The novel guanidine ME10092 protects the heart during ischemia-reperfusion

The novel guanidine N-(3,4-dimethoxy-2-chlorobenzylideneamino)-guanidine [ME10092; a metabolite to the strongly cardioprotective hydroxyguanidine N-(3,4-dimethoxy-2-chlorobenzylideneamino)-N'-hydroxyguanidine (PR5)] was administered intravenously to rats subjected to left coronary artery clamping followed by reperfusion. Administration of 1-10 mg/kg of ME10092 1 or 5 min before 10 min of coronary artery occlusion followed by 20 min reperfusion significantly and dose-dependently inhibited the reperfusion-induced burst of arrhythmia, and markedly improved the survival of the animals. This dose schedule also dose-dependently and significantly inhibited the ST-segment elevation seen on the ECG during the artery occlusion, and attenuated the secondary rise in ST-segment during the reperfusion. Even when ME10092 was administered 5 min after the start of the reperfusion, the ST-segment elevation became significantly attenuated. Administration of ME10092 (3 plus 1.5 mg/kg) to animals subjected to 1 h left coronary occlusion followed by 2 h reperfusion reduced the heart infarction size by about 40%. ME10092 also dose-dependently reduced the heart rate, both during normal conditions and during ischemia and reperfusion. Moreover, the highest dose of ME10092 used (10 mg/kg) strongly attenuated the reduction in blood pressure seen during 10 min left coronary occlusion, as well as it attenuated the rebound rise in blood pressure seen during the 20 min reperfusion phase; that is, resulting in a normalisation of the blood pressure disturbances caused by the ischemia-reperfusion. We also showed that after its p.o. administration, the PR5 hydroxyguanidine became completely metabolised to its guanidine ME10092, with no detectable traces of PR5 being present 30 and 60 min after the administration. Moreover, after the p.o. administration of ME10092, no signs of the formation of PR5 were seen on analysis of the rats' plasma. In view of the practically indistinguishable pharmacological effects of ME10092 and PR5, we suggest the strong cardioprotective effects of these compounds to be mediated by a direct effect by ME10092 per se.     

Perspectives on the cardioprotective effects of statins

Statins are inhibitors of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), the rate-limiting enzyme of cholesterol synthesis. In recent years, statins have become the major choice of treatment for hypercholesterolemia. Emerging evidence from both animal and human studies indicates that mechanisms independent of cholesterol lowering effects contribute to the observed clinical benefits of statins. The anti-hypertrophy effect of statins on the cardiac tissue represents one of such mechanisms. The beneficial effects of statins on cardiac hypertrophy and cardioprotection may be attributed to their functional influences on small G proteins such as Ras and Rho, resulting in an increase of endogenous nitric oxide (NO), reduction of oxidative stress, inhibition of inflammatory reaction, and decrease of the renin-angiotensin system activity as well as C-reactive protein (CRP) levels in cardiac tissues. Recent findings from in vitro and in vivo studies of statins on cardioprotective effects are summarized in this review. The unveiled novel mechanisms support the use of statins as the new mainstay therapeutic agents for various cardiovascular diseases and complications.     

Analytical pharmacology: the impact of numbers on pharmacology

Analytical pharmacology strives to compare pharmacological data to detailed quantitative models. The most famous tool in this regard is the Black/Leff operational model, which can be used to quantify agonism in a test system and predict it in any other system. Here we give examples of how and where analytical pharmacology has been used to classify drugs and predict mechanism of action in pharmacology. We argue for the importance of analytical pharmacology in drug classification and in prediction of drug mechanisms of action. Although some of the specifics of Black's models have been updated to account for new developments, the principles of analytical pharmacology should shape drug discovery for many years to come.     

氧化苦参碱心脏保护作用的研究进展

氧化苦参碱对心脏具有正性肌力、负性频率和负性自律性的作用,因此具有广谱抗心律失常作用。氧化苦参碱对冠脉狭窄缺血、缺血再灌注以及异丙肾上腺素、阿霉素、感染和免疫引起的心肌损伤都有保护作用,并能阻滞心肌肥大和纤维化发生发展。氧化苦参碱心脏保护作用的基本机制是其抗氧化、抗炎和免疫抑制以及抑制盐皮质激素（醛固酮）受体的表达,产生心肌保护作用。即通过激活Nrf2/HO-1信号通路和抑制转化生长因子（TGF）-β1及I型TGF-β1受体的表达,从而抑制下游的JAK/STAT、MAPK/Smad2/3和Notch的信号通路的机制,减少心肌细胞凋亡,减轻心肌损伤和抑制胶原合成,产生抑制心肌肥大和纤维化的作用。     

Cardiovascular pharmacology of the adenosine A1/A2-receptor agonist AMP 579: coronary hemodynamic and cardioprotective effects in the canine myocardium

The hemodynamic and cardioprotective properties of the novel adenosine A1/A2 receptor agonist AMP 579 (IS-[1a,2b,3b,4a(S*)]-4-[7-[[1-[(3-chloro-2-thienyl)methyl]propylamino]- 3H-imidazo[4,5-b]pyridin-3-yl]-N-ethyl-2,3-dihydroxy cyclopentanecarboxamide) were studied in two canine models designed to simulate (a) mild single-vessel coronary artery disease, and (b) myocardial ischemia/reperfusion injury. In the first model, a moderate stenosis was placed on the left circumflex coronary artery (LCCA), and the effects of AMP 579 on regional myocardial blood flow were assessed. AMP 579, 10 micrograms/kg/min, i.v., for 10 min, induced coronary dilation without causing endocardial steal. In the model of ischemia/reperfusion injury (60 min LCCA occlusion/5 h reperfusion), AMP 579, 10 micrograms/kg/min, i.v., administered for 15 min before ischemia significantly decreased myocardial infarct size. Control infarct size to area at risk (IS/AAR) equaled 34 +/- 3% (n = 9); IS/AAR for AMP 579-treated dogs equaled 16 +/- 4% (n = 9). Preconditioning (5 min LCCA occlusion + 10 min reperfusion) immediately before the 60-min LCCA occlusion also resulted in a marked decrease in IS/AAR: 9 +/- 3% (n = 6). The selective A1 agonist CPA reduced infarct size when administered at 3 micrograms/kg/min, i.v., for 15 min before LCCA occlusion: IS/AAR = 11 +/- 3% (n = 5). Pretreatment of animals with the adenosine-receptor antagonist 8-SPT, 10 mg/kg, i.v., attenuated the myocardial protective effects associated with preconditioning, CPA, and AMP 579, resulting in IS/AAR values of 28 +/- 7% (n = 7), 28 +/- 4% (n = 8), and 26 +/- 3% (n = 8), respectively. The ability of 8-SPT to block the cardioprotective effects suggests that these effects were mediated through an interaction with adenosine receptors. These experimental results indicate that AMP 579 is an effective coronary vasodilator, which also can protect the heart from ischemic injury. Thus AMP 579 has the potential to be useful in cardiovascular therapeutics.     

Studies on the signal cascade mechanism mediating the cardioprotective actions of bradykinin

The cardioprotective involvement of bradykinin was evaluated using the ACE inhibitor, lisinopril, and the APP inhibitor, 2-mercaptoethanol alone and in combination in rats with experimental myocardial infarction. The signal cascade mechanism mediating the cardioprotective actions of bradykinin was evaluated by administering aspirin and methylene blue prior to lisinopril and 2-mercaptoethanol combined treatment. Myocardial infarction was produced by occlusion of the left anterior descending coronary artery for 30 min followed by 4 h of reperfusion. Infarct size was measured by the TTC stain method. Serum free radical levels were estimated by the method developed by Yagi. A lead II electrocardiogram was monitored throughout the experiment. With the combined inhibition of both the enzymes ACE and APP, a better cardioprotection was observed. The observed cardioprotection was decreased with the prior administration of aspirin and methylene blue. The results suggest the cardioprotective role of bradykinin during experimental myocardial infarction. The results are further suggesting the involvement of both prostaglandins and nitric oxide pathways in the cardioprotective actions of bradykinin.     

Biological activities of guanidine compounds

Background: The guanidine group defines chemical and physicochemical properties of many compounds of medical interest and guanidine-containing derivatives constitute a very important class of therapeutic agents suitable for the treatment of a wide spectrum of diseases. Objective: To review the most important pharmacological properties, mechanisms of action and therapeutic uses of simple guanidine derivatives, cyclic analogues of guanidines as well as peptides, peptidomimetics and peptoids incorporating arginine. Methods: The review presents both the recent patent literature and original papers dealing with guanidine derivatives that show interesting biological activity and emphasizes the newest developing drugs. Conclusion: Recent achievements in the synthesis of guanidine-containing molecules with diverse chemical, biochemical and pharmacological properties make them of great importance to the design and development of novel drugs acting at CNS, anti-inflammatory agents, inhibitors of Na⁺/H⁺ exchanger, inhibitors of NO synthase, antithrombotic, antidiabetic and chemotherapeutic agents as well as guanidinium-based transporters and vectors.     

Effects of guanidine on synaptic transmission in the spinal cord of the frog

Summary The effects of guanidine on motoneurons of the isolated frog spinal cord were studied by adding the drug to the solution bathing the cord during intracellular recording. Guanidine (5·10^–4 M) did not alter the membrane potential of motoneurons.The main effect was a marked increase of the amplitudes and frequencies of small spontaneously occurring inhibitory postsynaptic potentials. The hyperpolarizing component of postsynaptic potentials evoked by stimulation of dorsal roots was also enhanced by guanidine. Higher concentrations of guanidine (5·10^–3 M) resulted in a very large and irreversible increase of the small spontaneously occurring inhibitory potentials, which now appeared in a regular, rhythmic pattern.The effects of guanidine could easily be blocked by increasing the magnesium ions (15 mM) in the bath solution.These results indicate that guanidine facilitates the release of an inhibitory transmitter in afferent terminals of the frog spinal cord either by a direct action on these terminals or indirectly by an action on nerve endings impinging on inhibitory interneurons.This work was supported by the Deutsche Forschungsgemeinschaft     

Potential cardioprotective actions of no-releasing aspirin

The use of low doses of aspirin on a daily basis has increased greatly in the past 20 years, based on observations that it can significantly reduce the risk of heart attacks and strokes. However, aspirin can also cause severe damage to the stomach. A modified version of aspirin that releases nitric oxide has been developed that seems to offer important advantages over its 103-year-old parent--namely, improved protection for the heart without the unwanted effects on the stomach.