sea-0400 and Hypertension

Topics: Aniline Compounds; Animals; Calcium Signaling; Cardiovascular Diseases; Humans; Hypertension; Kidney; Myocardial Reperfusion Injury; Phenyl Ethers; Reperfusion Injury; Sodium Chloride, Dietary; Sodium-Calcium Exchanger; Thiourea

Hypertension is the most common chronic disease, and is the leading risk factor for death caused by stroke, myocardial infarction, and end-stage renal failure. The critical importance of excess salt intake in the pathogenesis of hypertension is widely recognized. However, the molecular mechanisms underlying salt-sensitive hypertension remain obscure. Recent studies using selective inhibitors and genetically engineered mice provide compelling evidence that salt-sensitive hypertension is triggered by Ca2+ entry through Na+/Ca2+ exchanger type-1 (NCX1) in vascular smooth muscle. Intriguingly, endogenous Na+ pump inhibitors seem to be necessary for NCX1-mediated hypertension. These findings have enabled us to explain how high salt intake leads to hypertension, and further to describe the potential of vascular NCX1 as a new therapeutic or diagnostic target for salt-sensitive hypertension.

Topics: Aniline Compounds; Animals; Drug Design; Humans; Hypertension; Kidney; Mice; Muscle, Smooth, Vascular; Natriuresis; Phenyl Ethers; Sodium; Sodium Chloride, Dietary; Sodium-Calcium Exchanger; Sodium-Potassium-Exchanging ATPase; Thiourea

Hypertension is the most prevalent risk factor for stroke, myocardial infarction, or end-stage renal failure. The critical importance of excess salt intake in the pathogenesis of hypertension is widely recognized, but the mechanisms whereby salt intake elevates blood pressure have puzzled researchers. Recent studies using Na+/Ca2+ exchange inhibitors and genetically engineered mice provide evidence that vascular Na+/Ca2+ exchanger type 1 (NCX1) is involved in the development of salt-dependent hypertension. Endogenous cardiac glycosides, which may contribute to salt-dependent hypertension, seem to be necessary for NCX1-mediated hypertension. Intriguingly, studies using knock-in mice with modified cardiac glycoside binding affinity of Na+,K+-ATPases provide a clear demonstration that this cardiac glycoside-binding site plays an important role in blood pressure regulation. Taken all together: (1) endogenous cardiac glycosides are secreted after high salt intake; (2) these cardiac glycosides inhibit Na+,K+-ATPase in vascular smooth muscle cells; (3) this inhibition results in the elevation of local Na+ on the submembrane area; and (4) this elevation of local Na+ facilitates Ca2+ entry through NCX1, resulting in vasoconstriction. This proposed pathway may have enabled us to explain how to link dietary salt to hypertension.

Topics: Androstanols; Aniline Compounds; Animals; Blood Pressure; Calcium; Cardiac Glycosides; Cardiovascular System; Cell Membrane; Humans; Hypertension; Kidney; Muscle, Smooth, Vascular; Ouabain; Phenyl Ethers; Protein Binding; Sodium; Sodium-Calcium Exchanger; Sodium-Potassium-Exchanging ATPase; Sodium, Dietary; Vasoconstriction

Hypertension is the most common chronic disease and is the leading risk factor for death caused by stroke, myocardial infarction, and end-stage renal failure. The critical importance of excess salt intake in the pathogenesis of hypertension is widely recognized. However, the molecular mechanisms underlying salt-sensitive hypertension remain obscure. Recent studies using selective Na(+)/Ca(2+) exchanger (NCX) inhibitors and genetically engineered mice provide compelling evidence that salt-sensitive hypertension is triggered by Ca(2+) entry through NCX type 1 (NCX1) in arterial smooth muscle. Cardiotonic steroids, such as endogenous ouabain, which may contribute to the pathogenesis of salt-sensitive hypertension, seem to be necessary for NCX1-mediated hypertension. These findings have enabled us to explain how high salt intake leads to hypertension and further to describe the potential of vascular NCX1 as a new therapeutic or diagnostic target for salt-sensitive hypertension.

Topics: Aniline Compounds; Animals; Humans; Hypertension; Muscle Contraction; Muscle, Smooth, Vascular; Phenyl Ethers; Sodium-Calcium Exchanger; Sodium, Dietary

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.

Topics: Alternative Splicing; Aniline Compounds; Animals; Blood Pressure; Calcium; Hypertension; Immunoblotting; Immunohistochemistry; Male; Mesenteric Arteries; Mice; Mice, Transgenic; Muscle, Smooth, Vascular; Ouabain; Phenyl Ethers; Rats; Rats, Sprague-Dawley; Sodium Chloride, Dietary; Sodium-Calcium Exchanger; Vasoconstriction

Topics: Alternative Splicing; Aniline Compounds; Animals; Blood Pressure; Calcium; Hypertension; Mice; Mice, Transgenic; Muscle, Smooth, Vascular; Ouabain; Phenyl Ethers; Sodium Chloride, Dietary; Sodium-Calcium Exchanger