[Effect of MCI-154 on calcium sensitivity of vascular smooth muscle and its mechanism in hemorrhagic shock in rats].
OBJECTIVE
To observe the effects of new calcium sensitizer MCI-154 on calcium sensitivity of vascular smooth muscle following hemorrhagic shock (HS) in rats, and to explore its mechanism.


METHODS
The superior mesenteric artery (SMA) from HS model of rat was adopted to assay the calcium sensitivity via observing the contraction initiated by Ca2+ under depolarizing conditions (120 mmol/L K+) with isolated organ perfusion system. The experiment was conducted in two parts, the effects of MCI-154 on calcium sensitivity of vascular smooth muscle in HS, and to explore whether MCI-154 could regulate the calcium sensitivity through regulating Rho-kinase, protein kinase C (PKC) and protein kinase G(PKG).


RESULTS
Compared with the normal control group, the cumulative dose-response curve of SMA to Ca2+ in shock group was shifted to the right, the maximal contraction to Ca2+ was decreased significantly (P<0.01). MCI-154(10(-7), 10(-6), 10(-5), 10(-4) mol/L) pretreatment further shift the cumulative dose-response curve of Ca2+ to the right as compared to shock group (P<0.01). These result suggested that calcium desensitization existed in the vascular smooth muscle following HS, and MCI-154 further decreased the calcium sensitivity. Angiotensin II and phorbol 12-myristate-13-acetate (PMA), the Rho-kinase agonist and PKC agonist, increased the calcium sensitivity, made the cumulative dose-response curve of Ca2+ shift to the left. After MCI-154(10(-5) mol/L) pretreatment, the dose-response curve of Ca2+ was shifted to the right as compared to Ang II and PMA alone group (P<0.01). But, KT-5823, the PKG antagonist, antagonized MCI-154-induced right shift of the dose-response curve of Ca2+. It was suggested that MCI-154 induced the decrease of calcium sensitivity might be related to Rho-kinase, PKC and PKG.


CONCLUSIONS
The calcium sensitivity of vascular smooth muscle following HS is significantly decreased, MCI-154 can further decrease calcium sensitivity. MCI-154 may regulate calcium sensitivity of vascular smooth muscle through Rho-kinase, PKC and PKG.
Yang
Guang-ming
GM
State Key Laboratory of Trauma, Burns and Combined Injury, The Second Department of Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042, China.
Liu
Liang-ming
LM
D000818:Animals; D002118:Calcium / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D005260:Female; D066298:In Vitro Techniques; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000201:enzymology; D011493:Protein Kinase C / Q000378:metabolism; D011724:Pyridazines / Q000494:pharmacology*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D014665:Vasodilator Agents / Q000494:pharmacology*; D054460:rho-Associated Kinases / Q000378:metabolism
D011724:Pyridazines; D014665:Vasodilator Agents; C052228:MCI 154; D054460:rho-Associated Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D011493:Protein Kinase C; D002118:Calcium