Sirolimus Causes Relaxation of Human Vascular Smooth Muscle: A Novel Action of Sirolimus Mediated via ATP-Sensitive Potassium Channels

Ghatta, Srinivas; Tunstall, Radhika; Kareem, Sohail; Rahman, Mohamed Abdel; O’Rourke, Stephen T.

doi:10.1124/jpet.106.115329

Cited by 7 publications

(3 citation statements)

References 31 publications

(30 reference statements)

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“…This suggests that vessels with unimpaired relaxation in response to ACh (functioning endothelium) may have a potentiated response to SNP. Precontracted denuded human radial arteries have been shown to relax in response to increasing sirolimus concentrations in vitro , mediated by smooth muscle ATP‐K + channels [46]. While sirolimus was not directly added to organ baths in the present study, endothelium‐independent relaxation was greatest in the sirolimus group when compared to other drug groups.…”

Section: Discussionmentioning

confidence: 69%

The effects of immunosuppressants on vascular function, systemic oxidative stress and inflammation in rats

Shing¹,

Fassett²,

Brown³

et al. 2012

Transplant International

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Summary Immunosuppressants have been associated with increased cardiovascular disease risk. We determined the effects of calcineurin and mammalian target of rapamycin (mTOR) inhibitor administration on endothelial dysfunction and associated inflammation and oxidative stress in adult rats. Cyclosporine A (low and high dose), sirolimus, tacrolimus, everolimus and placebo were administered to 8‐week‐old male Wistar rats for 10 consecutive days. Aortic vascular endothelial and smooth muscle function were assessed ex vivo in organ baths. Maximal aortic contraction to noradrenaline in sirolimus‐treated rats was significantly greater than cyclosporine groups, everolimus and placebo, whereas endothelial‐dependent relaxation was significantly impaired with cyclosporine and tacrolimus compared with everolimus. Endothelial‐independent relaxation was impaired in tacrolimus‐treated rats compared with low dose cyclosporine, everolimus and sirolimus. Sirolimus was associated with a reduction in plasma interleukin (IL)‐1β and tumour necrosis factor (TNF)‐α and higher levels of catalase and total antioxidant status. In nontransplanted rats, vascular dysfunction was evident following administration of cyclosporine A, sirolimus and tacrolimus, whereas everolimus did not compromise aortic endothelial or smooth muscle function. At the doses administered in this model, the immunosuppressants exerted varying effects on vascular function.

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Section: Discussionmentioning

confidence: 69%

The effects of immunosuppressants on vascular function, systemic oxidative stress and inflammation in rats

Shing¹,

Fassett²,

Brown³

et al. 2012

Transplant International

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“…It also causes intracellular Ca +2 entry and is required for contraction by opening voltage-dependent Ca +2 channels located on the sarcolemmal membrane. 16 Sodium nitroprusside is a direct vascular relaxing agent independent of endothelium. It includes nitrous oxide (NO), which is released by a reduction reaction catalyzed in tissue.…”

Section: Discussionmentioning

confidence: 99%

Evaluation of the Effects of Bile on the Arterial Tonus in a Rabbit Model

Temiz

Mezili

Tiftikçioğlu

et al. 2015

Plastic and Reconstructive Surgery - Global Open

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Background:Hepatic artery anastomosis is an essential part of live-donor liver transplantation, and during this anastomosis, an unusual contact between bile and vessel ends is observed. In this study, the effects of this nonphysiological contact in a rabbit model were evaluated.Methods:The study was designed in 2 steps—in vitro and in vivo. Three groups were established for the in vitro study. In the first group, vessels were incubated in Krebs solution with 5% bile for 1 minute. In the second group, vessels were kept in Krebs solution with 5% bile for 5 minutes. Vessels in the control group were kept in Krebs solution without bile. All groups were examined for responses to vasodilator and vasoconstrictor agents in organ bath system. The specimens were evaluated immunohistochemically and histopathologically. In the in vivo step, microvascular anastomosis was performed bilaterally. Right carotid artery was anastomosed during bile contamination as study group, and left carotid artery was anastomosed without bile contamination as control group. Blood flow indexes were measured.Results:The results of the in vitro study revealed decreased responses to contractile and relaxing agents in the first study group compared with that of the control group (P < 0.0001). There was no response obtained in the second study group. The Doppler ultrasound results revealed no difference between preoperative and postoperative flow indexes (P > 0.05). There was no postoperative spasm in the study group. However, there was significant vasospasm in the control group (P < 0.05).Conclusions:Vessels exposed to bile have decreased contractile and relaxing responses, and this effect increases with exposure duration.

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“…Often induction therapies with lymphocyte-depleting agents [such as thymoglobulin (THYMO) or alemtuzumab (ALE), an anti-CD52 depleting humanized mAb that induces profound depletion of T and B lymphocytes] or with interleukin (IL)-2 receptor antagonists (IL2RA), such as basiliximab (BAS) or daclizumab (DAC), are utilized. In addition, many of these studies have taken advantage of the ability of sirolimus (SIR), a mammalian target of rapamycin (mTOR) inhibitor, to avoid nephrotoxicity [6], inhibit vascular smooth muscle proliferation [7,8] and exploit the synergistic effects with CSA [9]. Furthermore, SIR's ability to block cytokine-driven perfusion injuries after ischemia may have specific benefits for inhibiting the innate immune response more active after ECD or DCD renal transplantation [8,9].…”

Section: Introductionmentioning

confidence: 98%