Negative Inotropic Effects of C-Type Natriuretic Peptide are Attenuated in Hypertrophied Ventricular Myocytes Associated with Reduced Cyclic GMP Production

Abstract

We tested the hypothesis that the negative inotropic effects of C-type natriuretic peptide (CNP) would be diminished in renal hypertensive (one-kidney-one-clip, 1K1C) hypertrophic rabbit hearts and that this attenuated effect would be due either to decreased cyclic GMP production or to reduced signaling. Using isolated control and 1K1C ventricular myocytes, cell shortening data (video edge detection) were collected: (1) at baseline and after CNP 10(-8,-7) M, followed by KT5823 (KT), a cyclic GMP-dependent protein kinase inhibitor; or (2) at baseline, following KT pre-treatment and subsequent CNP 10(-8,-7) M. In addition, cyclic GMP levels were determined by radioimmunoassay at baseline and CNP 10(-7) M. In control myocytes, CNP decreased percent shortening (5.7 +/- 0.4 versus 4.0 +/- 0.4% at 10(-7) M), maximal rate of shortening (58.7 +/- 5.1 versus 45.2 +/- 3.6 microm/sec) and maximal rate of relaxation (57.1 +/- 4.9 versus 44.1 +/- 3.4 microm/sec) in a concentration-dependent manner. These effects were attenuated by subsequent KT administration. CNP failed to produce these negative functional effects in 1K1C myocytes. When pre-treated with KT, CNP had no negative functional effect in either normal and 1K1C myocytes. Basal levels of cyclic GMP were similar in control versus 1K1C myocytes; however, CNP produced a significant rise in cyclic GMP level in control (63.6 +/- 7.8 versus 83.5 +/- 11.3 pmol/10(5) myocytes) but not in 1K1C (49.2 +/- 2.6 versus 52.7 +/- 5.6) myocytes. Thus, CNP acted through the cyclic GMP protein kinase in control myocytes. We conclude that in hypertrophic cardiac myocytes, the decreased effect of CNP was because of decreased production of cyclic GMP.