Thiazide-like diuretics attenuate agonist-induced vasoconstriction by calcium desensitization linked to Rho kinase.
Lowering blood pressure using thiazide-like diuretics, including chlorthalidone and hydrochlorothiazide, has been proven to be effective in clinical studies. However, the mechanisms by which thiazide-like diuretics lower blood pressure are still poorly understood. To evaluate whether thiazide-like diuretics cause calcium desensitization in smooth muscle cells, we measured their effects on agonist-induced increase of blood pressure in Wistar rats in vivo and on agonist-induced vasoconstriction of aortic rings, DNA synthesis, and protein synthesis, RhoA, Rho kinase, and intracellular calcium in vascular smooth muscle cells in vitro. Thiazide-like diuretics significantly attenuated angiotensin II-induced or norepinephrine-induced increase of systolic blood pressure in rats. Thiazide-like diuretics inhibited agonist-induced vasoconstriction of aortic rings in a concentration-dependent manner in the presence and absence of endothelium. The inhibitory effects of thiazide-like diuretics were similar to that of the specific Rho kinase inhibitor Y27632. RT-PCR and immunoblotting showed that RhoA and Rho kinase were significantly reduced in vascular smooth muscle cells after administration of thiazide-like diuretics. In contrast, thiazide-like diuretics did not affect protein tyrosine phosphatase-2 (SHP-2) expression. Agonist-induced changes of intracellular calcium were not affected by thiazide-like diuretics. The study indicates that thiazide-like diuretics inhibit agonist-induced vasoconstriction by calcium desensitization in smooth muscle cells linked to the Rho-Rho kinase pathway.
Zhu
Zhiming
Z
Department of Hypertension and Endocrinology, Daping Hospital, Center for Hypertension and Metabolic Disease, Third Military Medical University, Chongqing Hypertension Institute, Chongqing, China. zhuzm@yahoo.com <zhuzm@yahoo.com>
Zhu
Shanjun
S
Liu
Daoyan
D
Cao
Tingbing
T
Wang
Lijuan
L
Tepel
Martin
M
D000209:Acute-Phase Proteins / Q000378:metabolism; D000804:Angiotensin II / Q000494:pharmacology; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000187:drug effects / Q000502:physiology; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000378:metabolism / Q000502:physiology*; D002752:Chlorthalidone / Q000031:analogs & derivatives* / Q000191:economics; D004247:DNA / Q000096:biosynthesis; D004232:Diuretics; D004351:Drug Resistance; D006852:Hydrochlorothiazide / Q000494:pharmacology*; D066298:In Vitro Techniques; D007425:Intracellular Membranes / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D008297:Male; D009124:Muscle Proteins / Q000096:biosynthesis; D009131:Muscle, Smooth, Vascular / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000494:pharmacology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D051381:Rats; D017208:Rats, Wistar; D049993:Sodium Chloride Symporter Inhibitors / Q000494:pharmacology*; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases
D000209:Acute-Phase Proteins; D000959:Antihypertensive Agents; D004232:Diuretics; D047908:Intracellular Signaling Peptides and Proteins; D009124:Muscle Proteins; D049993:Sodium Chloride Symporter Inhibitors; D014662:Vasoconstrictor Agents; C010781:acute-phase protein rho; D006852:Hydrochlorothiazide; D000804:Angiotensin II; D004247:DNA; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D002752:Chlorthalidone; D002118:Calcium; D009638:Norepinephrine