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Muscarinic and β-adrenergic regulation of heart rate, force of contraction and calcium current is preserved in mice lacking endothelial nitric oxide synthase

Abstract

>Nitric oxide (NO) is an ubiquitous signaling molecule produced from L-arginine by NO synthase (NOS). In the vasculature, NO mediates parasympathetic endothelium-dependent vasodilation. NO may also mediate the parasympathetic control of myocardial function1. This is supported by the observations that NOS3, the endothelial constitutive NOS, is expressed in normal cardiac myocytes from rodents2 and human3, and NOS and/or guanylyl cyclase inhibitors antagonize the effect of muscarinic agonists on heart rate4,5, atrio–ventricular conduction6, contractility2,4,7 and L-type calcium current1,2,5,6. Here we examine the autonomic regulation of the heart in genetically engineered mice deficient in NOS3 (NOS3-KO)(ref. 8). We show that the chronotropic and inotropic responses to both β-adrenergic and muscarinic agonists were unaltered in isolated cardiac tissue preparations from NOS3-KO mice, although these mice have a defective parasympathetic regulation of vascular tone8,9. Similarly, β-adrenergic stimulation and muscarinic inhibition of the calcium current did not differ in cardiac myocytes from NOS3-KO mice and those from wild-type mice. RT–PCR did not demonstrate upregulation of other NOS isoforms. Similarly, Gi/Go proteins and muscarinic receptor density were unaltered. These data refute the idea that NOS3 is obligatory for the normal autonomic control of cardiac muscle function10.

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Figure 1: β-adrenergic and muscarinic chronotropic and inotropic effects.
Figure 2: Regulation of ICa by ISO and CCh in WT and NOS3-KO mouse ventricular myocytes.
Figure 3: RT–PCR analysis of NOS isoforms and muscarinic receptor binding and Gi/Go content in hearts from WT and NOS3-KO mice.

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Acknowledgements

We thank P. Huang for providing the NOS3-KO mice, and M. Nose, J. Starbatty and F. Lefebvre for technical help. This work was supported by a Heisenberg grant of the Deutsche Forschungsgemeinschaft to T.E and by the Association Française contre les Myopathies, the Fondation pour la Recherche Médicale, and the Ministère de la Recherche et de l'Enseignement Supérieur (ACC-SV9).

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Correspondence to Rodolphe Fischmeister.

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Vandecasteele, G., Eschenhagen, T., Scholz, H. et al. Muscarinic and β-adrenergic regulation of heart rate, force of contraction and calcium current is preserved in mice lacking endothelial nitric oxide synthase. Nat Med 5, 331–334 (1999). https://doi.org/10.1038/6553

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