Abnormalities of sarcoplasmic reticulum Ca2+ mobilization in aortic smooth muscle cells from streptozotocin-induced diabetic rats.
1. Previously, we found that contractions in response to receptor-dependent (i.e. a(1)-adrenoceptor agonist phenylephrine) and -independent (i.e. cyclopiazonic acid) stimuli are decreased in rat aorta during late diabetes. The aim of the present study was to further investigate the changes of intracellular Ca(2+) homeostasis in diabetic aortic smooth muscle cells. Functional changes of inositol 1,4,5-trisphosphate (IP(3))- and ryanodine-sensitive Ca(2+) stores of the sarcoplasmic reticulum (SR) were evaluated using Fluo-3 acetoxymethyl ester fluorescence, western blot and organ bath techniques. 2. In aortic smooth muscle cells from diabetic rats, the Ca(2+) release and Ca(2+) influx caused by both 10 mmol/L phenylephrine (depletion of IP(3)-sensitive Ca(2+) stores) and 1 mmol/L ryanodine (depletion of ryanodine-sensitive Ca(2+) stores) were both significantly decreased compared with control. Moreover, protein expression levels of IP(3) (260 kDa) and ryanodine receptors (500 kDa) were reduced by 31.8 +/- 7.7 and 69.2 +/- 8.4%, respectively, in aortas from diabetic rats compared with those from control rats. 3. In diabetic rat aorta, phenylephrine-induced contractility was decreased to approximately two-thirds of that in controls, whereas ryanodine alone did not cause obvious contraction in aortas from either control or diabetic rats. 4. The present results suggest that the hyporeactivity of aortic smooth muscle to vasoconstrictors in diabetes results mainly from changes to the IP(3)-sensitive Ca(2+) release pathway. The SR Ca(2+) signalling pathway plays a crucial role in the development of diabetic vascular complications.
Ma
Li
L
Department of Pharmacology, Cardiac and Cerebral Vascular Research Center, Zhongshan Medical College, Sun Yat-Sen University, Guangzhou, China.
Zhu
Banghao
B
Chen
Xiangping
X
Liu
Jie
J
Guan
Yongyuan
Y
Ren
Jun
J
D000818:Animals; D001011:Aorta / Q000166:cytology*; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000187:drug effects; D003921:Diabetes Mellitus, Experimental / Q000378:metabolism*; D006943:Hyperglycemia; D007211:Indoles / Q000494:pharmacology; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects / Q000502:physiology; D032389:Myocytes, Smooth Muscle / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism*; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012433:Ryanodine / Q000494:pharmacology; D012519:Sarcoplasmic Reticulum / Q000378:metabolism*
D007211:Indoles; D012433:Ryanodine; D010656:Phenylephrine; D015544:Inositol 1,4,5-Trisphosphate; D002118:Calcium; C000543:cyclopiazonic acid