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Calcium and chloride channel activation by angiotensin II-AT₁ receptors in preglomerular vascular smooth muscle cells

¹Department of Physiology and Hypertension and Renal Center of Excellence, Tulane University Health Sciences Center, New Orleans, Louisiana; and Departments of ²Physiology and ³Vascular Biology Center, Medical College of Georgia, Augusta, Georgia

Submitted 24 November 2004 ; accepted in final form 2 June 2005

The pathways responsible for the rapid and sustained increases in [Ca²⁺]_i following activation of ANG II receptors (AT₁) in renal vascular smooth muscle cells were evaluated using fluorescence microscopy. Resting intracellular calcium concentration [Ca²⁺]_i averaged 75 ± 9 nM. The response to ANG II (100 nM) was characterized by a rapid initial increase of [Ca²⁺]_i by 74 ± 6 nM (n = 35) followed by a decrease to a sustained level of 12 ± 2 nM above baseline. The average time from peak to 50% reduction from the peak value (50% time point) was 32 ± 4 s. AT₁ receptor blockade with 1 µM candesartan (n = 5) prevented the responses to ANG II. In nominally calcium-free conditions (n = 8), the peak increase in [Ca²⁺]_i averaged 42 ± 7 nM but the sustained phase was absent and the 50% time point was reduced to 11 ± 4 s. L-type calcium channel blockade with diltiazem reduced the peak [Ca²⁺]_i to 24 ± 8 nM and the sustained level to 4 ± 2 nM (n = 10). In cells preincubated in low Cl^– (3.0 mM), the peak response to ANG II was suppressed as was the sustained response. Blockade of chloride channels with DIDS eliminated both the peak and sustained responses (n = 11); chloride channel blockade with DPC (n = 17) suppressed the peak increase in [Ca²⁺]_i to 18 ± 5 and also prevented the sustained response. IP3 receptor blockade by 10 µM TMB-8 (n = 6) reduced the peak to 22 ± 8 and prevented the sustained response. Exposure to 10 µM TMB-8 in the presence of Ca²⁺-free medium prevented the ANG II response (n = 9). In the presence of 100 µM DPC and 10 µM TMB-8 (n = 7), the ANG II response was also prevented. Thus the rapid initial increase in [Ca²⁺]_i is due not only to release from intracellular stores, but also to Ca²⁺ influx from the extracellular fluid. Although Ca²⁺ entry via L-type calcium channels is responsible for the major portion of the sustained response, other entry pathways participate. The finding that chloride channel blockers markedly attenuate both rapid and sustained responses indicates that chloride channel activation contributes to, rather than being the consequence of, the initial rapid response.

preglomerular smooth muscle cell; calcium influx; calcium mobilization; fluorescence cell microscopy; L-type Ca²⁺ channels; AT₁ receptor blockers; diltiazem; DIDS; DPC; candesartan

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