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Effects of MCI-154 on vascular reactivity and its mechanisms after hemorrhagic shock in rats
Guangming Yang1, Liangming Liu, Jing Xu
1State 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.
Abstract:
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.
Insights
This study found that the cardiotonic agent MCI-154 worsens vascular hyporeactivity and decreased calcium responses after hemorrhagic shock. These effects may involve Rho-kinase, protein kinase C, and protein kinase G signaling pathways.
Area of Science:
- Cardiovascular Physiology
- Pharmacology
- Vascular Biology
Background:
- Hemorrhagic shock leads to significant vascular hyporeactivity and impaired contractile responses to extracellular calcium.
- Understanding the mechanisms underlying these vascular dysfunctions is crucial for developing effective treatments.
Purpose of the Study:
- To investigate the effects of the novel cardiotonic agent 6-[4-(4'-pyridylamino)phenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride trihydrate (MCI-154) on vascular reactivity and contractile responses to extracellular Ca2+ ([Ca2+]o) following hemorrhagic shock.
- To explore the potential mechanisms involving Rho-kinase, protein kinase C (PKC), and protein kinase G (PKG).
Main Methods:
- In vivo studies assessed the pressor response to norepinephrine (NE) in rats subjected to hemorrhagic shock and treated with MCI-154.
- In vitro studies examined the effects of MCI-154 on superior mesenteric artery (SMA) contractility in response to NE and [Ca2+]o in hemorrhagic shock rat models.
- Investigated the involvement of Rho-kinase, PKC, and PKG using specific agonists and antagonists.
Main Results:
- Hemorrhagic shock significantly decreased NE-induced pressor responses, an effect further exacerbated by MCI-154.
- In vitro, MCI-154 reduced SMA contractile responses to NE and [Ca2+]o in hemorrhagic shock rats.
- MCI-154 partially inhibited Angiotensin II and PMA-induced increases in contractility and its effects were antagonized by a PKG antagonist.
Conclusions:
- MCI-154 worsens vascular hyporeactivity and decreases contractile responses to extracellular calcium after hemorrhagic shock.
- The observed effects of MCI-154 are potentially mediated through modulation of Rho-kinase, PKC, and PKG signaling pathways.
- Further research is needed to confirm the precise regulatory roles of these kinases in MCI-154's vascular actions post-hemorrhagic shock.
