Rademaker Miriam T, Charles Chris J, Espiner Eric A, Frampton Chris M, Nicholls M Gary, Richards A Mark
Christchurch Cardioendocrine Research Group, Department of Medicine, The Christchurch School of Medicine, Christchurch, New Zealand.
Clin Sci (Lond). 2004 Jun;106(6):569-76. doi: 10.1042/CS20030366.
Blockade of AngII (angiotensin II) and ET (endothelin)-1, established and potential therapeutic strategies respectively, for heart failure, may have an adverse effect on the cardiac secretion of the natriuretic peptides, hormones with actions beneficial in this disease. The present study investigates the roles of AngII and ET-1 in regulating the stretch-induced release of the natriuretic peptides during the development of heart failure. On seven separate days, eight sheep underwent incremental left ventricular pacing (155, 190 and 225 beats/min for 90 min each) with concurrent infusions of a vehicle control, AngII, ET-1, AngII+ET-1, losartan [AT1 (AngII type 1) receptor antagonist], bosentan (ET(A)/ET(B) receptor antagonist) or losartan+bosentan. Pacing-induced rises in LAP (left atrial pressure) were amplified by the simultaneous administration of separate AngII and ET-1, and attenuated following blockade of the peptides, with maximum effects observed during combined treatments. Although these changes in atrial pressure were paralleled by concomitant alterations in circulating levels of both ANP (atrial natriuretic peptide) and BNP (brain natriuretic peptide), the plasma natriuretic peptide/atrial pressure relationship tended to be augmented by AngII and ET-1 and diminished by their blockade. A significant difference was demonstrated between the enhanced plasma BNP response to increasing LAP during combined AngII+ET-1 administration and decreased response during losartan+bosentan treatment ( P <0.05). A similar, but non-significant, trend was evident for ANP. The present study indicates dual AngII/ET-1 blockade diminishes BNP (and to a lesser extent ANP) secretion in developing heart failure, suggesting that augmentation of the natriuretic peptide system during the combination of these therapies may be of benefit.
分别作为已确立的和潜在的心力衰竭治疗策略，阻断血管紧张素II（AngII）和内皮素-1（ET-1）可能会对利钠肽的心脏分泌产生不利影响，而利钠肽是对这种疾病具有有益作用的激素。本研究探讨了AngII和ET-1在心力衰竭发展过程中调节牵张诱导的利钠肽释放中的作用。在七个不同的日子里，八只绵羊接受递增的左心室起搏（分别以每分钟155、190和225次搏动，每次90分钟），同时输注载体对照、AngII、ET-1、AngII + ET-1、氯沙坦[AT1（1型AngII）受体拮抗剂]、波生坦（ET(A)/ET(B)受体拮抗剂）或氯沙坦 + 波生坦。单独给予AngII和ET-1可放大起搏诱导的左心房压力（LAP）升高，而阻断这些肽后LAP升高减弱，联合治疗时效果最为明显。尽管心房压力的这些变化与心房利钠肽（ANP）和脑利钠肽（BNP）循环水平的相应改变平行，但血浆利钠肽/心房压力关系倾向于因AngII和ET-1而增强，因它们的阻断而减弱。在联合给予AngII + ET-1期间血浆BNP对LAP升高的增强反应与氯沙坦 + 波生坦治疗期间的降低反应之间存在显著差异（P <0.05）。ANP也有类似但不显著的趋势。本研究表明，在心力衰竭发展过程中双重阻断AngII/ET-1可减少BNP（以及程度较轻的ANP）分泌，这表明在这些治疗联合应用期间增强利钠肽系统可能有益。
