Beta1-adrenergic receptor activation decreases ANP release via cAMP-Ca2+ signaling in perfused beating rabbit atria.

AIMS: Although a beta-adrenoceptor (beta-AR) blockade-induced increase in plasma atrial natriuretic peptide (ANP) levels is implicated in the therapeutic significance of beta-AR antagonists, the role of beta-AR in the regulation of ANP release is not clearly defined. The purpose of the present study was to define the role of beta-AR subtypes and the mechanisms responsible for regulation of atrial ANP release. MAIN METHODS: Experiments were performed in isolated perfused beating rabbit atria, including measurement of atrial contractile response, cAMP efflux, and atrial myocyte ANP release. KEY FINDINGS: beta-AR activation with (-)-isoproterenol decreased ANP release concomitantly with increases in cAMP efflux concentration, atrial dynamics, stroke volume and pulse pressure in a concentration-dependent manner. The ANP response was inversely related to the change in cAMP efflux concentrations. The isoproterenol-induced decrease in ANP release was inhibited by beta(1)-AR blockade with CGP 20712A but not by beta(2)-AR blockade with ICI 118551. The isoproterenol-induced decrease in ANP release was attenuated by the L-type Ca(2+) channel antagonist nifedipine and the cAMP-dependent protein kinase inhibitor KT5720. SIGNIFICANCE: These findings suggest that beta(1)-AR activation decreases ANP release via cAMP- and Ca(2+)-dependent mechanisms.

Cardiac mast cells regulate myocyte ANP release via histamine H2 receptor in beating rabbit atria.

It has been shown that histamine inhibits atrial natriuretic peptide (ANP) release. Because cardiac mast cells are the principal source of histamine in the heart, we hypothesized that cardiac mast cells are involved in the regulation of atrial ANP release. To test the hypothesis, experiments were performed in perfused beating rabbit atria allowing atrial pacing and measurements of changes in atrial stroke volume, intraatrial pulse pressure and myocyte ANP release. Mast cell degranulation with Compound 48/80 decreased atrial myocyte ANP release, and the response was blocked by a selective histamine H(2) receptor blocker, cimetidine, indicating that histamine was responsible for the decrease in ANP release. Mast cell stabilization with cromolyn blocked the Compound 48/80-induced decrease in ANP release. These data suggest that mast cell-derived histamine is involved in the regulation of cardiac ANP release. Thus, the cardiac mast cell-cardiomyocyte communication via the histamine-ANP pathway may implicate in the cardiac disorder associated with mast cell degranulation such as in acute coronary syndrome or cardiac hypertrophy.

K+ACh channel activation with carbachol increases atrial ANP release.

Although it has been known that atrial natriuretic peptide (ANP) release is regulated through muscarinic acetylcholine receptors (mAChR), the mechanism by which this neurotransmitter regulates atrial ANP release is largely unknown. This study tested the hypothesis that K(+)(ACh) channels mediate the action of mAChR on atrial myocyte ANP release. Experiments were performed in perfused beating rabbit atria. Carbachol (CCh), an agonist of cardiac mAChR, increased atrial myocyte ANP release concomitantly with a decrease in stroke volume and intra-atrial pulse pressure in a concentration-dependent manner. Isoproterenol, a beta-adrenoceptor agonist, decreased ANP release concomitantly with an increase in cAMP and mechanical dynamics. In the presence of isoproterenol, the CCh-induced increase in ANP release and decrease in cAMP efflux levels and mechanical dynamics were able to be repeated. The CCh-induced changes were blocked by selective M(2) mAChR antagonists. Tertiapin, a selective G-protein-gated K(+)(ACh) channel blocker, attenuated the CCh-induced increase in ANP release and decrease in mechanical dynamics in a concentration-dependent manner, but without a significant effect on the CCh-induced decrease in cAMP efflux levels. The CCh-induced changes in ANP release and atrial dynamics were inhibited in the atria from pertussis toxin-pretreated rabbits. These findings demonstrate that G-protein-gated K(+)(ACh) channels regulate atrial myocyte ANP release. The present study also shows that mAChR and adrenoceptors have opposing roles in the regulation of ANP release.

Altered role of C-type natriuretic peptide-activated pGC-cGMP-PDE3-cAMP signaling in hyperthyroid beating rabbit atria.

The role of C-type natriuretic peptide (CNP) in the pathophysiology of atrial function in hyperthyroidism has not been defined. This study was to define the role of CNP-activated particulate (p) guanylyl cyclase (GC)-cGMP-phosphodiesterase (PDE)3 signaling in the regulation of cAMP levels and contractile and secretory functions in the atria from hyperthyroid rabbits. Experiments were performed in perfused beating rabbit atria. CNP was used to activate pGC. In euthyroid atria from sham-treated rabbits, CNP (100 nM) increased cGMP and cAMP efflux by 176.7+/-17.7 and 55.3+/-10.0%, respectively. CNP decreased stroke volume and pulse pressure and ANP release by 51+/-7 and 41+/-2 and 60.4+/-3.2%, respectively. Pretreatment with milrinone blocked the CNP-induced increase of cAMP but without significant changes in decrease of atrial dynamics and ANP release. In hyperthyroid atria, CNP-induced increase of cGMP levels was accentuated, while CNP-induced increase of cAMP was attenuated. The gain of cAMP, i.e., change in cAMP efflux concentration in terms of cGMP was attenuated in the hyperthyroid compared to euthyroid atria. CNP rather increased atrial dynamics in hyperthyroid atria instead of decrease. CNP-induced decrease in atrial ANP release was attenuated. Pretreatment with milrinone blocked the CNP-induced increase of cAMP levels concomitantly with a decrease of atrial dynamics. The present study demonstrates that altered role of CNP-activated pGC-cGMP-PDE3-cAMP signaling is involved in the pathophysiology of hyperthyroid heart.