Restorative Effect of Atrial Natriuretic Peptide or Chronic Neutral Endopeptidase Inhibition on Blunted Cardiopulmonary Vagal Reflexes in Aged Rats

Abstract

Abstract-Arterial baroreflex function diminishes with age, but whether cardiopulmonary vagal reflexes are similarly altered with physiological aging has not been fully elucidated. In this study, predominantly cardiac high pressure mechanoreceptor-activated (ramp baroreflex) and cardiopulmonary chemoreceptor-activated (von Bezold-Jarisch reflex) vagal reflexes in conscious, instrumented rats were impaired by 30% to 40% (PϽ0.05) in 24-month-old (nϭ12) compared with 6-month-old rats (nϭ12). To determine whether this is a restorable deficit, the influence of atrial natriuretic peptide (ANP), either by infusion or blockade of its breakdown, was studied. ANP infusion was previously shown to enhance Bezold-Jarisch reflex and ramp baroreflex bradycardia in young adult rats. The present study confirmed that vagal reflex augmentation by ANP (50 pmol/kg per minute) also occurs in old rats (increased by 60Ϯ18% (Bezold-Jarisch reflex) and 91Ϯ15% (ramp baroreflex; PϽ0.05). Direct vagal stimulation in anesthetized animals showed that the target for ANP was not the cardiac vagus itself in old rats (nϭ7), although in young rats only, we confirmed the published finding that ANP enhances vagal bradycardia (by 58Ϯ14%, nϭ7). Neutral endopeptidase 24.11 degrades ANP and several other peptides. The neutral endopeptidase inhibitor candoxatrilat (5 mg/kg per day IV for 7 to 9 days) restored vagal reflex bradycardia in old rats (nϭ6) to levels similar to those in young neutral endopeptidase inhibitor-treated rats (nϭ6). Impaired cardiopulmonary vagal reflex control of heart rate is thus a feature of normal aging, and this deficit may be ameliorated by either ANP infusion or chronic neutral endopeptidase inhibition. Key Words: aged Ⅲ autonomic Ⅲ cardiac Ⅲ ischemia Ⅲ sensory afferent D iminished arterial baroreflex control of heart rate (HR) is a well-documented feature of aging (see reviews 1,2 ), but surprisingly few studies have examined the effect of aging on reflexes originating in the heart. It is generally accepted that low-pressure cardiopulmonary reflexes are less effective with advancing age and that this may play a role in the decreased ability of the elderly to regulate blood volume and maintain blood pressure during gravity challenges. 3,4 Whether other cardiocardiac vagal reflexes such as the cardiopulmonary chemoreflex (von Bezold-Jarisch [BJR]) or those activated by high-pressure ventricular stretch receptors (ramp baroreflex) are also compromised with age is not clear. The BJR is thought to be cardioprotective (promoting reflex bradycardia, hypotension, and vasodilatation) and is activated by 5-HT 3 receptors on ventricular vagal afferents. 5 Davidow and colleagues concluded that the BJR in conscious 14-and 24-month-old rats was reduced compared with 6-month-old rats, 6 whereas Sakima and colleagues 7 reported that the BJR was not diminished in older (16-to 20-month-old) rats.The potential for cardioprotection by enhancing parasympathetic activity has long been recognized and this avenue is underexploited by current ther...

A Familial Mutation Renders Atrial Natriuretic Peptide Resistant to Proteolytic Degradation

“…Additional studies in anesthetized canines demonstrated that ANPdependent decreases in monophasic action potential and effective refractory period are due to secondary autonomically mediated effects (33). Another study demonstrated that these vagal reflexes can be activated both by ANP infusion and by inhibiting its degradation by blocking NEP (26). The implication from the Hodgson-Zingman study is that in patients expressing fsANP, these vagal reflexes would be under more prolonged pressure because of the elevated levels of total ANP (wtANP ϩ fsANP), which would eventually lead to early onset atrial fibrillation.…”

Role of circulating factors in cardiac aging

“…In animals, increased levels of NPs or chronic inhibition of NEP are able to prevent the progression of cardiac aging (158,159). Similarly, in humans, simultaneous inhibition of NEP and Ang-II type-1 receptor (AT1R) with LCZ-696 (which is composed by Valsartan and Sacubitril) has shown to reduce significantly mortality and hospitalization in patients with HF (160).…”

The role of natriuretic peptides in regulation of cardiovascular system

“…Этот механизм, по-видимому, имеет отношение к феномену относительной или абсолютной (парадоксальной при гипотензии) брадикардии и проявляется даже при низких (негипотензивных) концентрациях ANP [7,77,84]. Важно, что введение ANP или увеличение его концентрации в циркулирующей крови, благодаря лекарственному воздействию (ингибитором нейтральной эндопептидазы), приводит к увеличению чувствительности кардиопульмональных вагусных рефлексов, включая рефлекс Бецольда-Яриша [320,321]. В то же время ANP обладает свойствами антагониста симпатической нервной системы, способного оказывать подавляющие эффекты на всех уровнях барорефлекторной дуги.…”