Reduction of blood pressure by store‐operated calcium channel blockers

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.