Wilkins M R, Needleman P
Royal Postgraduate Medical School, Hammersmith Hospital, London, United Kingdom.
Am J Physiol. 1992 Feb;262(2 Pt 2):F161-7. doi: 10.1152/ajprenal.1992.262.2.F161.
Atrial stretch causes the release of atriopeptin (AP, ANF) from preformed vesicular storage sites. The circulating hormone acts on unique receptor sites (containing guanylate cyclase) to release guanosine 3',5'-cyclic monophosphate (cGMP) that mediates the natriuresis and vasodilation and probably the suppression of renin, aldosterone, and vasopressin. The biological effects of atriopeptin are transient because of the rapid inactivation of the circulating hormone (by neutral endopeptidase or clearance receptors) or the second messenger (by cGMP-phosphodiesterase). Heart failure due to chronic cardiac volume overload [aortovenocaval (A-V) fistula] exhibits markedly elevated circulating AP blood levels and urinary cGMP levels, accompanied by induction of ventricular AP gene and protein expression and release. Pharmacological manipulation of endogenous AP, either by inhibiting cGMP phosphodiesterase (i.e., mediator prolongation) or neutral endopeptidase (i.e., prolongation of hormone half-life) in A-V fistula animals results in profound natriuresis and diuresis without hypotension. These pharmacological maneuvers bypass the suppressed renal response to exogenous AP seen in heart failure and provide a rational therapeutic strategy based on our understanding of the underlying physiological and pathological mechanisms.
心房牵张促使心房肽（AP，心钠素）从预先形成的囊泡储存部位释放。循环中的这种激素作用于独特的受体部位（含有鸟苷酸环化酶），以释放鸟苷3',5'-环磷酸（cGMP），后者介导利钠和血管舒张作用，可能还能抑制肾素、醛固酮和血管加压素。由于循环激素（通过中性内肽酶或清除受体）或第二信使（通过cGMP磷酸二酯酶）的快速失活，心房肽的生物学效应是短暂的。因慢性心脏容量超负荷（主动脉腔静脉瘘）导致的心力衰竭表现为循环中AP血水平和尿cGMP水平显著升高，同时伴有心室AP基因和蛋白表达及释放的诱导。在主动脉腔静脉瘘动物中，通过抑制cGMP磷酸二酯酶（即延长介质作用时间）或中性内肽酶（即延长激素半衰期）来对内源性AP进行药理学操作，会导致显著的利钠和利尿作用而无低血压。这些药理学操作绕过了心力衰竭中所见的对外源性AP的肾反应抑制，并基于我们对潜在生理和病理机制的理解提供了一种合理的治疗策略。
