FUNCTIONAL IMPAIRMENT OF RENAL AFFERENT ARTERIOLAR VOLTAGE-GATED CALCIUM CHANNELS IN RATS WITH DIABETES-MELLITUS

Experiments were performed to test the hypothesis that diabetes mellit us is associated with impaired afferent arteriolar responsiveness to o pening of voltage-gated calcium channels, Diabetes was induced by inje ction of streptozocin (65 mg/kg, i.v.) and insulin was administered vi a an osmotic minipump to achieve moderate hyperglycemia, Sham rats rec eived vehicle treatments. 2 wk later, the in vitro blood-perfused juxt amedullary nephron technique was used to allow videomicroscopic measur ement of afferent arteriolar contractile responses to increasing bath concentrations of either Bay K 8644 or K+. Baseline afferent arteriola r diameter in kidneys from diabetic rats (26.4 +/- 1.2 mu m) exceeded that of Sham rats (19.7 +/- 1.0 mu m) Bay K 8644 evoked concentration- dependent reductions in afferent diameter in both groups of kidneys; h owever, arterioles from Sham rats responded to 1 nM Bay K 8644 while 1 00 nM Bay K 8644 was required to contract arterioles from diabetic rat s. The EC(50) for K+-induced reductions in afferent arteriolar diamete r was greater in diabetic kidneys (40 +/- 4 mM) than in kidneys from S ham rats (28 +/- 4 mM; P < 0.05). In afferent arterioles isolated by m icrodissection from Sham rats and loaded with fura 2, increasing bath [K+] from 5 to 40 mM evoked a 98 +/- 12 nM increase in intracellular C a2+ concentration ([Ca2+](i)). [Ca2+](i) responses to 40 mM K+ were su ppressed in afferent arterioles from diabetic rats (Delta = 63 +/- 5 n M), but were normalized by decreasing bath glucose concentration from 20 to 5 mM. These observations indicate that the early stage of insuli n-dependent diabetes mellitus is associated with a functional defect i n afferent arteriolar L-type calcium channels, an effect which may con tribute to suppressed afferent arteriolar vasoconstrictor responsivene ss and promote glomerular hyperfiltration.