs 0.5 mg E₂ ; AUC ; 478±30 vs 574±23: maximal contraction: 181±9 vs 230±10: n=6 ; p<0.05 for both parameters). Maximal contractile response to endothelin-1 was also enhanced in SHR (control vs 0.5 mg E₂ vs 5 mg E₂ ; maximal contraction: 165±7 vs 189±7 vs 199±8: n=6 and p<0.05 between control and treated groups) but not in WKY. Blood pressure was not different between placebo and E₂-treated SHR (171±2 vs 174±4 mmHg).

In WKY, chronic high-dose estrogen replacement impairs endothelium-dependent relaxation to acetylcholine.; low-dose estrogen replacement does not affect endothelium-dependent relaxation in SHR and WKY. Estrogen replacement enhances the contraction to most of the contractile agonists tested except angiotensin II in both WKY and SHR. These results suggest that estrogen replacement affect the vascular tonus differently according to the vasoactive substances and/or hormones without significant effect on blood pressure.