Research Article: Comparative In Vitro Effects of Calcineurin Inhibitors on Functional Vascular Relaxations of Both Rat Thoracic and Abdominal Aorta

Date Published: June 18, 2013

Publisher: Hindawi Publishing Corporation

Author(s): Ashok Jadhav, Venkat Gopalakrishnan, Ahmed Shoker.

http://doi.org/10.1155/2013/718313

Abstract

Background and Aim. Calcineurin inhibitors (CNIs) have shown to develop hypertension in transplant patients. The in vitro incubation effects of cyclosporine (CsA) and tacrolimus (Tac) on vascular relaxations of rat thoracic aorta (TA) and abdominal aorta (AA) need to be investigated.
Methods. The optimal concentrations of CsA (1.0 mg/mL) and Tac (0.1 mg/mL) used to compare endothelium-dependent (acetylcholine (ACh)) and endothelium-independent (sodium nitroprusside (SNP)) vascular relaxation against the agonists in phenylephrine (PE-) constricted TA and AA of 13-week-old male Sprague Dawley rats (n = 6).
Results. In TA, the maximal vasodilator response elicited by ACh (control: Imax 98%) was significantly (P < 0.01) inhibited by CsA (Imax 10%) but not by Tac (Imax 97%). In AA, (control: IC50 50 nM; Imax 100%) CsA (IC50 7 μM; (P < 0.01) showed strong sensitivity to inhibit ACh-dependent vascular relaxation than Tac (IC50 215 nM (P < 0.05); Imax 98%). CsA and Tac failed to affect the inhibitory responses to SNP in both TA and AA. Conclusion. CsA exerts profound inhibitory effect on endothelium-dependent vasodilatation as compared to Tac in both TA and AA. Aortic rings from the thoracic region are more sensitive to CNIs, since the vasodilator response to ACh is solely mediated by NO while in the AA, ACh likely recruits other endothelial mediators besides NO to maintain vasodilatation.

Partial Text

The post-transplantation vasculopathy is an important complication after organ transplantation [1]. The initial pathological event is thought to be an allograft endothelial dysfunction, a condition in which there is decreased generation of endothelium-derived relaxing factor, nitric oxide (NO). Either its synthesis is reduced or its increased quenching by oxidative stress is thought to result in increased vascular smooth muscle (VSM) tone and elevation in blood pressure that is accompanied by endothelial damage and loss of homeostatic regulatory property of the vascular wall [2]. Diminished NO function is thought to play a major role in the progression of post-transplantation vasculopathy [3]. Transplantation immunosuppressants such as calcineurin inhibitors (CNIs) have substantial effects on vascular reactivity, especially on NO synthesis [3]. The main two CNI drugs namely, cyclosporine A (CsA) and tacrolimus (Tac), have been suggested to impair vascular endothelial function via decreased generation of NO release along with increased generation vasoconstrictor peptide, endothelin-1 (ET-1) that leads to elevated vascular tone and resultant hypertension [4–8]. It is now well accepted that these effects of CsA and Tac are due to their direct effects on the vasculature that are independent of their effects on the kidney [9]. In contrast, one study has proposed that administration of CsA promotes enhanced vasoconstriction of rat thoracic aortic (TA) rings via its direct effects on VSM cells, and it may not affect endothelium-dependent, NO-mediated vasodilatation [10]. The same group of investigators have also demonstrated that prolonged in vivo administration of CsA leads to both endothelium-dependent (vasodilator response to acetylcholine (Ach)) as well as endothelium-independent (sodium nitroprusside (SNP)) reduction in vasodilator responses in thoracic but not in the abdominal portions of rat aortic rings [11]. However, a rationale for such a remarkable degree of regional differences between segments of rat aortic rings was not adequately explained in that study. The study failed to show whether in vitro incubation with a CNI such as CsA or Tac would affect the vascular responses to agonists. The results with the CNIs on the regulation of vascular function are indeed very conflicting owing to differences in study protocol, drug doses and treatment durations [4–11]. To the best of our knowledge, there has not been any information on the relative impact of a comparative effect of both CsA and Tac on the responses to vasodilator agonists on TA versus abdominal aorta (AA).

Addition of either the vehicle (peanut oil 10%) in which higher concentrations of both CsA or Tac were prepared or the addition of appropriate concentrations of either CsA (1.0 mg/mL) or Tac (0.1 mg/mL) maintained in the organ bath for a period of 30 min in Krebs buffer failed to affect the basal tone, while PE-evoked steady tonic responses of TA or AA portions of rat aortic rings were enhanced and comparable (data not shown).

The major finding reported in the present study is the observation that CsA inhibits endothelium-dependent vasodilatation to a much greater extent than Tac, and this effect is more pronounced in thoracic than in abdominal region of the rat aorta. The acute in vitro comparative data reported in the present study is consistent with the incidence of hypertension development in previously normotensive liver or heart transplant recipients treated with CsA and Tac. Hypertension developed in about 80%–90% of patients those are receiving CsA compared to a relatively lower (50%–60%) incidence of hypertension in patients receiving Tac treatment [14–16]. Another recent report has also shown that Tac showed a significantly lower score (P < 0.05) than CsA when augmentation of arterial stiffening and small and large artery compliance index were considered following CsA and Tac treatment in renal transplant recipients receiving these two agents [17]. The significance of our present functional in vitro study is discussed in the light of the above clinical observations. Our short term in vitro functional study reveals that CsA is more potent than Tac in the inhibition of endothelium-dependent, ACh-induced vasodilatation in both TA and AA. There are regional variations in the responses to CNIs with TA being more sensitive to blockade than AA. In addition, we also found that CNIs did not affect the SNP-induced vasodilatation in thoracic and abdominal aorta.   Source: http://doi.org/10.1155/2013/718313

 

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