Blockade of endothelin ET(A), but not thromboxane, receptors offsets the cyclosporine-evoked hypertension and interrelated baroreflex and vascular dysfunctions.
The impairment of arterial baroreceptor and vasodilator functions are two major contributors to the hypertensive action of cyclosporine (CSA). In this study, in vivo and in vitro pharmacological studies were performed to investigate whether these effects of CSA are differentially modulated by endothelin and thromboxane signaling. The treatment of rats with CSA (25mg/kg/day i.p.) for 7 consecutive days caused significant increases in blood pressure (BP), attenuated reflex heart rate (HR) responses to vasopressor (phenylephrine, PE) and vasodepressor (sodium nitroprusside, SNP) agents, and reduced cumulative vasorelaxant responses elicited by acetylcholine (Ach, 1×10(-9)-1×10(-5)M) in PE-precontracted isolated aortas. These effects of CSA were blunted after concurrent i.p. administration of atrasentan (selective ETA blocker, 10mg/kg/day), but not terutroban (thromboxane receptor blocker, 10mg/kg/day). Moreover, atrasentan reversed the reductions in aortic protein expression of eNOS caused by CSA whereas terutroban was without effect. We also report that the favorable effect of atrasentan on CSA-evoked impairment in aortic Ach responsiveness disappeared in rats treated simultaneously with L-NAME (NOS inhibitor, 10mg/kg/day) but not BQ 788 (ETB receptor blocker, 0.1mg/kg/day) or indomethacin (cycloxygenase inhibitor, 5mg/kg/day). Together, the data implicate endothelin ETA receptors in baroreflex and vascular derangements which predispose to the hypertensive effect of CSA. Moreover, the facilitation of NOS, but not ETB receptors or cycloxygenase-derived prostanoids, signaling is pivotal for advantageous effect of atrasentan on the aortic CSA-Ach interaction.
Department of Pharmacology, Faculty of Pharmacy, Beirut Arab University, Lebanon.
Suzanne A
SA
Nasser
Department of Pharmacology, Faculty of Pharmacy, Alexandria University, Egypt.
Ahmed I
AI
Elmallah
Department of Pharmacology, Faculty of Medicine, American University of Beirut, Lebanon.
Ramzi
R
Sabra
Department of Pharmacology, Faculty of Medicine, Alexandria University, Egypt.
Mohamed M
MM
Khedr
Department of Pharmacology, Faculty of Pharmacy, Alexandria University, Egypt.
Mahmoud M Mohy
MM
El-Din
Department of Pharmacology, Faculty of Pharmacy, Alexandria University, Egypt. Electronic address: mahelm@hotmail.com.
Mahmoud M
MM
El-Mas
D000818:Animals; D000077868:Atrasentan; D001794:Blood Pressure / Q000187:drug effects; D016572:Cyclosporine; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D065130:Endothelin A Receptor Antagonists / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D008297:Male; D009281:Naphthalenes / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D011422:Propionates / Q000494:pharmacology*; D011759:Pyrrolidines / Q000494:pharmacology*; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000187:drug effects* / Q000378:metabolism; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D065130:Endothelin A Receptor Antagonists; D009281:Naphthalenes; D011422:Propionates; D011759:Pyrrolidines; D044022:Receptor, Endothelin A; D017482:Receptors, Thromboxane; D014665:Vasodilator Agents; D009569:Nitric Oxide; D016572:Cyclosporine; C501362:terutroban; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D000077868:Atrasentan
Acetycholine relaxations; Arterial baroreceptors; Cyclosporine; Endothelin receptors; Hypertension; Thromboxane receptors