title: Reduction of blood pressure by store-operated calcium channel blockers.
abstract: The voltage-operated Ca(2+) channels (VOCC), which allow Ca(2+) influx from the extracellular space, are inhibited by anti-hypertensive agents such as verapamil and nifedipine. The Ca(2+) entering from outside into the cell triggers Ca(2+) release from the sarcoplasmic reticulum (SR) stores. To refill the depleted Ca(2+) stores in the SR, another type of Ca(2+) channels in the cell membrane, known as store-operated Ca(2+) channels (SOCC), are activated. These SOCCs are verapamil and nifedipine resistant, but are SKF 96465 (SK) and gadolinium (Gd(3+) ) sensitive. Both SK and Gd(3+) have been shown to reduce [Ca(2+) ]i in the smooth muscle, but their effects on blood pressure have not been reported. Our results demonstrated that both SK and Gd(3+) produced a dose-dependent reduction in blood pressure in rat. The combination of SK and verapamil produced an additive action in lowering the blood pressure. Furthermore, SK, but not Gd(3+) suppressed proliferation of vascular smooth muscle cells in the absence or presence of lysophosphatidic acid (LPA). SK decreased the elevation of [Ca(2+) ]i induced by LPA, endothelin-1 (ET-1) and angiotensin II (Ang II), but did not affect the norepinephrine (NE)-evoked increase in [Ca(2+) ]i . On the other hand, Gd(3+) inhibited the LPA and Ang II induced change in [Ca(2+) ]i , but had no effect on the ET-1 and NE induced increase in [Ca(2+) ]i . The combination of verapamil and SK abolished the LPA- or adenosine-5'-triphosphate (ATP)-induced [Ca(2+) ]i augmentation. These results suggest that SOCC inhibitors, like VOCC blocker, may serve as promising drugs for the treatment of hypertension.
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Department of Physiology and Pathophysiology, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Yan-Jun
authors.initials: YJ
authors.lastname: Xu
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Department of Physiology and Pathophysiology, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Vijayan
authors.initials: V
authors.lastname: Elimban
authors.affiliation: Institute of Cardiovascular Sciences, St. Boniface Hospital Research Centre, Department of Physiology and Pathophysiology, Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada.
authors.forename: Naranjan S
authors.initials: NS
authors.lastname: Dhalla
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002118:Calcium / Q000378:metabolism*; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D015220:Calcium Channels / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D004247:DNA / Q000096:biosynthesis; D004305:Dose-Response Relationship, Drug; D005682:Gadolinium / Q000494:pharmacology; D007093:Imidazoles / Q000494:pharmacology; D008246:Lysophospholipids / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D014700:Verapamil / Q000494:pharmacology
chemical_list: D002121:Calcium Channel Blockers; D015220:Calcium Channels; D007093:Imidazoles; D008246:Lysophospholipids; D004247:DNA; D005682:Gadolinium; D014700:Verapamil; C063159:1-(2-(3-(4-methoxyphenyl)propoxy)-4-methoxyphenylethyl)-1H-imidazole; C032881:lysophosphatidic acid; D002118:Calcium
keywords: Ca2+ antagonists; antihypertensive agents; cell proliferation; hypertension; intracellular Ca2+