KCa3.1 channels maintain endothelium‐dependent vasodilatation in isolated perfused kidneys of spontaneously hypertensive rats after chronic inhibition of NOS

• Published in: British journal of pharmacology 2012-10, Vol.167 (4), p.854-867
• Main Authors: Simonet, Serge, Isabelle, Marc, Bousquenaud, Mélanie, Clavreul, Nicolas, Félétou, Michel, Vayssettes‐Courchay, Christine, Verbeuren, Tony J
• Format: Article
• Language: English
• Subjects: Arterial hypertension. Arterial hypotension; Biological and medical sciences; Blood and lymphatic vessels; Cardiology. Vascular system; EDHF‐mediated responses; KCa2.3; KCa3.1; L‐NAME chronic treatment; Medical sciences; perfused rat kidney; Pharmacology. Drug treatments; Research Papers; SHR
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1111/j.1476-5381.2012.02062.x

BACKGROUND AND PURPOSE The purpose of the study was to investigate renal endothelium‐dependent vasodilatation in a model of severe hypertension associated with kidney injury. EXPERIMENTAL APPROACH Changes in perfusion pressure were measured in isolated, perfused kidneys taken from 18‐week‐old Wistar–Kyoto rat (WKY), spontaneously hypertensive rats (SHR) and SHR treated for 2 weeks with Nω‐nitro‐L‐arginine methyl ester in the drinking water (L‐NAME‐treated SHR, 6 mg·kg−1·day−1). KEY RESULTS Acetylcholine caused similar dose‐dependent renal dilatation in the three groups. In vitro administration of indomethacin did not alter the vasodilatation, while the addition of Nw‐nitro‐L‐arginine (L‐NA) produced a differential inhibition of the vasodilatation, (inhibition in WKY > SHR > L‐NAME‐treated SHR). Further addition of ODQ, an inhibitor of soluble guanylyl cyclase, abolished the responses to sodium nitroprusside but did not affect the vasodilatation to acetylcholine. However, the addition of TRAM‐34 (or charybdotoxin) inhibitors of Ca2+‐activated K+ channels of intermediate conductance (KCa3.1), blocked the vasodilatation to acetylcholine, while apamin, an inhibitor of Ca2+‐activated K+ channels of small conductance (KCa2.3), was ineffective. Dilatation induced by an opener of KCa3.1/KCa2.3 channels, NS‐309, was also blocked by TRAM‐34, but not by apamin. The magnitude and duration of NS‐309‐induced vasodilatation and the renal expression of mRNA for KCa3.1, but not KCa2.3, channels followed the same ranking order (WKY < SHR < L‐NAME‐treated SHR). CONCLUSIONS AND IMPLICATIONS In SHR kidneys, an EDHF‐mediated response, involving activation of KCa3.1 channels, contributed to the mechanism of endothelium‐dependent vasodilatation. In kidneys from L‐NAME‐treated SHR, up‐regulation of this pathway fully compensated for the decrease in NO availability.