Endothelial nitric oxide attenuates Na+/Ca2+ exchanger‐mediated vasoconstriction in rat aorta

• Published in: British journal of pharmacology Vol. 154; no. 5; pp. 982 - 990
• Main Authors: Zhao, J, Majewski, H
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.07.2008; Nature Publishing; Nature Publishing Group
• Subjects: 15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid - pharmacology; Adenine - analogs & derivatives; Adenine - pharmacology; Adenylyl Cyclase Inhibitors; Adenylyl Cyclases - metabolism; Animals; aorta; Aorta, Thoracic - drug effects; Aorta, Thoracic - enzymology; Aorta, Thoracic - metabolism; Biological and medical sciences; Dinoprost - metabolism; endothelium; Endothelium, Vascular - drug effects; Endothelium, Vascular - enzymology; Endothelium, Vascular - metabolism; Enzyme Inhibitors - pharmacology; Guanylate Cyclase - antagonists & inhibitors; Guanylate Cyclase - metabolism; In Vitro Techniques; Indomethacin - pharmacology; Male; Medical sciences; Na+/Ca2+ exchanger; NG-Nitroarginine Methyl Ester - pharmacology; nitric oxide; Nitric Oxide - metabolism; Nitric Oxide Synthase - antagonists & inhibitors; Nitric Oxide Synthase - metabolism; Nitroprusside - pharmacology; Oxadiazoles - pharmacology; Pharmacology. Drug treatments; Potassium - metabolism; Prostaglandin-Endoperoxide Synthases - metabolism; Quinoxalines - pharmacology; Rats; Rats, Sprague-Dawley; Research Papers; Sodium - metabolism; Sodium-Calcium Exchanger - antagonists & inhibitors; Sodium-Calcium Exchanger - metabolism; Thiourea - analogs & derivatives; Thiourea - pharmacology; Vasoconstriction; Vasoconstrictor Agents - pharmacology; Vasodilator Agents - pharmacology; Rat; Rodentia; Vasoconstriction; Artery; Endothelium; Na+/Ca2+ exchanger; Vasomotricity; Vertebrata; Mammalia; Na; Animal; Nitric oxide; Blood vessel; exchanger; Aorta; Circulatory system; Ca
• ISSN: 0007-1188; 1476-5381
• DOI: 10.1038/bjp.2008.178

Background and purpose: The Na+/Ca2+ exchanger (NCX) may be an important modulator of Ca2+ entry and exit. The present study investigated whether NCX was affected by prostacyclin and nitric oxide (NO) released from the vascular endothelium, as NCX contains phosphorylation sites for PKA and PKG. Experimental approach: Rat aortic rings were set up in organ baths. Tension was measured across the ring with a force transducer. Key results: Lowering extracellular [Na+] ([Na+]o) to 1.18 mM induced vasoconstriction in rat endothelium‐denuded aortic rings. This effect was blocked by the NCX inhibitor KB‐R7943 (2‐2‐[4‐(4‐nitrobenzyloxy)phenyl] ethyl isothiourea methanesulphonate; 1 μM). In endothelium‐intact aortic rings, decreasing [Na+]o did not constrict the aortic rings significantly, but after treatment with the guanylate cyclase inhibitor ODQ (1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one; 1 μM) or the NOS inhibitor L‐NAME (Nω‐nitro‐L‐arginine methyl ester; 50 μM), a vasoconstriction that was similar in size to that in endothelium‐denuded preparations was evident. The vasorelaxation induced by the NO donor sodium nitroprusside sodium nitroprusside dihydrate (30 nM) was the same in the endothelium‐denuded aortic rings preconstricted with either low Na+ (1.18 mM), the thromboxane A2 agonist U46619 (9,11‐dideoxy‐9α, 11α‐methanoepoxy prostaglandin F2α; 0.1 μM) or high K+ (80 mM). Conclusions and implications: The results suggest that the endothelium inhibits NCX operation via guanylate cyclase/NO. This is stronger than for other constrictors such as phenylephrine and may relate to concomitant NCX‐stimulated NO release from the endothelium. This finding may be important where NCX operates in reverse mode, such as during ischaemia, and highlights a new mechanism whereby the endothelium modulates Ca2+ homoeostasis in vascular smooth muscle. British Journal of Pharmacology (2008) 154, 982–990; doi:10.1038/bjp.2008.178; published online 12 May 2008