Salt-sensitive hypertension is triggered by Ca2+ entry via Na+/Ca2+ exchanger type-1 in vascular smooth muscle.
Excessive salt intake is a major risk factor for hypertension. Here we identify the role of Na(+)/Ca(2+) exchanger type 1 (NCX1) in salt-sensitive hypertension using SEA0400, a specific inhibitor of Ca(2+) entry through NCX1, and genetically engineered mice. SEA0400 lowers arterial blood pressure in salt-dependent hypertensive rat models, but not in other types of hypertensive rats or in normotensive rats. Infusion of SEA0400 into the femoral artery in salt-dependent hypertensive rats increases arterial blood flow, indicating peripheral vasodilation. SEA0400 reverses ouabain-induced cytosolic Ca(2+) elevation and vasoconstriction in arteries. Furthermore, heterozygous NCX1-deficient mice have low salt sensitivity, whereas transgenic mice that specifically express NCX1.3 in smooth muscle are hypersensitive to salt. SEA0400 lowers the blood pressure in salt-dependent hypertensive mice expressing NCX1.3, but not in SEA0400-insensitive NCX1.3 mutants. These findings indicate that salt-sensitive hypertension is triggered by Ca(2+) entry through NCX1 in arterial smooth muscle and suggest that NCX1 inhibitors might be useful therapeutically.
Department of Pharmacology, School of Medicine, Fukuoka University, Fukuoka 814-0180, Japan. tiwamoto@cis.fukuoka-u.ac.jp
Takahiro
T
Iwamoto
Satomi
S
Kita
Jin
J
Zhang
Mordecai P
MP
Blaustein
Yuji
Y
Arai
Shigeru
S
Yoshida
Koji
K
Wakimoto
Issei
I
Komuro
Takeshi
T
Katsuragi
D017398:Alternative Splicing / Q000235:genetics / Q000502:physiology; D000814:Aniline Compounds / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism; D006973:Hypertension / Q000209:etiology* / Q000378:metabolism; D015151:Immunoblotting; D007150:Immunohistochemistry; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D051379:Mice; D008822:Mice, Transgenic; D009131:Muscle, Smooth, Vascular / Q000187:drug effects*; D010042:Ouabain / Q000378:metabolism; D010647:Phenyl Ethers / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017673:Sodium Chloride, Dietary / Q000378:metabolism; D019831:Sodium-Calcium Exchanger / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014661:Vasoconstriction / Q000187:drug effects
D000814:Aniline Compounds; D010647:Phenyl Ethers; C430918:SEA 0400; D017673:Sodium Chloride, Dietary; D019831:Sodium-Calcium Exchanger; C110374:sodium-calcium exchanger 1; D010042:Ouabain; D002118:Calcium