Synergisms of cardiovascular effects between iptakalim and amlodipine, hydrochlorothiazide or propranolol in anesthetized rats

The primary object of this fundamental research was to survey the synergistic cardiovascular effects of iptakalim, a novel ATP–sensitive potassium channel(KATP) opener, and clinical first-line antihypertensive drugs, such as calcium antagonists, thiazide diuretics and β receptor blockers by a 2×2 factorial-design experiment. It would provide a theoretical basis for the development of new combined antihypertensive therapy program after iptakalim is applied to the clinic. Amlodipine besylate, hydrochlorothiazide and propranolol were chosen as clinical first-line antihypertensive drugs. Blood pressure, heart rate(HR) and cardiac functions were observed in anesthetized normal rats by an eightchannel physiological recorder. The results showed that iptakalim monotherapy in a low dose could produce significant antihypertensive effect. There was no interaction between iptakalim and amlodipine on the maximal changes of systolic blood pressure(SBP), diastolic blood pressure(DBP), mean arterial blood pressure(MABP), the left ventricular systolic pressure(LVSP), and the left ventricular end-diastolic pressure(LVEDP)(P>0.05). However, the effects of combination iptakalim/amlodipine on the maximal changes of SBP, DBP, MABP, LVSP and LVEDP were more obvious than those of iptakalim or amlodipine monotherapy. And there was strong positive interaction between iptakalim and amlodipine on the maximal changes of HR(P>0.05). According to the maximal changes of DBP, MABP, LVSP and LVEDP(P<0.05) of combination iptakalim with hydrochlorothiazide, there was strong positive interaction between them. But there was no interaction between iptakalim and hydrochlorothiazide on the maximal drop of SBP and HR(P>0.05). According to the maximal drops of DBP, MABP of combination iptakalim with propranolol, there was strong positive interaction between them(P<0.05). But there was no interaction between iptakalim and propranolol on the maximal changes of SBP, LVSP,LVEDP and HR(P>0.05). In conclusion, it was the first time to study the effects of amlodipine, hydrochlorothiazide or propranolol, which had different mechanisms of action from iptakalim, on cardiovascular effects of iptakalim in anesthetized normal rats. This study proved that the combination of iptakalim with hydrochlorothiazide or propranolol respectively had significant synergism on lowering blood pressure, while the combination of iptakalim/amlodipine had additive action on lowering blood pressure. Meanwhile the antihypertensive effect was explicit, stable and long-lasting. Iptakalim thus appears suitable for the clinical treatment of hypertensive people who need two or more kinds of antihypertensive agents.

Stimulation of endothelial non-neuronal muscarinic receptor attenuates the progression of atherosclerosis via inhibiting endothelial cells activation

Objective To investigate the effects of non-neuronal muscarinic receptors(NNMR) stimulation on atherosclerosis and endothelial cells activation.Methods Atherosclerosis model was established in ApoE^(-/-)mice by a high fat diet for 7 weeks.During the experimental periods,animals were received a low(7 mg/kg/d) or a high(21 mg/kg/d) dose of arecoline by gavage.At the termination of the treatments,serum total cholesterol and NO levels were measured,and the aorta morphology was analyzed by hematoxylin and eosin staining.The gene expression of monocyte chemoattractant protein-1(MCP-1) and adhesion molecules in the thoracic aortas was determined by RT-PCR,and the MCP-1 protein expression and NFkB activity were detected by Western blot analysis.NO production,MCP-1 secretion in cultured rat aortic endothelial cells(RAECs),and monocyte-endothelium adhesion assay were also performed after arecoline treatments.Results Arecoline efficiently decreased atherosclerotic plaque areas,increased serum nitric oxide(NO) content,suppressed the mRNA and protein expression of MCP-1,and modulated the IκB-αdegradation and P65 phosphorylation in the aortae of ApoE^(-/-) mice.Furthermore,arecoline promoted NO production and suppressed MCP-1 secretion in cultured RAECs after ox-LDL exposure,and either atropine or NG-nitro-L-arginine methylester could abrogate these effects.Arecoline also significantly inhibited the adherence of U937 monocytes to the ox-LDL injured human umbilical vein endothelial cells,which could be abolished by atropine.Conclusion Our results indicate that arecoline attenuates the progression of atherosclerosis and inhibits endothelial cells activation and adherence by stimulating endothelial NNMR.These effects,at least in part,are due to its modulation on NF-kB activity.

Proteomic identification of human serum biomarkers associated with high altitude pulmonary edema

Objective High altitude pulmonary edema(HAPE), a life-threatening disease, has no biological markers used for the routine prevention, diagnosis and treatment. The aim of this study was to identify serum proteins differentially expressed in patients with HAPE for discovering essential biomarkers. Methods A complete serum proteomic analysis was performed on 10 HAPE patients and on 10 high altitude and 11 sea level healthy people as control using two-dimensional gel electrophoresis, followed by matrixassisted laser desorption/ionization mass spectrometry and peptide mass fingerprinting. Finally, two most significantly changed proteins were validated by enzyme-linked immunosorbent assay(ELISA). Results Eight protein spots stained with differential intensity, respresenting 5 distinct proteins were identified in patients compared with healthy controls through analysis of these composite gels. Among them, four proteins, namely alpha 1-antitrypsin(α1-AT), Haptoglobin(Hp), apolipoprotein A-I(apoA-1) and Complement C3 increased remarkably, while one protein, apolipoprotein A-IV(apoA-IV) decreased significantly. The variation of α1-AT and Haptoglobin, as detected by ELISA, was consistent with the results from proteomic analysis. Conclusions It is well known that Hp, α1-AT and complement C3 are associated with inflammation and apoA-1 and apoA-IV play important roles in lipid absorption, transport and metabolism. Therefore, the significant expression changes of Hp, α1-AT and complement C3 and apoA-1 and apoA-IV between HAPE patients and their corresponding healthy controls highlight the role of inflammatory response system and lipid metabolism system in the pathophysiology of HAPE.