Interaction of dimercaptosuccinic acid (DMSA) with angiotensin II on calcium mobilization in vascular smooth muscle cells.
Dimercaptosuccinic acid (DMSA) was shown to lower blood pressure in rat models of arterial hypertension. Thus, there is evidence that-besides its chelating properties-DMSA has a direct vascular effect, e.g. through scavenging of reactive oxygen species (ROS). We speculated that, in addition, intracellular calcium mobilization may be involved in this action. Therefore, the present study examined the effects of DMSA on Ca(2+) mobilization in cultured vascular smooth muscle cells (VSMCs) from rat aorta. Intracellular free Ca(2+) concentration ([Ca(2+)](i)) was measured with fura-2 AM. In a first series of experiments DMSA, 10(-11) to 10(-6)M, induced an immediate dose-dependent up to 4-fold rise of [Ca(2+)](i) (P<0.001) which was almost completely blunted by the calcium channel blocker verapamil or the intracellular calcium release blocker TMB-8. In a second series of experiments, when VSMCs were exposed acutely to DMSA (10(-11) to 10(-6)M), the angiotensin (ANG) II (10(-8)M)-induced rise in [Ca(2+)](i) to 295+/-40nM was attenuated at the average by 49% independent of the dose of DMSA. Preincubation of VSMCs with DMSA (10(-6)M) for 60min reduced basal [Ca(2+)](i) by 77% (P<0.001) and dose-dependently attenuated the ANG II (10(-8)M)-induced rise in [Ca(2+)](i) between 28 and 69% at concentrations between 10(-9) and 10(-5)M DMSA, respectively (P<0.05 and <0.01). In the presence of TMB-8, which attenuated the ANG II (10(-8)M)-induced rise in [Ca(2+)](i) by 66%, DMSA (10(-6)M) had no additional suppressive effect on [Ca(2+)](i). The results suggest that DMSA acutely raises [Ca(2+)](i) by stimulating transmembrane calcium influx via L-type calcium channels and by calcium release from intracellular stores followed by a decrease in [Ca(2+)](i) probably due to cellular calcium depletion. Thus, in addition to its action as scavenger of ROS, which in part mediate the vasoconstrictor response, e.g. to ANG II, DMSA may exert its hypotensive effect through decreasing total cell calcium, thereby attenuating the vasoconstrictor-induced rise in [Ca(2+)](i) in VSMCs.
Kramer
Herbert J
HJ
Department of Medicine, Renal Section, Medizinische Universitäts-Poliklinik, Wilhelmstrasse 35-37, University of Bonn, D-53111, Bonn, Germany. hkramer@uni-bonn.de
Mensikova
Vera
V
Bäcker
Angela
A
Meyer-Lehnert
Harald
H
Gonick
Harvey C
HC
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D002118:Calcium / Q000378:metabolism*; D002614:Chelating Agents / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D004113:Succimer / Q000494:pharmacology*
D002614:Chelating Agents; D000804:Angiotensin II; D004113:Succimer; D002118:Calcium