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1 New York Medical College, Department of Physiology, Valhalla, New York 10595
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ABSTRACT |
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 TOP
 ABSTRACT
 INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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We assessed whether pregnancy results in
enhanced nitric oxide (NO)-mediated control of myocardial oxygen
consumption. Rats were studied before (C), at 1 wk (1w) or 2 wk (2w) of
pregnancy, and at 4 days after giving birth (
4d). Left ventricular
endothelial NO synthase (eNOS) protein expression was determined by
immunoblotting. Oxygen consumption of left ventricular tissue samples
was measured in vitro in response to increasing doses of bradykinin
with or without addition of the NOS inhibitor
NG-nitro-L-arginine methyl
ester (L-NAME). Echocardiography indicated an increased
cardiac output during pregnancy. Myocardial eNOS protein expression
significantly increased by 46 ± 9 and 39 ± 8% at 1w and
2w, respectively, and returned to control levels at 4d. Bradykinin
(10
4 M) decreased cardiac oxygen consumption in a
NO-dependent manner by 17 ± 2% at C, by 21 ± 2% at 1w, by
24 ± 2% at 2w (P < 0.05 vs. C and 4d), and by
18 ± 1% at 4d. Myocardial eNOS protein expression is
transiently increased during pregnancy in rats, and this increase is
associated with enhanced NO-dependent control of myocardial oxygen
consumption at a time when cardiac output is increased.
nitric oxide; heart; cardiac output
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INTRODUCTION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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PREGNANCY, A CHRONIC volume overload (14) state, is associated with peripheral arterial vasodilation (26) leading to a reduction in systemic and pulmonary vascular resistance (7, 25, 26) and a decrease in mean arterial blood pressure (4). Furthermore, cardiac output is increased (20) due to an acceleration of heart rate (3, 7), an enhanced myocardial performance (10), and the reduction in peripheral vascular resistance (4) resulting in an elevated stroke volume (3, 7).
Although the role of nitric oxide (NO) in peripheral vasodilation in pregnancy was identified (2), the influence of NO on cardiac function has not been previously determined. Three different isoforms of NO synthase catalyze the oxidation of L-arginine to citrulline and NO: the endothelial NO synthase (eNOS), the neuronal NO synthase (nNOS), and the inducible NO synthase (iNOS) (22). Whereas myocardial iNOS expression is most recognizable in disease states (13, 16), eNOS seems to be important under physiological conditions (28).
Numerous previous studies indicated an increased eNOS expression in several vascular beds in pregnancy (11, 30, 32). In contrast, renal eNOS protein expression gradually decreases during pregnancy in rats and reaches the nadir at day 19 of gestation (1) in these animals. On the other hand, renal iNOS and nNOS protein expression progressively increase and peak at day 13 of pregnancy in rats (1). In another study, Weiner et al. (30) demonstrated that calcium-dependent NOS activity in uterine arteries, heart, skeletal muscle, esophagus, and cerebellum of guinea pigs was significantly elevated after 50 days of gestation (30). Furthermore, a calcium-independent NOS activity was detectable in some tissues of those animals, but the average was below 10% of total NOS activity and not affected by pregnancy (30). To our knowledge, nothing is known about the myocardial expression of the NOS isoforms in pregnancy in rats.
In addition to vasodilatation, NO generated by eNOS and derived from the vascular endothelium is of significance in the modulation of tissue oxygen consumption. NO decreases mitochondrial respiration and tissue respiration through the reversible inhibition of cytochrome-c oxidase, the complex IV of the mitochondrial electron transport chain. Previously we have shown that modulation of myocardial oxygen consumption by endogenous NO is enhanced during exercise when cardiac output and work are elevated. Like exercise, pregnancy is also associated with an increased cardiac output and cardiac oxygen consumption. However, nothing is known about the role of NO in the regulation of myocardial oxygen consumption in pregnancy.
Therefore, the aim of our study was to determine the impact of eNOS-derived NO in the modulation of mitochondrial respiration in the heart of pregnant rats with the use of agents that release NO either spontaneously or through the activation of eNOS. Furthermore, we investigated whether changes in the eNOS protein expression as well as in the modulation of myocardial oxygen consumption are associated with hemodynamic changes in pregnancy. We hypothesized that 1) myocardial eNOS protein expression is increased in pregnancy and consequently that 2) agents that directly stimulate the release of endogenous NO through endothelial surface receptor activation (bradykinin) or indirectly stimulate the release of NO through an elevation of local kinins (amlodipine and enalapril) will decrease myocardial oxygen consumption in tissue from pregnant rats to a higher extent than in nonpregnant rats.
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MATERIALS AND METHODS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Animals studied.
Nine-week-old female Spraque-Dawley rats were studied before pregnancy
(control, n = 16), at 1 wk (1w, n = 16)
and 2 wk (2w, n = 16) of pregnancy, and at 4 days after
giving birth (4d, n = 16). The protocol of the study
was approved by the Institutional Care and Use Committee of New York
Medical College and conforms to the current guidelines for the use and
care of animals of the National Institutes of Health and the American
Physiological Society.
Echocardiography. Rats underwent echocardiography to document changes in cardiac function indicative of an increased myocardial oxygen consumption after sedation with pentobarbital sodium (25 mg/kg body wt ip). The echocardiographic measurements were performed with a 13-MHz linear transducer (Acuson, Mountain View, CA) in 10 animals of each group. Images were obtained in the parasternal long and short axes and were analyzed by an experienced sonographer blinded to the study design. Left ventricular (LV) chamber dimensions and wall thickness were measured in a plane below the mitral valve and perpendicular to the LV in an M-mode recording (23). LV chamber volumes were assessed in a two-dimensional parasternal long axis view, and ejection fraction (EF) was calculated as previously described (29). The diameter of the LV outflow tract (LVOT) was measured at the base of the aortic valve during systole (29). LVOT flow velocity was obtained using the PW-Doppler, and stroke volume (SV) was calculated as SV = LVOT velocity time integral × LVOT area (29).
Preparation of rat myocardial tissue slices and measurement of
tissue oxygen consumption.
Rats were killed with pentobarbital sodium (50 mg/kg body wt ip). Body
weights were measured, and hearts were removed immediately, freed of
connective tissue, fat, and blood, and weighed. The atria, the septum,
and the right ventricle were discarded, and the left ventricle was cut
into 30-mg slices. Tissue was then incubated in Krebs bicarbonate
solution to equilibrate for at least 2 h, and oxygen uptake of the
tissue was measured as previously published (31). The
effects of increasing concentrations of the endogenous NO-releasing
substances bradykinin (107 to 104 M),
amoldipine (107 to 105 M), enalapril
maleate (107 to 104 M), and the exogenous
NO donor S-nitroso-N-acetylpenicillamine (SNAP;
107 to 104 M) were studied in the presence
or absence of the NOS inhibitor NG-nitro-L-arginine methyl
ester (L-NAME; 104 M). Sodium cyanide
(103 M), an inhibitor of complex IV of the electron
transport chain, was added after the completion of concentration
response curve to each agonist to confirm that changes in tissue oxygen
consumption originate from mitochondria (31).
Calculation of tissue oxygen consumption. Tissue respiration was calculated as the rate of decrease in oxygen concentration, assuming an initial oxygen concentration of 224 nmol/ml and was expressed as nanomoles O2 consumed per minute and gram of tissue (19). The effects of bradykinin, enalapril maleate, amlodipine, and SNAP on tissue oxygen consumption were expressed as percent change of baseline oxygen consumption.
Quantification of NOS protein expression. The protein expressions of eNOS, iNOS, and nNOS were analyzed by Western blot using specific antibodies followed by densitometry. In six rats of each group, LV tissue samples were pulverized in liquid nitrogen and afterward resuspended in homogenization buffer containing protease inhibitors as previously published (12). After sonification for 60 s, samples were centrifuged at 10,000/min for 10 min. Briefly, 100 µg of protein were separated on a 7.5% SDS-PAGE, followed by electrotransfer to a PVDF (Amersham, Piscataway, NY). Positive controls for eNOS (human umbilical vein endothelial cells), iNOS (cytokine-stimulated macrophage), and nNOS (rat pituitary gland) supplied by the manufacturer (Transduction Laboratories, San Diego, CA) were loaded on each blot. The transferred proteins were incubated with a 1:500 dilution of a monoclonal anti-eNOS antibody, a monoclonal anti-iNOS antibody, and a monoclonal anti-nNOS antibody (Transduction Laboratories) at 4°C overnight. The bound primary antibody was detected by a peroxidase-coupled anti-mouse antibody (Amersham, dilution 1:2,000) followed by a chemiluminescent reaction using luminol (SuperSignal West Pico, Pierce, Rockford, IL). Afterward, the membrane was exposed to a film, and bands were analyzed by densitometry as previously published (12). To compensate for blot-to-blot variations, an internal standard (eNOS positive control) was loaded twice on each SDS-PAGE, and the densitometry results are expressed in percent as a ratio between sample and standard intensity.
Data calculation and statistical analysis. All the data in tables, text, and figures are presented as means ± SE. Echocardiographic parameters, protein expression, and baseline oxygen consumption were compared using a one-way ANOVA followed by Dunnett's post hoc test. Changes in tissue oxygen consumption caused by bradykinin, amlodipine, enalapril maleate, and SNAP were analyzed by two-way repeated measures ANOVA followed by Tukey's post hoc test. A P value of <0.05 was considered statistically significant.
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RESULTS |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Heart size. Before pregnancy and at week 1 of gestation, the heart weighed 0.71 ± 0.02 and 0.75 ± 0.02 g, respectively. At week 2 of pregnancy (0.88 ± 0.02 g) and still at 4 days after giving birth (0.85 ± 0.01 g), the heart weight was found to be significantly increased by 24 ± 3 and 20 ± 2% (P < 0.05), respectively, compared with control.
Echocardiographic variables.
The LV end-diastolic diameter (LVEDD) was significantly elevated at
week 2 of gestation, whereas LV end-systolic diameter (LVESD) remained constant during the first 2 wk of pregnancy
(Table 1). However, at 4 days after
giving birth, LVEDD and LVESD were both significantly increased by
25 ± 2 and 42 ± 5%, respectively, compared with control
(P < 0.05). End-diastolic wall thickness of the
interventricular septum (IVSD) and the LV posterior wall (LVPWD) were
also significantly elevated at week 2 of gestation, indicating a ventricular hypertrophy. Moreover, EF was significantly augmented at week 2 of gestation (80 ± 1%,
P < 0.05 vs. control) and returned to control levels
at 4 days after giving birth (67 ± 2%, Table 1). In contrast,
cardiac output was increased at weeks 1 and 2 of
gestation and also at 4 days after giving birth compared with
prepregnant values (P < 0.05 vs. control).
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NOS protein in nonpregnant and pregnant rats.
A representative Western blot for eNOS is shown in Fig.
1A. In rats, pregnancy was
associated with a significant increase in eNOS protein expression in
heart tissue homogenates by 46 ± 9% at week 1 (P < 0.05 vs. control) and by 39 ± 8% at
week 2 (P < 0.05 vs. control) of gestation
(Fig. 1B). At 4 days after giving birth, eNOS protein
expression in rat hearts did not significantly differ from levels
before pregnancy. In the heart, nNOS and iNOS protein expression were
not detectable in any of the groups (data not shown).
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Baseline tissue oxygen consumption in hearts of pregnant and
nonpregnant rats.
Baseline myocardial tissue oxygen consumption in control rats, rats at
1 wk of pregnancy, and rats at 4 days after giving birth did not differ
significantly in the absence or presence of the NOS inhibitor
L-NAME (Table 2). However, at
week 2 of gestation, LV tissue samples of rats had a
significantly lower baseline oxygen consumption compared with the other
groups in the presence or absence of L-NAME
(P < 0.05 vs. all other groups, Table 2).
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Effect of bradykinin on cardiac tissue oxygen consumption.
Cumulative doses of bradykinin (107 to 104
M) caused concentration-dependent decreases in oxygen consumption in
tissue from nonpregnant rats (from 0 ± 0 to 17 ± 2%,
Fig. 2A). However, after 1 wk
of gestation, this response to bradykinin (104 M) was
more pronounced (21 ± 2%), reached statistical significance at
week 2 of gestation (24 ± 2%, P < 0.05 vs. control and 4d), and returned to control levels in the group
of rats at 4 days after giving birth (18 ± 1%).
Bradykinin-induced (107 to 104 M) reduction
in myocardial oxygen consumption was significantly attenuated by
L-NAME (104 M) in all groups
(P < 0.05, Fig. 2B). Despite the presence
of L-NAME, bradykinin at a dose of 104 M
tended to reduced oxygen consumption in heart tissue of rats at 2 wk of
gestation to a higher extent than in all other groups.
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Effect of enalapril maleate on cardiac tissue oxygen consumption.
In cardiac muscles from nonpregnant control rats, the
angiotensin-converting enzyme inhibitor enalapril maleate
(107 to 104 M) caused a reduction in tissue
oxygen consumption, in a dose-dependent manner, from 1 ± 1 to
20 ± 2% (Fig. 3A). At
week 1 of pregnancy, cardiac tissue oxygen consumption
responded to increasing doses of enalapril maleate in the same manner
(Fig. 3A). However, after 2 wk of pregnancy, enalapril
maleate (104 M) decreased cardiac muscle oxygen
consumption by 29 ± 2% (P < 0.05 vs. control,
1w, and 4d). The response in tissue oxygen consumption to enalapril
maleate returned to control in rat hearts at 4 days after giving birth
(Fig. 3A). Furthermore, enalapril maleate-induced
(107 to 104 M) decrement in tissue oxygen
consumption was significantly attenuated by L-NAME (Fig.
3B; P < 0.05 vs. without
L-NAME). However, despite the presence of
L-NAME, enalapril maleate at a dosage of 104
M tended to reduced oxygen consumption in cardiac tissue of rats at 2 wk of gestation to a higher extent than in all other groups.
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Effect of amlodipine on cardiac tissue oxygen consumption.
Cumulative doses of amlodipine (107 to 105
M) resulted in a concentration-dependent decrease in oxygen consumption
from 2 ± 1 to 18 ± 2% in cardiac samples from
nonpregnant rats (Fig. 4A). At
week 1 of pregnancy, the response in tissue oxygen
consumption to amlodipine (105 M) was unchanged
(18 ± 2%). However, after 2 wk of gestation, cumulative doses
of amlodipine decreased rat heart oxygen consumption to a higher extent
(28 ± 1%, P < 0.05 vs. control, 1w, and 4d) compared with control, and the dose-response curve returned to control levels in rats at 4 days after giving birth (18 ± 1%, Fig. 4A). Coincubation with the NOS synthase
inhibitor L-NAME significantly attenuated the response to
amlodipine in all groups (P < 0.05 vs. without
L-NAME, Fig. 4B).
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Inhibition of oxygen consumption by exogenous NO.
The NO donor SNAP (107 to 105 M) reduced
tissue oxygen consumption in a dose-dependent manner from 3 ± 1 to 33 ± 2% in hearts of nonpregnant rats, in the presence
(Fig. 5B) and absence of L-NAME (Fig. 5A). Furthermore, the
attenuation of heart tissue oxygen consumption by SNAP was not
different in all groups of rats (Fig. 5A) and was unaffected
by L-NAME (Fig. 5B).
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DISCUSSION |
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TOP
ABSTRACT
INTRODUCTION
MATERIALS AND METHODS
RESULTS
DISCUSSION
REFERENCES
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Three major findings emerge from this study investigating the relationship between myocardial eNOS protein expression and myocardial oxygen consumption in pregnancy. Myocardial eNOS protein expression is significantly increased in rats at weeks 1 and 2 of gestation and returns to control levels shortly after giving birth. The elevation in eNOS protein expression at week 2 of pregnancy is associated with an enhanced kinin-mediated and NO-related modulation of myocardial oxygen consumption that returns to control after giving birth. Moreover, at week 2 of gestation, the increase in myocardial eNOS protein expression is accompanied by an increase in EF and cardiac output.
Pregnancy, cardiac function, and cardiac size. Pregnancy, a chronic volume-overload state, is associated with cardiovascular adaptations to support the development of the fetus. In the present study, we found an increased LVEDD and EF that accounted for the augmentation of SV and cardiac output at week 2 of gestation. Furthermore, we observed an increased heart weight and an elevated end-diastolic thickness of the posterior wall and the septum, indicating a mild hypertrophy at week 2 of gestation that started to reverse after giving birth. These results are in accord with previous studies in pregnancy in humans (21, 24) and strongly support the concept that pregnancy is associated with increased myocardial oxygen consumption.
Pregnancy and myocardial NOS expression. Numerous studies indicated an increased eNOS expression in several vascular beds in pregnancy (11, 30, 32). To our knowledge, we show for the first time that eNOS protein expression is elevated in the myocardium of pregnant rats and returns to control levels at 4 days after giving birth. Our results are in accord with a previous study (30) that found an augmented calcium-dependent NOS activity in guinea pig hearts during pregnancy. An enhanced eNOS and nNOS gene transcription or an augmented mRNA stability seemed to account for the increase in the calcium-dependent NOS activity, because mRNA levels of both enzymes were found to be elevated during pregnancy. However, eNOS and nNOS protein expression were not analyzed in this investigation (30). In our present study, no nNOS protein expression was detectable in the LV wall of nonpregnant and pregnant rats, excluding a key role of nNOS in the myocardium during pregnancy in this species. Weiner at al. (30) also observed a calcium-independent NOS activity in several tissues, although the heart was not mentioned, suggesting some iNOS expression. This iNOS activity was below 10% of the total NOS activity and not affected by pregnancy. In our study, we did not detect any iNOS protein expression, which is not surprising, because iNOS expression in the myocardium seems to be most important under inflammatory conditions (13).
Pregnancy and myocardial oxygen consumption. The real physiological focus of our study, however, was the potential additional control by NO of cardiac oxygen consumption during pregnancy. Our findings clearly demonstrate that drugs that stimulate endogenous NO release like bradykinin, amlodipine, and the angiotensin-converting enzyme inhibitor enalapril maleate significantly reduced myocardial oxygen consumption via a NOS-dependent mechanism in nonpregnant and pregnant rats. Moreover, the increased response to bradykinin or substances that increase local kinin concentrations at week 2 of pregnancy indicates that NO-mediated control of myocardial oxygen consumption is significantly enhanced. In summary, these data suggest the potential importance of endogenous NO derived from eNOS to more closely match oxygen supply and myocardial oxygen demand in pregnancy.
There is ample evidence that bradykinin via bradykinin II receptor can in part regulate myocardial oxygen consumption via a NO-dependent mechanism (17-19). Also in the present study, increasing doses of bradykinin reduced myocardial oxygen consumption in a dose-dependent manner in all groups of rats. However, the reduction in tissue oxygen consumption in response to bradykinin was significantly enhanced at week 2 of pregnancy. These findings indicate an augmented NO production at week 2 of gestation and further support Western blot analysis, showing a transiently increased cardiac eNOS protein expression at this time. We have previously shown that NOS inhibition completely abolished bradykinin-induced reduction in myocardial oxygen consumption in mice. In the present study, the NOS inhibitor L-NAME significantly reduced the response to bradykinin; however, it did not have the potency to abolish the bradykinin effects completely, perhaps due to the upregulation of eNOS. Angiotensin-converting enzyme inhibitors like enalapril lead to an accumulation of endogenous kinins, i.e., by kininase II inhibition. Kinins bind to the bradykinin II receptor and stimulate the release of NO (15, 34). In the present study, enalapril maleate also reduced myocardial oxygen consumption in pregnant rats via a NO-dependent mechanism. The reduction in myocardial oxygen consumption was more pronounced in the group of rats at 2 wk of gestation than in all other groups and confirms the increase in myocardial NO production. Amlodipine was also shown to release NO from blood vessels via a kinin-dependent mechanism and to decrease myocardial tissue oxygen consumption. In the present study amlodipine reduced myocardial oxygen consumption in a dose-dependent manner in all groups of rats, but the response to amlodipine was significantly increased in rats at week 2 of gestation. These findings further support the hypothesis that endogenous myocardial NO production is transiently increased during pregnancy and associated with an enhanced NO-mediated control of myocardial oxygen consumption at this time. In our study, the NO donor SNAP decreased myocardial tissue oxygen consumption in a dose-dependent NOS-independent manner in nonpregnant and pregnant rats. There was no statistically significant difference in the SNAP-induced reduction in tissue oxygen consumption detectable between the different groups of rats, indicating no differences in the complex I, II, and the most likely target of NO the cytochrome-c oxidase (complex IV) between pregnant and nonpregnant rats. Therefore, our results clearly show that increased myocardial eNOS protein expression and kinin-induced endogenous NO production are associated with an enhanced NO-dependent regulation of myocardial tissue oxygen consumption at 2 wk of pregnancy in rats. Despite a significant increase in eNOS protein expression at 1 wk of pregnancy, we observed only a nonsignificant trend toward an enhanced modulation of myocardial oxygen consumption by bradykinin and did not see any changes in response to amlodipine or enalapril maleate at this time. Recently published studies indicated that eNOS activity is dependent on the phosphorylation of the protein (6, 8, 9). One could speculate that despite the augmentation of eNOS protein at week 1 of pregnancy, adaptive mechanisms that induce an increase in eNOS activity, e.g., via a phosphorylation on serine-1177 or a dephosphorylation on threonine-495 in response to bradykinin, amlodipine, or enalapril maleate stimulation are delayed in the time course of pregnancy. Furthermore, it remains to be determined why baseline tissue oxygen consumption in rat hearts at week 2 of gestation was lower than in all other groups and did not increase after coincubation with L-NAME. We have previously shown that basal NO release, in the absence of a stimulus like flow or drugs, has only negligible effects on isolated tissue oxygen consumption, since there are no flow or agonists to stimulate NO production. Consequently, other factors independent of basal NO release may account for the reduction in baseline oxygen consumption in the rats at 2 wk of gestation.Limitations of study. Although the present study observed an enhanced modulation of myocardial oxygen consumption by agonists during pregnancy, we did not elucidate the exact site responsible for the augmented NO release. The changes could occur in any step from the bradykinin II receptor to intracellular signal transduction to the biosynthesis of NO in the myocardium. Further studies are necessary to answer this question.
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ACKNOWLEDGEMENTS |
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A. Linke was supported by Deutsche Forschungsgemeinschaft Grant Li 946/1-1 (Bonn, Germany). This work was supported by National Institutes of Health Grants PO-I-43023, HL-50142, and HL-61290 (to T. H. Hintze).
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FOOTNOTES |
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Address for reprint requests and other correspondence: T. H. Hintze, Dept. of Physiology, New York Medical College, Valhalla, NY 10595 (E-mail: Thomas_Hintze{at}nymc.edu).
The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
10.1152/ajpheart.00108.2002
Received 9 February 2002; accepted in final form 23 May 2002.
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TOP
ABSTRACT
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MATERIALS AND METHODS
RESULTS
DISCUSSION
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, Control (before
pregnancy, n = 6); 
, at week
1 of pregnancy (n = 6); 
, at
week 2 of pregnancy (n = 6);
, at 4 days after giving birth (n = 6).
*P < 0.05 vs. baseline (dosage 10
P < 0.05 vs. control and 4 days after giving birth.
§P < 0.05 for absence of L-NAME vs.
presence of L-NAME for control, 1 wk of pregnancy, and 2 wk
of pregnancy. #P < 0.05 for absence of
L-NAME vs. presence of L-NAME for all groups.
P < 0.05 vs. control, week 1 of
pregnancy, and 4 days after giving birth. §P < 0.05 for absence of L-NAME vs. presence of L-NAME
for control, 1 wk of pregnancy, and 2 wk of pregnancy.
#P < 0.05 for absence of L-NAME vs.
presence of L-NAME for all groups.
