The Relationship Between Hypertension And Impairment Of Aortic Diastolic And Contractile Function In Chronic Kidney Disease Rats

BackgroundChronic kidney disease（CKD）has become a serious social problem,which threatens human health.The prevalence of CKD now exceeds 10%worldwide,and nearly 1.18 million people died from it in 2016.Common complications of CKD include hypertension,heart disease,abnormal lipid metabolism,electrolyte imbalances,secondary hyperparathyroidism and anemia.Hypertension is one of the most important risk factors for the progression of CKD,which increases the incidence of cardiovascular events and affects the prognosis of CKD patients.Controlling blood pressure is key for delaying progression of CKD.However,with the prevalence rate of hypertension in CKD patients around 85%,efforts to control hypertension have clearly been unsatisfactory.The pathogenesis of hypertension in CKD patients is so complex and multifactorial that it is resistant to treatment.In addition to pathogenic factors such as fluid retention,renin-angiotensin-aldosterone system（RAAS）activation,vascular compliance changes and vascular calcification,new research has indicated that changes in large artery function and the high level of parathyroid hormone（PTH）may be novel factors acting to induce hypertension in CKD.Blood vessels are regulated by various factors in the organism including catecholamines,thromboxane and endothelial-derived vasoactive substances.Blood vessels shrink or relax after stimulation by these factors,which then impacts blood pressure directly.There has been little research to determine if CKD influences the effect of these substances on the arteries to raise blood pressure.In this study,the aortic reactivity of vasoactive agents and the content of related receptor proteins on the vascular wall were compared between CKD and control rats.We also examined if PTH affected vessel function directly or indirectly in CKD rats.Our goal was to explore the pathogenesis of hypertension in CKD and find new approaches for clinical treatment.ObjectiveTo investigate the mechanism of aortic systolic and diastolic reaction in chronic kidney disease（CKD）rats with hypertension.Methods（1）CKD model:Female Sprague-Dawley rats were randomly divided into sham-operation（Sham）and CKD groups.CKD was induced by 5/6 nephrectomy.Serum levels of creatinine（Cre）,calcium（Ca）,phosphorus（P）and parathyroid hormone（PTH）were measured at 0,8,and 16 weeks after operation and caudal artery pressure was tested at 0 and 16 weeks after operation.（2）Aortic tension determination:The thoracic aorta was dissected from the rats and peripheral tissues were removed from the blood vessels under a microscope.Vascular rings were prepared from the thoracic aorta and fixed to the clamp of a vascular tension tester.The tension variations in thoracic aortas were measured after induction by vasoconstrictor/vasodilator and PTH using the cumulative concentration administration method.（3）The expression of corresponding receptors in the thoracic aorta were examined in western blots.Results（1）Serum Cre,Ca,P,PTH,systolic and diastolic pressure were all significantly elevated in CKD rats 16 weeks post-nephrectomy compared with the sham group.（2）The CKD group showed an increased contraction response（162.66± 14.29 vs 121.39± 15.47,P<0.01）to thromboxane-A2 analogue U46619 compared with shams,but there was no difference in contractility after stimulation by high potassium solution（60 mmollL K+）and phenylephrine.（3）Both endothelium-dependent relaxation induced by acetylcholine（Ach）and non-endothelium-dependent relaxation induced by sodium nitroprusside（SNP）decreased in the CKD group;Ach:67.78 ± 6.18 vs 83.92± 5.42,P<0.01;SNP:95.45± 1.33 vs 98.90± 0.60,P<0.01.（4）PTH did not affect vessel function directly.After pretreating the thoracic aorta with PTH（50 pg/mL）,the contractions induced by U46619 decreased in CKD rats（114.51 ± 4.44 vs 162.66± 14.29,P<0.01）,but there was no change in the thoracic aorta without endothelium.（5）Compared with the control group,expression of thromboxane-A2（TXA₂）receptors in the thoracic aorta was higher and expression of endothelial nitric oxide synthase was lower in CKD rats,while expression of alpha 1a adrenergic receptor protein and L-type calcium channel protein showed no significant change between the two groups.ConclusionThe contractility of thoracic aorta stimulated by the same dose of TXA₂ analogues in CKD rats was enhanced and may be related to the increase in TXA₂ receptors in their thoracic aorta;The endothelium-dependent and non-endothelium-dependent relaxation function of the thoracic aorta in CKD rats was impaired.These changes may be involved in the development of hypertension in CKD rats.By the way,parathyroid hormone had no direct effect on the tension of thoracic aorta in CKD rats,but it can indirectly decrease the contractile response of vasoconstrictor,which worked through releasing nitric oxide from vascular endothelial cells.