Effects of MCI-154 on vascular reactivity and its mechanisms after hemorrhagic shock in rats.
The objectives of this study were to investigate the effects of 6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate (MCI-154), a newly developed cardiotonic agent, on vascular reactivity and contractile responses to extracellular Ca2+ ([Ca2+]o) after hemorrhagic shock and primarily explore its mechanism. In vivo, the effects of MCI-154 (0.1, 0.5, 1.0, and 2.0 mg/kg) on the pressor effect of norepinephrine (NE) in rats subjected to hemorrhagic shock (30 mm Hg for 2 h) were observed and in vitro, the effects of MCI-154 (10(-7), 10(-6), 10(-5), 10(-4) mol/L) on vascular reactivity and contractile responses to [Ca2+]o of superior mesenteric artery (SMA) from hemorrhagic shock rats and its relationship to Rho-kinase, protein kinase C (PKC), and protein kinase G (PKG) were observed. The results showed that the NE-induced pressor response after hemorrhagic shock was significantly decreased (P<0.01), and MCI-154 made it decrease further. In vitro, MCI-154 further decreased the contractile responses of SMA to NE and Ca2+ after hemorrhagic shock as compared with untreated hemorrhagic shock group (P<0.01). Angiotensin II (Ang II), with Rho-kinase stimulating action, and PMA, a PKC agonist increased the contractile responses to [Ca2+]o of SMA after hemorrhagic shock. MCI-154 (10(-5) mol/L) partly inhibited Ang II and PMA-induced increase of the contractile responses to [Ca2+]o of SMA (P<0.01). KT-5823, the PKG antagonist, antagonized MCI-154-induced decrease of the contractile responses to [Ca2+]o. Taken together, these results suggested that the vascular reactivity and contractile responses to [Ca2+]o of vascular smooth muscle after hemorrhagic shock were significantly decreased. MCI-154 worsened hemorrhagic shock-induced vascular hyporeactivity and the decrease of contractile responses to [Ca2+]o. These effects were possibly regulated by Rho-kinase, PKC, and PKG, but this needs further confirmation.
Yang
Guangming
G
State Key Laboratory of Trauma, Burns and Combined Injury, Department 2, Research Institute of Surgery, Daping Hospital, The Third Military Medical University, Chongqing 400042, People's Republic of China.
Liu
Liangming
L
Xu
Jing
J
Li
Tao
T
D000818:Animals; D002118:Calcium / Q000494:pharmacology* / Q000502:physiology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D017869:Cyclic GMP-Dependent Protein Kinases / Q000502:physiology; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000502:physiology; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000503:physiopathology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000503:physiopathology*; D009638:Norepinephrine / Q000378:metabolism / Q000494:pharmacology; D011493:Protein Kinase C / Q000502:physiology; D017346:Protein Serine-Threonine Kinases / Q000502:physiology; D011724:Pyridazines / Q000494:pharmacology*; D051381:Rats; D017208:Rats, Wistar; D012771:Shock, Hemorrhagic / Q000503:physiopathology*; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014680:Veins / Q000187:drug effects / Q000503:physiopathology; D054460:rho-Associated Kinases
D002316:Cardiotonic Agents; D047908:Intracellular Signaling Peptides and Proteins; D011724:Pyridazines; D014662:Vasoconstrictor Agents; C052228:MCI 154; D017346:Protein Serine-Threonine Kinases; D054460:rho-Associated Kinases; D017869:Cyclic GMP-Dependent Protein Kinases; D011493:Protein Kinase C; D002118:Calcium; D009638:Norepinephrine