Adenosine-Stimulated Atrial Natriuretic Peptide Release Through A ₁ Receptor Subtype

Abstract

Abstract-Adenosine acts as an important protector of ischemic myocardium through coronary vasodilation and the depression of cardiac contractility. The protective effect of adenosine may partly relate to the cardiac hormone atrial natriuretic peptide (ANP). The aim of the present study was to investigate the effects of adenosine and the adenosine receptor subtype on atrial hemodynamics and ANP release using isolated perfused beating rat atria. Adenosine, a nonselective adenosine receptor agonist, increased the ANP release with negative inotropism in a dose-dependent manner. Adenosine-stimulated ANP release was attenuated by a selective A 1 antagonist but not A 2A antagonist or A 3 antagonist. The order of potency of the various agonists for the ANP release was A 1 agonistsϾ ϾA 3 agonistϭ adenosineϾA 2A agonist. The order of potency for the negative inotropy was A 1 agonistsϾadenosineϭA 2A agonistϾA 3 agonist. The negative inotropism and ANP release by a specific A 1 agonist (N 6 -cyclopentyl-adenosine) were also attenuated by A 1 antagonist but not A 2A antagonist or A 3 antagonist. Treatment with A 1 agonist resulted in a decrease of cAMP contents in atria and perfusates. The agonist-stimulated ANP release was significantly attenuated in the presence of forskolin, isoproterenol 8-Br-cAMP, or an adenylyl cyclase inhibitor. These results suggest that the A 1 receptor subtype is responsible for the adenosine-induced ANP release and negative inotropism through adenylyl cyclase-cAMP pathway. Key Words: adenosine Ⅲ natriuretic peptides Ⅲ cyclin AMP Ⅲ heart Ⅲ hypertension, experimental Ⅲ receptor Ⅲ kidney A denosine is recognized as an important signaling molecule in heart. Adenosine originates from the hydrolysis of S-adenosylhomocysteine (SAH) by SAH hydrolase during normal condition or from the hydrolysis of AMP by 5Ј-nucleotidase during ischemic or hypoxic conditions. 1 Adenosine effects are mediated through 4 distinct receptors, A 1 , A 2A , A 2B , and A 3 , initially defined pharmacologically based on their effects on adenylyl cyclase (AC; inhibition or stimulation) and their selectivity for agonists and antagonists. [2][3][4] All the receptor subtypes appear to be expressed in cardiomyocytes. 4 In the cardiovascular system, adenosine causes coronary vasodilation, the reduction of heart rate and cardiac contractility, and the attenuation of stimulatory actions of catecholamines on heart. 5 Endogenous release of adenosine during myocardial ischemia and hypoxia induces a potent protective effect in paracrine and autocrine ways. 6 Adenosine produced during a brief period of ischemia or exogenously administered adenosine causes a cardioprotective effect manifested by a reduction of infarct size or decreased myocardial stunning during ischemic preconditioning 7 via activation of A 1 and A 3 receptor subtypes. 5,8 Myocardial adenosine and ADP levels are increased during hypoxia and in severely hypertrophied hearts. Therefore, adenosine can exert effects on the ischemic or overloaded heart that are of considerable scie...

Natriuretic Peptides: Physiologic and Analytic Considerations

“…Recently, in isolated perfused beating rat atria, adenosine in a dose-dependent fashion induced cAMP dependent ANP release. 41 Adenosine is known to exert cardioprotective actions, including coronary vasodilation and suppression of myocardial contractility, and these effects may potentially be mediated via activation of the natriuretic peptide system. Another endogenous substance that is released from cell membranes during myocardial ischemia is lysophosphatidyl choline.…”

Natriuretic Peptides

“…Yuan et al 19 have recently established a relationship between adenosine and ANP release. Adenosine protects the ischemic myocardium by means of coronary vasodilatation and suppression of cardiac contractility.…”

Comparative effects of angiotensin II and angiotensin-(4-8) on blood pressure and ANP secretion in rats

“…Isolated perfused beating atria were prepared using a previously described method [ 23 ]. In brief, hearts were rapidly excised after decapitation, and left atria were dissected and inserted into cannula, and ligated by a silk.…”