Abstract 068: Impact of Renal Outer Medullary Potassium Channel Inhibition on Afferent Arteriolar Tone in Rats With Type 1 Diabetes

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The bee venom toxin tertiapin Q (TPQ) evokes tubuloglomerular feedback-independent afferent arteriolar constriction in kidneys from rats with streptozotocin-induced type 1 diabetes (STZ rats). Because TPQ inhibits both Kir1.1 and Kir3.x channels, the contribution of Kir1.1 (renal outer medullary potassium channel; ROMK) to afferent arteriolar tone in diabetes remains uncertain. To test the hypothesis that Kir1.1 exerts a tonic dilator influence on the afferent arteriole during diabetes, we compared afferent arteriolar responses to the novel, small molecule Kir1.1-selective inhibitor Compound C (CmpdC) to those evoked by TPQ. The ex vivo blood-perfused juxtamedullary nephron technique was used to monitor afferent arteriolar lumen diameter before and during exposure to TPQ (1-100 nM) or CmpdC (10 nM-10 μM). Neither agent altered afferent arteriolar diameter in kidneys from normal rats. In kidneys from STZ rats (blood glucose concentration = 465 ± 12 mg/dl), baseline afferent arteriolar diameter averaged 22.9 ± 0.6 μm ( n = 30). Both TPQ and CmpdC evoked concentration-dependent arteriolar constriction, with 100 nM TPQ decreasing diameter by 2.5 ± 0.6 μm ( n = 6; P < 0.001 vs baseline) and 100 nM CmpdC reducing diameter by 1.7 ± 0.6 μm ( n = 10; P = 0.004 vs baseline; P = 0.42 vs 100 nM TPQ). During subsequent exposure to 10 μM CmpdC, arteriolar diameter was 2.1 ± 0.8 μm below baseline. The similar effects of the Kir1.1/3.x inhibitor TPQ and the Kir1.1-selective inhibitor CmpdC on arteriolar diameter in kidneys from STZ rats support the contention that Kir1.1 exerts a tonic afferent arteriolar dilator influence during type 1 diabetes. In follow-up studies, the NKCC inhibitor furosemide (30-300 μM) administered via the bath did not alter afferent arteriolar diameter in kidneys from STZ rats; however, prior exposure to furosemide prevented the vasoconstrictor response to 100 nM CmpdC (Δ diameter = -0.4 ± 0.3 μm; n = 8) although the response to 100 nM TPQ remained intact (Δ diameter = -2.6 ± 1.3 μm; n = 6). The differential impact of furosemide pretreatment on arteriolar responses to TPQ and CmpdC suggests a complex interplay between the furosemide-sensitive vascular NKCC1 and tubular NKCC2, and the TPQ- and CmpdC-sensitive Kir1.1 expressed in both the vasculature and tubule.