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Cardiovascular Research Center and Cardiology Division, Department of Medicine, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts 02129
To study
the role of endothelial nitric oxide synthase (eNOS) in cardiac
function, we compared eNOS expression, contractility, and relaxation in
the left ventricles of wild-type and eNOS-deficient mice. eNOS
immunostaining is localized to the macro- and microvascular endothelium
throughout the myocardium in wild-type mice and is absent in
eNOS
/ mice. Whereas blood pressure is elevated in eNOS/ mice, baseline cardiac contractility
(dP/dtmax) is similar in wild-type and
eNOS/ mice (9,673 ± 2,447 and 9,928 ± 1,566 mmHg/s,
respectively). The 
-adrenergic agonist isoproterenol (Iso) at doses
of 
1 ng causes enhanced increases in dP/dtmax in
eNOS/ mice compared with wild-type controls in vivo
(P < 0.01) as well as in Langendorff isolated heart
preparations (P < 0.02). -Adrenergic receptor binding
(Bmax) is not significantly different in the two groups of
animals (Bmax = 41.4 ± 9.4 and 36.1 ± 5.1 fmol/mg for
wild-type and eNOS/). Iso-stimulated ventricular
relaxation is also enhanced in the eNOS/ mice, as measured by dP/dtmin in the isolated heart.
However, baseline ventricular relaxation is normal in
eNOS/ mice (
= 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 ( = 8.3 ± 2.4 ms).
cGMP levels in the left ventricle are unaffected by eNOS gene deletion
(wild-type: 3.1 ± 0.8 pmol/mg, eNOS/: 3.1 ± 0.6 pmol/mg), leading us to examine the level of another physiological regulator of cGMP. Atrial natriuretic 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 inotropic
and lusitropic responses to -adrenergic stimulation, and it also
appears to regulate baseline ventricular relaxation in conjunction with ANP.
left ventricle; contractility; diastolic relaxation
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