Effects of Calcineurin Inhibitors on Rat Thoracic and Abdominal Aortae Contractibility and Vasodilatation

Abstract

Context: Calcineurin inhibitors (CNIs) therapy such as cyclosporine (CsA) and tacrolimus (Tac) are associated with hypertension. Objective: Compare the differential effect of these two agents on thoracic and abdominal aortae. Methods: Thirteen weeks old male Sprague-Dawley rats were treated with CsA (15 mg/kg), Tac (0.15 mg/kg) and vehicle for 15 days. At the end of study, rats were anesthetised, and blood pressure (BP) and heart rate (HR) were measured. Both thoracic (TA) and abdominal (AA) aortae were assessed for the contractibility responses with α1 agonist phenylephrine (PE) against terazosin, a α1 receptor blocker. In addition, vascular relaxation was assessed using endothelium-dependent, Acetylcholine-induced and endothelium-independent sodium nitroprusside-induced pathways in PEconstricted TA and AA. Results: Elevated arterial BP was noted in Tac group, however, HR did not showed any changes in Tac and CsA groups as compared to controls. PEinduced contractibility of TA but not AA was increased significantly and equally by CsA (EC50, 55 ± 7.06 nM) and Tac (EC50, 50 ± 6.6 nM) treatment as compared to control (104 ± 14 nM). ACh-induced endothelium-dependent relaxation was attenuated by both CsA (TA: Imax 66 ± 8.79 %, AA: Imax 74 ± 11.38 %) and Tac (TA: Imax 39 ± 9.55 %, AA: Imax 70 ± 20.06 %), however its intensity was higher in TA by Tac group (controls: 97-98 ± 2.6-2 %). Similarly, SNP-induced endothelium-independent vascular relaxation was also affected by CsA and Tac treatment, TA (IC50 control, 47 ± 11.2 nM, vs. CsA, 214 ± 27.9 nM and Tac, 191 ± 30.8 nM, p< 0.05) and AA (IC50 control, 164 ± 45.1 nM, vs. CsA, 424 ± 53.4 nM and Tac, 520 ± 104.1 nM, p< 0.05). Conclusions: Our functional data confirms that CNIs have differential effects on rat TA and AA via either alternation of vascular relaxations or contractions.