natriuretic peptides stimulate the cardiac sodium pump via nprccoupled nos activation natriuretic peptides nps and their receptors nprs are expressed in the heart but their effects on myocyte function are poorly understood because nprs are coupled to synthesis of cgmp an activator of the sarcolemmal nak pump we examined whether atrial natriuretic peptide anp regulates the pump we voltage clamped rabbit ventricular myocytes and identified electrogenic nak pump current arising from the 32 nak exchange and normalized for membrane capacitance as the shift in membrane current induced by 100 micromoll ouabain ten nanomoles per liter anp stimulated the nak pump when the intracellular compartment was perfused with pipette solutions containing 10 mmoll na but had no effect when the pump was at near maximal activation with 80 mmoll na in the pipette solution stimulation was abolished by inhibition of cgmpactivated protein kinase with kt5823 nitric oxide noactivated guanylyl cyclase with 1h124oxadiazole43aquinoxalin1one odq or no synthase with ngnitrolarginine methyl ester lname since synthesis of cgmp by npra and nprb is not no dependent or odq sensitive we exposed myocytes to ap811 a highly selective ligand for the nprc clearance receptor it abolished anpinduced pump stimulation conversely the selective nprc agonist anp423 reproduced stimulation the stimulation was blocked by lname to examine no production in response to anp423 we loaded myocytes with the nosensitive fluorescent dye diacetylated diaminofluorescein2 and examined them by confocal microscopy anp423 induced a significant increase in fluorescence which was abolished by lname we conclude that nps stimulate the nak pump via an nprc and nodependent pathway