title: Nitric oxide synthase/K+ channel cascade triggers the adenosine A(2B) receptor-sensitive renal vasodilation in female rats.
abstract: Adenosine A2B-receptors mediate the adenosine-evoked renal vasodilations in male rats. Here, we tested whether this finding could be replicated in female renal vasculature and whether K(+) hyperpolarization induced by nitric oxide synthase (NOS) and/or heme oxygenase (HO) accounts for adenosine A2B receptor-sensitive renal vasodilations. In phenylephrine-preconstricted perfused kidneys, vasodilations caused by the adenosine analog 5'-N-ethylcarboxamidoadenosine (NECA, 1.6-50 nmol) were attenuated after blockade of adenosine A2B (alloxazine) but not A2A [8-(3-Chlorostyryl) caffeine, CSC] or A3 receptors (N-(2-methoxyphenyl)-N'-[2-(3-pyridinyl)-4-quinazolinyl]-urea, VUF 5574), confirming the preferential involvement of A2B receptors in NECA responses. NOS activation mediated the A2B receptor-mediated NECA response because: (i) NOS inhibition (N(ω)-nitro-L-arginine-methyl ester, L-NAME) attenuated NECA vasodilations, (ii) concurrent L-NAME/alloxazine exposure caused more inhibition of NECA responses, and (iii) inhibition of NECA responses by alloxazine disappeared in L-arginine-supplemented preparations. Although HO inhibition (zinc protoporphyrin) failed to modify NECA responses, the attenuation of these responses by alloxazine disappeared in hemin (HO inducer)-treated preparations. NECA vasodilations were also attenuated after exposure to BaCl2, glibenclamide but not tetraethylammonium (blockers of inward rectifier, ATP-sensitive, and Ca(2+)-dependent K(+)-channels, respectively). The combined alloxazine/BaCl2/glibenclamide infusion caused no additional attenuation of NECA vasodilations. Vasodilations caused by minoxidil (K(+)-channel opener) were reduced by L-NAME or BaCl2/glibenclamide, supporting the importance of NOS signaling in K(+) hyperpolarization. NECA or minoxidil vasodilations were attenuated by ouabain, Na(+)/K(+)-ATPase inhibitor, and in KCl-preconstricted preparations. Overall, facilitation of adenosine A2B receptor/NOS/K(+) channel/Na(+)/K(+)-ATPase cascade underlies NECA vasodilations in female rats. Enhancing HO activity, albeit not causally related to NECA vasodilations, improves the pharmacologically compromised (alloxazine) NECA response.
authors: Department of Pharmacology and Toxicology, Faculty of Pharmacy, Alexandria University, Alexandria, Egypt.
authors: Hanan M
authors: HM
authors: El-Gowelli
authors: Sahar M
authors: SM
authors: El-Gowilly
authors: Lamia K
authors: LK
authors: Elsalakawy
authors: Mahmoud M
authors: MM
authors: El-Mas
mesh_terms: D019830:Adenosine-5'-(N-ethylcarboxamide) / Q000494:pharmacology; D000818:Animals; D005260:Female; D066298:In Vitro Techniques; D054086:KATP Channels / Q000502:physiology*; D007668:Kidney / Q000187:drug effects / Q000502:physiology*; D008914:Minoxidil / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000502:physiology*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D043704:Receptor, Adenosine A2B / Q000502:physiology*; D000254:Sodium-Potassium-Exchanging ATPase / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D054086:KATP Channels; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D043704:Receptor, Adenosine A2B; D014665:Vasodilator Agents; D019830:Adenosine-5'-(N-ethylcarboxamide); D008914:Minoxidil; D019001:Nitric Oxide Synthase; D000254:Sodium-Potassium-Exchanging ATPase