12-Hydroxyeicosatetraenoic acid participates in angiotensin II afferent arteriolar vasoconstriction by activating L-type calcium channels

Shih S. Yiu, Xueying Zhao, Edward W. Inscho, and John D. Imig

Vascular Biology Center, Medical College of Georgia, Augusta, GA 30912

Corresponding Author: jdimig{at}mail.mcg.edu

The lipoxygenase (LO) metabolite, 12(S)-hydroxyeicosatetraenoic acid (12(S)-HETE), constricts renal vessels, contributes to the vascular response to angiotensin II and has been implicated in cardiovascular and renal diseases. The current studies were performed to determine if renal microvascular 12(S)-HETE production is stimulated by angiotensin II and the contribution of voltage-dependent L-type calcium channels to the vasoconstriction elicited by 12(S)-HETE. Renal microvessel 12(S)-HETE and cyclooxygenase (COX) metabolite production was measured. Angiotensin II increased renal microvascular 12(S)-HETE production by 64%, whereas COX metabolite production was not altered. Renal microvessels also expressed platelet-type 12-LO and leukocyte-type 12-LO. Other experiments were performed using the juxtamedullary nephron preparation. Afferent arterioles averaged 21 ± 1 um and 12(S)-HETE caused a graded decrease in vessel caliber. The afferent arteriolar response to 12(S)-HETE was abolished during L-type calcium channel inhibition with diltiazem. In additional studies, freshly isolated renal microvascular smooth muscle cells were studied using single cell calcium fluorescence microscopy. Basal renal microvascular smooth muscle cell [Ca2+]i averaged 93 ± 5 nmol/L. 12(S)-HETE (5 umol/L) increased smooth muscle [Ca2+]i to a peak value of 340 ± 55 nmol/L before stabilizing at 115 ± 6 nmol/L. The [Ca2+]i response to 12(S)-HETE was also assessed in the absence of extracellular Ca2+ and during blockade of calcium channels with diltiazem. In these studies, the initial peak [Ca2+]i response following exposure to 5 umol/L 12(S)-HETE was greatly attenuated. These results demonstrate that renal microvascular 12(S)-HETE production is increased in response to angiotensin II and activation of voltage-gated L-type calcium channels is an important mechanism responsible for the afferent arteriolar vasoconstriction elicited by 12(S)-HETE.

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