Contractile Function And Mechanism Of Coronary Artery In Spontaneous Hypertensive Rats

Hypertension is a systemic disease with small arterial sclerosis as the basic lesion.Hypertension is a chronic noninfectious disease.It causes damage to target organs such as heart,brain and kidney,which seriously damages human life and health,and its morbidity and mortality have been increasing year by year.Coronary heart disease is one of the most important target organ damage caused by hypertension.Epidemiological surveys show that more than half of patients with coronary heart disease combined with hypertension,and the prevalence rate of coronary heart disease among normal people was four times lower than that of patients with hypertension.Therefore,more and more attention has been paid to the study of the changes of coronary artery function and mechanism caused by hypertension.Objective:To study the differences of coronary systolic and diastolic function between SHR and Wistar rats,and to explore its related mechanism.Methods:Using SHR and Wistar adult rats,male,16-18 weeks.The systolic blood pressure and diastolic blood pressure of rats were measured by tail-pressure method.The systolic and diastolic function of rats was measured by B-scan ultrasonography.The rats were sacrificed by carbon dioxide anesthesia,the heart was removed,then left and right coronary arteries were isolated under a microscope to prepare an isolated coronary artery of 1.8-2.0 mm in length,and the tension of the arterial ring was measured by an angiotension meter.To investigate the effect of different agonists on the induction of coronary contraction and that after used the blockade.We primary cultured coronary artery smooth muscle cells and used laser confocal microscopy to detect calcium-influx（store-operated channel,SOC）regulation of Ca²⁺influx in rat coronary artery smooth muscle cells.Results:（1）SHR systolic pressure and diastolic pressure were significantly increased compared with Wistar rats.（2）Cardiac ultrasonographic findings suggested that the interventricular septal thickness at diastole（IVSd）,systolic left ventricular posterior wall thickness（SHR）,Left ventricular posterior wall end-diastolic thickness（LVPWs）and diastolic left ventricular posterior wall end-systolic thickness（LVPWd）of SHR were significantly higher than that of Wistar rats.（3）Compared with the Wistar group,the high potassium（60mM）-induced coronary systolic function and calcium chloride（CaCl₂）-induced coronary vasoconstriction in the SHR group were significantly reduced.Sodium nitroprusside（SNP）also caused a significant decrease in coronary artery diastolic function in SHR than in Wistar group.In addition,5-hydroxytryptamine（5-HT）,thromboxane A2 analogues（9,11-dideoxy-11α,9α-epoxymethanopros-taglandin,U46619）,endothelin-1（Endothelin-1,ET-1）were separately given,well the Coronary artery contraction in the SHR group was similarly significantly lower than that in the Wistar group.SHRs were incubated with nifedipine（1μM）,a voltage-dependent calcium channel（VDCC）channel blocker（nifedipine）.The SHR group had significantly decreased coronary artery contraction induced by different agonists compared with the Wistar group.In the calcium-free KH solution containing nifedipine（1μM）,the 5-HT and U46619 induced coronary artery contraction in the SHR group was still significantly lower than that in the Wistar group.（4）To further explore its related mechanisms,we found that 5-HT_2AA receptor blocker（sarpogrelate）1μM can completely eliminate coronary artery contraction induced by 5-HT;Respectively with protein kinase inhibitors:phospholipase C_β（PLC_β）inhibitor（U73122）;Rho-associated protein kinase inhibitor（Y27632）and protein kinase C（PKC）inhibitor（rottlerin）could significantly inhibited the coronary artery Contraction induced by 5-HT.After blocked by Y27632（10μM）and rottlerin（10μM）,5-HT-induced coronary constriction in SHR group was significantly more than Wistar group.In addition,the SOC inhibitor SKF96365 and2-APB could significantly inhibited 5-HT-induced coronary artery contraction.After the coronary artery was blocked with 2-APB（50μM）,its constriction induced by5-HT was significantly increased in SHR group.（5）Measurement of calcium in the coronary arterial smooth muscle cells by laser confocal indicated that the SOC-mediated Ca²⁺influx in the SHR group was significantly higher than that in the Wistar group.CONCLUSION:The contractile reactivity of hypertensive coronary artery is significantly reduced,and it is closely related to the L-type calcium channel of coronary artery smooth muscle cells and the abnormal signal pathway of PLC,PKC and Rho kinase.