Laizure, Casey

Parker, Robert B.

Ryan Yates, C.

Elsevier - Publisher Connector 

Altered aldosterone disposition in P-Glycoprotein knockout mice 

JACC March 19,2003 ABSTRACTS - Cardiac Function and Heart Failure 203A 
POSTER SESSION 
1183 Myocardial Function: Basic 
OXPHOS is abnormal in these patients. 
Patients and methods: Eleven patients with severe CHF underwent skeletal muscle 
biopsy. Protem content (mglg wet weight), citrate synthase activity (CS, I” mU/mg pro- 
tein) and mi&hondrial complex I to IV activity (Cl to IV) were measured in the biopsy 
samoles and compared with values obtained in a control aroup free of heart and muscle 
Tuesday, April 01, 2003, Noon-2:00 p.m. 
McCormick Place, Hall A 
Presentation Hour: 1:OO p.m.-2:OO p.m. 
_ 
disease. To correct for a possible difference in number of mitochondria, Cl to IV activities 
were expressed as percentages of CS activity. Statistical significance level was set at 
0.05. 
Results: As shown in the Table, protein content, CII actwity and Clll activity were signifi- 
cantly lower in CHF (data given as mean * standard deviation). 
1183-62 Altered Aldosterone Disposition in P-Glycoprotein 
Knockout Mice 
Robert B. Parker, C. Ryan Yates. S. Casey Laizure, University of Tennessee, Memphis, 
TN 
Background: Elevated aldosterone concentrations play an important role in heart failure 
pathogenesis affecting the heart, kidneys, and brain. P-glycoprotein (P-gp), a cell mem- 
brane efflux pump expressed by the human MDRI gene, actively secretes aldosrerone 
from the adrenal cortex. P-gp is also expressed on the apical surface of aldosterone tar- 
get tissues including the brain and heart. where it impedes cellular substrate uptake. In 
this study we compared the plasma and tissue distribution of aldosterone in wild-type 
(WT) and P-gp knockout (KO) mice. 
Methods: Adult male P-gp KO and genetically matched WT mice received 1.0 Gi i.v. 
[3H]-aldosterone. Groups of 3-4 mice were sacrificed at various times after aldosterone 
injection. Plasma, brain, and heart samples were collected and assayed for plasma and 
tissue radioactivity. 
Results: Compared to Wl mice, [3H]-aldosterone activity [disintegrations per min (dpm)] 
in plasma and brain was higher in KO mice (data 45 minutes after injection shown in 
table). Area under the curve (AUC,.,, m,n ) for plasma (1.6 x 106vs 2.9 x I@ dpm-mini 
ml), brain (6.1 x lo5 YS 1.6 x I@ dpm-min/g), and heart (2.0 x Id vs 3.2 x 106dpm*min/ 
g) was also higher in KO mice. 
WT mice KO mice p value 
Plasma (dpm/ml) 25915+1761 32145~3705 0.02 
Brain (dpm/g) 10789*2363 20092*1543 0.001 
Brain/Plasma 0.42 zt 0.10 0.63 * 0.11 0.03 
Heart (dpmIg) 30772 f 9246 31647*6361 NS 
Heart/Plasma 1.09 * 0.25 0.69 f 0.10 NS 
Mean f SD 
Conclusion: P-gp enhances aldosterone plasma clearance and limits its braln uptake. 
Overall exposure (AU&,, minS ) to aldosterone I” plasma and tissues is increased in the 
absence of P-gp. P-gp may play an important role in aldostarone tissue accumulation 
and activity. 
1183-63 Glu298Asp Variant of the Endothelial Nitric Oxide 
Synthase Gene in Patients With Left Ventricular 
Dysfunction 
Maria Giovanna Colombo, Mana Grazia Andreassi, Nicoletta Botto, Serena Masetti, 
Sam&ha Manfredi. Umberto Paradossi. Andrea Biaoini. CNR. Institute of Clinical 
Physiology, G. Pasqulnucci Hospital, Massa, Italy 
Background. An early reduction of exercise capacity after endothelial NO Synthase 
(eNOS) inhibition has been recently reported. Moreover, ventricular dysfunction and 
remodeling after myocardial infarction have been shown to be markedly increased in 
eNOS-deficient as compared to wild-type mice. Therefore, functionally important variants 
of eNOS could influence lefi ventricular (LV) systolic performance. 
Objective. To assess whether the Glu296Asp polymorphism (G694T) of the eNOS gene 
is associated with the occurrence of LV systolic dysfunction. 
Methods. We performed PCRlrestriction fragment length polymorphism analysis to 
detect the missense Glu296Asp vanant in exon 7 of the eNOS gene in 73 patients with 
LV dysfunction (LV ejection fraction ~40% assessed by echocardiography) consecutively 
admitted to our institute and 67 control subjects free of cardiovascular disease. Causes 
of LV dysfunction included coronary ariery disease (n=49), valvular (n=l4) and idiopatic 
(ll=lO). 
Results. The frequencies of the eNOS GluIGlu, GluiAsp and Asp/Asp genotypes in the 
oatients’ orouo were sionificantlv different from those of controls (45.2%. 34.2% and _ _ _ 
20.6% vs 35.6%. 55.2% and 9.2%, respectively; c2=8.278, p=O.O16). In comparison to 
Glu296 carriers, homozygosity for Asp296 was associated with an Odds Ratio of 2.5 
(95% Cl, 1 .Ol to 6.43, p = 0.04) for LV dysfunction. 
Conclusions. The Glu296Asp polymorphism of the eNOS gene is associated with the 
occurence of LV systolic dysfunction suggesting that this genetic variant could be 
involved in the pathogen&s of heart failure. 
1183-64 Abnormal Skeletal Muscle Mitochondrial Oxidative 
Phosphorylation in Severe Chronic Heart Failure 
Conclusion: Both OXPHOS and protein content are abnormal in skeletal muscle of 
patients with severe CHF. The lower CII and Clll activities could be related to oxidative 
stress. The low protein content reflects malnutrition. 
Protein content 
cs 
CVCS ratio 
cwcs ratio 
CIIUCS ratio 
CIWCS ratio 
CHF (n=l 1) Control (n=20) P 
109*31 166+32 <O.OOl 
177+94 135+40 NS 
17+6% 21 *6% NS 
16r3% 21 *6% 0.016 
48*35% 101 * 39 % 0.001 
106 *33 % 106+30% NS 
1183-65 Mitotic Cell Death as a Result of Cell Cycle Re-Entry Is a 
Unique Option for Senescent Cardiomyocytes in 
Addition to Apoptosis and Mitosis 
Hiroaki Shimomura Fumio Terasaki, Tetsuya Hayashi, Yasushl Kitaura, Masanori 
Hosokawa, Osaka Medw College, Takatsuki, Japan, Kyoto University. Kyoto, Japan 
Background: It is believed that cardiomyocytes loose potential for proliferation after birth 
and stay at the GO phase. However, binucleation of cardiomyocytes increases during 
aging, which possibly results from cell cycle w-entry and mitosis. Cell cycle reentry may 
play one of key roles in myocardlal remodeling during aging. Methods: To clarify the 
possibility of cell cycle re-entry and related morphological alterations in aging cardlomyo- 
cytes. we studied young (7 week-old) and old (90 week-old) mouse hearts both immuno- 
histochemically and ultrastructurally. All data were quantitatively evaluated by the 
percentage index. Results: lmmunohistochemically, Ki-67-positive nuclei were 6.07% in 
young mice and 9.68% in old mice (p<O.OOl). Ultrastructurally, m&phase mitotic nuclei 
were observed in a few cardiomyocytes of old mice, where nuclear envelopes had disap- 
peared and nuclear chromatin was compacted as segments of homogenous electron- 
dense mass. In some mitotic cardiomyocytes, cytoplasm was severely degenerated with 
disorganized intracellular organelles and cytoplasmic vacuolization. but plasma mem- 
brane was well preserved. The mitotic cardiomyocytes with cytoplasmic degeneration 
seemed to undergo mitotic cell death. Apoptotlc nuclei were also observed in aging 
heart, where nuclear chromatin was condensed and marginated beneath the well-pre- 
served nuclear membrane. In old mice, each index was 0.22% in mitosis, 0.15% in apop- 
tosis and 0.07% in mltotlc cell death. All indexes were 0% in young mice. In aging heart, 
potential of cell cycle reentry may be amplified in cardiomyocytes. It is possible that, as 
the result of cell cycle reentry, myocardial cell death also occur in the mitotic phase. 
Conclusion: We conclude that cardiomyocyles in agirlg heart potentially w-enter cell 
cycle, and apoptosis, mitotic cell death and mitotic nuclear division are the options for 
cardiomyocytes having reentered the cell cycle in aging heart. However, it is not clear 
whether mitotic cell death is a part of apoptosis or is another distinct form of myocardial 
cell death. 
1183-66 Upregulation of eNOS Contributes to the Control of 
Myocardial Oxygen Consumption During Pregnancy in 
the Dog 
Jeffrev G. William& Fabio Recchia, AxeI Linke, Gautam Churla, John McClung, Thomas 
H. Hintze. New York Medical College, Valhalla, NY 
Pregnancy is associated with an increase in eNOS and NO production in almost all vas- 
cular beds in the mother. however the potential role of eNOS to regulate myocardial oxy- 
gen consumption during this high cardiac output state has not been addressed. 
Echocardiography was performed at 40, 50. and 60 days in awake pregnant dogs and 
the heart harvested for measurement of: 1) eNOS and 2) the ability of drugs that stimu- 
late NO production to regulate myocardial oxygen uptake. Stroke volume (34 * 1 to 36 f 
1 ml), heart rate (70 r 5 to 96 + 4 b/min) and cardiac output (2.3 * 1 to 3.6 f .2 Umin) 
increased from control to 60 days whereas ejection fraction did not change (63 to 66%). 
LV mass increased from 72 -t 2 to 90 f 4 grams. ENOS protein increased by 179%. 
Bradykinin, ramaprilat and amlodipine all reduced myocardial oxygen consumption in 
normal heart (maximum of 22, 22, and 21%) and this was enhanced during pregnancy 
(27.30 and 26%, ~~0.05). The NO donor SNAP reduced oxygen consumption by a simi- 
lar amount in both normal and pregnant dogs (30%). All of these changes reversed post 
partum. Thus there is an upregulation of eNOS during pregnancy at a time where cardiac 
Pascal Vantrimpont, Kees Schoonderwoerd, Gerard De Jong. Jasper Scholte, Aggie output is chronically increased and this is associated with enhanced NO dependent con- 
Balk, Maarten Simoons, Erasmus Medrcal Center. Rotterdam, The Netherlands trol of myocardial oxygen consumption. 
Background: Skeletal muscle dysfunction plays an important role in the exercise intoler- 
ance of chronic heart failure (CHF) and several mechanisms have been invoked to 
explain it. However, little is known about the mitochondrial oxidative phosphorylation 
(OXPHOS) of skeletal muscle in CHF patients. We hypothesized that skeletal muscle 


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Altered aldosterone disposition in P-Glycoprotein knockout mice

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