Natriuretic peptide receptor B signaling in the cardiovascular system: protection from cardiac hypertrophy

Pagel-Langenickel, Ines; Buttgereit, Jens; Bäder, Michael; Langenickel, Thomas

doi:10.1007/s00109-007-0183-4

Cited by 39 publications

(29 citation statements)

References 127 publications

(132 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Here, we report the development of BMN 111, through in vitro and in vivo approaches, which is resistant to degradation by NEP and designed to elicit the growthpromoting effects of native CNP through a subcutaneous route of administration. We also examined the cardiovascular effects of BMN 111, since it is well established that natriuretic peptides, including CNP, induce vasodilation (Clavell et al, 1993;Charles et al, 1995;Igaki et al, 1998;Scotland et al, 2005;Pagel-Langenickel et al, 2007), and then evaluated the growth-potential at doses that were considered hemodynamically acceptable [,10% drop in blood pressure (BP) and ,25% increase in heart rate (HR)] in mice and monkeys. This article focuses on the pharmacological effects of daily subcutaneous administrations of BMN 111 in mice (normal and ACH models) and normal juvenile cynomolgus monkeys.…”

Section: Introductionmentioning

confidence: 99%

Neutral Endopeptidase-Resistant C-Type Natriuretic Peptide Variant Represents a New Therapeutic Approach for Treatment of Fibroblast Growth Factor Receptor 3–Related Dwarfism

Wendt

Dvorak-Ewell

Bullens

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Achondroplasia (ACH), the most common form of human dwarfism, is caused by an activating autosomal dominant mutation in the fibroblast growth factor receptor-3 gene. Genetic overexpression of C-type natriuretic peptide (CNP), a positive regulator of endochondral bone growth, prevents dwarfism in mouse models of ACH. However, administration of exogenous CNP is compromised by its rapid clearance in vivo through receptor-mediated and proteolytic pathways. Using in vitro approaches, we developed modified variants of human CNP, resistant to proteolytic degradation by neutral endopeptidase, that retain the ability to stimulate signaling downstream of the CNP receptor, natriuretic peptide receptor B. The variants tested in vivo demonstrated significantly longer serum half-lives than native CNP. Subcutaneous administration of one of these CNP variants (BMN 111) resulted in correction of the dwarfism phenotype in a mouse model of ACH and overgrowth of the axial and appendicular skeletons in wild-type mice without observable changes in trabecular and cortical bone architecture. Moreover, significant growth plate widening that translated into accelerated bone growth, at hemodynamically tolerable doses, was observed in juvenile cynomolgus monkeys that had received daily subcutaneous administrations of BMN 111. BMN 111 was well tolerated and represents a promising new approach for treatment of patients with ACH.

show abstract

Section: Introductionmentioning

confidence: 99%

Neutral Endopeptidase-Resistant C-Type Natriuretic Peptide Variant Represents a New Therapeutic Approach for Treatment of Fibroblast Growth Factor Receptor 3–Related Dwarfism

Wendt

Dvorak-Ewell

Bullens

et al. 2015

J Pharmacol Exp Ther

View full text Add to dashboard Cite

show abstract

“…The reduction in the systolic load at rest and during exercise in HF is due to the vasodilator effect of CNP, which is mainly attributed to natriuretic peptide effects on cGMP to an activation of a particulate guanylyl cyclase (Wright, et al, 1996). CNP activates the Natriuretic peptide receptor-B (NPR-B) receptor to stimulate the production and release of cGMP (Lumsden et al, 2010;Kuhn, 2015;Pagel-Langenickel et al, 2007). CNP is also able to induce vasorelaxation by hyperpolarization (Barton et al, 1998).…”

Section: Discussionmentioning

confidence: 99%

“…In fact, CNP has been reported variably to have a positive inotropic effect (Hirose, et al, 1998;Wollert et al, 2003;Pagel-Langenickel et al, 2007;Zhou et al, 2009), a negative inotropic effect (Qvigstad et al, 2010;Moltzau et al, 2013Moltzau et al, , 2014a, or biphasic (Pagel-Langenickel et al, 2007) inotropic effects on LV contractile performance. These disparate observations may be due to the confounding effects of anesthesia, open-chest surgery, tissue preparations, loading conditions, species differences, and the dosages of CNP used.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

C-Type Natriuretic Peptide Improves Left Ventricular Functional Performance at Rest and Restores Normal Exercise Responses after Heart Failure

Cheng

Ohte

et al. 2016

Journal of Pharmacology and Experimental Therapeutics

View full text Add to dashboard Cite

In heart failure (HF), the impaired left ventricular (LV) arterial coupling and diastolic dysfunction present at rest are exacerbated during exercise. C-type natriuretic peptide (CNP) is elevated in HF; however, its functional effects are unclear. We tested the hypotheses that CNP with vasodilating, natriuretic, and positive inotropic and lusitropic actions may prevent this abnormal exercise response after HF. We determined the effects of CNP (2 mg/kg plus 0.4 mg/kg per minute, i.v., 20 minutes) on plasma levels of cGMP before and after HF and assessed LV dynamics during exercise in 10 chronically instrumented dogs with pacing-induced HF. Compared with the levels before HF, CNP infusion caused significantly greater increases in cGMP levels after HF. After HF, at rest, CNP administration significantly reduced LV end-systolic pressure (P ES ), arterial elastance (E A ), and end-diastolic pressure. The peak mitral flow (dV/dt max ) was also increased owing to decreased minimum LVP (LVP min ) and the time constant of LV relaxation (t) (P , 0.05). In addition, LV contractility (E ES ) was increased. The LV-arterial coupling (E ES /E A ) was improved. The beneficial effects persisted during exercise. Compared with exercise in HF preparation, treatment with CNP caused significantly less important increases in P ES but significantly decreased t (34.2 vs. 42.6 ms) and minimum left ventricular pressure with further augmented dV/dt max . Both E ES , E ES /E A (0.87 vs. 0.32) were increased. LV mechanical efficiency improved from 0.38 to 0.57 (P , 0.05). After HF, exogenous CNP produces arterial vasodilatation and augments LV contraction, relaxation, diastolic filling, and LV arterial coupling, thus improving LV performance at rest and restoring normal exercise responses after HF.

show abstract

“…Once considered primarily a regulator of vascular smooth muscle proliferation (Suga et al 1992), more recent work shows that the hormone is intimately involved in skeletal growth, is nutrition dependent (Prickett et al 2007a), and participates in maintaining foetal-maternal welfare (Prickett et al 2007b). CNP also appears to have a cardioprotective role by inhibiting ventricular remodelling after cardiac injury (Pagel-Langenickel et al 2007). Knowledge that CNP synthesis (outside the reproductive system) is E 2 -sensitive opens up prospects of important new roles within the skeleton and other tissues which now need to be strongly pursued.…”

Section: Discussionmentioning

confidence: 99%

Effect of sex steroids on plasma C-type natriuretic peptide forms: stimulation by oestradiol in lambs and adult sheep

Prickett¹,

Barrell²,

Wellby³

et al. 2008

Journal of Endocrinology

View full text Add to dashboard Cite

Although C-type natriuretic peptide (CNP) is crucial to postnatal endochondral growth, roles for the hormone in pubertal bone growth and the physiological effects of sex steroid substitution on CNP synthesis are not known. Using a plasma marker of CNP tissue synthesis (amino-terminal proCNP, NTproCNP), we have studied the effect of exogenous oestrogen (E 2 ) or testosterone (T) on plasma CNP forms and bone alkaline phosphatase (bALP) in pre-pubertal lambs.Responses to E 2 in non-cycling adult ewes were also studied. In 15-week-old intact ewe lambs, E 2 promptly increased plasma NTproCNP and CNP (P!0 . 001) to peak on day 2, and bALP (P!0 . 001 peaking on day 7), whereas no significant stimulation in response to T was observed in male lambs. Linear bone growth and live weight were unaffected. In adult anoestrous ewes, basal concentrations of CNP forms and bALP were lower than in ewe lambs, in keeping with skeletal maturity, but adults responded similarly to E 2 . Prompt and sustained increases in NTproCNP and CNP, and a later threefold rise in bALP (all P!0 . 001), were induced by E 2 . Possible contributions to these increases in plasma CNP forms by reproductive tissues (a known site of E 2 -induced CNP expression) were excluded by showing similar E 2 -induced CNP responses in adult ewes after surgical removal of reproductive tissues. These results are the first to show that E 2 stimulates plasma CNP forms and bALP in lambs and adult sheep and raise the possibility that CNP also participates in bone formation in the mature skeleton.

show abstract

Natriuretic peptide receptor B signaling in the cardiovascular system: protection from cardiac hypertrophy

Cited by 39 publications

References 127 publications

Neutral Endopeptidase-Resistant C-Type Natriuretic Peptide Variant Represents a New Therapeutic Approach for Treatment of Fibroblast Growth Factor Receptor 3–Related Dwarfism

Neutral Endopeptidase-Resistant C-Type Natriuretic Peptide Variant Represents a New Therapeutic Approach for Treatment of Fibroblast Growth Factor Receptor 3–Related Dwarfism

C-Type Natriuretic Peptide Improves Left Ventricular Functional Performance at Rest and Restores Normal Exercise Responses after Heart Failure

Effect of sex steroids on plasma C-type natriuretic peptide forms: stimulation by oestradiol in lambs and adult sheep

Contact Info

Product

Resources

About