Increased myogenic tone in skeletal muscle arterioles of diabetic rats. Possible role of increased activity of smooth muscle Ca2+ channels and protein kinase C

Objective: The diabetes mellitus-induced microangiopathy is still not clear ly characterized. In this study we aimed to elucidate the effect of strepto zotocin (STZ)-induced diabetes on myogenic response of isolated rat skeleta l muscle arterioles and the mechanisms responsible for its alterations. Met hods: Male rats were divided into two groups: (1) control rats (C, plasma g lucose: 6.4+/-0.5 mmol/l, n=40) 2) diabetic rats (DM, 65 mg/kg STZ iv, plas ma glucose: 25.7+/-0.7 mmol/l, n=40). Changes in diameter of isolated, cann ulated gracilis skeletal muscle arterioles (similar to 130 mu m in diameter ) were measured by video-microscopy. Results: Step increases in perfusion p ressure (PP; from 10 to 140 mmHg) elicited significantly greater constricti ons in DM than in C gracilis arterioles, in the presence of the endothelium (E). Also, a step increase in PP (from 40 to 100 mmHg) elicited greater an d faster constrictions in DM vs. C arterioles. There were no significant di fferences in the pressure-passive diameter (in Ca2+ free solution) curves o f arterioles. Dilations to acetylcholine were impaired in arterioles of DM as compared to those of C rats (EC50, C: 4.0+/-0.9X10(-9)mol/l, DM: 4.8+/-2 .0X10(-8) mol/l (p<0.01), and unaffected by inhibition of nitric oxide synt hesis with L-NNA (10(-4) mol/l). Arteriolar constrictions to norepinephrine (NE) were significantly greater in DM compared to those of C rats (EC50, C : 6.2+/-0.6X10(-7) mol/l, DM: 8.0+/-2.0X10(-8) mol/l, p<0.01) both in the p resence and absence of E. In the absence of the E, constrictions to increas es in pressure, or Ca2+ (0.25-7.5 mmol/l), or the voltage-dependent Ca2+-ch annel agonist Bay K 8644 (EC50; DM: 4.2+/-1.5X10(-10) mol/l, C: 1.7+/-0.8X1 0(-9) mol/l, p<0.05) or the protein kinase C activator phorbol 12-myristate 13-acetate (PMA, EC50; DM: 6+/-2X10(-9) mol/l, C: 2+/-1X10(-8) mol/l, p<0. 05) were significantly greater in arterioles of DM compared to those of C r ats. Conclusion: The novel findings of our study are that in diabetes melli tus the myogenic response of rat skeletal muscle arterioles is enhanced, wh ich seems to be independent from the impaired endothelial function present simultaneously, and likely due to the increased activity of voltage-depende nt Ca2+ channels and/or upregulation of protein kinase C in arteriolar smoo th muscle. (C) 1999 Elsevier Science B.V. All rights reserved.