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 clearly characterized. In this study we aimed to elucidate the effect of streptozotocin (STZ)-induced diabetes on myogenic response of isolated rat skeletal muscle arterioles and the mechanisms responsible for its alterations.


METHODS
Male rats were divided into two groups: (1) control rats (C, plasma glucose: 6.4 +/- 0.5 mmol/l, n = 40) (2) diabetic rats (DM, 65 mg/kg STZ i.v., plasma glucose: 25.7 +/- 0.7 mmol/l, n = 40). Changes in diameter of isolated, cannulated gracilis skeletal muscle arterioles (approximately 130 microns in diameter) were measured by video-microscopy.


RESULTS
Step increases in perfusion pressure (PP; from 10 to 140 mmHg) elicited significantly greater constrictions 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 and faster constrictions in DM vs. C arterioles. There were no significant differences in the pressure-passive diameter (in Ca2+ free solution) curves of arterioles. Dilations to acetylcholine were impaired in arterioles of DM as compared to those of C rats (EC50, C: 4.0 +/- 0.9 x 10(-9) mol/l, DM: 4.8 +/- 2.0 x 10(-8) mol/l (p < 0.01), and unaffected by inhibition of nitric oxide synthesis 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 +/- 0.6 x 10(-7) mol/l, DM: 8.0 +/- 2.0 x 10(-8) mol/l, p < 0.01) both in the presence and absence of E. In the absence of the E, constrictions to increases in pressure, or Ca2+ (0.25-7.5 mmol/l), or the voltage-dependent Ca(2+)-channel agonist Bay K 8644 (EC50; DM: 4.2 +/- 1.5 x 10(-10) mol/l, C: 1.7 +/- 0.8 x 10(-9) mol/l, p < 0.05) or the protein kinase C activator phorbol 12-myristate 13-acetate (PMA, EC50; DM: 6 +/- 2 x 10(-9) mol/l, C: 2 +/- 1 x 10(-8) mol/l, p < 0.05) were significantly greater in arterioles of DM compared to those of C rats.


CONCLUSIONS
The novel findings of our study are that in diabetes mellitus the myogenic response of rat skeletal muscle arterioles is enhanced, which seems to be independent from the impaired endothelial function present simultaneously, and likely due to the increased activity of voltage-dependent Ca2+ channels and/or upregulation of protein kinase C in arteriolar smooth muscle.
Ungvari
Z
Z
Institute of Pathophysiology, Semmelweis University of Medicine, Budapest, Hungary.
Pacher
P
P
Kecskemeti
V
V
Papp
G
G
Szollár
L
L
Koller
A
A
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D001160:Arterioles; D002120:Calcium Channel Agonists / Q000494:pharmacology; D015220:Calcium Channels / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism / Q000503:physiopathology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D004789:Enzyme Activation; D066298:In Vitro Techniques; D008297:Male; D018715:Microscopy, Video; D018482:Muscle, Skeletal / Q000098:blood supply*; D009131:Muscle, Smooth, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D019335:Nitroarginine / Q000494:pharmacology; D009638:Norepinephrine / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism*; D051381:Rats; D017208:Rats, Wistar; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014662:Vasoconstrictor Agents / Q000494:pharmacology
D002120:Calcium Channel Agonists; D015220:Calcium Channels; D014662:Vasoconstrictor Agents; D019335:Nitroarginine; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D019001:Nitric Oxide Synthase; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate; D009638:Norepinephrine