Abstract

Atrial natriuretic peptide (ANP) and B-type natriuretic peptide (BNP) are cardiac hormones, which are involved in the regulation of blood pressure and fluid homeostasis. The major determinant for ANP and BNP release are atrial and ventricular wall stretch, but also some vasoactive factors such as endothelin-1 (ET-1) can enhance cardiac hormone secretion. The mechanical stretch rapidly activates multiple signal transduction pathways in cardiac cells, but the cellular mechanisms mediating stretch-induced ANP secretion are still unknown. The aim of the present study was to examine the cellular mechanisms of autocrine/paracrine factors and stretch-induced ANP secretion.

Genistein, a potent protein tyrosine kinase (PTK) inhibitor, rapidly increased cardiac contractile force and ANP secretion in perfused rat heart. This effect of genistein may be unrelated to the inhibition of PTKs since this stimulation was blocked by a L-type calcium channel antagonist and Ca²⁺/calmodulin-dependent protein kinase II inhibitor. Pregnancy hormone relaxin increased heart rate and ANP secretion in perfused spontaneously beating heart, suggesting that relaxin may have a role in modulating cardiac function. Cellular mechanisms of atrial wall stretch-induced ANP secretion were also studied. This enhanced secretion was blocked by sarcoplasmic reticulum Ca²⁺-ATPase inhibitor thapsigargin and PTK inhibitor lavendustin A, indicating that thapsigargin sensitive Ca²⁺ pools and activation of PTK orPTK cascade have an important role in the regulation of stretch-secretion coupling. In addition, protein phosphatase inhibitor okadaic acid accelerated stretch-induced ANP secretion, suggesting that precise balance of protein kinase and phosphatase activity plays a role in mechanical stretch-induced ANP secretion. Finally interactions of endothelial factors regulating ANP exocytosis were studied. The potent nitric oxide synthase inhibitor L-NAME increased basal and atrial wall stretch-induced ANP secretion in the presence of ET-1, suggesting that nitric oxide may tonically inhibit ANP secretion.