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Endothelin ETA Receptor‐Mediated Nitric Oxide Synthase Inhibition Underlies Cyclosporine Impairment Of Cholinergic Vasorelaxations In Rats
Author(s) -
Nasser Suzanne A,
Elmallah Ahmed I,
Sabra Ramzi,
Khedr Mohamed M,
ElDin Mahmoud M Mohy,
ElMas Mahmoud M
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.lb597
Subject(s) - losartan , sodium nitroprusside , endocrinology , captopril , endothelin receptor , chemistry , medicine , pharmacology , nitric oxide , nitric oxide synthase , angiotensin ii , thromboxane a2 , receptor , acetylcholine , endothelin 1 , blood pressure
Impairment of endothelium‐dependent relaxations contributes to vascular dysfunction caused by cyclosporine (CSA). We tested whether vasoconstrictor pathways of angiotensin II, endothelin‐1 (ET‐1), and/or thromboxane A2 (TXA2) modulate the attenuating effect of cyclosporine (CSA) on acetylcholine (ACh) vasorelaxations in the rat aorta. Cumulative relaxations caused by ACh (1×10 −9 –1×10 −5 M), but not sodium nitroprusside (1×10 −10 –3×10 −6 M), were blunted in phenylephrine‐precontracted aortas obtained from CSA (25 mg/kg/day i.p., 7 days)‐treated rats. This detrimental effect of CSA was preserved in rats treated simultaneously with terutroban (TXA2 receptor blocker), losartan (AT 1 receptor blocker), captopril (angiotensin converting enzyme inhibitor) or losartan plus captopril. In contrast, selective blockade of ETA receptors by atrasentan significantly increased ACh relaxations and virtually abolished the reductions in ACh responses caused by CSA. The atrasentan effect disappeared in rats treated with L‐NAME (NOS inhibitor) but not BQ788 (ETB receptor blocker) or indomethacin (cycloxygenase inhibitor). It is concluded that NOS downregulation by ETA receptors contributes to the depressant effect of CSA on cholinergic vasorelaxations. Neither ETB receptors nor cycloxygenase‐derived prostanoids are involved in the favorable effect of atrasentan on the aortic CSA‐ACh interaction.