ENDOTHELIN ACTS AS A PARACRINE REGULATOR OF STRETCH-INDUCED ATRIAL-NATRIURETIC-PEPTIDE RELEASE

Several lines of evidence suggest a paracrine regulatory role for endo thelin (ET) in the release of atrial natriuretic peptide (ANP). To inv estigate this possibility, we used the ET A-type receptor (ET(A)-R) co mpetitive inhibitor cyclo(D-Asp-Pro-D-Val-Leu-D-Trp) (BQ-123) in isola ted perfused atria to determine the effect of endogenously produced ET on the release of ANP. Initially, we found that high pressure (8-10 m mHg) increased the mean ANP secretion rate by 117.3 +/- 21.2% (P < 0.0 5). Next, we found that at high pressure 50 nM of exogenously applied ET significantly augmented the stretch-induced release of ANP (P < 0.0 5) and that this response could be significantly attenuated in a dose- dependent manner by 1 and 3 mu M BQ-123 (P < 0.05). These experiments proved the efficacy of the inhibitor in our model. Subsequently, we fo und that the stretch-induced release of ANP was significantly reduced to 51.5 +/- 13.0 and 22.3 +/- 11.8% by 1 and 3 mu M BQ-123, respective ly (P < 0.05). Because the perfused atria model eliminates systemic ca rdiovascular effects, allows control and direct recording of the intra -atrial pressure, and preserves the potential endothelium-myocyte cont rol system, we conclude that the stretch-induced release of ANP is par tially regulated by ET and that the ET is locally produced and constit utes a paracrine control system.