Inhibition of atrial wall stretch-induced cardiac hormone secretion by lavendustin A, a potent tyrosine kinase inhibitor

The cellular processes linking mechanical wall stretch to atrial natriureti c peptide (ANP) and B-type natriuretic peptide (BNP) secretion from the hea rt are unclear. In the present study, a paced perfused rat heart preparatio n was used to study the signaling mechanisms of atrial wall stretch-induced secretion of ANP and BNP. Vehicle or drugs were infused into the perfusate for 40 min and right atrial wall stretch was superimposed for 10 min after 25-min drug infusions by elevating the level of the pulmonary artery cannu la tip. Lavendustin A, a potent inhibitor of protein tyrosine kinases, at t he concentrations of 0.5 and 1.3 mu M decreased atrial wall stretch-induced ANP secretion (53% and 68%, respectively, P < 0.001) in the perfused rat h eart preparation, whereas no difference in the hemodynamic variables (heart rate, contractile force and perfusion pressure) mere noted between groups. Lavendustin A also completely abolished the wall stretch-induced secretion of BNP. Several other protein kinase inhibitors including staurosporine (p rotein kinase C inhibitor), ML-9 (myosin light chain kinase inhibitor), KN- 62 (Ca2+/calmodulin-dependent protein kinase II inhibitor) and H-89 (protei n kinase A inhibitor) had no significant effect on atrial wall stretch-stim ulated ANP secretion. In a separate series of experiments, in which the rig ht atria were stretched for 2 h, administration of lavendustin A (1 mu M) b ut not staurosporine (30 nM) significantly decreased sustained wall stretch -induced ANP secretion. Okadaic acid, a potent protein phosphatase A2 (PPA2 ) and PP1 inhibitor, at the concentration of 100 nhl had no effect on basal ANP secretion but significantly accelerated the ANP secretory response to atrial wall stretch (P < 0.05). In conclusion, the findings that inhibitors of protein tyrosine kinase and protein phosphatase selectively modulated a trial wall stretch-induced ANP secretion suggest a new mechanism involving endogenous protein tyrosine activity in the regulation of natriuretic pepti de exocytosis from cardiac myocytes.