POSITIVE CHRONOTROPIC AND INOTROPIC EFFECTS OF C-TYPE NATRIURETIC PEPTIDE IN DOGS

We have recently reported that C-type natriuretic peptide (CNP) has a positive chronotropic effect in dogs. We further investigated the effe ct of CNP on canine cardiac functions: 1) in situ, by exploring the ef fects of isoproterenol (10 mu g), angiotensin II (ANG II, 5 mu g), and CNP (40 mu g) injections (n = 8) on computerized epicardial mapping o f atrial activation to detect a shift in pacemaker location; 2) by exa mining the presence of natriuretic peptide receptor (NPR)-A and -B mRN As in atrial and nodal tissues using semiquantitative reverse-transcri ption polymerase chain reaction; 3) in vitro, using spontaneously beat ing right atrial preparations (n = 6), by recording the transmembrane potentials of sinoatrial node (SAN) cells before and after injection o f CNP (25 mu g); and 4) by observing the effects of CNP (25 mu g) on c ontractile force of paced isolated right atrial preparations (n = 6). The results indicate that 1) the site of earliest extracellular electr ical activation in the SAN remains mostly unchanged in response to CNP , whereas it shifts to the superior region of the SAN after isoprotere nol and ANG II injections; 2) NPR-A and -B mRNAs are present in atrial and nodal tissues; 3) CNP significantly increases the maximal rate of diastolic depolarization and decreases the action potential duration at 75 and 90% of repolarization; and 4) CNP significantly increases at rial contractile force. These results suggest that CNP modifies cardia c ionic currents to produce positive chronotropic and inotropic effect s by stimulation of NPR-B receptors, located in the SAN region, and th at CNP plays a role in the modulation of cardiac function.