C-type natriuretic peptide has a negative inotropic effect on cardiac myocytes

Nir, Amiram; Zhang, Dong Fang; Fixler, Ruhama; Burnett, John C.; Eilam, Y.; Hasin, Yonathan

doi:10.1016/s0014-2999(00)00927-4

Cited by 34 publications

(27 citation statements)

References 21 publications

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“…Natriuretic peptides have been reported to have diverse effects on cardiac function in different models [13,21]. Our current data demonstrating functional decrements were consistent with other reports [28,29]. After chronic nitroglycerin administration, these effects of natriuretic peptides and nitric oxide were greatly reduced.…”

Section: Discussionsupporting

confidence: 92%

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes

Tan¹,

Zhang²,

Anyadike³

et al. 2007

Pharmacological Research

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Abstractexposure to nitrates causes tachyphylaxis to nitric oxide (NO), which reduces the effects of the second messenger cyclic GMP. We tested the hypothesis that prolonged exposure to NO would also blunt the effects of natriuretic peptides. Cardiac myocytes were isolated from control (N=7) and chronic nitroglycerin (patched, N=7) rabbits. Patched animals received a transdermal nitroglycerin patch (0.3 mg/hr for 5 days). Myocyte function was determined at baseline, after CNP (C-type natriuretic peptide, 10 −8 and 10 −7 M) or BNP (Brain natriuretic peptide, 10 −8 and 10 −7 M) or SNAP (S-nitroso-N-acetyl-penicilliamine, a NO donor, 10 −6 and 10 −5 M) followed by KT5823 (a cyclic GMP protein kinase inhibitor, 10 −6 M). Soluble and particulate guanylyl cyclase activities were measured in vitro and phosphoprotein analysis was performed. In control animals, CNP 10 −8 M (5.14±0.5%) and 10 −7 M (4.4±0.7%) significantly reduced percentage shortening from baseline (6.1±1.6%). KT5823 restored percentage shortening to 4.9±0.8%. Similar data were obtained with BNP and SNAP. In patched animals, CNP, BNP, SNAP had no significant effects on percentage shortening. The data on maximal rate of shortening and relaxation were consistent with these results. Guanylyl cyclase activities were not different in the control and patched animals. The myocytes from control and patched animals had similar protein phosphorylation patterns. Our data suggested that in addition to NO, the responses to both natriuretic peptides were downregulated after chronic exposure to nitroglycerin, but these effects were not due to changes in either guanylyl cyclase or cyclic GMP protein kinase, suggesting an altered downstream pathway.

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Section: Discussionsupporting

confidence: 92%

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes

Tan¹,

Zhang²,

Anyadike³

et al. 2007

Pharmacological Research

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“…CNP modulates the growth, proliferation, and hypertrophy of smooth muscle cells, cardiomyocytes and fibroblasts [31][32][33], and cGMP is implicated in all of these studies when CNP binds to its receptor NPRB. Additionally, our data on increased cGMP in the hearts of CNP-transgenic mice is congruent with findings in isolated rat and rabbit cardiomyocytes generating cGMP after CNP stimulation [34,35].…”

Section: Discussionsupporting

confidence: 89%

Cardiomyocyte‐restricted over‐expression of C‐type natriuretic peptide prevents cardiac hypertrophy induced by myocardial infarction in mice

Wang

Waard

Sterner-Kock

et al. 2007

European J of Heart Fail

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Objective: Infused C-type natriuretic peptide (CNP) was recently found to play a cardioprotective role in preventing myocardial ischaemia/ reperfusion (I/R) injury and improving cardiac remodelling after myocardial infarction (MI) in rats. Our study aimed to investigate the effect of cardiomyocyte-specific CNP over-expression on I/R injury and MI in transgenic mice. Methods and results:We generated transgenic (TG) mice over-expressing CNP in cardiomyocytes. Elevated CNP expression on RNA and protein levels was demonstrated by RNase-protection assay and radioimmunoassay. Male TG mice and age-matched wild-type (WT) littermates were subjected to 1-hour global myocardial ischaemia and 23 h of reperfusion or permanent ligation of the coronary artery for 3 weeks.Infarct size did not differ between the WT and TG groups in mice subjected to I/R. In mice that underwent permanent ligation of coronary arteries, both left and right ventricular hypertrophy were prevented by CNP over-expression 3 weeks post-MI. Histological analysis revealed less necrosis, muscular degeneration and inflammation in infarcted TG mice. Impairment of cardiac function was less pronounced in transgenic animals than in the wild-type controls. Conclusions: Over-expression of CNP in cardiomyocytes does not affect I/R-induced infarct size but prevents cardiac hypertrophy induced by MI. Therefore, CNP may represent a potent therapeutic target for the treatment of patients with cardiac hypertrophy induced by myocardial infarction or other aetiology.

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“…CNP stimulation of mouse myocardium has been shown to produce positive inotropic responses and increase Ca 2+ transients (Wollert et al, 2003), whereas in another study in rats it induced a NIR but the Ca 2+ transients were unaltered (Nir et al, 2001). Further, similar to our results, CNP was shown to induce an initial increase in contractility followed by a slowly developing NIR in mice (Pierkes et al, 2002).…”

Section: Both Negative and Positive Inotropic Effects Of Cnp?mentioning

confidence: 98%

“…CNP has been reported to cause both positive (Beaulieu et al, 1997;Hirose et al, 1998;Wollert et al, 2003) and negative inotropic responses (NIR) (Brusq et al, 1999;Nir et al, 2001;Pierkes et al, 2002;Su et al, 2005;Zhang et al, 2005a) in normal hearts, as well as positive lusitropic responses (LR) in normal rat and mouse hearts (Brusq et al, 1999;Pierkes et al, 2002). In a previous study, we showed that cGMP generated by NPR-B increases β1-adrenoceptor-mediated positive inotropic responses through inhibition of PDE3, and also found that stimulation of NPR-B alone (by CNP) in failing rat hearts induced a NIR (Qvigstad et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

SERCA2 activity is involved in the CNP‐mediated functional responses in failing rat myocardium

Moltzau

Aronsen

Meier

et al. 2013

British J Pharmacology

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Background and Purposes Myocardial C‐type natriuretic peptide (CNP) levels are increased in heart failure. CNP can induce negative inotropic (NIR) and positive lusitropic responses (LR) in normal hearts, but its effects in failing hearts are not known. We studied the mechanism of CNP‐induced NIR and LR in failing hearts and determined whether sarcoplasmatic reticulum Ca2+ ATPase2 (SERCA2) activity is essential for these responses. Experimental Approach Contractility, cGMP levels, Ca2+ transient amplitudes and protein phosphorylation were measured in left ventricular muscle strips or ventricular cardiomyocytes from failing hearts of Wistar rats 6 weeks after myocardial infarction. Key Results CNP increased cGMP levels, evoked a NIR and LR in muscle strips, and caused phospholamban (PLB) Ser16 and troponin I (TnI) Ser23/24 phosphorylation in cardiomyocytes. Both the NIR and LR induced by CNP were reduced in the presence of a PKG blocker/cGMP analogue (Rp‐8‐Br‐Pet‐cGMPS) and the SERCA inhibitor thapsigargin. CNP increased the amplitude of the Ca2+ transient and increased SERCA2 activity in cardiomyocytes. The CNP‐elicited NIR and LR were not affected by the L‐type Ca2+ channel activator BAY‐K8644, but were abolished in the presence of isoprenaline (induces maximal activation of cAMP pathway). This suggests that phosphorylation of PLB and TnI by CNP causes both a NIR and LR. The NIR to CNP in mouse heart was abolished 8 weeks after cardiomyocyte‐specific inactivation of the SERCA2 gene. Conclusions and Implications We conclude that CNP‐induced PLB and TnI phosphorylation by PKG in concert mediate both a predictable LR as well as the less expected NIR in failing hearts.

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C-type natriuretic peptide has a negative inotropic effect on cardiac myocytes

Cited by 34 publications

References 21 publications

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes

Chronic nitrates blunt the effects of not only nitric oxide but also natriuretic peptides in cardiac myocytes

Cardiomyocyte‐restricted over‐expression of C‐type natriuretic peptide prevents cardiac hypertrophy induced by myocardial infarction in mice

SERCA2 activity is involved in the CNP‐mediated functional responses in failing rat myocardium

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