Massett Michael P, Ungvari Zoltan, Csiszar Anna, Kaley Gabor, Koller Akos
Department of Physiology, New York Medical College, Valhalla 10595, USA.
Am J Physiol Heart Circ Physiol. 2002 Dec;283(6):H2282-7. doi: 10.1152/ajpheart.00544.2002.
Protein kinase C (PKC) and mitogen-activated protein (MAP) kinases have been implicated in the modulation of agonist-induced contractions of large vessels. However, their role in pressure- and agonist-induced constrictions of skeletal muscle arterioles, which have a major role in regulating peripheral resistance, is not clearly elucidated. Thus constrictions of isolated rat gracilis muscle arterioles (approximately 80 microm in diameter) to increases in intraluminal pressure and to norepinephrine (NE) or angiotensin II (ANG II) were assessed in the absence or presence of chelerythrine, PD-98058, and SB-203580 (inhibitors of PKC, p42/44 and p38 MAP kinase pathways, respectively). Arteriolar constriction to NE and ANG II were significantly reduced by chelerythrine (by approximately 90%) and unaffected by SB-203580, whereas PD-98058 decreased only ANG II-induced constrictions (by approximately 60%). Pressure-induced increases in wall tension (from 0.1 to 0.7 N/m) resulted in significant arteriolar constrictions (50% maximum) that were abolished by chelerythrine without altering smooth muscle intracellular Ca(2+) concentration (Ca(2+)) (fura 2 microfluorimetry). PD-98058 and SB-203580 significantly decreased the magnitude of myogenic tone (by 20% and 60%, respectively) and reduced the sensitivity of the myogenic mechanism to wall tension, causing a significant rightward shift in the wall tension-myogenic tone relationship without affecting smooth muscle [Ca(2+)i]. MAP kinases were demonstrated with Western blotting. Thus in skeletal muscle arterioles 1) PKC is involved in both myogenic and agonist-induced constrictions, 2) PD-98058-sensitive p42/44 MAP kinases modulate both wall tension-dependent and ANG II-induced constrictions, whereas 3) a SB-203580-sensitive p38 MAP kinase pathway seems to be specifically involved in the mechanotransduction of wall tension.
蛋白激酶C（PKC）和丝裂原活化蛋白（MAP）激酶与大血管中激动剂诱导的收缩调节有关。然而，它们在调节外周阻力中起主要作用的骨骼肌小动脉压力和激动剂诱导的收缩中的作用尚未明确阐明。因此，在不存在或存在白屈菜红碱、PD-98058和SB-203580（分别为PKC、p42/44和p38 MAP激酶途径的抑制剂）的情况下，评估了离体大鼠股薄肌小动脉（直径约80微米）对管腔内压力升高以及去甲肾上腺素（NE）或血管紧张素II（ANG II）的收缩情况。白屈菜红碱显著降低了小动脉对NE和ANG II的收缩（约90%），而SB-203580对其无影响，而PD-98058仅降低了ANG II诱导的收缩（约6%）。压力诱导的壁张力增加（从0.1至0.7 N/m）导致显著的小动脉收缩（最大50%），白屈菜红碱可消除该收缩，且不改变平滑肌细胞内Ca(2+)浓度（[Ca(2+)]i）（fura 2微荧光测定法）。PD-98058和SB-203580显著降低了肌源性张力的幅度（分别降低20%和60%），并降低了肌源性机制对壁张力的敏感性，导致壁张力-肌源性张力关系显著右移，而不影响平滑肌[Ca(2+)i]。通过蛋白质印迹法证实了MAP激酶的存在。因此，在骨骼肌小动脉中：1）PKC参与肌源性和激动剂诱导的收缩；2）PD-98058敏感的p42/44 MAP激酶调节壁张力依赖性和ANG II诱导的收缩，而3）SB-203580敏感的p38 MAP激酶途径似乎特别参与壁张力的机械转导。
