title: Facilitation by the renin-angiotensin system of cyclosporine-evoked hypertension in rats: Role of arterial baroreflexes and vasoreactivity.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  RESULTS
  CSA (25mg/kg/day i.p. for 7days) caused significant increases in BP that were paralleled with (i) reduced BRS measured by phenylephrine (BRSPE) or sodium nitroprusside (BRSSNP), (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 BRSSNP, 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 ETA/ETB receptor blockade (atrasentan/BQ788). By contrast, the blockade of thromboxane receptors (terutroban) failed to alter the CSA-evoked facilitation of Ang II responsiveness.
  
  
  CONCLUSIONS
  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.
authors: Department of Pharmacology, Faculty of Pharmacy, Beirut Arab University, Lebanon.
authors: Suzanne A
authors: SA
authors: Nasser
authors: Department of Pharmacology, Faculty of Medicine, American University of Beirut, Lebanon.
authors: Ramzi
authors: R
authors: Sabra
authors: Department of Pharmacology, Faculty of Pharmacy, Alexandria University, Egypt.
authors: Ahmed I
authors: AI
authors: Elmallah
authors: Department of Pharmacology, Faculty of Pharmacy, Alexandria University, Egypt.
authors: Mahmoud M Mohy
authors: MM
authors: El-Din
authors: Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Egypt.
authors: Mohamed M
authors: MM
authors: Khedr
authors: Department of Pharmacology, Faculty of Pharmacy, Alexandria University, Egypt. Electronic address: mahelm@hotmail.com.
authors: Mahmoud M
authors: MM
authors: El-Mas
mesh_terms: D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D000109:Acetylcholine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000378:metabolism; D000077868:Atrasentan; D017704:Baroreflex / Q000187:drug effects*; D001794:Blood Pressure / Q000187:drug effects; D002216:Captopril / Q000494:pharmacology; D016572:Cyclosporine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology*; D007213:Indomethacin / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis; D009599:Nitroprusside / Q000494:pharmacology; D009842:Oligopeptides / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D011422:Propionates / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D051381:Rats; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology*; D014661:Vasoconstriction / Q000187:drug effects*; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D009281:Naphthalenes; D009842:Oligopeptides; D010880:Piperidines; D011422:Propionates; D011759:Pyrrolidines; D000804:Angiotensin II; D009599:Nitroprusside; D010656:Phenylephrine; C086539:BQ 788; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; D016572:Cyclosporine; D002216:Captopril; C501362:terutroban; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019808:Losartan; D000109:Acetylcholine; D000077868:Atrasentan; D007213:Indomethacin
keywords: Arterial baroreceptors; Cyclosporine; Endothelin receptors; Endothelium-dependent relaxations; Hypertension; Renin-angiotensin system