Chapter 7. Summary and conclusions

1. The present study shows that PTK inhibitor genistein acutely increased cardiac contractile force, perfusion pressure and ANP secretion to the perfusate. Diltiazem, an L-type Ca²⁺ channel antagonist, and KN-62, an inhibitor of CaM kinase II, inhibited the inotropic and ANP secretory effects of genistein, showing that genistein either directly or indirectly modulates those cellular processes which regulate the intracellular concentration of Ca²⁺.

2. ANP secretion and heart rate were increased by relaxin, indicating that this pregnancy hormone may act via autocrine/paracrine routes to regulate cardiac function. The ANP secretory effect appears to be mediated by PKC and PKA since selective protein kinase inhibitors blocked the relaxin-stimulated ANP secretion.

3. Thapsigargin, a selective inhibitor of sarcoplasmic reticulum Ca²⁺ adenosine triphosphatase, completely blocked stretch-activated ANP exocytosis from right atrial myocytes. This finding suggests that the stretch-induced increase in ANP secretion is linked to its capacity to mobilize a thapsigargin-sensitive intracellular Ca²⁺ pool.

4. Atrial wall stretch-induced ANP and BNP secretion were markedly decreased by lavendustin A, a potent PTK inhibitor. This dose-dependent inhibition of wall stretch-induced increase in cardiac hormone secretion occurred at the concentrations similar to or even below those shown to inhibit the activities of PTKs in vitro, suggesting that PTKs have an essential role in stretch-secretion coupling.

5. Okadaic acid accelerated atrial wall stretch-induced ANP secretion. Because the only targets of okadaic acid are the catalytic subunits of PP 1 and A2, these enzymes appear to play a significant role in atrial wall stretch-induced ANP secretion.

6. NO may act as a regulator of basal and stretch-induced cardiac hormone release since the NOS inhibitor L-NAME enhanced ANP secretion in the presence of ET-1. The endothelin ET_A/B-receptor antagonist bosentan, and endothelin ET_B-receptor agonist sarafotoxin 6C failed to influence basal or atrial stretch-induced increase in ANP secretion. Therefore, under these experimental conditions ET-1 or stimulation of ET_B-receptors are not the mediators of acute atrial wall stretch-induced ANP secretion.