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

Nitric oxide (NO) is an ubiquitous signaling molecule produced from L-argin ine by NO synthase (NOS). In the Vasculature, NO mediates parasympathetic e ndothelium-dependent vasodilation. NO may also mediate the parasympathetic control of myocardial function(1). This is supported by the observations th at NOS3, the endothelial constitutive NOS, is expressed in normal cardiac m yocytes from rodents(2) and human(3), and NOS and/or guanylyl cyclase inhib itors antagonize the effect of muscarinic agonists on heart rate(4,5), atri o-ventricular conduction(6), contractility(2,4,7) and L-type calcium curren t(1,2,5,6). Here we examine the autonomic regulation of the heart in geneti cally engineered mice deficient in NOS3 (NOS3-KO)(ref. 8). We show that the chronotropic and inotropic responses to both beta-adrenergic and muscarini c agonists were unaltered in isolated cardiac tissue preparations from NOS3 -KO mice, although these mice have a defective parasympathetic regulation o f Vascular tone(8,9). Similarly, beta-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 upre gulation of other NOS isoforms. Similarly, G(i)/G(o) proteins and muscarini c receptor density were unaltered. These data refute the idea that NOS3 is obligatory for the normal autonomic control of cardiac muscle function(10).