Facilitation by the renin-angiotensin system of cyclosporine-evoked hypertension in rats: Role of arterial baroreflexes and vasoreactivity

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• 作者：Suzanne A. Nasser^a ; Ramzi Sabra^b ; Ahmed I. Elmallah^c ; Mahmoud M. Mohy El-Din^c ; Mohamed M. Khedr^d ; Mahmoud M. El-Mas^c ; ^{mahelm@hotmail.com" class="auth_mail" title="E-mail the corresponding author}
• 关键词：CSA ; cyclosporine ; PE ; phenylephrine ; SNP ; sodium nitroprusside ; Ang II ; angiotensin II ; RAS ; renin-angiotensin system ; BP ; blood pressure ; MAP ; mean arterial pressure ; HR ; heart rate ; BRS ; baroreflex sensitivity ; eNOS ; endothelial nitric oxide synthase
• 刊名：Life Sciences
• 出版年：2016
• 出版时间：15 October 2016
• 年：2016
• 卷：163
• 期：Complete
• 页码：1-10
• 全文大小：1407 K

文摘

Cyclosporine (CSA) elevates blood pressure (BP) and alters arterial baroreflex sensitivity (BRS) and vasoreactivity. In this study we determined whether the renin-angiotensin system (RAS) interplays with other vasopressor pathways in mediating the CSA actions.

Materials and methods

Whole animal and isolated vascular preparations were employed to determine the effects of pharmacologic interruption of angiotensin II (Ang II), endothelin (ET), or thromboxane (TXA2) signaling on the adverse cardiovascular effects of CSA.

Key findings

CSA (25 mg/kg/day i.p. for 7 days) caused significant increases in BP that were paralleled with (i) reduced BRS measured by phenylephrine (BRS_PE) or sodium nitroprusside (BRS_SNP), (ii) enhanced aortic contractile responses to Ang II and U-46619 (thromboxane analogue), and (iii) reduced aortic eNOS expression and acetylcholine, but not SNP, vasorelaxations. Except for the reduced BRS_SNP, the CSA effects disappeared upon concurrent administration of losartan (angiotensin AT₁ receptor antagonist), captopril (angiotensin converting enzyme inhibitor), or their combination. Moreover, CSA augmentation of Ang II contractions was abolished after cyclooxygenase inhibition (indomethacin) or endothelin ET_A/ET_B receptor blockade (atrasentan/BQ788). By contrast, the blockade of thromboxane receptors (terutroban) failed to alter the CSA-evoked facilitation of Ang II responsiveness.

Significance

The facilitation of baroreflex control and inhibition of vascular responsiveness to Ang II and thromboxane contribute to the BP lowering effect of RAS inhibitors in CSA-treated rats. Further, endothelin receptors and vasoconstrictor prostanoids contribute to the CSA-evoked exaggeration of Ang II vascular responsiveness and hypertension.