(Circulation. 2000;101:498.)
© 2000 American Heart Association, Inc.
Clinical Investigation and Reports |
From the Department of Internal Medicine (N.Nagaya, T.S., S.F., F.S., H.O., S.K., N.Nakanishi, Y.G., K.M.) and Research Institute (T.N., K.K.), National Cardiovascular Center, Osaka, Japan; Cardiovascular Division (M.U.), Osaka Police Hospital, Osaka, Japan; and the Third Department of Internal Medicine (Y.M.), Chiba University School of Medicine, Chiba, Japan.
| Abstract |
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Methods and ResultsHemodynamic, renal, and hormonal responses to intravenous infusion of human AM (0.05 µg · kg-1 · min-1) were examined in 7 patients with CHF and 7 normal healthy subjects (NL). In NL group, AM significantly decreased mean arterial pressure (-16 mm Hg, P<0.05) and increased heart rate (+12 bpm, P<0.05). In CHF group, AM also decreased mean arterial pressure (-8 mm Hg, P<0.05) and increased heart rate (+5 bpm, P<0.05), but to a much lesser degree (P<0.05 versus NL). AM markedly increased cardiac index (CHF, +49%; NL, +39%, P<0.05) while decreasing pulmonary capillary wedge pressure (CHF, -4 mm Hg; NL, -2 mm Hg, P<0.05). AM significantly decreased mean pulmonary arterial pressure only in CHF (-4 mm Hg, P<0.05). AM increased urine volume (CHF, +48%; NL, +62%, P<0.05) and urinary sodium excretion (CHF, +42%; NL, +75%, P<0.05). Only in CHF, plasma aldosterone significantly decreased during (-28%, P<0.05) and after (-36%, P<0.05) AM infusion. These parameters remained unchanged in 7 patients with CHF and 6 healthy subjects who received placebo.
ConclusionsIntravenous infusion of AM has beneficial hemodynamic and renal effects in patients with CHF.
Key Words: heart failure hemodynamics cardiac output natriuretic peptides
| Introduction |
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Recently, Rademaker et al have demonstrated beneficial hemodynamic and renal effects of AM infusion in sheep with CHF induced by rapid pacing.9 In humans, systemically administered AM has been shown to significantly decrease mean arterial pressure in healthy subjects without any adverse effects.10 11 These findings raise the possibility that intravenous infusion of AM may also be beneficial in human subjects with CHF. However, there has been no clinical study to address the effects of AM in patients with CHF. Thus, the purposes of this study were (1) to investigate the hemodynamic, renal, and hormonal effects of short-term intravenous infusion of human AM in patients with CHF, and (2) to compare the effects of AM in CHF patients with those in normal healthy subjects (NL).
| Methods |
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2.0
mg/dL) and (2) systolic blood pressure <100 mm Hg. There
was no significant difference in baseline characteristics between
CHF-AM group and CHF-placebo group (Table 1
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Preparation of Human AM
Human AM was obtained from the Peptide Institute Inc, Osaka,
Japan. The homogeneity of human AM was confirmed by reverse-phase,
high-performance liquid chromatography and
amino acid analysis. AM was dissolved in saline with 4%
D-mannitol and was sterilized by passage through a 0.22-µm filter
(Millipore Co). Then, randomly selected vials were submitted for
sterility and pyrogen testing. The chemical nature and content of the
human AM in vials were verified by high-performance liquid
chromatography and radioimmunoassay.
Study Protocol
All cardiovascular drugs were withdrawn at least
24 hours before beginning the study procedure. A 7.5F Swan-Ganz
catheter (TOO21H-7.5F, Baxter Co) was positioned in the
pulmonary artery through a jugular vein. One 22-gauge cannula
was inserted into a radial artery for hemodynamic
measurements and blood sampling. Another 22-gauge cannula was inserted
into a forearm vein for infusion of 0.9% saline, with or without AM. A
bladder catheter was inserted for urine sampling. After an
equilibration period of 60 minutes, saline was infused at a rate of 0.5
mL/min for 30 minutes. Baseline measurements were obtained during this
period. Then, AM (0.05 µg · kg-1
· min-1) was intravenously
administered at a rate of 0.5 mL/min for 30 minutes, followed by
30-minute saline infusion in CHF-AM group and NL-AM group (Figure 1
). Additionally, saline alone was
intravenously administered for 90 minutes in CHF-placebo
group and NL-placebo group. The patients were blinded as to which
infusion was being given. Hemodynamic
parameters including heart rate, mean arterial
pressure, mean pulmonary arterial pressure, and
pulmonary capillary wedge pressure were measured at 5-minute
intervals during the protocol. At 15-minute intervals, cardiac output
was determined by thermodilution method in triplicate. Blood samples
were taken at 30-minute intervals before, during, and after infusion of
AM or placebo; collection of urine samples followed the same
regimen. Urine volume, urinary sodium excretion, urinary
potassium excretion, and creatinine clearance were
calculated with standard formulas.
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Hormonal Analysis
Plasma total AM, mature AM, atrial natriuretic
peptide (ANP) and brain natriuretic peptide (BNP) were
measured by immunoradiometric assay using a specific kit for each
(Shionogi Co, Ltd).12 13 Plasma cyclic adenosine
3', 5'-monophosphate (cAMP), cyclic guanosine 3', 5'-monophosphate
(cGMP), renin, aldosterone, norepinephrine, and
epinephrine were measured with commercially available
kits.14 15 Serum sodium and potassium were measured by
flame photometry.
Statistical Analysis
All data were expressed as mean±SEM unless otherwise indicated.
Comparisons of parameters between the 2 groups were made by
Fishers exact test or unpaired Students t test.
Comparisons of clinical parameters between 4 groups were
made by 1-way ANOVA, followed by Newman-Keuls test. Comparisons of the
time course of parameters between 4 groups were made by
2-way ANOVA for repeated measures, followed by Newman-Keuls test.
P<0.05 was considered statistically significant.
| Results |
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At the end of AM infusion, cardiac index markedly rose in both groups
compared with baseline values (CHF-AM, +49%; NL-AM, +39%,
P<0.05, Figure 3
). Stroke
volume index also rose in both groups (CHF-AM, +40%; NL-AM, +17%,
P<0.05). AM significantly decreased systemic vascular
resistance in both groups (CHF-AM, -38%; NL-AM, -40%,
P<0.05). Infusion of AM resulted in a significant decrease
in pulmonary vascular resistance only in the CHF-AM group
(-34%, P<0.05), which had significantly higher
pulmonary vascular resistance than NL-AM group at baseline.
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Renal Responses to AM
Infusion of AM significantly increased urine volume (CHF-AM,
+48%; NL-AM, +62%, P<0.05, Figure 4
) and urinary sodium excretion (CHF-AM,
+42%; NL-AM, +75%, P<0.05). AM also increased urinary
excretion of potassium in both groups (CHF-AM, +29%; NL-AM, +44%,
P<0.05). Creatinine clearance increased
significantly only in NL-AM group (+29%, P<0.05). The
renal parameters remained unchanged in CHF-placebo group
and NL-placebo group.
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Hormonal Responses to AM
Baseline plasma total AM and mature AM were significantly higher
in CHF-AM group than in NL-AM group (Table 2
). At the end of AM infusion, plasma
total AM increased
3-fold in both groups compared with baseline
values, whereas plasma-mature AM markedly increased (CHF-AM, 12-fold;
NL-AM, 14-fold). During AM infusion, plasma cAMP was significantly
increased (CHF-AM, +16%; NL-AM, +20%, P<0.05), whereas
plasma cGMP was not changed in either group.
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Baseline plasma renin and aldosterone were significantly higher in CHF-AM group than in NL-AM group. AM did not significantly change plasma renin in either group. In CHF-AM group, plasma aldosterone was significantly decreased at the end of AM infusion (-28%, P<0.05) and remained reduced even 30 minutes after discontinuation of the infusion (-36%, P<0.05). In contrast, no significant change in plasma aldosterone was observed in NL-AM group.
In NL-AM group, AM significantly increased plasma norepinephrine (+38%, P<0.05). In contrast, there was no significant change in plasma norepinephrine in CHF-AM group (-8%, P=NS). Plasma epinephrine was not changed in either group. Plasma ANP and BNP tended to decrease in CHF-AM group during AM infusion, although these changes did not reach statistical significance. The neurohumoral parameters remained unchanged in CHF-placebo group and NL-placebo group.
| Discussion |
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Earlier studies have shown that AM dose-dependently increases cAMP levels in platelets and in cultured vascular smooth muscle cells.1 2 In the present study, intravenous infusion of AM significantly increased plasma cAMP in association with decreases in mean arterial pressure. It is therefore possible that AM may relax vascular smooth muscle through a cAMP-dependent mechanism. Lainchbury et al have shown that a markedly low dose of AM (0.008 µg · kg-1 · min-1) decreases mean arterial pressure by 7.7 mm Hg in healthy human subjects without a significant increase in plasma cAMP.10 The discrepancy may be explained in part by the difference in the dose of AM. AM is also known to regulate vascular tone through an endothelium-derived NO-dependent mechanism.16 Recently it has been reported that the vasorelaxant effect of AM is attenuated in patients with CHF, partly because of impaired production of NO in endothelial cells.17 These findings may support our results that AM decreased mean arterial pressure to a much lesser degree in CHF-AM group than in NL-AM group. The fall in mean arterial pressure was associated with a significant increase in heart rate in both groups, which is consistent with a previous study.11
Interestingly, AM significantly decreased mean pulmonary arterial pressure and pulmonary vascular resistance only in CHF-AM group, which had higher baseline values for both parameters than NL-AM group. It has been reported that there are many binding sites for AM in the lung18 and that AM preferentially dilates pulmonary arterial resistance vessels.19 20 Circulating AM has been shown to be increased and to be partially metabolized in the lungs of patients with pulmonary hypertension.21 These findings raise the possibility that AM plays a role in regulation of pulmonary vascular tone. Although further studies are necessary to demonstrate a specific pulmonary vasodilator effect of AM in patients with CHF, it is interesting to speculate that AM may be more effective in patients with increased pulmonary vascular resistance secondary to severe left heart failure.
This study demonstrated that AM markedly increased cardiac index and stroke volume index in both groups. This is consistent with results obtained from a previous animal study using conscious sheep.4 Considering the strong vasodilator effect of AM,1 2 4 a significant decrease in mean arterial pressure may be responsible for increased cardiac index during infusion. On the other hand, a recent binding study has shown abundant binding sites for AM in the ventricular myocardium.18 In fact, AM has been shown to increase cardiac cAMP,22 which is known to mediate the positive inotropic action of ß-adrenergic stimulants. Alternatively, Szokodi et al have shown that AM produces a positive inotropic action through cAMP-independent mechanisms.5 These findings suggest that the increases in cardiac index and stroke volume index may be attributable not only to the fall in cardiac afterload but also to the direct positive inotropic action of AM.
In the present study, AM slightly but significantly increased urine volume and urinary sodium excretion in both CHF-AM group and NL-AM group, consistent with the results obtained from earlier animal studies.3 9 However, AM did not significantly increase creatinine clearance in CHF-AM group. Edwards et al have reported that AM dose-dependently increases intracellular cAMP levels in the cortical thick ascending limb and distal convoluted tubule dissected from rat kidney.23 These findings suggest that AM can directly inhibit tubular sodium resorption. In a previous human study, however, intravenous infusion of AM at 0.008 µg · kg-1 · min-1 did not induce diuresis or natriuresis in healthy subjects.10 The dose of the peptide may have been insufficient to reach a threshold for renal bioactivity. Because renal effects of systemically administered AM are relatively weak in both studies, significance of AM in the treatment of renal dysfunction remains to be determined.
The renin-angiotensin-aldosterone system is known to be excessively activated in patients with CHF, leading to adverse effects. In this study, CHF-AM group had high plasma renin and aldosterone, indicating activation of the renin-angiotensin-aldosterone system. Surprisingly, AM significantly decreased plasma aldosterone only in CHF-AM group, although there was no significant change in plasma renin. In vitro, AM has been shown to inhibit Ang II-induced secretion of aldosterone from dispersed rat adrenal zona glomerulosa cells.24 Thus, it is interesting to speculate that AM may play a compensatory role in the pathophysiology of CHF by inhibiting the augmented production of aldosterone. It should be noted that AM significantly increased plasma norepinephrine in NL-AM group but not in CHF-AM group. This suggests baroreceptor-mediated sympathetic discharge in response to the significant fall in blood pressure during AM infusion in NL-AM group. The reflex increase in sympathetic outflow might indirectly increase cardiac index and stroke volume index in NL-AM group. Although AM tended to decrease plasma NE, ANP, and BNP in CHF-AM group, these changes did not reach statistical significance. Further studies are necessary to elucidate the beneficial hormonal effects of AM.
It remains unclear whether exogenous AM functions at pathophysiological or pharmacological levels. It is generally supposed that AM-gly, an intermediate form of AM, is converted to mature AM, a 52-amino acid peptide with a C-terminal amide structure that exerts biological actions. However, most of immunoreactive AM in human plasma is in fact not mature AM, but AM-gly.12 Therefore, in the present study, mature AM was measured by a newly developed immunoradiometric assay kit. Unlike total AM (consisting of mature AM and AM-gly), plasma mature AM markedly increased during AM infusion, suggesting that infusion of AM produces biological actions at pharmacological levels. Baseline plasma mature AM was significantly higher in CHF-AM group than in NL-AM group. Nevertheless, AM at pharmacological levels increased plasma cAMP in association with cardiovascular effects in CHF-AM group. Thus, the additional administration of AM may be effective in patients with CHF.
Conclusions
Intravenous infusion of AM has beneficial
hemodynamic and renal effects in patients with CHF.
Further clinical trials are needed to investigate the potential
therapeutic benefit of AM in CHF.
| Acknowledgments |
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| Footnotes |
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Received April 9, 1999; revision received September 9, 1999; accepted September 15, 1999.
| References |
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