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GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

P2X Receptor-Stimulated Calcium Responses in Preglomerular Vascular Smooth Muscle Cells Involves 20-Hydroxyeicosatetraenoic Acid

Vascular Biology Center (X.Z., J.D.I.) and Department of Physiology, Medical College of Georgia, Augusta, Georgia (E.W.I., J.D.I.); and Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas (J.R.F., V.R.G.)

The current study tested the hypothesis that endogenous 20-hydroxyeicosatetraenoic acid (20-HETE) contributes to the increase in intracellular calcium ([Ca²⁺]_i) elicited by P2X receptor activation in renal microvascular smooth muscle cells. Vascular smooth muscle cells obtained from rats were loaded with fura-2 and studied using standard single cell fluorescence microscopy. Basal renal myocyte [Ca²⁺]_i averaged 96 ± 5 nM. ATP (10 and 100 µM) increased vascular smooth muscle cell [Ca²⁺]_i by 340 ± 88 and 555 ± 80 nM, respectively. The cytochrome P450 hydroxylase inhibitor, N-methylsulfonyl-12,12-dibromododec-11-enamide (DDMS), or the 20-HETE antagonist, 20-hydroxyeicosa-6(Z),15(Z)-dienoic acid (20-HEDE), significantly attenuated the peak myocyte [Ca²⁺]_i responses to 10 and 100 µM ATP. ATP (100 µM) increased vascular smooth muscle cell [Ca²⁺]_i by 372 ± 93 and 163 ± 55 nM in the presence of DDMS or 20-HEDE, respectively. The P2X receptor agonist, ,-methylene-ATP (10 µM), increased myocyte [Ca²⁺]_i by 78 ± 12 nM, and this response was significantly attenuated by DDMS (40 ± 15 nM). In contrast, the vascular smooth muscle cell [Ca²⁺]_i evoked by the P2Y agonist, UTP (100 µM), was not altered by DDMS or 20-HEDE. The effect of 20-HETE on [Ca²⁺]_i was also assessed, and the peak increases in [Ca²⁺]_i averaged 62 ± 12 and 146 ± 70 nM at 20-HETE concentrations of 1 and 10 µM, respectively. These results demonstrate that 20-HETE plays a significant role in the renal microvascular smooth muscle cell [Ca²⁺]_i response to P2X receptor activation.

Address correspondence to: Dr. John D. Imig, Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912-2500. E-mail: jdimig{at}mail.mcg.edu

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