Modulation of mouse cardiac function in vivo by eNOS and ANP

To study the role of endothelial nitric oxide synthase (eNOS) in cardiac fu nction, we compared eNOS expression, contractility, and relaxation in the l eft ventricles of wild-type and eNOS-deficient mice. eNOS immunostaining is localized to the macro- and microvascular endothelium throughout the myoca rdium in wild-type mice and is absent in eNOS-/- mice. Whereas blood pressu re is elevated in eNOS -/- mice, baseline cardiac contractility (dP/dt(max) ) is similar in wild-type and eNOS-/- mice (9,673 +/- 2,447 and 9,928 +/- 1 ,566 mmHg/s, respectively). The beta-adrenergic agonist isoproterenol (Iso) at doses of greater than or equal to 1 ng causes enhanced increases in dP/ dt(max) in eNOS-/- mice compared with wild-type controls in vivo (P < 0.01) as well as in Langendorff isolated heart preparations (P < 0.02). beta-Adr energic receptor binding (B-max) is not significantly different in the two groups of animals (B-max = 41.4 +/- 9.4 and 36.1 +/- 5.1 fmol/mg for wild-t ype and eNOS-/-). Iso-stimulated ventricular relaxation is also enhanced in the eNOS-/- mice, as measured by dP/dt(min) in the isolated heart. However , baseline ventricular relaxation is normal in eNOS-/- mice (tau = 5.2 +/- 1.0 and 5.6 +/- 1.5 ms for wild-type and eNOS-/-,respectively), whereas it is impaired in wild-type mice after NOS inhibition (tau = 8.3 +/- 2.4 ms), cGMP levels in the left ventricle are unaffected by eNOS gene deletion (wil d-type: 3.1 +/- 0.8 pmol/mg, eNOS-/-: 3.1 +/- 0.6 pmol/mg), leading us to e xamine the level of another physiological regulator of cGMP. Atrial natriur etic peptide (ANP) expression is markedly upregulated in the eNOS-/- mice, and exogenous ANP restores ventricular relaxation in wild-type mice treated with NOS inhibitors. These results suggest that eNOS attenuates both inotr opic and lusitropic responses to beta-adrenergic stimulation, and it also a ppears to regulate baseline ventricular relaxation in conjunction with ANP.