title: Negative functional effects of natriuretic peptides are attenuated in hypertrophic cardiac myocytes by reduced particulate guanylyl cyclase activity.
abstract: We tested the hypothesis that the negative functional effects of natriuretic peptides would be blunted in thyroxine (T4)-induced hypertrophic cardiac myocytes. We also studied the causes of these changes. Ventricular myocytes were obtained from control (n=8) and T4 (0.5 mg/kg/16 days) treated rabbit hearts (n=7). Cell shortening parameters were studied with a video edge detector. We also determined particulate (pGC) and soluble (sGC) guanylyl cyclase activity and cyclic GMP levels. Myocyte function was examined at baseline and after brain natriuretic peptide (BNP 10(-7,-6) M) or C-type natriuretic peptide (CNP 10(-7,-6) M) or zaprinast (cyclic GMP phosphodiesterase inhibitor 10(-6)M) followed by BNP or CNP. Baseline function was similar in control and T4 myocytes. BNP (5.7 +/- 0.2 to 4.3 +/- 0.1%) and CNP (5.7 +/- 0.4 to 4.2 +/- 0.2%) significantly reduced percent shortening in control myocytes. These reductions were not observed with T4 (BNP, 5.7 +/- 0.6 to 5.6 +/- 0.6; CNP, 5.6 +/- 0.4 to 5.5 +/- 0.5). BNP and CNP responded similarly after zaprinast. Baseline cyclic GMP was similar in control and T4, but BNP only increased cyclic GMP in controls. The activity of pGC was similar at baseline in control and T4, but the stimulated activity was significantly lower in T4 myocytes. Both basal and stimulated sGC activity were similar in control and hypertrophic myocytes. These results demonstrated that the ability of natriuretic peptides to reduce ventricular myocyte function was blunted in T4 hypertrophic myocytes. This blunted response was related to the reduced ability of natriuretic peptides to increase cyclic GMP levels due to a reduced stimulated particulate guanylyl cyclase activity.
authors.affiliation: Heart and Brain Circulation Laboratory, Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 088854-8021, USA.
authors.forename: Mark
authors.initials: M
authors.lastname: Meyer
authors.forename: Qihang
authors.initials: Q
authors.lastname: Zhang
authors.forename: Kiranpreet
authors.initials: K
authors.lastname: Khurana
authors.forename: Peter M
authors.initials: PM
authors.lastname: Scholz
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Weiss
mesh_terms: D015106:3',5'-Cyclic-GMP Phosphodiesterases / Q000037:antagonists & inhibitors; D000818:Animals; D048429:Cell Size / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism; D006162:Guanylate Cyclase / Q000378:metabolism*; D066298:In Vitro Techniques; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000201:enzymology* / Q000648:ultrastructure*; D020097:Natriuretic Peptide, Brain / Q000494:pharmacology; D020098:Natriuretic Peptide, C-Type / Q000494:pharmacology; D045265:Natriuretic Peptides / Q000494:pharmacology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology; D011688:Purinones / Q000494:pharmacology; D011817:Rabbits; D013974:Thyroxine / Q000494:pharmacology
chemical_list: D045265:Natriuretic Peptides; D010726:Phosphodiesterase Inhibitors; D011688:Purinones; D020097:Natriuretic Peptide, Brain; D020098:Natriuretic Peptide, C-Type; D015106:3',5'-Cyclic-GMP Phosphodiesterases; D006162:Guanylate Cyclase; C011145:zaprinast; D006152:Cyclic GMP; D013974:Thyroxine