Decreased expression of myocardial eNOS and caveolin in dogs with hypertrophic cardiomyopathy

Because nitric oxide (NO) regulates cardiac and vessel contraction, we compared the expression and activity of the endothelial NO synthase (eNOS) and caveolin, which tonically inhibits eNOS in normal and hypertrophic cardiomyopathic hearts. NOS activity (l-[3H]citrulline formation), eNOS immunostaining, and caveolin abundance were measured in heart tissue of 23 mongrel dogs before and at 3 and 7 wk of perinephritic hypertension (PHT). Hemodynamic parameters in vivo and endothelial NO-dependent relaxation of macro- and coronary microvessels in vitro were assessed in the same animals. eNOS immunostaining and total calcium-dependent NOS activity decreased at 7 wk in all four heart cavities (in left ventricle, from 17.0 ± 1.3 to 0.2 ± 0.2 fmol · min−1 · mg protein−1, P < 0.001). Caveolin-1 and -3 also decreased in PHT dog hearts. Accordingly, basal vascular tone was preserved, but maximal endothelial NO-dependent relaxation was impaired in all vessels from 7-wk PHT dogs. The latter had preserved systolic function but impaired diastolic relaxation [relaxation time constant ( T 1), 25.1 ± 0.9 vs. 22.0 ± 1 ms in controls; P < 0.05]. Peripheral infusion of the NOS inhibitor N G -nitro-l-arginine methyl ester increased mean aortic pressure in both groups and reduced diastolic ( T 1, 31.9 ± 1.4 ms) and systolic function in PHT dogs (DP40, 47.5 ± 2.5 vs. 59.4 ± 3.8 s−1 in control animals). In conclusion, both eNOS and caveolin proteins are decreased in the hypertrophic hearts of PHT dogs. This is associated with altered maximal (but not basal) vascular relaxation and impaired diastolic function. Further degradation of cardiac function after NOS inhibition suggests a critical role of residual NOS activity, probably supported by the concurrent downregulation of caveolin.