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1 Department of Internal Medicine and 2 Research Institute, National Cardiovascular Center, Suita, Osaka 565, Japan
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ABSTRACT |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Plasma
adrenomedullin (AM), a novel hypotensive peptide, has been shown to
increase in heart failure (HF). This study sought to examine the
cardiovascular and renal effects of intravenous infusion of AM in HF
rats and sham-operated rats (control) using two doses of AM that would
not induce hypotension. Rat AM-(1
50) was intravenously
administered at rates of 0.01 (low) and 0.05 (high)
µg · kg body
wt
1 · min1.
Low-dose AM increased urine flow (+21% in HF, +29% in control) and
urinary sodium excretion (+109% in HF, +123% in control) without changes in any hemodynamic variables. In contrast, high-dose AM slightly decreased mean arterial pressure (
3% in HF, 5%
in control) and significantly increased cardiac output (+20% in HF,
+12% in control). Infusion of high-dose AM resulted in significant
decreases in right ventricular systolic pressure (11%) and
right atrial pressure (28%) only in HF rats. High-dose AM
significantly increased glomerular filtration rate (+10% in HF, +16%
in control) and effective renal plasma flow (+25% in HF, +46% in
control) as well as urine flow and urinary sodium excretion. In
summary, intravenous infusion of AM exerted diuresis and natriuresis
without inducing hypotension and, in the higher dose, produced
beneficial hemodynamic and renal vasodilator effects in rats with
compensated HF.
myocardial infarction
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INTRODUCTION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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ADRENOMEDULLIN (AM) is a novel hypotensive peptide originally isolated from human pheochromocytoma (8). AM peptide and mRNA have been reported to be expressed not only in adrenal medulla but also in the heart, kidney, lung, and endothelium (5, 23). AM has been shown to promote vasodilatation (1), diuresis, and natriuresis (6, 10, 11) and to inhibit aldosterone production in normal animals (27). Recently, AM has been shown to have a positive inotropic action in the perfused rat heart (25, 26). We and others have shown that plasma AM levels are increased in patients with heart failure (HF) (7, 15). Tissue levels of AM peptide and mRNA have been shown to be increased in the heart, kidney, and lungs of HF rats (13). These findings suggest that AM may play a role in the regulation of volume and pressure homeostasis in HF via its renal, vascular, cardiac, and endocrine effects. However, the potential effects of AM as a therapeutic agent for HF are not fully understood. Recently, Rademaker et al. (22) showed that intravenous infusion of high-dose AM maintained urine flow despite a marked decrease in arterial pressure in HF sheep induced by rapid pacing. It is still unclear, however, whether intravenous infusion of AM elicits a beneficial renal effect at a dose that would not induce hypotension. In addition, there has been no report concerning the effects of AM on pulmonary hypertension secondary to left ventricular failure.
The present study was designed to investigate the effects of intravenous infusion of relatively low-dose AM on renal function and systemic and pulmonary hemodynamics in a rat model of HF produced by left coronary ligation.
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METHODS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Model of HF. Male Wistar rats weighing 180-220 g were used in this study. Myocardial infarction was produced by a previously described method (16). In brief, after rats were anesthetized by intraperitoneal injection of pentobarbital sodium (30 mg/kg body wt), they were intubated with a polyethylene tube (PE-240) and artificially ventilated using a volume-regulated respirator. The heart was exposed via a left thoracotomy, and the left coronary artery was ligated 2-3 mm from its origin between the pulmonary artery conus and the left atrium using a 6-0 Prolene suture. To reduce deaths due to arrhythmia, we pretreated the rats with an intraperitoneal injection of xylocaine (1-2 mg/kg) before coronary artery ligation and observed the electrocardiogram on the monitor. If ventricular tachycardia or fibrillation was observed, we injected additional xylocaine intraperitoneally or tapped the heart gently using a cotton applicator (17). These procedures were effective for converting the fatal arrhythmia to sinus rhythm. Finally, the heart was restored to its normal position and the lungs were hyperinflated to help evacuate air from the thoracic cavity before the chest was closed. The control rats received a sham operation involving thoracotomy and cardiac exposure but without coronary artery ligation. The surviving rats were maintained on standard rat chow.
The HF and control rats were randomly assigned to five groups. Low-dose AM (0.01 µg · kg body wt1 · min1;
HF, n = 8; control,
n = 9), high-dose AM (0.05 µg · kg body wt1 · min1;
HF, n = 10; control,
n = 9), or saline (HF,
n = 10) was intravenously administered
in each group. The saline group was prepared to rule out a time-course
effect during the intravenous infusion protocol.
Study protocol.
Approximately 4 wk after surgery, subsequent experimental procedures
were performed. Rats were anesthetized by intraperitoneal injection of
Inactin (100 mg/kg body wt) and placed on a heating pad to maintain
body temperature at 37-38°C throughout the study. Tracheostomy
was performed with a PE-240 tube. A polyethylene catheter (PE-10) was
inserted into the right femoral artery to measure the heart rate (HR)
and mean arterial pressure (MAP). A polyethylene catheter (PE-50) was
inserted into the right jugular vein and was advanced through the right
atrium into the right ventricle for measurement of mean right atrial
pressure (RAP) and right ventricular systolic pressure (RVSP). These
hemodynamic variables were measured using a pressure transducer (model
P23 ID; Gould, Glen Burnie, MD) connected to a polygraph and were recorded by a thermal recorder (7758 B System; Hewlett-Packard, Palo
Alto, CA). A thermomicroprobe was advanced into the ascending aorta via
the right carotid artery and connected to a cardiac output (CO)
computer (Cardiotherm-500; Columbus Instruments). For measurement of
CO, 0.1 ml of 0.9% saline at room temperature was injected as a bolus
via the jugular vein catheter. A second PE-50 catheter was inserted
into the left jugular vein for the infusion of saline containing 5%
inulin and 1.8% p-aminohippuric acid
(PAH) at a rate of 0.2 ml · 100 g body
wt1 · h1.
A third PE-50 catheter was inserted into the left femoral vein for the
continuous infusion of AM or saline at a rate of 0.3 ml · 100 g body
wt1 · h1.
Finally, a PE-100 catheter was inserted into the bladder to collect
urine. After an equilibration period of 60 min, we measured RAP at
baseline. Then the catheter was advanced into the right ventricle by
monitoring the pressure. Urine was collected over two periods of 20 min
each, and 150-µl blood samples were drawn at the midpoint of each
urine collection for measurement of PAH and inulin. Simultaneously, we
recorded hemodynamic variables, including HR, MAP, RVSP, and CO. The
averaged values in the two periods were used as the values before AM
infusion. After the control measurements and samples were obtained, AM
(0.01 µg · kg body
wt1 · min1
or 0.05 µg · kg body
wt1 · min1)
was intravenously administered. Thirty minutes later, all measurements were repeated over two periods of 20 min and the averaged values in the
two periods were used as the values after AM infusion.
Analysis.
Urinary concentration of sodium was measured by flame photometry.
Inulin was measured by the anthrone method. PAH was measured by
Marshall's method. Glomerular filtration rate (GFR) and effective renal plasma flow (ERPF) were determined from inulin and PAH clearance, respectively. Effective renal blood flow (ERBF) was calculated as
ERPF/(1 hematocrit); renal vascular resistance (RVR) was determined as (MAP RAP)/ERBF. The filtration fraction was
calculated as GFR/ERPF.
Measurement of AM, ANP, cAMP, and cGMP. The plasma concentrations of AM and ANP were determined by radioimmunoassay after extraction with Sep-Pak C18 cartridges (Millipore; Waters, Milford, MA), as previously reported (12, 23). The urinary concentrations of cAMP and cGMP were determined with radioimmunoassay kits (cAMP assay kit and cGMP assay kit; Yamasa Shoyu, Chiba, Japan), as previously reported (4). A normal value of plasma AM in rats was established from nine sham-operated rats.
Statistical analysis. Numerical values were expressed as means ± SD unless otherwise indicated. Comparisons of variables between two groups were made by Student's unpaired t-test. Comparisons of values among three or more groups were made using one-way ANOVA followed by Scheffé's multiple comparison test. Changes in hemodynamic and renal variables during AM infusion were analyzed with Student's paired t-test. A P value <0.05 was considered significant.
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RESULTS |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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Physiological profiles. The physiological profiles of the five experimental groups are summarized in Table 1. Moderate to large infarcts were observed in three HF groups, and the mean infarct size was similar in the three groups. HF rats showed significantly increased weights of the right ventricle and the lungs compared with control rats. Plasma ANP levels were markedly increased in HF rats compared with control rats. MAP and CO at baseline were significantly decreased in HF rats compared with control rats (Figs. 1 and 2). RVSP and RAP at baseline were significantly increased in HF rats. These results suggest the presence of chronic HF in this experimental model.
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Effects of AM on systemic and pulmonary circulation.
Infusion of saline did not significantly change MAP, CO, RVSP, or RAP
in HF rats (Table 2). The infusion of
low-dose AM (0.01 µg · kg body
wt1 · min1)
did not significantly alter any hemodynamic variables in either HF or
control rats (Fig. 1). In contrast, high-dose AM (0.05 µg · kg body
wt1 · min1)
produced a slight decrease in MAP and a marked increase in CO in both
HF and control rats (Fig. 2). High-dose AM
significantly reduced RVSP and RAP in HF rats, although it did not
significantly alter these variables in control rats. HR was not
significantly changed during infusion of low-dose AM (HF, 383 ± 31 to 386 ± 30 beats/min; control, 390 ± 47 to 400 ± 40 beats/min) or high-dose AM (HF, 372 ± 25 to 371 ± 20 beats/min;
control, 380 ± 25 to 378 ± 26 beats/min).
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Effects of AM on renal function.
Infusion of saline did not change any renal variables in HF rats (Table
2). Infusion of low-dose AM (0.01 µg · kg body
wt1 · min1)
significantly increased urine volume (UV) and urinary sodium excretion
(UNaV) in both HF and control
rats, but it did not change GFR or ERPF (Fig.
3). RVR was not significantly changed by
low-dose AM (HF, 2.7 ± 0.4 to 2.6 ± 0.4 mmHg · ml1 · min · kg;
control, 2.7 ± 0.4 to 2.6 ± 0.5 mmHg · ml1 · min · kg).
In contrast, high-dose AM (0.05 µg · kg body
wt1 · min1)
resulted in slight, but significant, increases in GFR and ERPF as well
as increases in UV and UNaV in
both HF and control rats (Fig. 4). RVR in
both groups was significantly decreased by high-dose AM (HF, 2.8 ± 0.8 to 2.4 ± 1.0 mmHg · ml1 · min · kg;
control, 2.6 ± 0.7 to 1.9 ± 0.7 mmHg · ml1 · min · kg,
P < 0.05, respectively).
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Neurohumoral measurements.
Plasma AM levels in HF rats treated with saline were significantly
increased compared with a normal value of plasma AM in rats (3.5 fmol/ml). Plasma AM levels in HF rats treated with low-dose AM tended
to be increased (1.4-fold) compared with those in HF rats treated with
saline, but not to a statistically significant extent (Table
3). In contrast, plasma AM levels in HF
rats treated with high-dose AM were significantly elevated (sevenfold)
compared with those in HF rats treated with saline. Interestingly, the same dose of AM (0.05 µg · kg body
wt1 · min1)
resulted in different changes in plasma AM levels between HF rats (56 ± 29 fmol/ml) and control rats (30 ± 8 fmol/ml).
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DISCUSSION |
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Top
Abstract
Introduction
Methods
Results
Discussion
References
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In this study, we examined the cardiovascular and renal effects of intravenous infusion of AM in HF rats and sham-operated control rats using two doses of AM that did not induce a marked decrease in arterial pressure. We demonstrated for the first time 1) that intravenous infusion of low-dose AM significantly increased UV and UNaV without changes in GFR, ERPF, or any hemodynamic variables in HF and control rats. We also demonstrated 2) that high-dose AM infusion significantly decreased MAP and increased CO in both HF and control rats, whereas high-dose AM significantly reduced RVSP and RAP only in HF rats with pulmonary hypertension, and 3) that high-dose AM significantly increased GFR and ERPF as well as UV and UNaV in both groups. These results suggest that AM plays a role in the regulation of pressure and volume homeostasis via renal and cardiovascular effects in HF.
To date, the biological actions of AM have been examined in a variety
of normal animals, whereas the therapeutic effects of AM on HF are not
fully understood. Intravenous infusion of AM has been shown to produce
a marked decrease in arterial pressure via its strong vasorelaxant
effect mediated by the accumulation of cAMP (22, 24). However, the
AM-induced hypotension may cause adverse effects in HF such as
decreased renal perfusion pressure. Thus, in a preliminary study, we
determined two doses of AM that would not induce a marked decrease in
arterial pressure. In this study, infusion of low-dose AM (0.01 µg · kg body
wt1 · min1)
did not significantly decrease MAP, whereas high-dose AM (0.05 µg · kg body
wt1 · min1)
produced a slight but significant decrease in MAP from baseline value
(6 mmHg in HF rats; 3 mmHg in control rats).
In this study, we showed that high-dose AM increased CO in HF and control rats. This is consistent with results from a previous study using conscious sheep (22). One of the mechanisms underlying this increase in CO may be a fall of cardiac afterload by decreasing MAP. Recently, Szokodi et al. (26) showed that AM produced a direct positive inotropic action via Ca2+ release from intracellular ryanodine- and thapsigargin-sensitive Ca2+ stores, activation of protein kinase C, and Ca2+ influx through L-type Ca2+ channels. These findings suggest that the increase in CO may be attributed not only to the fall of cardiac afterload but also to the positive inotropic action of AM.
Interestingly, in this study, AM significantly decreased RVSP only in HF rats with pulmonary hypertension, not in control rats. It has been reported that there are many binding sites of AM in the lung (19) and that AM preferentially dilates pulmonary arterial resistance vessels (3, 18). Circulating AM has been shown to be increased and to be partially metabolized in the lungs of patients with pulmonary hypertension (14, 28). These findings raise the possibility that AM is involved in the pathophysiology of pulmonary hypertension. Recently, Lippton et al. (9) showed that AM does not alter pulmonary arterial pressure under conditions of resting pulmonary vascular tone, whereas it produces a dose-dependent reduction in pulmonary arterial pressure under conditions of increased pulmonary vascular tone, consistent with our results. Thus it may be interesting to speculate that AM is more effective in rats with increased pulmonary vascular resistance secondary to severe left HF.
AM has been shown to have diuretic and natriuretic activities in normal animals (6, 10, 11). In this study, we demonstrated that low-dose AM significantly increased UV and UNaV without increases in GFR or ERPF in both HF and control rats. Edwards et al. (2) have reported that AM dose dependently increases intracellular cAMP levels in the cortical thick ascending limb and distal convoluted tubule dissected from rat kidney. These findings suggest that AM has a direct action on the renal tubules via the accumulation of cyclic AMP, and thereby AM may be involved in the regulation of urine flow and UNaV. However, in the present study, intravenous infusion of AM did not increase urinary cAMP level, consistent with a previous report (11). It is possible that AM stimulated intracellular cAMP at the tissue level sufficiently to induce a biological response but insufficiently to induce a measurable rise in urinary level. In addition, AM did not significantly increase urinary cGMP level. This result suggests that the renal action of AM might not be mediated mainly by the nitric oxide-cGMP pathway in rats. Moreover, in this study we showed that intravenous administration of high-dose AM significantly increased GFR and RPF in both HF and control rats, supporting the earlier findings that intrarenal infusion of AM increases GFR and RPF (6, 11). These results suggest that AM dilates renal arteries as well as peripheral vessels. Recently, Rademaker et al. (22) showed that intravenous infusion of AM increases UNaV without an increase in urine flow or creatinine clearance in pacing-induced HF sheep. In their study, MAP at baseline was considerably low (72 mmHg) in HF sheep, and AM infusion induced a further reduction in MAP to 63 mmHg. Thus the discrepancy between their results and ours with regard to changes in UV and GFR may be explained, in part, by the difference in renal perfusion pressure.
It remains unclear whether exogenous AM functions at pathophysiological
or pharmacological levels. In this study, plasma AM levels in HF rats
treated with low-dose AM tended to be increased (1.4-fold) compared
with those in HF rats treated with saline, but not to a statistically
significant extent. In contrast, plasma AM levels in HF rats treated
with high-dose AM were significantly elevated compared with those in HF
rats treated with saline (sevenfold). Accordingly, intravenous infusion
of low-dose AM may cause natriuresis and diuresis at pathophysiological
levels, whereas high-dose infusion may induce hemodynamic effects as
well as natriuresis and diuresis at pharmacological levels. In this
study, the same dose of AM (0.05 µg · kg body
wt1 · min1)
resulted in different increases in plasma AM levels between HF rats (56 ± 29 fmol/ml) and control rats (30 ± 8 fmol/ml). These results
raise the possibility that the clearance of AM may be decreased in HF rats.
Limitations. First, we could not assess the effect of AM on other vasoactive peptides such as renin and aldosterone because their measurements require a large volume of blood. Second, we could only measure RVSP as an index of pulmonary arterial systolic pressure. A more detailed analysis of pulmonary arterial pressure is needed to examine effects of AM on pulmonary circulation. Finally, this study was conducted in rats with chronic HF that was relatively well compensated. The effects of AM in the acute phase, or in the development of HF, need further study.
In conclusion, intravenous infusion of AM exerted diuresis and natriuresis without inducing hypotension and in the higher dose produced beneficial hemodynamic and renal vasodilator effects in rats with compensated HF.Perspectives
The natriuretic and diuretic effects of AM infusion without a marked decrease in arterial pressure suggest that AM may be beneficial in the treatment of HF. Moreover, intravenous infusion of AM at pharmacological levels produced vasodilatation and increased CO in association with diuresis and natriuresis. These findings, together with the direct inotropic effect of AM (26), imply that AM may have a place among inotropic and vasodilator agents such as phosphodiesterase inhibitors. Thus intravenous infusion of AM may be a new therapeutic approach to the treatment of HF. Because AM has the great advantage of being an endogenous substance, large-scale human studies are necessary to confirm a potential therapeutic benefit of AM in patients with HF.| |
ACKNOWLEDGEMENTS |
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We thank Yoko Saito for technical assistance.
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FOOTNOTES |
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This work was supported in part by the Special Coordination Funds for Promoting Science and Technology (Encouragement System of Center of Excellence from the Science and Technology Agency of Japan.)
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. §1734 solely to indicate this fact.
Address for reprint requests: T. Nishikimi, Dept. of Internal Medicine, National Cardiovascular Center, 5-7-1 Fujishirodai, Suita, Osaka 565, Japan.
Received 13 July 1998; accepted in final form 22 September 1998.
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REFERENCES |
|---|
|
Top
Abstract
Introduction
Methods
Results
Discussion
References
|
|---|
1.
Chien, Y. W.,
R. W. Barbee,
A. A. Macphee,
E. D. Flohlich,
and
N. C. Trippodo.
Increased ANF secretion after volume expansion is preserved in rats with heart failure.
Am. J. Physiol.
254 (Regulatory Integrative Comp. Physiol. 23):
R185-R191,
1988
2.
Edwards, R. M.,
W. Trizna,
E. Stack,
and
N. Aiyar.
Effect of adrenomedullin on cAMP levels along the rat nephron: comparison with CGRP.
Am. J. Physiol.
271 (Renal Fluid Electrolyte Physiol. 40):
F895-F899,
1996
3.
Heaton, J.,
B. Lin,
J. K. Chang,
S. Steinberg,
A. Hyman,
and
H. Lippton.
Pulmonary vasodilation to adrenomedullin: a novel peptide in humans.
Am. J. Physiol.
268 (Heart Circ. Physiol. 37):
H2211-H2215,
1995
4.
Honma, M.,
T. Satoh,
J. Takezawa,
and
M. Ui.
An ultrasensitive method for the simultaneous determination of cyclic AMP and cyclic GMP in small-volume samples from blood and tissue.
Biochem. Med.
18:
257-273,
1977[Medline].
5.
Ichiki, Y.,
K. Kitamura,
K. Kangawa,
M. Kawamoto,
H. Matsuo,
and
T. Eto.
Distribution and characterization of immunoreactive adrenomedullin in human tissue and plasma.
FEBS Lett.
338:
6-10,
1994[Medline].
6.
Jougasaki, M.,
C.-M. Wei,
L. L. Aarhus,
D. M. Heublein,
S. M. Sandberg,
and
J. C. Burnett, Jr.
Renal localization and actions of adrenomedullin: a natriuretic peptide.
Am. J. Physiol.
268 (Renal Fluid Electrolyte Physiol. 37):
F657-F663,
1995
7.
Jougasaki, M.,
C.-M. Wei,
L. J. McKinley,
and
J. C. Burnet, Jr.
Elevation of circulating and ventricular adrenomedullin in human congestive heart failure.
Circulation
92:
286-289,
1995
8.
Kitamura, K.,
K. Kangawa,
M. Kawamoto,
Y. Ichiki,
S. Nakamura,
H. Matsuo,
and
T. Eto.
Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma.
Biochem. Biophys. Res. Commun.
192:
553-560,
1993[Medline].
9.
Lippton, H.,
J.-K. Chang,
Q. Hao,
W. Summer,
and
A. L. Hyman.
Adrenomedullin dilates the pulmonary vascular bed in vivo.
J. Appl. Physiol.
76:
2154-2156,
1994
10.
Majid, D. S. A.,
P. J. Kadowitz,
D. H. Coy,
and
L. G. Navar.
Renal responses to intra-arterial administration of adrenomedullin in dogs.
Am. J. Physiol.
270 (Renal Fluid Electrolyte Physiol. 39):
F200-F205,
1996
11.
Miura, K.,
T. Ebara,
M. Okumura,
T. Matsuura,
S. Kim,
T. Yukimura,
and
H. Iwao.
Attenuation of adrenomedullin-induced renal vasodilation by N-nitro-L-arginine but not glibenclamide.
Br. J. Pharmacol.
115:
917-924,
1995[Medline].
12.
Miyata, A.,
K. Kangawa,
and
H. Matsuo.
Molecular forms of atrial natriuretic peptides in rat tissues and plasma.
J. Hypertens. 4, Suppl.
2:
S9-S11,
1986.
13.
Nishikimi, T.,
T. Horio,
T. Sasaki,
F. Yoshihara,
S. Takishita,
A. Miyata,
H. Matsuo,
and
K. Kangawa.
Cardiac production and secretion of adrenomedullin are increased in heart failure.
Hypertension
30:
1369-1375,
1997
14.
Nishikimi, T.,
S. Nagata,
T. Sasaki,
S. Tomimoto,
H. Matsuoka,
S. Takishita,
K. Kitamura,
A. Miyata,
H. Matsuo,
and
K. Kangawa.
Plasma concentrations of adrenomedullin correlate with the extent of pulmonary hypertension in patients with mitral stenosis.
Heart
78:
390-395,
1997
15.
Nishikimi, T.,
Y. Saito,
K. Kitamura,
T. Ishimitsu,
T. Eto,
K. Kangawa,
H. Matsuo,
T. Omae,
and
H. Matsuoka.
Increased plasma levels of adrenomedullin in patients with heart failure.
J. Am. Coll. Cardiol.
26:
1424-1431,
1995[Abstract].
16.
Nishikimi, T.,
K. Uchino,
and
E. D. Flohlich.
Effects of 
1-adrenergic blockade on intrarenal hemodynamics in heart failure rats.
Am. J. Physiol.
262 (Regulatory Integrative Comp. Physiol. 31):
R198-R203,
1992
17.
Nishikimi, T.,
H. Yamagishi,
K. Takeuchi,
and
T. Takeda.
An angiotensin 2 receptor antagonist attenuates left ventricular dilatation after myocardial infarction in the hypertensive rat.
Cardiovasc. Res.
29:
856-861,
1995[Medline].
18.
Nossaman, B. D.,
C. J. Feng,
A. D. Kaye,
B. Dewitt,
D. H. Coy,
W. A. Murphy,
and
P. J. Kadowitz.
Pulmonary vasodilator responses to adrenomedullin are reduced by NOS inhibitors in rats but not in cats.
Am. J. Physiol.
270 (Lung Cell. Mol. Physiol. 14):
L782-L789,
1996
19.
Owji, A. A.,
D. M. Smith,
H. A. Coppock,
D. G. Morgan,
R. Bhogal,
M. A. Ghatel,
and
S. R. Bloom.
An abundant and specific binding site for the novel vasodilator adrenomedullin in the rat.
Endocrinology
136:
2127-2134,
1995[Abstract].
20.
Parkes, D. G.,
and
C. N. May.
Direct cardiac and vascular actions of adrenomedullin in conscious sheep.
Br. J. Pharmacol.
120:
1179-1185,
1997[Medline].
21.
Pfeffer, J. M.,
M. A. Pfeffer,
and
E. Braunwald.
Influence of chronic captopril therapy on the infarcted left ventricle of the rat.
Circ. Res.
57:
84-95,
1985
22.
Rademaker, M. T.,
C. J. Charles,
L. K. Lewis,
T. G. Yandle,
G. J. S. Cooper,
D. H. Coy,
A. M. Richards,
and
M. G. Nicholls.
Beneficial hemodynamic and renal effects of adrenomedullin in an ovine model of heart failure.
Circulation
96:
1983-1990,
1997
23.
Sakata, J.,
T. Shimokubo,
K. Kitamura,
M. Nishizono,
Y. Iehiki,
K. Kangawa,
H. Matsuo,
and
T. Eto.
Distribution and characterization of immunoreactive rat adrenomedullin in tissue and plasma.
FEBS Lett.
352:
105-108,
1994[Medline].
24.
Sugo, S.,
N. Minamino,
K. Kangawa,
K. Miyamoto,
K. Kitamura,
J. Sakata,
T. Eto,
and
H. Matsuo.
Endothelial cells actively synthesize and secrete adrenomedullin.
Biochem. Biophys. Res. Commun.
201:
1160-1166,
1994[Medline].
25.
Szokodi, I.,
P. Kinnunen,
and
H. Ruskoaho.
Inotropic effect of adrenomedullin in the isolated perfused rat heart.
Acta Physiol. Scand.
156:
151-152,
1996[Medline].
26.
Szokodi, I.,
P. Kinnunen,
P. Tavi,
M. Weckstrom,
M. Toth,
and
H. Ruskoaho.
Evidence for cAMP-independent mechanisms mediating the effects of adrenomedullin, a new inotropic peptide.
Circulation
97:
1062-1070,
1998
27.
Yamaguchi, T.,
K. Baba,
Y. Doi,
K. Yano,
K. Kitamura,
and
T. Eto.
Inhibition of aldosterone production by adrenomedullin, a hypotensive peptide, in the rat.
Hypertension
28:
308-314,
1996
28.
Yoshibayashi, M.,
T. Kamiya,
K. Kitamura,
Y. Saito,
K. Kangawa,
T. Nishikimi,
H. Matsuoka,
T. Eto,
and
H. Matsuo.
Plasma levels of adrenomedullin in primary and secondary pulmonary hypertension in patients <20 years of age.
Am. J. Cardiol.
79:
1556-1558,
1997[Medline].
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M. Luodonpaa, H. Leskinen, M. Ilves, O. Vuolteenaho, and H. Ruskoaho Adrenomedullin modulates hemodynamic and cardiac effects of angiotensin II in conscious rats Am J Physiol Regulatory Integrative Comp Physiol, June 1, 2004; 286(6): R1085 - R1092. [Abstract] [Full Text] [PDF]
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 K. Nakanishi, H. Osada, M. Uenoyama, F. Kanazawa, N. Ohrui, Y. Masaki, T. Hayashi, Y. Kanatani, T. Ikeda, and T. Kawai Expressions of adrenomedullin mRNA and protein in rats with hypobaric hypoxia-induced pulmonary hypertension Am J Physiol Heart Circ Physiol, June 1, 2004; 286(6): H2159 - H2168. [Abstract] [Full Text] [PDF]
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T. Nishikimi, F. Yoshihara, A. Kanazawa, I. Okano, T. Horio, N. Nagaya, C. Yutani, H. Matsuo, H. Matsuoka, and K. Kangawa Role of increased circulating and renal adrenomedullin in rats with malignant hypertension Am J Physiol Regulatory Integrative Comp Physiol, December 1, 2001; 281(6): R2079 - R2087. [Abstract] [Full Text] [PDF]
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P. Kinnunen, I. Szokodi, M. G. Nicholls, and H. Ruskoaho Impact of NO on ET-1- and AM-induced inotropic responses: potentiation by combined administration Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2000; 279(2): R569 - R575. [Abstract] [Full Text] [PDF]
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I. Hamanaka, Y. Saito, T. Nishikimi, T. Magaribuchi, S. Kamitani, K. Kuwahara, M. Ishikawa, Y. Miyamoto, M. Harada, E. Ogawa, et al. Effects of cardiotrophin-1 on hemodynamics and endocrine function of the heart Am J Physiol Heart Circ Physiol, July 1, 2000; 279(1): H388 - H396. [Abstract] [Full Text] [PDF]
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N. Nagaya, T. Nishikimi, F. Yoshihara, T. Horio, A. Morimoto, and K. Kangawa Cardiac adrenomedullin gene expression and peptide accumulation after acute myocardial infarction in rats Am J Physiol Regulatory Integrative Comp Physiol, April 1, 2000; 278(4): R1019 - R1026. [Abstract] [Full Text] [PDF]
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) and in sham-operated
control rats (
). There were no significant changes in mean arterial
pressure (MAP), cardiac output (CO), right ventricular systolic
pressure (RVSP), or right atrial pressure (RAP) in either HF or
control. Before, before infusion of AM or saline; after, after infusion
of AM or saline. Values are means ± SE.
* P < 0.05 vs. control.
P < 0.05 vs.
before.
