Skip to main content
PMC home page
The Journal of Clinical Investigation logoLink to The Journal of Clinical Investigation
. 1996 Dec 1;98(11):2564–2571. doi: 10.1172/JCI119075

Functional impairment of renal afferent arteriolar voltage-gated calcium channels in rats with diabetes mellitus.

P K Carmines 1, K Ohishi 1, H Ikenaga 1
PMCID: PMC507714  PMID: 8958219

Abstract

Experiments were performed to test the hypothesis that diabetes mellitus is associated with impaired afferent arteriolar responsiveness to opening of voltage-gated calcium channels. Diabetes was induced by injection of streptozocin (65 mg/kg, i.v.) and insulin was administered via an osmotic minipump to achieve moderate hyperglycemia. Sham rats received vehicle treatments. 2 wk later, the in vitro blood-perfused juxtamedullary nephron technique was used to allow videomicroscopic measurement of afferent arteriolar contractile responses to increasing bath concentrations of either Bay K 8644 or K+. Baseline afferent arteriolar diameter in kidneys from diabetic rats (26.4+/-1.2 microm) exceeded that of Sham rats (19.7+/-1.0 microm). Bay K 8644 evoked concentration-dependent reductions in afferent diameter in both groups of kidneys; however, arterioles from Sham rats responded to 1 nM Bay K 8644 while 100 nM Bay K 8644 was required to contract arterioles from diabetic rats. The EC50 for K+-induced reductions in afferent arteriolar diameter was greater in diabetic kidneys (40+/-4 mM) than in kidneys from Sham rats (28+/-4 mM; P < 0.05). In afferent arterioles isolated by microdissection from Sham rats and loaded with fura 2, increasing bath [K+] from 5 to 40 mM evoked a 98+/-12 nM increase in intracellular Ca2+ concentration ([Ca2+]i). [Ca2+]i responses to 40 mM K+ were suppressed in afferent arterioles from diabetic rats (delta = 63+/-5 nM), but were normalized by decreasing bath glucose concentration from 20 to 5 mM. These observations indicate that the early stage of insulin-dependent diabetes mellitus is associated with a functional defect in afferent arteriolar L-type calcium channels, an effect which may contribute to suppressed afferent arteriolar vasoconstrictor responsiveness and promote glomerular hyperfiltration.

Full Text

The Full Text of this article is available as a PDF (207.7 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Agrawal D. K., McNeill J. H. Vascular responses to agonists in rat mesenteric artery from diabetic rats. Can J Physiol Pharmacol. 1987 Jul;65(7):1484–1490. doi: 10.1139/y87-232. [DOI] [PubMed] [Google Scholar]
  2. Bank N., Lahorra M. A., Aynedjian H. S. Acute effect of calcium and insulin on hyperfiltration of early diabetes. Am J Physiol. 1987 Jan;252(1 Pt 1):E13–E20. doi: 10.1152/ajpendo.1987.252.1.E13. [DOI] [PubMed] [Google Scholar]
  3. Cameron N. E., Cotter M. A. Impaired contraction and relaxation in aorta from streptozotocin-diabetic rats: role of polyol pathway. Diabetologia. 1992 Nov;35(11):1011–1019. doi: 10.1007/BF02221675. [DOI] [PubMed] [Google Scholar]
  4. Carmines P. K., Fowler B. C., Bell P. D. Segmentally distinct effects of depolarization on intracellular [Ca2+] in renal arterioles. Am J Physiol. 1993 Nov;265(5 Pt 2):F677–F685. doi: 10.1152/ajprenal.1993.265.5.F677. [DOI] [PubMed] [Google Scholar]
  5. Carmines P. K., Navar L. G. Disparate effects of Ca channel blockade on afferent and efferent arteriolar responses to ANG II. Am J Physiol. 1989 Jun;256(6 Pt 2):F1015–F1020. doi: 10.1152/ajprenal.1989.256.6.F1015. [DOI] [PubMed] [Google Scholar]
  6. Casellas D., Navar L. G. In vitro perfusion of juxtamedullary nephrons in rats. Am J Physiol. 1984 Mar;246(3 Pt 2):F349–F358. doi: 10.1152/ajprenal.1984.246.3.F349. [DOI] [PubMed] [Google Scholar]
  7. Chen J., Fleming J. T. Juxtamedullary afferent and efferent arterioles constrict to renal nerve stimulation. Kidney Int. 1993 Oct;44(4):684–691. doi: 10.1038/ki.1993.301. [DOI] [PubMed] [Google Scholar]
  8. Chiamvimonvat N., O'Rourke B., Kamp T. J., Kallen R. G., Hofmann F., Flockerzi V., Marban E. Functional consequences of sulfhydryl modification in the pore-forming subunits of cardiovascular Ca2+ and Na+ channels. Circ Res. 1995 Mar;76(3):325–334. doi: 10.1161/01.res.76.3.325. [DOI] [PubMed] [Google Scholar]
  9. Christiansen J. S., Gammelgaard J., Frandsen M., Parving H. H. Increased kidney size, glomerular filtration rate and renal plasma flow in short-term insulin-dependent diabetics. Diabetologia. 1981 Apr;20(4):451–456. doi: 10.1007/BF00253406. [DOI] [PubMed] [Google Scholar]
  10. Christlieb A. R. Renin, angiotensin, and norepinephrine in alloxan diabetes. Diabetes. 1974 Dec;23(12):962–970. doi: 10.2337/diab.23.12.962. [DOI] [PubMed] [Google Scholar]
  11. Conger J. D., Falk S. A., Robinette J. B. Angiotensin II-induced changes in smooth muscle calcium in rat renal arterioles. J Am Soc Nephrol. 1993 May;3(11):1792–1803. doi: 10.1681/ASN.V3111792. [DOI] [PubMed] [Google Scholar]
  12. Falcone J. C. Endothelial cell calcium and vascular control. Med Sci Sports Exerc. 1995 Aug;27(8):1165–1169. [PubMed] [Google Scholar]
  13. Fleming J. T., Parekh N., Steinhausen M. Calcium antagonists preferentially dilate preglomerular vessels of hydronephrotic kidney. Am J Physiol. 1987 Dec;253(6 Pt 2):F1157–F1163. doi: 10.1152/ajprenal.1987.253.6.F1157. [DOI] [PubMed] [Google Scholar]
  14. Franckowiak G., Bechem M., Schramm M., Thomas G. The optical isomers of the 1,4-dihydropyridine BAY K 8644 show opposite effects on Ca channels. Eur J Pharmacol. 1985 Aug 15;114(2):223–226. doi: 10.1016/0014-2999(85)90631-4. [DOI] [PubMed] [Google Scholar]
  15. Fulton D. J., Hodgson W. C., Sikorski B. W., King R. G. Attenuated responses to endothelin-1, KCl and CaCl2, but not noradrenaline, of aortae from rats with streptozotocin-induced diabetes mellitus. Br J Pharmacol. 1991 Dec;104(4):928–932. doi: 10.1111/j.1476-5381.1991.tb12528.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. González E., Salomonsson M., Kornfeld M., Gutierrez A. M., Morsing P., Persson A. E. Different action of angiotensin II and noradrenaline on cytosolic calcium concentration in isolated and perfused afferent arterioles. Acta Physiol Scand. 1992 Jul;145(3):299–300. doi: 10.1111/j.1748-1716.1992.tb09369.x. [DOI] [PubMed] [Google Scholar]
  17. Groschner K., Schuhmann K., Baumgartner W., Pastushenko V., Schindler H., Romanin C. Basal dephosphorylation controls slow gating of L-type Ca2+ channels in human vascular smooth muscle. FEBS Lett. 1995 Oct 2;373(1):30–34. doi: 10.1016/0014-5793(95)01012-4. [DOI] [PubMed] [Google Scholar]
  18. Grynkiewicz G., Poenie M., Tsien R. Y. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem. 1985 Mar 25;260(6):3440–3450. [PubMed] [Google Scholar]
  19. Hashimoto Y., Ideura T., Yoshimura A., Koshikawa S. Autoregulation of renal blood flow in streptozocin-induced diabetic rats. Diabetes. 1989 Sep;38(9):1109–1113. doi: 10.2337/diab.38.9.1109. [DOI] [PubMed] [Google Scholar]
  20. Hayashi K., Epstein M., Loutzenhiser R., Forster H. Impaired myogenic responsiveness of the afferent arteriole in streptozotocin-induced diabetic rats: role of eicosanoid derangements. J Am Soc Nephrol. 1992 May;2(11):1578–1586. doi: 10.1681/ASN.V2111578. [DOI] [PubMed] [Google Scholar]
  21. Head R. J., Longhurst P. A., Panek R. L., Stitzel R. E. A contrasting effect of the diabetic state upon the contractile responses of aortic preparations from the rat and rabbit. Br J Pharmacol. 1987 Jun;91(2):275–286. doi: 10.1111/j.1476-5381.1987.tb10282.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Hostetter T. H., Troy J. L., Brenner B. M. Glomerular hemodynamics in experimental diabetes mellitus. Kidney Int. 1981 Mar;19(3):410–415. doi: 10.1038/ki.1981.33. [DOI] [PubMed] [Google Scholar]
  23. Hurst R. D., Stevanovic Z. S., Munk S., Derylo B., Zhou X., Meer J., Silverberg M., Whiteside C. I. Glomerular mesangial cell altered contractility in high glucose is Ca2+ independent. Diabetes. 1995 Jul;44(7):759–766. doi: 10.2337/diab.44.7.759. [DOI] [PubMed] [Google Scholar]
  24. Inazu M., Sakai Y., Homma I. Contractile responses and calcium mobilization in renal arteries of diabetic rats. Eur J Pharmacol. 1991 Oct 2;203(1):79–84. doi: 10.1016/0014-2999(91)90793-p. [DOI] [PubMed] [Google Scholar]
  25. Inman S. R., Porter J. P., Fleming J. T. Reduced renal microvascular reactivity to angiotensin II in diabetic rats. Microcirculation. 1994 Jul;1(2):137–145. doi: 10.3109/10739689409148269. [DOI] [PubMed] [Google Scholar]
  26. Iwashima Y., Pugh W., Depaoli A. M., Takeda J., Seino S., Bell G. I., Polonsky K. S. Expression of calcium channel mRNAs in rat pancreatic islets and downregulation after glucose infusion. Diabetes. 1993 Jul;42(7):948–955. doi: 10.2337/diab.42.7.948. [DOI] [PubMed] [Google Scholar]
  27. Jensen P. K., Christiansen J. S., Steven K., Parving H. H. Strict metabolic control and renal function in the streptozotocin diabetic rat. Kidney Int. 1987 Jan;31(1):47–51. doi: 10.1038/ki.1987.7. [DOI] [PubMed] [Google Scholar]
  28. Jourdon P., Feuvray D. Calcium and potassium currents in ventricular myocytes isolated from diabetic rats. J Physiol. 1993 Oct;470:411–429. doi: 10.1113/jphysiol.1993.sp019866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Kokubun S., Reuter H. Dihydropyridine derivatives prolong the open state of Ca channels in cultured cardiac cells. Proc Natl Acad Sci U S A. 1984 Aug;81(15):4824–4827. doi: 10.1073/pnas.81.15.4824. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Lee S. L., Ostadalova I., Kolar F., Dhalla N. S. Alterations in Ca(2+)-channels during the development of diabetic cardiomyopathy. Mol Cell Biochem. 1992 Feb 12;109(2):173–179. doi: 10.1007/BF00229773. [DOI] [PubMed] [Google Scholar]
  31. Loutzenhiser R., Epstein M., Horton C. Inhibition by diltiazem of pressure-induced afferent vasoconstriction in the isolated perfused rat kidney. Am J Cardiol. 1987 Jan 23;59(2):72A–75A. doi: 10.1016/0002-9149(87)90180-9. [DOI] [PubMed] [Google Scholar]
  32. Loutzenhiser R., Hayashi K., Epstein M. Divergent effects of KCl-induced depolarization on afferent and efferent arterioles. Am J Physiol. 1989 Oct;257(4 Pt 2):F561–F564. doi: 10.1152/ajprenal.1989.257.4.F561. [DOI] [PubMed] [Google Scholar]
  33. MacLeod K. M., McNeill J. H. The influence of chronic experimental diabetes on contractile responses of rat isolated blood vessels. Can J Physiol Pharmacol. 1985 Jan;63(1):52–57. doi: 10.1139/y85-009. [DOI] [PubMed] [Google Scholar]
  34. Meininger G. A., Zawieja D. C., Falcone J. C., Hill M. A., Davey J. P. Calcium measurement in isolated arterioles during myogenic and agonist stimulation. Am J Physiol. 1991 Sep;261(3 Pt 2):H950–H959. doi: 10.1152/ajpheart.1991.261.3.H950. [DOI] [PubMed] [Google Scholar]
  35. Mitchell K. D., Navar L. G. Tubuloglomerular feedback responses during peritubular infusions of calcium channel blockers. Am J Physiol. 1990 Mar;258(3 Pt 2):F537–F544. doi: 10.1152/ajprenal.1990.258.3.F537. [DOI] [PubMed] [Google Scholar]
  36. Mogensen C. E. Glomerular filtration rate and renal plasma flow in short-term and long-term juvenile diabetes mellitus. Scand J Clin Lab Invest. 1971 Sep;28(1):91–100. doi: 10.3109/00365517109090667. [DOI] [PubMed] [Google Scholar]
  37. Navar L. G., Inscho E. W., Majid S. A., Imig J. D., Harrison-Bernard L. M., Mitchell K. D. Paracrine regulation of the renal microcirculation. Physiol Rev. 1996 Apr;76(2):425–536. doi: 10.1152/physrev.1996.76.2.425. [DOI] [PubMed] [Google Scholar]
  38. Nishio Y., Kashiwagi A., Ogawa T., Asahina T., Ikebuchi M., Kodama M., Shigeta Y. Increase in [3H]PN 200-110 binding to cardiac muscle membrane in streptozocin-induced diabetic rats. Diabetes. 1990 Sep;39(9):1064–1069. doi: 10.2337/diab.39.9.1064. [DOI] [PubMed] [Google Scholar]
  39. Ogawa T., Kashiwagi A., Kikkawa R., Shigeta Y. Increase of voltage-sensitive calcium channels and calcium accumulation in skeletal muscles of streptozocin-induced diabetic rats. Metabolism. 1995 Nov;44(11):1455–1461. doi: 10.1016/0026-0495(95)90146-9. [DOI] [PubMed] [Google Scholar]
  40. Ohishi K., Okwueze M. I., Vari R. C., Carmines P. K. Juxtamedullary microvascular dysfunction during the hyperfiltration stage of diabetes mellitus. Am J Physiol. 1994 Jul;267(1 Pt 2):F99–105. doi: 10.1152/ajprenal.1994.267.1.F99. [DOI] [PubMed] [Google Scholar]
  41. Scholey J. W., Meyer T. W. Control of glomerular hypertension by insulin administration in diabetic rats. J Clin Invest. 1989 Apr;83(4):1384–1389. doi: 10.1172/JCI114026. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Schuhmann K., Groschner K. Protein kinase-C mediates dual modulation of L-type Ca2+ channels in human vascular smooth muscle. FEBS Lett. 1994 Mar 21;341(2-3):208–212. doi: 10.1016/0014-5793(94)80458-3. [DOI] [PubMed] [Google Scholar]
  43. Takeda K., Schini V., Stoeckel H. Voltage-activated potassium, but not calcium currents in cultured bovine aortic endothelial cells. Pflugers Arch. 1987 Nov;410(4-5):385–393. doi: 10.1007/BF00586515. [DOI] [PubMed] [Google Scholar]
  44. Takenaka T., Harrison-Bernard L. M., Inscho E. W., Carmines P. K., Navar L. G. Autoregulation of afferent arteriolar blood flow in juxtamedullary nephrons. Am J Physiol. 1994 Nov;267(5 Pt 2):F879–F887. doi: 10.1152/ajprenal.1994.267.5.F879. [DOI] [PubMed] [Google Scholar]
  45. Turlapaty P. D., Lum G., Altura B. M. Vascular responsiveness and serum biochemical parameters in alloxan diabetes mellitus. Am J Physiol. 1980 Dec;239(6):E412–E421. doi: 10.1152/ajpendo.1980.239.6.E412. [DOI] [PubMed] [Google Scholar]
  46. Vallon V., Blantz R. C., Thomson S. Homeostatic efficiency of tubuloglomerular feedback is reduced in established diabetes mellitus in rats. Am J Physiol. 1995 Dec;269(6 Pt 2):F876–F883. doi: 10.1152/ajprenal.1995.269.6.F876. [DOI] [PubMed] [Google Scholar]
  47. Wang D. W., Kiyosue T., Shigematsu S., Arita M. Abnormalities of K+ and Ca2+ currents in ventricular myocytes from rats with chronic diabetes. Am J Physiol. 1995 Oct;269(4 Pt 2):H1288–H1296. doi: 10.1152/ajpheart.1995.269.4.H1288. [DOI] [PubMed] [Google Scholar]
  48. White R. E., Carrier G. O. Vascular contraction induced by activation of membrane calcium ion channels is enhanced in streptozotocin-diabetes. J Pharmacol Exp Ther. 1990 Jun;253(3):1057–1062. [PubMed] [Google Scholar]
  49. Wilkes B. M., Kaplan R., Mento P. F., Aynedjian H. S., Macica C. M., Schlondorff D., Bank N. Reduced glomerular thromboxane receptor sites and vasoconstrictor responses in diabetic rats. Kidney Int. 1992 Apr;41(4):992–999. doi: 10.1038/ki.1992.151. [DOI] [PubMed] [Google Scholar]
  50. Williams B. Glucose-induced vascular smooth muscle dysfunction: the role of protein kinase C. J Hypertens. 1995 May;13(5):477–486. doi: 10.1097/00004872-199505000-00001. [DOI] [PubMed] [Google Scholar]
  51. Williams B., Schrier R. W. Effect of elevated extracellular glucose concentrations on transmembrane calcium ion fluxes in cultured rat VSMC. Kidney Int. 1993 Aug;44(2):344–351. doi: 10.1038/ki.1993.250. [DOI] [PubMed] [Google Scholar]
  52. Williamson J. R., Chang K., Frangos M., Hasan K. S., Ido Y., Kawamura T., Nyengaard J. R., van den Enden M., Kilo C., Tilton R. G. Hyperglycemic pseudohypoxia and diabetic complications. Diabetes. 1993 Jun;42(6):801–813. doi: 10.2337/diab.42.6.801. [DOI] [PubMed] [Google Scholar]

Articles from Journal of Clinical Investigation are provided here courtesy of American Society for Clinical Investigation

RESOURCES