Abstract 3631: Mechanism of Natriuretic Peptide (NP) Mediated Pulmonary Vasodilation
Atrial and C-type natriuretic peptides (ANP, CNP) play a role in many vascular beds as vasodilators. ANP binds to natriuretic peptide receptor (NPR) -A and -C, where as CNP binds to NPR-B and NPR-C. NPR-A and -B are particulate guanylate cylase linked receptors, while NPR-C acts a clearance receptor and has been linked to EDHF effects of CNP via Gi protein. The role of NPR-C in NP-mediated pulmonary vasodilation remains unknown. Furthermore the role of endothelium in mediating vasoactive effects of NP is controversial. We sought to elucidate the role of NPR-C and explore the endothelium dependence of the vasodilatory actions of NPs in the pulmonary vasculature. Using isolated ventilated-perfused rat lungs, we monitored pulmonary artery (PA) pressures upon exposure to Angiotensin (Ang) II. We then assessed the vasoconstrictive effects of Ang II on the vascular bed pretreated with ANP, CNP, or the selective NPR-C ligand, cANF. In parallel, isolated PA rings constricted with phenylephrine were used to assess the dose dependent effects of NPs on vessel relaxation in endothelium intact/denuded vessels, or in presence or absence of various inhibitors. Ang II mediated vasoconstriction in isolated perfused lung was attenuated 41± 6% by ANP and 51±3% by CNP, but not cANF. Similarly, where cANF had no significant vasodilatory effect in constricted PA rings, ANP and CNP vasodilated the PA rings 105±17% and 150±9%, respectively. Maximum vasodilatory effect (Rmax) is reported for 1 μM dose of NPs. However, only CNP produced an endothelium-dependent vasodiatory effect (Rmax Intact endothelium: 150±9%, Endothelium denuded: 110±8%; p <0.05). The endothelium dependent vasodilatory effect of CNP was completely abolished by pretreatment with L-NAME, a NO synthase inhibitor, or iberiotoxin, a large-conductance calcium activated potassium channel (BK) blocker. Conversely, pretreatment with a gap-junction inhibitor, 18α-glycyrrhetinic acid, or a cyclooxygenase inhibitor, indomethacin, had no effect on endothelium-dependent vasodiation. NPR-C plays a limited role in NP-mediated pulmonary vasodilation. CNP has endothelial-dependent vasodilatory action, which is mediated by NO and endothelial BK channels.