Effects of Tamoxifen on Arteriolar Vasomotor Control in Glycolytic Skeletal Muscle of Aged Rats

BACKGROUND AND PURPOSE: Advanced aging and cancer are inextricably linked as evidenced by the increased tumor diagnoses in aged individuals. Tamoxifen (TAM), a selective estrogen receptor (E R ) agonist, is a common treatment used to attenuate tumor proliferation in breast cancers testing positive for human epidermal growth factor receptor 2 (HER2+), a protein which promotes aggressive tumor growth. Interestingly, TAM has been implicated as a cardioprotective agent. However, the direct effect of TAM on the vasculature varies based upon the dependent tissue; acting as an E R antagonist in breast tissue and an E R agonist in uterine and bone tissue. Whereas TAM vasodilates coronary arterioles in an endothelium-dependent and nitric oxide (NO)-mediated manner, its effect on skeletal muscle vasculature remains unknown. Therefore, the goal of this work was to elucidate the effects of TAM on the vasoreactivity of glycolytic skeletal muscle arterioles. Methods: Old (24-26 mo) female Fischer-344 rats were euthanized under a deep plane of isoflurane anesthesia and the white gastrocnemius muscle excised. First order arterioles (1A) were isolated, cannulated, and pressurized to 60 cmH 2 O. Subsequently, endothelium-dependent vasodilation to cumulative doses of acetylcholine (ACh) (10 -9 to 10 -4 M) was assessed. Thereafter, 1As were incubated with TAM (10 -5 M) in the absence and presence of eNOS blockade with L-NAME (10 -5 M), and ACh dose-responses were performed again, followed by maximal diameter and wall thickness measurements. Results: Maximal ACh-mediated relaxation with TAM incubation tended to increase ACh-mediated arteriolar relaxation (~7.5%; p=0.260). L-NAME + TAM vasodilatory responses tended to be lower compared to ACh control and ACh+TAM (p=0.09). Conclusion: These preliminary data highlight the potential of TAM to improve vasoreactivity in the vasculature of glycolytic skeletal muscle from aged animals. Additionally, vasodilation was nominally, albeit not significantly, reduced in the presence of eNOS inhibition (L-NAME), suggesting that vasodilation to ACh as well as ACh + TAM may be endothelium and NO-dependent. Together these data support that, in the absence of estrogen, as found in post-menopausal females, tamoxifen may mimic the effects of estrogen (17β estradiol) by eliciting vasodilation via binding to E R in skeletal muscle arterioles. Ruth L. Kirschstein National Research Service Awards from the National Heart, Lung, and Blood Institute awarded to Andrew G. Horn (1F31HL167618-02). This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.