The Guanylyl Cyclase-deficient Mouse Defines Differential Pathways of Natriuretic Peptide Signaling

Abstract

A genetic model of salt-resistant hypertension has been developed recently through disruption of the guanylyl cyclase-A (GC-A) natriuretic peptide receptor gene (Lopez, M. J., Wong, S. K., Kishimoto, I., Dubois, S., Mach, V., Friesen, J., Garbers, D. L., and Beuve, A. (1995) Nature 378, 65-68). These genetically altered mice were used to determine which of the natural peptides with natriuretic peptide-like structures regulate blood pressure through the GC-A receptor. Atrial natriuretic peptide (ANP) or B-type natriuretic peptide (BNP) half-maximally relaxed precontracted aortic rings in wild-type mice at about 24 nM, but failed to relax such aortas in GC-A null mice, even at micromolar concentrations. Ctype natriuretic peptide (CNP), in contrast, caused halfmaximal relaxation at concentrations of 335 and 146 nM in aortas from either wild-type or null mice, respectively, suggesting that this peptide acted through a receptor other than GC-A. Since the in vitro results with aortic smooth muscle do not necessarily reflect the physiology of the smaller blood vessels important in blood pressure regulation, the blood pressures of conscious mice infused with the various peptides were determined. ANP caused decreases in blood pressure when infused at rates of 500 ng/kg/min, a rate which resulted in a plasma concentration of 0.8 nM. In the null mice, in contrast, ANP failed to lower blood pressure even at infusion rates of 50 g/kg/min. Much higher infusion rates for CNP (50 g/kg/min), which yielded final plasma concentrations of 18.3 nM, were required to lower blood pressure in wild-type mice, but the effects of CNP were not altered in GC-A null mice. Thus, two natriuretic peptides (ANP, BNP) act through GC-A whereas another (CNP) acts through another receptor to regulate blood pressure.

Increased Sensitivity to Endothelial Nitric Oxide (NO) Contributes to Arterial Normotension in Mice with Vascular Smooth Muscle-selective Deletion of the Atrial Natriuretic Peptide (ANP) Receptor

“…The EC 50 for CNP was 93.2 Ϯ 19 nM in floxed GC-A and 136 Ϯ 23 nM in SMC GC-A KO mice, and for 8p-CPT-cGMP, it was 33.7 Ϯ 13 M versus 32.6 Ϯ 6.6 M (no significant difference). The lower potency of CNP relative to that of ANP is similar to previous reports (25).…”

“…We cannot exclude that the CNP/GC-B system was up-regulated at the level of the local, endothelial synthesis and/or secretion of CNP (11). However, we and others have shown previously that the potency of CNP for vasodilation or reduction of blood pressure is much lower as compared with ANP (2,25,27). Even more, CNPdeficient mice do not exhibit arterial hypertension (28).…”

“…Floxed GC-A mice (n ϭ 10) and SMC GC-A KO littermates (n ϭ 9) were treated with the inhibitor of NO synthase, L-NAME (ϳ100 mg/kg/day), via drinking water for 21 days according to published studies (24). Arterial blood pressure and heart rate were measured in conscious mice by tail-cuff plethysmography (Softron, Tokyo) as described previously (17,25), before and during oral L-NAME treatment.…”

Regulation of C-type natriuretic peptide expression

“…The founding member of the family, ANP, discovered in the rat atrium and found to possess profound natriuretic properties by de Bold in 1981 [19], is now known to play an important role in maintaining cardiovascular and fluid homeostasis [48]. BNP, synthesized primarily in the heart, not the brain, has similar actions.…”

“…Since CNP action is predominantly paracrine rather than endocrine, however, it has not been shown to have the same systemic effect as ANP in lowering blood pressure [48], and is likely to play a role in local (e.g. coronary circulation, or microcirculation) rather than systemic control of blood flow [3].…”