钙增敏剂MCI-154抗休克作用及其机制

钙增敏剂MCI-154有明显的拮抗失血性休克及内毒素休克的作用,特别是对休克失代偿期有良好的疗效.与传统的加强心肌收缩的药物不同,本品不会明显增加休克动物心肌细胞内的钙超载,而主要通过增加心肌收缩蛋白对Ca2 的敏感性而改善休克动物的心功能,其增加心肌细胞内Ca2 水平及cAMP含量的作用明显比米力农弱.本品降低休克动物血管平滑肌细胞内游离Ca2 浓度,恢复钙调蛋白活性及c蛋白激酶C的表达,以及相对增加Calponin-α的表达,从而改善休克舒张功能.     

Comparison of the effects of MCI-154, a new cardiotonic agent, and some Ca2+-sensitizing agents on the response of the contractile system to Ca2+ in skinned cardiac muscle

Several cardiotonic agents (MCI-154, sulmazole, pimobendan and adibendan) were examined for their ability to influence Ca2+-activated tension development and MgATP-activated tension development in the absence of free Ca2+ (rigor tension), using the chemically skinned fiber from guinea pig papillary muscles. MCI-154, sulmazole, pimobendan and adibendan all increased the tension development induced by pCa (-log[Ca2+]M) 5.8 in a concentration-dependent manner (10(-6) to 10(-4) M). The order of the potency was as follows: MCI-154 greater than pimobendan greater than adibendan greater than sulmazole. MCI-154 enhanced the maximum tension developed at pCa 4.4 but sulmazole, pimobendan and adibendan did not enhance it. MCI-154, but not sulmazole, pimobendan and adibendan, enhanced the tension development induced by pMgATP (-log[MgATP]M) 6.0 in the absence of free Ca2+. MCI-154, sulmazole, pimobendan and adibendan concentration-dependently (10(-7) to 10(-4) M) increased the force of contraction in isolated guinea pig papillary muscles. The order of the potency was as follows: MCI-154 greater than adibendan greater than pimobendan greater than sulmazole. These results demonstrated that the Ca2+-sensitizing action on the contractile system may be involved in the positive inotropic action of MCI-154, sulmazole, pimobendan and adibendan, and that MCI-154 is the most potent among these drugs. Furthermore, sulmazole, pimobendan and adibendan did not enhance the interaction of actin and myosin, suggesting that the mechanism of actions of these drugs are qualitatively different from that of MCI-154.     

6-[4-(4′-吡啶)氨基苯]-4,5-二氢-3(2H)哒嗪酮抗兔和大鼠失血性休克效应及初步机理

目的　研究新型钙增敏强心剂 6 [4 (4′ 吡啶 )氨基苯 ] 4 ,5 二氢 3(2H)哒嗪酮 (MCI 15 4 )抗失血性休克效应并探讨其初步机理。方法　以改良Wigger法 ,即股动脉放血并维持血压 5 .33kPa 2h建立失血性休克动物模型 ,观察MCI 15 4对失血性休克大鼠 12、2 4和 4 8h存活率的影响 ;以彩色频谱多普勒观察MCI 15 4对失血性休克家兔心脏射血分数、每搏输出量及肝动脉、肠系膜上动脉、右肾动脉平均血流量和血流阻力指数的影响。结果　MCI 15 4组休克大鼠 12、2 4和 4 8h存活率分别为 17/ 2 0、15 / 2 0和13/ 2 0 ,明显高于生理盐水组的 11/ 2 0、8/ 2 0、4 / 2 0 ;MCI 15 4治疗后 2h ,能显著降低休克家兔肝、肾动脉血流阻力指数 ;治疗后 4h能明显增加休克家兔心脏射血分数、每搏输出量及肠系膜上动脉、肾动脉血流量 ,显著降低肝动脉血流阻力指数。结论　MCI 15 4有较满意的抗失血性休克效应 ,其机理可能与增强休克动物心脏功能和增加主要器官血流量有关。     

In vitro characterization of the effects of MCI-154, a novel cardiotonic agent, on cardiac tissues

In vitro cardiac effects of a cardiotonic drug, MCI-154, for which the main action mechanism was proposed to be the enhancement of Ca2+ sensitivity of cardiac contractile proteins, were investigated. MCI-154 (3 x 10(-8)-3 x 10(-4) M) increased the developed tension in isolated ventricular muscles from cats, dogs, guinea pigs and rats and increased that of isolated left atrial muscles of guinea pigs and rats. However, species differences were observed in the responses to MCI-154. The positive inotropic potency of MCI-154 was stronger than those of amrinone and milrinone. In the isolated right atria from guinea pigs and rats, properties of the chronotropic effect of MCI-154 were different from those of amrinone and milrinone. The positive inotropic action of MCI-154 was not affected by phentolamine, propranolol, cimetidine and tetrodotoxin. MCI-154 did not inhibit cardiac Na+,K+-ATPase. MCI-154 moderately stimulated Ca2+-uptake of isolated cardiac sarcoplasmic reticulum (SR), but induced no release of Ca2+ from the SR. These results support the view that the main mechanism for the action of MCI-154 is the enhancement of Ca2+ sensitivity of cardiac contractile proteins.     

Magnesium modulates contractile responses of rat aorta to thiocyanate: A possible relationship to smoking-induced atherosclerosis.

Thiocyanate anions (SCN-) as the end products of tobacco smoke and found in the blood of cigarette smokers have been implicated in atherogenesis and heart diseases. Magnesium deficiency has also been implicated in the etiology of atherogenesis. The contractile responses of rat aorta to SCN- and the modulation of extracellular magnesium ions ([Mg2+]o) on the effect of SCN- were, therefore, studied in isolated rat aortic rings. SCN- exposure at a range of concentrations (from 10(-5) to 5 x 10(-2) M) induces contractile responses of isolated rat aortic rings with and without endothelium in a concentration-dependent manner. Significant differences in responsiveness to SCN- were found in rat aortic ring segments with and without endothelial cells. Preincubation of these vessels with low [Mg2+]o markedly shifted the contractile concentration-effect curves to the left, and the contractile effects of SCN- in rat aortic rings were potentiated. In contrast to lowering [Mg2+]o, increasing [Mg2+]o to 2.4 mM was found to dramatically attenuate the contractile responses to SCN-. In the absence of extracellular Ca2+ ([Ca2+]o), SCN--induced contractions were, however, almost abolished after exposure to Mg2+-free medium. In order to investigate the mechanisms of [Mg2+]o modulation of SCN--induced contractile response of rat aorta, changes in intracellular Ca2+ ([Ca2+]i) were measured in cultured primary smooth muscle cells isolated from rat aorta. The resting level of [Ca2+]i in the rat aortic smooth muscle cells was 80.6 +/- 6.6 nM. Exposure of these cells to SCN- (5 x 10(-5) to 5 x 10(-3) M) produced rises in [Ca2+]i in a concentration-dependent manner. Preincubation of these cells with low [Mg2+]o (0 or 0.3 mM, the lowest physiological range) for 24 h significantly potentiated increments in [Ca2+]i induced by SCN-. These rises in [Ca2+]i induced by SCN- were completely inhibited by pretreating the cells with 2.4 mM [Mg2+]o for 24 h. These results support a hypothesis whereby cigarette smoking or exposure to smoking can induce cardiovascular diseases, at least partly, probably by causing spasm and thickening of arterial blood vessels as a consequence of large rises in [Ca2+]i in vascular smooth muscle cells. The chronic presence of or exposure to both thiocyanate and low Mg2+ in the blood of smokers can result in rapid flux of Ca2+ into vascular smooth muscle cells, thus accelerating or initiating atherosclerotic processes in smokers.     

Effects of MCI-154 on Ca2+ activation of skinned human myocardium

We investigated the effects of MCI-154, a new inotropic agent, on tension development in saponin-skinned human trabeculae carneae. The skinned fibers were activated by buffer solutions containing varying concentrations of Ca2+ (10(-8)-10(-4) M). In the sigmoidal tension vs. pCa (-log[Ca2+]M) relationship, the Ca2+ concentration required for half-maximal activation was shifted leftward in the presence of MCI-154. Furthermore, maximal Ca2+-activated tension development was increased in a concentration-dependent manner by MCI-154. Our results suggest that the inotropic effect of MCI-154 may be due, in part, to an increased sensitivity of the myofilaments to Ca2+ and enhancement of maximal Ca2+-activated tension development.     

6-［4-(4′-吡啶)氨基苯］-4，5-二氢-3(2H)哒嗪酮抗兔和大鼠失血性休克效应及初步机理

目的 研究新型钙增敏强心剂6-［4-(4′-吡啶)氨基苯］-4，5-二氢-3(2H)哒嗪酮(MCI-154)抗失血性休克效应并探讨其初步机理。方法 以改良Wigger法，即股动脉放血并维持血压5.33 kPa 2 h建立失血性休克动物模型，观察MCI-154对失血性休克大鼠12、24和48 h存活率的影响；以彩色频谱多普勒观察MCI-154对失血性休克家兔心脏射血分数、每搏输出量及肝动脉、肠系膜上动脉、右肾动脉平均血流量和血流阻力指数的影响。结果 MCI-154组休克大鼠12、24和48 h存活率分别为17/20、15/20和13/20，明显高于生理盐水组的11/20、8/20、4/20；MCI-154治疗后2 h，能显著降低休克家兔肝、肾动脉血流阻力指数；治疗后4 h能明显增加休克家兔心脏射血分数、每搏输出量及肠系膜上动脉、肾动脉血流量，显著降低肝动脉血流阻力指数。结论 MCI-154有较满意的抗失血性休克效应，其机理可能与增强休克动物心脏功能和增加主要器官血流量有关。     

精氨酸加压素对失血性休克大鼠血管反应性的影响

目的探讨精氨酸加压素(AVP)对失血性休克大鼠血管反应性的影响,并初步探讨其与Rho激酶的关系。方法在体实验,观察大鼠失血性休克后AVP对去甲肾上腺素(NE)升压反应的影响;离体实验,测定失血性休克大鼠肠系膜上动脉(SMA)环对NE的收缩反应和去极化状态下(120mmol·L-1K+)对Ca2+的收缩反应,反映其对缩血管物质和钙的反应性。结果失血性休克(4kPa,2h)后大鼠对NE的升压反应显著下降。AVP0.1和0.4U·kg-1,iv,随后再将AVP溶于3倍失血量的复方氯化钠溶液分别以0.01和0.04U·kg-1·min-1的速度于30min内用输液泵输注,3～4h后可使NE的升压反应恢复至正常组水平。失血性休克后SMA对NE和钙的反应性显著下降,对NE和Ca2+的收缩反应量效曲线明显右移,最大反应(Emax)降低;加入NE和Ca2+前分别用0.5和5nmol·L-1AVP孵育10min可使NE和Ca2+的收缩反应量效曲线明显左移,Emax显著增高。Rho激酶拮抗剂HA1077预处理可部分取消AVP所致的Ca2+Emax变化,使Emax回降。结论AVP能升高失血性休克大鼠血管对NE的敏感性及反应效能和血管平滑肌对钙的反应效能。     

Contractile proteins: possible targets for the cardiotonic action of MCI-154, a novel cardiotonic agent?

The effect on the contractile protein system of MCI-154, a novel and potent cardiotonic agent, was examined by using thin bundles of chemically skinned fibers from the guinea-pig papillary muscles. MCI-154 increased the Ca2+ sensitivity of the contractile protein system of the cardiac skinned fibers. Moreover, MCI-154 enhanced the maximum tension developed at pCa 4.4. These results suggest that an increase in responses of the contractile protein system to Ca2+ ion is, at least in part, responsible for the positive inotropic action of MCI-154.     

Withdrawal of magnesium enhances coronary arterial spasms produced by vasoactive agents.

1 The influence of external magnesium ions ([Mg2+]o) on the sensitivity (i.e. EC50) and contractility (maximum response) of isolated large and small coronary arteries of the dog, obtained from different regions of the myocardium, to vasoactive agents was studied. 2 Removal of [Mg2+]o from the physiological salt solution enhanced, while elevation in [Mg2+]o to 4.8 mM, lowered the contractile sensitivity to three different agents, 5-hydroxytryptamine (5-HT), angiotensin II and KCl. 3 Contractility, of both large and small coronary arteries, to 5-HT and angiotensin II was potentiated and depressed, respectively, by withdrawal and elevation of [Mg2+]o; maximum responses to KCl were not altered by 0 or 4.8 mM [Mg2+]o. 4 Cumulative concentration-contractile effect curves to CaCl2 were shifted leftward on removal of [Mg2+]o; elevation of [Mg2+]o to 4.8 mM shifted the CaCl2 concentration-effect curves to the right. Maximal contractile responses to CaCl2 were enhanced by removal of, and reduced by elevation of, [Mg2+]o. 5 The calcium channel blocking agent, verapamil (10(-6)M), inhibited completely contractile responses to KCl; contractile responses elicited by angiotensin II and 5-HT were attenuated by verapamil. 6 A variety of pharmacological antagonists (phentolamine, propranolol, methysergide, atropine, diphenhydramine), as well as use of a prostaglandin cyclo-oxygenase inhibitor, did not modify the altered contractile responses evoked by angiotensin II or KCl in different concentrations of Mg2+. 7 These results suggest: (1) [Mg2+]o may exert considerably greater influence on receptor-operated rather than membrane-potential sensitive channels involved in Ca2+ transport in coronary arterial smooth muscle; (2) Mg2+ interferes with the affinity (binding) of certain agonists (5-HT and angiotensin II) for their respective receptors in coronary vascular muscle; and (3) a functional pool of Ca2+ which is resistant to Ca2+-depletion, but accessible to activation by 5-HT and angiotensin II is present in canine coronary arterial smooth muscle.     

Inhibitory actions of MCI-154 on guinea-pig femoral artery and vein preparations.

In guinea-pig femoral artery and vein preparations, the effects of MCI-154 were investigated on: (1) membrane depolarizations produced by 29.6 mM [K+]0 (high-K) solution and noradrenaline (NA) and on e.j.p.s produced by perivascular nerve stimulation; (2) contractions produced by NA, high-K and perivascular nerve stimulation; and, (3) endothelium-dependent relaxation produced by acetylcholine (ACh). In both femoral artery and vein preparations, MCI-154 (up to 10(-5) M) did not change the resting membrane potential or the depolarization produced by high-K. In preparations of femoral vein but not femoral artery, MCI-154 reduced NA-induced depolarization. The contractions produced by NA and high-K were reduced by MCI-154, the former more than the latter. The actions of MCI-154 were more pronounced in the vein than in the artery. The excitatory junction potential and contractions produced by perivascular nerve stimulation in guinea-pig saphenous artery preparations were inhibited by MCI-154 (greater than 10(-7) M). ACh-induced relaxations of guinea-pig femoral artery preparations precontracted with high-K were not affected by MCI-154. It was concluded that MCI-154 is an antagonist at postjunctional alpha 2-adrenoceptors, and, at high concentrations, inhibits voltage-dependent Ca2+ influx in vascular smooth muscle cells. These actions may contribute to the hypotensive effect of this drug.     

Effects of ischemic preconditioning on vascular reactivity and calcium sensitivity after hemorrhagic shock and their relationship to the RhoA–Rho-kinase pathway in rats

We investigated the effect of ischemic preconditioning (IPC) on vascular reactivity and calcium sensitivity after hemorrhagic shock and its relationship to the RhoA–Rho-kinase pathway. Using hemorrhagic-shock rats (40 mm Hg for 3 hours) and isolated rings of the superior mesenteric artery (SMA), the effects of IPC (abdominal aorta occlusion applied 2 hours before shock) on the pressor effect of norepinephrine (3 μg/kg), vascular reactivity and calcium sensitivity of SMA, and the activity and role of RhoA and Rho-kinase were investigated. IPC with 1-minute occlusion plus 5-minute loosening of aneurysm clips thrice significantly increased survival time and prevalence of survival at 24 hours of hemorrhagic-shock rats. This IPC condition also significantly increased the pressor response of norepinephrine and significantly improved the vascular reactivity and calcium sensitivity of the SMA. The activity of Rho-kinase and RhoA in the SMA decreased after hemorrhagic shock, but increased after IPC. Y-27632 (Rho-kinase antagonist) and C3 Transferase (RhoA antagonist) significantly decreased IPC-induced increase in vascular reactivity and calcium sensitivity. These results suggested that IPC can improve shock-induced vascular hyporeactivity and calcium desensitization. The RhoA–Rho-kinase pathway played an important part in this process. These findings suggested that the RhoA–Rho-kinase pathway may be a potential target to treat vascular hyporeactivity in severe trauma, shock, or multiple-organ dysfunction syndrome.     

TRPC, cGMP-dependent protein kinases and cytosolic Ca2+

Ca2+, nitric oxide (NO), and protein kinase G (PKG) are important signaling molecules that play pivotal roles in many physiological processes such as vascular tone control, platelet activation, and synaptic plasticity. TRPC channels allow Ca2+ influx, thus contributing to the production of NO, which subsequently stimulates PKG. It has been demonstrated that PKG can phosphorylate human TRPC3 at Thr-11 and Ser-263 and that this phosphorylation inactivates TRPC3. These two PKG phosphorylation sites, Thr-11 and Ser-263 in human TRPC3, are conserved in other members of the TRPC3/6/7 subfamily, suggesting that PKG may also phosphorylate TRPC6 and TRPC7. In addition, protein kinase C (PKC) also inactivates TRPC3, partly through activating PKG. The PKG-mediated inhibition of TRPC channels may provide a feedback control for the fine tuning of [Ca2+]i levels and protect the cells from the detrimental effects of excessive [Ca2+]i and/or NO.     

6-[4-(4′-吡啶)氨基苯]-4,5-二氢-3(2H)哒嗪酮对大鼠胸主动脉环收缩功能的影响

目的研究新型钙增敏强心剂6-[4-(4′-吡啶)氨基苯]-4,5-二氢-3(2H)哒嗪酮(MCI-154)的扩血管作用机制。方法采用生物张力换能器及生理记录仪测定大鼠离体胸主动脉环和蜕膜胸主动脉环的收缩张力。结果MCI-154可浓度依赖性抑制1nmol.L-1~10μmol.L-1去甲肾上腺素(pD2′为4.21±0.23)和80mmol.L-1KCl(IC50为7μmol.L-1)引起的血管环收缩,提示其可通过抑制血管平滑肌细胞膜上受体操纵性和电压依赖性钙通道而减少胞外钙内流。在无Ca2+K-H液中,MCI-154预处理可浓度依赖性降低3μmol.L-1苯肾上腺素(IC50为5μmol.L-1)及20mmol.L-1咖啡因(IC50为16μmol.L-1)引起的血管环收缩张力,提示其可抑制血管平滑肌细胞胞内钙释放。在1μmol.L-1Ca2+溶液中,MCI-154可显著降低蜕膜血管环收缩张力(IC50为10μmol.L-1),提示其可降低血管平滑肌对Ca2+的敏感性。结论MCI-154可通过抑制血管平滑肌胞外钙内流、胞内钙释放和降低其对Ca2+敏感性来降低血管平滑肌收缩张力,体外具有扩血管效应。     

Opioid receptor antagonists increase [Ca^2＋]i in rat arterial smooth muscle cells in hemorrhagic shock

INTRODUCTION Circulation hypotension induced by hemorrhagicshock is one of the main causes of death after severewounds or trauma. When the hemorrhagic shock hasdeveloped to a decompensatory stage, it is difficult toreverse the hypotension using usual vasoconstrictor,such as norepinephrine. One of the explanations ofhypotension is due to the hyposensitivity of arterialsmooth muscle cells (SMC) to vascular constrictorstimuli[1,2]. Previous studies showed that the vascularhyporesponse was r…     

Effects of MCI-154 on calcium sensitivity of contractile system and calcium release from sarcoplasmic reticulum in saponin-skinned rat myocardium.

AIM: To explore the possible mechanisms underlying the positive inotropic effect of MCI-154. METHODS: Skinned fibers with disrupted or preserved sarcoplasmic reticulum (SR) were prepared by saponin 500 or 50 mg.L-1. The tension-pCa relationship and pCa50 of saponin (500 mg.L-1)-skinned fibers were taken as the indices of Ca2+ sensitivity of contractile proteins. The amplitude of caffeine-induced contracture was an index of Ca2+ release from SR in saponin (50 mg.L-1)-skinned fibers. RESULTS: 1) MCI-154 (0.1 mmol.L-1) showed a Ca2+ sensitizing effect on contractile proteins. The pCa50 was increased to 5.84 (5.54-6.14) compared with control value 5.54 (5.30-5.79) (P < 0.01, n = 8). Hill coefficient n was decreased by 0.29 (P < 0.01, n = 8); 2) No contracture was produced by MCI-154 in preparations with preserved SR. Caffeine-induced contracture before and after MCI-154 treatment were not changed (P > 0.05, n = 4). CONCLUSION: MCI-154 directly enhances the Ca2+ sensitivity of contractile protein but has little effect on Ca2+ release from SR in rat skinned cardiac fibers.     

三羟异黄酮对失血性休克大鼠肠系膜上动脉收缩反应性的影响

目的研究三羟异黄酮(genistein,GST)对失血性休克大鼠肠系膜上动脉收缩反应性的影响及其可能机制。方法建立大鼠失血性休克(3.9kPa,2h)模型。采用离体血管环张力测定实验,观察三羟异黄酮及酪氨酸蛋白磷酸酶抑制剂钒酸钠(sodiumorthovannadate,Na3VO4)对休克大鼠肠系膜上动脉血管收缩反应性的影响;采用细胞贴附式膜片钳记录技术,观察三羟异黄酮及钒酸钠对休克大鼠肠系膜上动脉平滑肌细胞大电导钙激活钾通道(largeconductancecalciumactivatedpotassiumchannel,BKCa)活动的影响。结果失血性休克导致大鼠肠系膜上动脉对去甲肾上腺素(noradrenine,NE)的收缩反应性降低,三羟异黄酮可在一定的剂量范围内明显改善失血性休克引起的血管低反应性;钒酸钠则可引起休克血管收缩反应性的进一步降低,且该作用可被0.1mmol·L-1TEA部分阻断;进一步的研究显示,失血性休克可引起大鼠肠系膜上动脉血管平滑肌细胞BKCa通道活动的增强,三羟异黄酮可抑制休克血管平滑肌细胞BKCa通道活动,且该作用可被钒酸钠逆转。结论三羟异黄酮可通过干预由PTK介导的酪氨酸蛋白磷酸化,防止失血性休克血管平滑肌细胞BKCa通道活动的增强,从而有效恢复失血性休克大鼠肠系膜上动脉对NE的收缩反应性。     

Inhibition of cardiac phosphodiesterase III by the novel cardiotonic agent 6-[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride

The novel cardiotonic agent 6[4-(4'-pyridyl)aminophenyl]-4,5-dihydro-3(2H)-pyridazinone hydrochloride (MCI-154) was investigated for its cardiovascular effects and its mechanism of action. In the anaesthetized rat MCI-154 (0.01-0.3 mumol/kg i.v., bolus injection) produced a dose-dependent increase in left ventricular dP/dt, and a decrease in mean arterial pressure. A relatively small increase in heart rate was observed. The drug inhibited selectively canine cardiac phosphodiesterase III (IC50 2.5 +/- 0.6 mumol/l). In skinned porcine trabeculae, MCI-154 produced only a small increase in the Ca2+-sensitivity of the contractile proteins. The results suggest that MCI-154 is a potent cardiotonic agent, and that inhibition of phosphodiesterase III may be a important component of this effect.     

Protein kinase C inhibitors enhance endothelin-1 and attenuate vasopressin and angiotensin II evoked [Ca2+]i elevation in the rat cardiomyocyte.

Primary cultures of neonatal rat cardiomyocytes were pretreated for 16 h with either nonselective (staurosporine, 100 nM) or selective (NPC15437, 20 microM) protein kinase C (PKC) inhibitors. These inhibitors did not affect the basal cytosolic free calcium, [Ca2+]i, level (106 +/- 12 nM) as determined by fura-2 fluorescence methodology. Both agents significantly enhanced the maximal [Ca2+]i responses to endothelin-1 (ET-1) and attenuated the peak [Ca2+]i responses to arginine vasopressin and angiotensin II. They did not alter the EC50 values of any of these agonists. Since depletion of [Ca2+]o led to only partial attenuation of the enhanced response to ET-1 in the treatment groups, it is likely that PKC inhibition results in an exaggerated intracellular mobilization of Ca2+ to ET-1. It is concluded that PKC modulates agonist(s)-evoked intracellular Ca2+ mobilization and that the nature of regulation is governed by the agonist.     

埃他卡林对大鼠尾动脉平滑肌细胞［Ca2+］i， PKA和PKC活性的影响埃他卡林对大鼠尾动脉平滑肌细胞［Ca2+］i， PKA和PKC活性的影响

细胞内钙参与了对几乎所有类型细胞的各种生理活动的调节[1],并通过影响PKA和PKC等大分子蛋白,进一步调控细胞的分裂和增殖。以ATP敏感型钾通道(KATP)为靶点的钾通道开放剂(KCO)是一类新型的抗高血压药物[2,3]。KCO激活血管平滑肌KATP,间接抑制钙通道的开放,从而使[Ca2 ]i降低,