MECHANISM OF ANOXIA-INDUCED ATRIAL-NATRIURETIC-PEPTIDE RELEASE IN THEISOLATED RAT ATRIA

Our laboratory has recently shown that locally produced endothelin (ET ) is involved in the atrial natriuretic peptide (ANP) response to a ph ysical stimulus, stretch. The aim of this study was to determine if fa ctors locally produced in the atria were involved in the ANP response to a chemical stimulus, anoxia. Reduced oxygen tension is a potent sti mulus of ANP release, and our results show that, when isolated perfuse d atria were exposed to anoxic conditions, the ANP secretion rate incr eased by a maximum of 129 +/- 8% of the baseline. Exposure to anoxia c aused neither an elevation in perfusate creatinine phosphokinase, a ch ange in atrial morphology detectable by electron microscopy, nor inter fered with the return toward the baseline ANP secretion rate with reox ygenation, suggesting that this response was not due to myocyte damage . When the atria were pretreated with either 3 mu M BQ-123, an endothe lin receptor inhibitor, or 10 mu M indomethacin, a cyclooxygenase inhi bitor, the ANP response to anoxia was nearly abolished. To clarify the association between ET and prostaglandins, we showed that the ANP res ponse to 50 nM ET-1 was totally blocked at both high and low pressure by 10 mu M indomethacin, but the increased contractility response to E T was unaffected. Therefore, we have concluded that the anoxia-induced ANP response is mediated by locally produced ET, which, in turn, stim ulates the production of prostaglandins. Prostaglandins appear to be r esponsible for the increased ANP secretion rate.