Elsevier

Surgery

Volume 164, Issue 5, November 2018, Pages 1087-1092
Surgery

Tamsulosin attenuates abdominal aortic aneurysm growth

https://doi.org/10.1016/j.surg.2018.06.036Get rights and content

Abstract

Background

Tamsulosin, an α1A-adrenergic receptor inhibitor, is prescribed to treat benign prostatic hyperplasia in men >60 years of age, the same demographic most susceptible to abdominal aortic aneurysm. The goal of this study was to investigate the effect of tamsulosin on abdominal aortic aneurysm pathogenesis.

Methods

Abdominal aortic aneurysms were induced in WT C57BL/6 male mice (n = 9-18/group), using an established topical elastase abdominal aortic aneurysm model. Osmotic pumps were implanted in mice 5 days before operation to create the model, administering either low dose (0.125 µg/day tamsulosin), high dose (0.250µg/day tamsulosin), or vehicle treatments with and without topical application of elastase. Blood pressures were measured preoperatively and on postoperative days 0, 3, 7, and 14. On postoperative day 14, aortic diameter was measured before harvest. Sample aortas were prepared for histology and cytokine analysis.

Results

Measurements of systolic blood pressure did not differ between groups. Mice treated with the low dose of tamsulosin and with the high dose of tamsulosin showed decreased aortic diameter compared with vehicle-treated control (93% ± 24 versus 94% ± 30 versus 132% ± 24, respectively; P = .0003, P = .0003). Cytokine analysis demonstrated downregulation of pro-inflammatory cytokines in both treatment groups compared with the control (P < .05). Histology exhibited preservation of elastin in both low- and high-dose tamsulosin-treated groups (P = .0041 and P = .0018, respectively).

Conclusion

Tamsulosin attenuates abdominal aortic aneurysm formation with increased preservation of elastin and decreased production of pro-inflammatory cytokines. Further studies are necessary to elucidate the mechanism by which tamsulosin attenuates abdominal aortic aneurysm pathogenesis.

Introduction

Abdominal aortic aneurysms (AAAs) were the primary cause of 9,863 deaths in 2014, making this disease the 10th leading cause of death for men >65 years of age in the United States.1, 2 The risk of AAA rupture is associated with size and rate of expansion.3 AAA rupture is associated with a mortality of 50%–80%, and operative repair carries substantial morbidity.4 Currently, there is no medical therapy for AAA, and operative repair represents the only intervention to treat this disease.

The α1A-adrenergic receptor, a G protein-coupled receptor (GPCR), is located in the prostate but also on the membrane of vascular smooth muscle cells (VSMCs), which comprise a substantial portion of the aortic wall and play an important role in the pathogenesis of AAAs.5, 6 Activation of this GPCR ultimately leads to stimulation of muscle contraction via the inositol trisphosphate (IP3) and diacylglycerol (DAG) pathway. The receptor first sends phospholipase C to cleave phosphatidylinositol bisphosphate (PIP2), a membrane phospholipid, into IP3 and DAG. DAG remains in the membrane and later activates protein kinase C (PKC).7 IP3, a phosphorylated second messenger suggested to be involved in AAA pathogenesis, travels into the cell, binds to L-type calcium channels, and leads to release of intracellular Ca2+ from both the endoplasmic reticulum and store-operated Ca2+ channels further down the pathway.7, 8 Activation of this pathway results in increased intracellular free Ca2+ concentration and ultimately, vascular smooth muscle contraction.

Tamsulosin is an α1A-adrenergic receptor inhibitor commonly prescribed to treat benign prostatic hyperplasia (BPH) in men >60years old, the same demographic most susceptible to AAA formation. Histologic evidence of BPH has been observed at 8% of men in their thirties and increases to more than 70% prevalence in men >60 years of age.9 The demand for BPH treatment, such as tamsulosin, will likely increase in the United States as the population ages.10 By inhibiting the α1A-adrenergic receptor, tamsulosin decreases the amount of IP3 in VSMCs and the downstream products that result from this pathway. The goal of this study was to investigate the effect of tamsulosin, an FDA-approved drug for the treatment of BPH, on AAA pathogenesis, because it was hypothesized that it would attenuate AAA size and rate of growth in a manner independent of blood pressure.

Section snippets

Animal housing

We placed 8- to 12-week old WT C57BL/6 male mice (Jackson Laboratory, Bar Harbor, ME) in housing that was maintained at 70°F and 50% humidity in 12-hour light-dark cycles as required by our institutional animal protocols. All mice were provided drinking water and fed either a minimal phytoestrogen diet (2017 Teklad Global 16% Protein Rodent Diet, Harlan Labs, Inc., Frederick, MD). Animal protocols were approved by the Institutional Animal Care and Use Committee (No. 3848) of the University of

Results

Tamsulosin did not decrease systolic blood pressure among the treated groups. We observed no difference between the systolic blood pressures at basal conditions in the saline + saline, saline + elastase, low dose + elastase or high dose + elastase groups at any time point (P > .05; Table 1).

Day 14 aneurysm formations decreased with tamsulosin treatment in a topical elastase model. Mice treated with the low dose of tamsulosin showed a decreased abdominal aortic diameter on day 14 compared with

Discussion

The present study sought to evaluate the effects of tamsulosin on AAA growth. Tamsulosin treatment was then investigated in a topical elastase murine model, with resultant attenuation of AAA formation and preservation of elastin in the aortic wall. Mean systolic blood pressures did not differ between the groups. Pro-inflammatory cytokines critical to AAA pathogenesis were also downregulated by tamsulosin treatment. IP3 levels were suppressed in vitro in tamsulosin-treated, murine, aortic smooth

Acknowledgments

We thank Anthony Herring, Cindy Dodson, and Sheila Hammond for their knowledge and technical expertise.

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    • Cited by (0)

    Supported by the National Institutes of Health under Award Numbers T32HL007849, R01 HL132395, and R01 HL081629.

    Presented at the 13th Annual Academic Surgical Congress.

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