The Impact of Tamoxifen on Vasomotor Function in Highly Oxidative Skeletal Muscle of Aged Rats

Introduction: Certain anti-cancer therapies, such as the anthracycline doxorubicin, impair cardiovascular function.Tamoxifen (TAM) is a selective estrogen receptor modulator that is commonly used to mitigate breast cancer reoccurrence. Systemically, TAM can act as an estrogen receptor (E R ) agonist or antagonist in a tissue-specific manner. As the median age of breast cancer diagnosis is 62 years old, it is important to understand the effects of TAM in the vasculature of older individuals. The tissue-specific vascular mechanisms of TAM are unclear, but studies suggest TAM may be cardioprotective by mediating endothelial-induced vasodilation. However, the effects of TAM are unknown in the skeletal muscle vasculature. Therefore, we sought to investigate the effect of TAM on the vasoreactivity of first-order arterioles (1A) from oxidative skeletal muscle in an aged rodent model. Methods: Old (22-26 mo) female Fischer 344 rats (n=5) were euthanized under a deep plane of anesthesia and the gastrocnemius complex was removed. 1As from the highly-oxidative red portion of the gastrocnemius were isolated, cannulated, and pressurized at 60 cmH 2 O and allowed to equilibrate for 60 min to develop spontaneous tone. Thereafter, endothelium-dependent vasorelaxation responses to cumulative doses of acetylcholine (ACh; 10 -9 to 10 -4 M) were determined under each of the following conditions: 1) control, 2) TAM incubation (10µM), and 3) TAM (10µM) + L-NAME (10 -5 M) incubation. Results: With TAM incubation, maximal ACh-mediated relaxation (%) was significantly increased (55 ± 10 vs 30 ± 8%; p<0.05). Combined incubation with TAM + L-NAME significantly reduced maximal dilation to ACh (32 ± 6 %,(p<0.05). Conclusion: These preliminary data suggest that TAM may improve endothelium-dependent dilation in the highly-oxidative red portion of the gastrocnemius muscle from aged rats. It is possible that TAM exerts agonistic effects, similar to estrogen, by binding to E R s in the vasculature of oxidative skeletal muscle which may improve endothelial function with advancing age. Further investigation is needed to identify the specific vascular control mechanisms of TAM as well as the determination of muscle perfusion distribution with TAM in response to metabolic challenges such as exercise. 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.