Elevated glucose potentiates contraction of isolated rat resistance arteries and augments protein kinase C-induced intracellular calcium release.
The effect of elevated glucose on arterial contractions and intracellular calcium ([Ca++]i) release induced by protein kinase C (PKC) activation and potassium depolarization (KCl) was investigated. Mesenteric resistance arteries (phi < 200 microm) isolated from male Wistar rats were studied using an arteriograph system that allowed control of transmural pressure (TMP) and measurement of lumen diameter. Arteries were incubated in either 11 or 44 mmol/L glucose and the concentration-response to Indolactam V (ILV; a specific PKC activator; LC Laboratories, Woburn, MA) and KCl was determined, as well as the sensitivity to Ca++ in the presence of either agonist. An additional group of arteries were incubated in 5.5 mmol/L glucose and the concentration-response to ILV was compared versus 11 and 44 mmol/L glucose. Arteries in 44 mmol/L glucose were more sensitive to both ILV and KCl, contracting to 10.0 micromol/L ILV, 53.9 +/- 10.1% in 11 mmol/L versus 85.1 +/- 2.0% in 44 mmol/L glucose (P < .01); arteries in 5.5 mmol/L glucose responded the least to ILV, contracting only 36.0 +/- 4% to 10.0 micromol/L ILV (P < .01 v 11 and 44 mmol/L glucose). The KCl EC50 (ie, the value at which the agonist produced 50% maximal contraction) for 11 versus 44 mmol/L glucose was 41.3 +/- 4.8 versus 31.1 +/- 1.2 mmol/L (P < .05). There was no change in Ca++ sensitivity in elevated glucose for either agonist; however, Ca++ sensitivity was augmented threefold for ILV versus KCl, demonstrating an agonist-dependent modulation of Ca++ sensitivity. The Ca++ EC50 for ILV and KCl in 11 versus 44 mmol/L was 0.18 +/- 0.05 versus 0.21 +/- 0.05 and 0.59 +/- 0.09 versus 0.60 +/- 0.10 micromol/L (P < .01 v ILV). The effect of elevated glucose on [Ca++]i release from the sarcoplasmic reticulum (SR) was investigated in arteries incubated in zero Ca++ buffer containing either 11 or 44 mmol/L glucose by measuring the contraction produced by 50 mmol/L caffeine, 3.0 micromol/L ILV, or 60 mmol/L KCl. Contraction to caffeine in 11 versus 44 mmol/L glucose was comparable, constricting 42.0 +/- 6.0% in 11 mmol/L and 36.0 +/- 4.4% in 44 mmol/L glucose (P > .05), and contraction to KCl was almost undetectable in both glucose concentrations. However, contraction to ILV increased from 5.6 +/- 0.9% in 11 mmol/L to 18.7% +/- 2.2% in 44 mmol/L glucose (P < .01), indicating that although the amount of Ca++ in the SR (caffeine-sensitive stores) was not increased in elevated glucose, PKC-induced release of [Ca++]i was enhanced, a consequence that may explain the noted glucose-induced increase in contraction to PKC activation.
Cipolla
M J
MJ
Department of Surgery, Oregon Health Sciences University, Portland, USA.
D000818:Animals; D002118:Calcium / Q000502:physiology*; D005947:Glucose / Q000494:pharmacology / Q000502:physiology*; D008297:Male; D008638:Mesenteric Arteries / Q000502:physiology*; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology*; D011493:Protein Kinase C / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000187:drug effects; D014655:Vascular Resistance / Q000187:drug effects
D011493:Protein Kinase C; D005947:Glucose; D002118:Calcium