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Important role of endogenous norepinephrine and epinephrine in the development of in vivo pressure-overload cardiac hypertrophy

Antonio Rapacciuolo, MD^*, Giovanni Esposito, MD^*, Kathleen Caron, PhD, Lan Mao, MD^*, Steven A. Thomas, MD, PhD and Howard A. Rockman, MD^*

^* Department of Medicine, Duke University Medical Center, Durham, North Carolina, USA
University of North Carolina at Chapel Hill, Chapel Hill, North Carolina, USA
Department of Pharmacology, University of Pennsylvania, Philadelphia, Pennsylvania, USA

View larger version (23K): [in a new window]   Figure 1 Effect of pressure overload on development of cardiac hypertrophy in control and Dbh–/– mice. (a) The LVW/BW ratio was measured in control and Dbh–/– mice seven days after either a sham operation or TAC. *p < 0.00001 for TAC control group vs. sham operation control group. p < 0.005 for TAC control group vs. TAC Dbh–/– group. p < 0.01 for TAC Dbh–/– group vs. sham operation Dbh–/– group. (b) The LVW/TL ratio was used as an index of the hypertrophic response after TAC. *p < 0.001 for TAC control group vs. either sham operation control group or TAC Dbh–/– group. Sham operation control group (n = 12); TAC control group (n = 13); sham operation Dbh–/– group (n = 13); and TAC Dbh–/– group (n = 11). Data are from the control and Dbh–/– mice with pressure gradients >40 mm Hg.

View larger version (24K): [in a new window]   Figure 2 Relationship between pressure load and induction of cardiac hypertrophy for all banded mice. The index of LV mass (LVW/BW) is plotted against the trans-stenotic systolic pressure gradient produced by TAC for all of the banded control (n = 17, solid circles) and Dbh–/– (n = 17, open circles) animals. Linear regression analysis was significant for the control mice (y = 0.0286x + 2.8325, r = 0.66, p < 0.01 by ANOVA), but not for the Dbh–/– mice (0.0032x + 3.2665, r = 0.20, p = NS). The slopes of the two regression lines were significantly different (p < 0.005) by multivariate ANOVA.

View larger version (31K): [in a new window]   Figure 3 Effect of pressure overload on activation of MAPK pathways. Representative autoradiograms and summary data of MAPK activity for each of the three major pathways are shown. (a) ERK 1/2: *p < 0.0005 for sham operation control group vs. TAC control group. (b) JNK 1/2: *p < 0.0001 for sham operation control group vs. TAC control group. (c) p38: *p < 0.0005 for sham operation control group vs. TAC control group. (d) p38ß: *p < 0.001 for sham operation control group vs. TAC control group. p = NS for sham operation Dbh–/– group vs. TAC Dbh–/– group for the aforementioned MAPKs.

View larger version (28K): [in a new window]   Figure 4 Effect of exogenous administration of norepinephrine (NE) and angiotensin II (Ang II) on activation of the MAPK pathways. Representative autoradiograms for each of the three major MAPK pathways are shown. The increase in ERK and JNK activity in the hearts of Dbh–/– mice after infusion of norepinephrine and angiotensin II was equal to or greater than that of the control hearts.

View larger version (16K): [in a new window]   Figure 5 Role of norepinephrine and epinephrine in regulating activation of the renin-angiotensin system after aortic constriction. The renal renin messenger ribonucleic acid (mRNA) level was significantly increased in the banded control mice compared with the sham-operated mice, but not in the banded Dbh–/– mice. *p < 0.001 for sham operation control group vs. TAC control group; p = NS for sham operation Dbh–/– group vs. TAC Dbh–/– group. Sham operation: n = 6 in control group and n = 4 in Dbh–/– group; TAC: n = 4 in control group and n = 6 in Dbh–/– group.