This study was designed to gain additional insight into the mechanism of the slow force response (SFR) to stretch of cardiac muscle. SFR and changes in intracellular Na<SUP>+</SUP> concentration ([Na<SUP>+</SUP>]<SUB>i</SUB>) were assessed in cat papillary muscles stretched from 92% to ≈98% of L<SUB>max</SUB>. The SFR was 120±0.6% (n=5) of the rapid initial phase and coincided with an increase in [Na<SUP>+</SUP>]<SUB>i</SUB>. The SFR was markedly depressed by Na<SUP>+</SUP>-H<SUP>+</SUP> exchanger inhibition, AT1 receptor blockade, nonselective endothelin-receptor blockade and selective ETA-receptor blockade, extracellular Na<SUP>+</SUP> removal and inhibition of the reverse mode of the Na<SUP>+</SUP>-Ca<SUP>2+</SUP> exchange by KB-R7943. KB-R7943 prevented the SFR but not the increase in [Na<SUP>+</SUP>]<SUB>i</SUB>. Inhibition of endothelin-converting enzyme activity by phosphoramidon suppressed both the SFR and the increase in [Na<SUP>+</SUP>]<SUB>i</SUB>. The SFR and the increase in [Na<SUP>+</SUP>]<SUB>i</SUB> after stretch were both present in muscles with their endothelium (vascular and endocardial) made functionally inactive by Triton X-100. In these muscles, phosphoramidon also suppressed the SFR and the increase in [Na<SUP>+</SUP>]<SUB>i</SUB>. The data provide evidence that the last step of the autocrine-paracrine mechanism leading to the SFR to stretch is Ca<SUP>2+</SUP> entry through the reverse mode of Na<SUP>+</SUP>-Ca<SUP>2+</SUP> exchange.Facultad de Ciencias MédicasCentro de Investigaciones Cardiovasculares