To the Editor: Okoshi and colleagues1 studied the modulatory role of neuregulin-1 on parasympathetic activity in the heart. This interesting study on isolated cardiomyocytes showed that het- erozygous gene deletion of neuregulin-1 abrogated the inhibitory activity of the muscarinic cholinergic system on -adrenergic signaling. Because protein levels of M2 muscarinic receptors and G protein subunits were unchanged in neuregulin-1-deficient cardiomyocytes, the authors proposed that neuregulins support normal parasympathetic modulation of excess -adrenergic stim- ulation of the heart. In a recent article in Circulation,2 we reported that exog- enously administrated neuregulin-1 attenuated -adrenergic re- sponses of isolated papillary muscles in the absence of exoge- nous muscarinic activation. Our data suggested that neuregulin-1 also had direct antiadrenergic effects, rather than a mere support- ing role in the antiadrenergic effects of the parasympathetic system. To further reinforce our conclusion, after reading the article by Okoshi et al, we repeated our experiments in papillary muscles pretreated with atropine to inhibit background musca- rinic activity from parasympathetic nerve endings. The results of these experiments indicated that the antiadrenergic effects of neuregulin-1 disappeared when muscarinic receptors were blocked. Our findings and those by Okoshi et al seem to be consistent as they both reveal a unique and powerful interaction between the parasympathetic system and neuregulin signaling. More specifically, it appears that both components rely on cooperativity for an inhibitory effect on the adrenergic system. One aspect of the article by Okoshi et al, however, is unclear to us. The authors made their observations of neuregulin-1 gene deletion in isolated cardiomyocytes, whereas neuregulin-1 is an endothelial factor, which according to our (unpublished) and others' observations is not or is only minimally expressed in cardiomyocytes.3 How do the authors explain this? Also, did the authors try to rescue the carbachol-resistant NRG-1 / phenotype with exogenous neuregulin-1?