Alterations in ventricular myocyte contraction caused by C-type natriuretic peptide and nitric oxide in eNOS-/- mice

TY - JOUR

T1 - Alterations in ventricular myocyte contraction caused by C-type natriuretic peptide and nitric oxide in eNOS-/- mice

AU - Su, Jun

AU - Tse, James

AU - Scholz, Peter M.

AU - Weiss, Harvey R.

N1 - Funding Information: The study was supported, in part, by NIH grant HL 40320.

PY - 2005/12

Y1 - 2005/12

N2 - Lack of endothelial nitric oxide synthase (eNOS) may affect the sensitivity of cyclic GMP signaling through soluble guanylyl cyclase (sGC). We hypothesized that in eNOS knockout (eNOS-/-) mice, stimulation of guanylyl cyclase would have enhanced effects inhibiting cardiac contraction. We measured cell shortening and calcium transients in isolated ventricular myocytes from adult eNOS-/- and wild-type (WT) mice after stimulating particulate guanylyl cyclase (pGC) with C-type natriuretic peptide (CNP, 10-8 and 10 -7:M) or sGC with S-nitroso-N-acetyl-penicillamine (SNAP, NO donor, 10-6 and 10-5:M). Although sGC activity was increased by +71% in eNOS-/-, SNAP had similar effects in the two groups (%shortening -39% control vs. -37% eNOS-/-), suggesting that the cyclic GMP pathway was desensitized in eNOS-/- myocytes. CNP had significantly smaller effects on cell contraction (%shortening -34% control vs. -14% eNOS-/-) and pGC activity was not changed in eNOS-/- myocytes. Similar effects were also produced by guanylin and carbon monoxide, stimulators of pGC and sGC. CNP's effects on Ca2+ transients were also attenuated in eNOS-/- myocytes. SNAP did not alter Ca 2+ transients in eNOS-/- or control cells. In the eNOS-/- mice, cyclic GMP-dependent protein kinase and cyclic AMP phosphodiesterase activity were reduced. This study demonstrated that the downstream cyclic GMP pathway was attenuated in eNOS-/- mice and this was partially compensated for by increased sGC, but not pGC activity in ventricular myocytes.

AB - Lack of endothelial nitric oxide synthase (eNOS) may affect the sensitivity of cyclic GMP signaling through soluble guanylyl cyclase (sGC). We hypothesized that in eNOS knockout (eNOS-/-) mice, stimulation of guanylyl cyclase would have enhanced effects inhibiting cardiac contraction. We measured cell shortening and calcium transients in isolated ventricular myocytes from adult eNOS-/- and wild-type (WT) mice after stimulating particulate guanylyl cyclase (pGC) with C-type natriuretic peptide (CNP, 10-8 and 10 -7:M) or sGC with S-nitroso-N-acetyl-penicillamine (SNAP, NO donor, 10-6 and 10-5:M). Although sGC activity was increased by +71% in eNOS-/-, SNAP had similar effects in the two groups (%shortening -39% control vs. -37% eNOS-/-), suggesting that the cyclic GMP pathway was desensitized in eNOS-/- myocytes. CNP had significantly smaller effects on cell contraction (%shortening -34% control vs. -14% eNOS-/-) and pGC activity was not changed in eNOS-/- myocytes. Similar effects were also produced by guanylin and carbon monoxide, stimulators of pGC and sGC. CNP's effects on Ca2+ transients were also attenuated in eNOS-/- myocytes. SNAP did not alter Ca 2+ transients in eNOS-/- or control cells. In the eNOS-/- mice, cyclic GMP-dependent protein kinase and cyclic AMP phosphodiesterase activity were reduced. This study demonstrated that the downstream cyclic GMP pathway was attenuated in eNOS-/- mice and this was partially compensated for by increased sGC, but not pGC activity in ventricular myocytes.

KW - Calcium transients

KW - Cardiac myocyte function

KW - Cyclic GMP affected cyclic AMP phosphodiesterases

KW - Cyclic GMP protein kinase

UR - https://www.scopus.com/pages/publications/27644509746

UR - https://www.scopus.com/pages/publications/27644509746#tab=citedBy

U2 - 10.1016/j.yjmcc.2005.08.008

DO - 10.1016/j.yjmcc.2005.08.008

M3 - Article

C2 - 16236310

SN - 0022-2828

VL - 39

SP - 920

EP - 928

JO - Journal of Molecular and Cellular Cardiology

JF - Journal of Molecular and Cellular Cardiology

IS - 6

ER -