(Circulation. 1997;95:1214-1221.)
© 1997 American Heart Association, Inc.
Articles |
Potent and Long-Lasting Vasodilatory Effects of Adrenomedullin in Humans
Comparisons Between Normal Subjects and Patients With Chronic Heart Failure
the Second Department of Internal Medicine, Iwate Medical University, Morioka, Iwate, Japan.
Correspondence to Motoyuki Nakamura, MD, Second Department of Internal Medicine, Iwate Medical University, Uchimaru, Morioka, Iwate 020, Japan.
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Abstract |
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Background Adrenomedullin (ADM) is a recently discovered hypotensive peptide that has been isolated from human pheochromocytoma cells. Observations that ADM is produced from cardiovascular tissue and is found in plasma suggest that it may be important in the regulation of regional vascular resistance.
Methods and Results Limb vascular responses to ADM were examined in 10 healthy subjects and compared with those in 18 patients with chronic heart failure (CHF). The peptide increased forearm blood flow (FBF) from 2.7±0.3 to 11.8±0.9 mL·min-1·100 mL-1 in the control group and from 2.4±0.3 to 6.5±0.7 mL·min-1·100 mL-1 in the CHF group. The ADM-induced FBF increase was significantly impaired in the CHF group (P<.01). After cessation of the infusion, an increased FBF level was sustained for >60 minutes in the control group, whereas in the CHF group the response returned to the baseline in <30 minutes. The ADM infusion increased forearm skin blood flow in both groups (P<.05), whereas the skin blood flow response was impaired in the CHF group (P<.01). The role of nitric oxide in ADM-induced vasorelaxation was also studied in 11 healthy subjects and 6 patients with CHF. FBF and skin blood flow responses during ADM administration were significantly attenuated by NG-monomethyl-L-arginine administration in healthy control subjects (P<.05), whereas both flow responses remained the same in the CHF group.
Conclusions These observations demonstrate that ADM exerts a potent and long-lasting vasodilatory effect on skeletal muscle arteries with involvement of nitric oxide–dependent mechanisms in normal human peripheral vasculature and that these vascular effects are significantly attenuated in patients with CHF, in part because of impaired production of nitric oxide in the forearm resistance vessels.
Key Words: adrenomedullin • endothelium • heart failure • endothelium-derived factors
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Introduction |
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Adrenomedullin is a newly identified peptide that was originally isolated from human pheochromocytoma cells.1 It shares slight homology with the amino acid sequence of human calcitonin gene–related peptide, one of the most potent vasodilator peptides known.1 Several studies in animals have shown that the vasodilating properties of ADM are potent and long lasting.1 2 It has been reported that the peptide is produced not only in normal adrenal medulla but also in the cardiovascular system, including heart, lung, aorta, vascular smooth muscle cells, and endothelial cells.1 3 4 5 6 7 8 9 Immunoreactivity of ADM has been found in human plasma, and the circulating level of the peptide in patients with CHF has been reported to rise with the clinical severity of CHF. Plasma levels are also positively correlated with left ventricular function6 and pulmonary arterial pressure.10 11 12 Furthermore, plasma levels of ADM in early and subacute phases of acute myocardial infarction complicated with heart failure are clearly higher than normal control levels.13 These observations suggest that ADM may be an important factor in the regulation of local and systemic vascular tone by its operation as a paracrine and circulating hormone. By virtue of its potent vasodilatory effects, it may thus act as part of a counteracting mechanism to reduce elevated cardiac afterload in CHF.
However, the potency and mechanism of the vascular effects of human ADM in the human vascular bed remain unknown. ADM increases the intracellular accumulation of cAMP in vascular smooth muscle cells via its specific receptors.14 15 16 Several animal studies17 18 19 20 recently have demonstrated that the vasodilatory effects of ADM are largely dependent on NO, although the role of NO in the vasodilatory effects of ADM varies with species and vascular region. These findings suggest that ADM regulates vascular tone through a cAMP-dependent mechanism as well as an endothelium-derived NO-dependent mechanism. Indeed, several recent studies21 22 demonstrated that NO production from the peripheral vascular bed is impaired in patients with CHF. Consequently, it may be speculated that if NO is involved in ADM-induced vascular effects, the vasodilatory potency of ADM may be blunted in the peripheral vascular bed in this disorder. The present study was therefore designed to address the following three issues: (1) Is human ADM a potent and long-lasting vasodilator in human forearm vasculature? (2) Is NO involved in the ADM-mediated vasodilatory mechanism? (3) Is ADM-mediated blood flow to the limb vascular bed attenuated in patients with CHF?
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Methods |
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Subjects
Twenty-five healthy volunteers and 24 patients with CHF participated in this study (Table
s 1 and 2). The healthy volunteers were evaluated carefully by physical examination and the use of routine blood tests, ECG, and chest radiography, and no abnormalities were observed. As shown in Tables 1 and 2, 18 patients with CHF and 10 age- and sex-matched healthy subjects were enrolled in study A. The origin of CHF was primary dilated cardiomyopathy in 6 patients, valvular heart disease in 11, and old myocardial infarction with mitral regurgitation in 1 patient. In terms of the clinical severity of CHF, 12 patients were NYHA functional class II and 6 patients were NYHA class III. The mean±SEM values of pulmonary capillary wedge pressure and cardiac index obtained within 1 month before or after the study were 13±2 mm Hg and 2.7±0.1 L·min-1·m-2, respectively. The ages of the subjects ranged from 33 to 67 years, with a mean of 55±2 years. Digoxin and diuretics, including furosemide and spironolactone, were administered orally in 17 and 12 patients, respectively. Seven patients were treated with ACE inhibitors. In 2 patients receiving nitrates, administration of the drug was discontinued at least 48 hours before the study commenced. At the time of the experiment, all patients were clinically stable with no signs or symptoms of heart failure at rest. None had gross peripheral edema or clinical evidence of peripheral vascular disease, nor did any exhibit diabetes mellitus, hypertension, or hypercholesterolemia.
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All subjects received their normal diet with their usual sodium intake, but water intake was limited several hours before the study to avoid frequent urination during the experimental period. The study was started after a light lunch had been consumed and continued for 
3.5 to 4 hours. The ambient temperature ranged from 23°C to 26°C, and changes in room temperature during each study period were within 1°C. Subjects remained in a supine position throughout the study. Cigarette smoking was prohibited during and for at least 4 hours before the study. The study protocols were approved by our hospital ethics committee, and informed consent was obtained from all subjects.
Measurement of Blood Flow
FBF was measured with a plethysmograph as described previously.23 Briefly, after forearm volume was measured by water displacement, a disposable 20-gauge arterial catheter with a guiding wire (PA-04020, Arrow International) was inserted into the brachial artery in the nondominant arm under local anesthesia (1% procainamide). A venous occlusion cuff was attached to the upper arm and a pediatric cuff to the wrist. A gallium-indium-in-silicone rubber strain gauge (model SG-24, Medasonic) was carefully placed on the upper third of the forearm and allowed to rest comfortably on a support slightly above the level of the heart. Measurement of FBF was performed as follows: after the wrist cuff was inflated to 160 to 180 mm Hg, the upper-arm cuff was inflated to 40 mm Hg by use of a rapid cuff inflator (model E20, Hokanson) for 7.5 seconds in each 15-second cycle. The mean values of the data from the final minute of the recording interval for each dose of each agent were used for statistical analysis.
Forearm SBF was measured at the same time with the use of a laser Doppler flowmeter (model ALF 2100, Advance). The probe was placed midway along the dorsal aspect of the forearm. The output signal was measured in units of voltage. The device had a 2-mW helium-neon laser and emitted monochromatic light at a wavelength of 632.8 nm. The SBF data were stored in a computer, and values obtained during the cuff-deflated period were used for statistical analysis.
After the catheter, strain gauge, and flowmeter were in place, a minimum period of 20 minutes was allowed for the subjects to become accustomed to the experimental conditions before blood flow measurements were started.
Drugs
ADM (Peptide Institute) was dissolved in 0.1% acetic acid and passed through a 0.2-µm filter for sterilization (Gelman Sci). The aliquots were kept at -80°C until immediately before infusion. L-NMMA (Calbiochem) was diluted in 5% glucose and passed through a 0.2-µm filter for sterilization immediately before experimental use. ACh was prepared for each experiment by the dilution of an Obisot vial (Dai-ich Seiyaku). ADM and ACh were diluted in 5% glucose according to a previously prepared forearm volume dilution curve, with a maximum infusion volume of 0.5 mL/min. The dose infusion time for each agent was 2 minutes.
Experimental Protocols
Study A
This protocol was followed in 18 patients with CHF and 10 age- and sex-matched healthy volunteers (Table 1
, study A). The protocol consisted of infusions of ADM and ACh in four increasing doses, with the order of the two agents randomized. After baseline recordings were completed, the agents were infused through the arterial cannula. ACh was infused at rates of 4, 8, 16, and 24 nmol·min-1·100 mL-1 tissue (0.75, 1.5, 3.0, and 4.5 µg·min-1·100 mL-1 tissue). ADM was administered in four incremental doses: 1.25, 2.5, 5.0, and 7.5 pmol·min-1·100 mL-1 tissue (7.5, 15, 30, and 45 ng·min-1·100 mL-1 tissue). After completion of the ADM infusion, FBF and SBF were measured serially at intervals of 5, 10, 20, 30, 40, and 60 minutes. To avoid the possibility of the dead-space volume containing the agents being infused, the volume was discarded promptly and replaced by a vehicle solution.
In all subjects, an indwelling cannula was inserted into an antecubital vein 5 cm below the upper-arm cuff to measure plasma concentrations of cAMP in the venous effluent from the arterially infused arm. Blood samples were taken before and within 1 minute after ADM administration. During blood sampling (usually beginning 30 seconds after upper-cuff inflation), the wrist cuff was kept inflated to avoid blood inflow from the hand circulation. The samples were promptly placed in ice and centrifuged. The plasma obtained after centrifugation was stored at -80°C. Plasma concentrations of cAMP were measured by use of a commercial radioimmunoassay kit (Yamasa Shoyu), with intra-assay and interassay variations of 4.2% and 6.2%, respectively.
Study B
This protocol was used in a further sample of 11 healthy subjects and 6 patients with CHF (Tables 1 and 2, study B). In both groups, baseline FBF and SBF were measured and the same four doses of ADM used in study A were administered via the brachial artery. When blood flow had returned to baseline values 90 minutes after cessation of the ADM infusion, 16 µmol/min (4 mg/min) of the NO synthase inhibitor L-NMMA was infused through the arterial cannula for 5 minutes. Baseline and ADM-induced FBF and SBF values were measured repeatedly by use of plethysmography and laser Doppler flowmetry, respectively.
Study C
The purpose of this protocol was to examine whether responses to sequential infusions of ADM remained unchanged in the absence of L-NMMA. Four subjects were assigned to a time-control study (Table 1) in which the four step-up doses of ADM were administered twice over the same time period as in study B but without the addition of L-NMMA. FBF and SBF were measured on two occasions at least 90 minutes apart by use of the methods described above.
Statistical Analysis
Data are presented as mean±SEM. Comparisons between baseline and postinfusion levels were made by use of one-way ANOVA and t test with the error mean square from ANOVA. The differences in FBF or SBF responses before and after L-NMMA and between groups were tested by use of two-way ANOVA for repeated measurements. Differences in baseline values between the two groups were tested by use of unpaired t test or 
2 test. Pearson's correlation coefficients were used to examine the relationship between maximum blood flow response induced by ADM and baseline characteristics. All calculated probability values are two-tailed, and a value of P<.05 was considered significant.
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Results |
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Tables 1 and 2
summarize the clinical and laboratory findings for 25 healthy volunteers and 24 patients with CHF. All subjects completed the study protocols without complications, and none were allergic to the experimental agents. No significant changes in heart rate or systemic blood pressure were found during the study protocols (Tables 3 and 4).
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Baseline Characteristics and Vascular Responses
When all data from the healthy subjects were collected (n=25), no significant relationship was found between ADM-mediated maximum FBF response and age (r=-.03), total serum cholesterol levels (r=-.03), or fasting blood sugar levels (r=-.12). There was also no correlation between these clinical parameters and maximum SBF responses to ADM (age, r=.06; total serum cholesterol levels, r=.01; fasting blood sugar levels, r=-.25). There was no significant difference in ADM-induced maximum blood flow response between women and men (FBF, 12.2±1.1 versus 11.8±0.8 mL·min-1·100 mL-1, P=NS; SBF, 0.14±0.02 versus 0.18±0.02 V, P=NS). Although plasma cAMP levels rose significantly after ADM infusion (Table 3), no correlation was found with blood flow responses (FBF, r=.20; SBF, r=.16).
When all data from the CHF patients were collected (n=24), the ADM-induced maximum increases in FBF and SBF were not significantly correlated with baseline forearm vascular resistance (FBF, r=-.22; SBF, r=-.17). No significant correlation was observed between the maximum increase in FBF or SBF and resting hemodynamic parameters. There was no significant difference in peak FBF owing to NYHA functional class (class II, 6.9±0.6 versus class III, 5.1±0.9 mL·min-1·100 mL-1 forearm volume) or origin of heart failure (valvular heart disease, from 2.4±0.4 to 6.8±1.0 mL·min-1·100 mL-1 forearm volume; primary cardiomyopathy, from 2.3±0.3 to 5.9±0.7 mL·min-1·100 mL-1 forearm volume; P=NS). The peak FBF and SBF induced by ADM in patients treated with ACE inhibitors did not differ significantly from values in patients not receiving ACE inhibitors (FBF, 6.6±1.2 versus 6.4±0.9 mL·min-1·100 mL-1 forearm volume, P=NS; SBF, 0.15±0.03 versus 0.13±0.03 V, P=NS). Venous plasma levels of cAMP obtained from the experimental arm tended to be augmented by ADM administration into the brachial artery in the CHF group (Table 3).
Comparisons of Vasodilatory Responses Between Control Subjects and CHF Patients
No significant differences in baseline characteristics such as age, sex, systolic blood pressure, heart rate, laboratory data, and smoking status were observed between the CHF group and the control group (Table 2, study A). Among the healthy control subjects, ADM increased FBF to >4x the baseline value (from 2.7±0.3 to 11.8±0.9 mL·min-1·100 mL-1 tissue; P<.01); in contrast, the increase in FBF among patients with CHF was <3x the baseline value (from 2.4±0.3 to 6.5±0.7 mL·min-1·100 mL-1 tissue; P<.01) (Fig 1). A subsequent two-way ANOVA indicated that the ADM-induced FBF response was significantly impaired in the patient group (P<.01). The increase in FBF after ADM infusion in the control group was sustained for >60 minutes, whereas in patients with CHF, the response returned to the baseline value within 30 minutes after cessation of infusion (Fig 1). The calculated physiological half-time of the decremental effect of FBF tended to be shorter in CHF patients than in control subjects (10.3±2.1 versus 18.1±4.0 minutes; P=.06).
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) and 18 patients with CHF (
). *P<.05, **P<.01 versus baseline.
Infusion of ADM increased SBF significantly in both groups (control group, from 0.09±0.01 to 0.17±0.03 V, P<.05; CHF group, from 0.09±0.01 to 0.14±0.02 V, P<.05) (Fig 2). SBF responses were significantly impaired in patients with CHF compared with healthy subjects (P<.01 by two-way ANOVA), but there was no significant difference in the decay curve after cessation of ADM between the two groups. In both groups, SBF returned to baseline values within 20 minutes after infusion ceased.
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Intra-arterial infusion of the 4-, 8-, 16-, and 24-nmol·min-1·100 mL-1 forearm volume doses of ACh increased FBF to 2.7±0.5, 4.1±1.2, 7.9±1.4, and 16.1±1.0 mL·min-1·100 mL-1 in the normal group and 2.6±0.3, 3.1±0.5, 5.2±0.8, and 10.7±1.8 mL·min-1·100 mL-1 in CHF patients, respectively. Changes in FBF due to ACh were significantly impaired in CHF patients compared with the control group (P<.01) (Table 2). On a molar basis, ADM was significantly more potent than ACh (ie, on the order of picomoles versus nanomoles).
Effects of NO Synthase Blockade on Vasodilatory Responses
As shown in Table 4, baseline FBF and SBF decreased in both groups after L-NMMA infusion. Fig 3 indicates that the NO synthase inhibitor significantly blunted changes in FBF relative to baseline values during ADM infusion in the control group (P<.02), whereas ADM-induced FBF response did not differ before and after L-NMMA infusion. Similarly, L-NMMA significantly inhibited changes in SBF above baseline values during ADM infusion (P<.05), whereas no effect on SBF was observed in the CHF group (Fig 4).
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The time-control study of sequential ADM administration shows similar dose-response data for FBF and SBF (Table 5).
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Discussion |
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The present study has demonstrated for the first time that in human peripheral vessels, infusion of picomolar amounts of ADM causes rapid and long-lasting vasorelaxation of skeletal muscle arteries, with some partial involvement of NO mechanisms. We have also demonstrated that these vascular effects are significantly attenuated in the resistance vessels of patients with CHF.
Intravenous administration of ADM in rats has been shown to induce prolonged hypotension lasting >30 minutes.1 In contrast to this sustained vascular effect, the vasodilatory effects of human ADM on rat mesenteric artery disappear within 10 minutes.24 In cats, baseline values are restored in the hindlimb vascular bed within 2 minutes, or 10-fold less potent than ACh,25 and in the pulmonary vascular bed within several minutes.26 A recent report indicates that the pulmonary vasodilatory potency of ADM differs in these two animals.27 It has also been shown that the systemic hemodynamic effects of a prohormone of ADM are species specific.28 These data suggest that the vascular effects of ADM may vary with the species and region of the vascular bed studied. To estimate the concentration of ADM necessary to cause vasorelaxation in normal human peripheral vasculature, the circulating ADM concentration in the forearm vascular bed during intra-arterial infusion of ADM can be calculated from the forearm volume (eg, 1000 mL) and peak FBF (eg, 10 mL·min-1·100 mL-1 tissue volume) at a given dose of ADM (eg, 7.5 pmol·min-1·100 mL-1). According to the examples given above, circulating levels of ADM in the vascular bed would be calculated to be <10-9 mol/L (750 pmol/L). This concentration is clearly lower than that observed in isolated rat mesenteric artery, in which the half-maximal value of vasodilation for ADM has been reported to be >10-8 mol/L.24 Furthermore, in the present study, the peripheral vascular effect in humans continued for >60 minutes, and the vasodilatory potency of ADM on a molar basis was clearly higher than that of ACh. These observations indicate that human ADM exhibits rapid onset and long-lasting vasodilatory potency in human peripheral vessels.
It has been shown that ADM increases cAMP levels in platelets and in cultured vascular smooth muscle cells.1 14 15 16 It is therefore possible that ADM may relax vascular smooth muscle by increasing the level of intracellular cAMP. However, although blood flow was significantly elevated in both patients and normal control subjects in the present study, no significant relationship was observed between increases in FBF or SBF and plasma cAMP concentrations in the venous effluent. A possible explanation for this lack of relationship could be the fact that plasma cAMP measurement in venous effluent may not be a sensitive way to estimate alterations in cAMP levels in vascular smooth muscle cells. Alternatively, the dose of ADM may have been insufficient to produce a cAMP-induced full vasodilatory response in the peripheral vessels, and thus other vasodilator mechanisms may be involved in the ADM-induced vascular effects.
Overall blood flow changes in the forearm vasculature, including skeletal muscle, skin, and bone, were determined by venous occlusion plethysmography. Forearm SBF changes were measured simultaneously by use of laser Doppler flowmetry. Because the percentage of blood flow in connective tissue and bone is relatively small in the forearm, these measurements permitted us to predict skeletal muscle blood flow change by subtracting changes in SBF from those of FBF. Because ADM infusion increased FBF to >4x the baseline value with only a relatively smaller elevation in forearm SBF, it appears that ADM predominantly dilates skeletal muscle arteries in the human forearm vascular bed.
It has been postulated that elevated vascular tone of intramuscular resistance vessels in CHF increases cardiac afterload and reduces the supply of nutritive blood flow to working skeletal muscle. One of the mechanisms underlying this elevation in vascular tone may be an increase in the release of vasoconstricting factors such as catecholamine, angiotensin II, and endothelin. Another may be an attenuation in vascular response to vasodilative factors such as natriuretic peptides and the NO stimulator ACh .21 22 23 However, no studies have yet determined whether the potent and prolonged vasodilatory effects induced by ADM are impaired or preserved in the resistance vessels of patients with CHF. We have demonstrated a clear impairment of the vasodilatory effects of ADM in the limb vascular bed in patients with CHF. Although definite mechanisms for the attenuation of ADM-induced vasodilation in this patient group could not be established, the following possibilities may be worthy of consideration.
First, we have demonstrated that FBF and SBF responses induced by the maximum dose of ADM were significantly reduced by NO synthase inhibitors in healthy subjects. This finding is consistent with previous experimental studies using animals.18 19 20 The present observation suggests that a relatively high dose of ADM stimulates NO production from vascular tissue, indicating that NO may be partially involved in ADM-induced vasodilation. However, this NO-dependent vasodilatory mechanism was found to be impaired in patients with CHF. In fact, several recent studies have demonstrated that agonist-induced NO production from the endothelium is impaired in the forearm vascular bed of patients with CHF.21 22 These observations suggest indirectly that the impaired vascular response induced by ADM in patients with CHF may be attributable in part to vascular endothelial dysfunction. Second, because circulating levels of the peptide have been reported to be elevated, there may be ADM-specific receptor downregulation as suggested in an example of the effect of atrial natriuretic peptide on the peripheral vascular bed in heart failure.23 29 Third, although most of the patients in the present study had been receiving diuretics for several months and none had gross peripheral edema at the time of the study, subclinical sodium and water retention in the vascular tissue may have contributed in part to the outcome. Last, microvascular structural changes in the skeletal muscle and skin as demonstrated in patients with heart failure due to cardiomyopathy30 may reduce the vasodilatory effect of ADM in resistance vessels.
In perfused rat heart, Szokodi et al31 demonstrated that ADM exerts a potent positive inotropic action. Several other studies2 32 also indicated that systemic infusion in mammals increases cardiac output and stroke volume, suggesting that ADM has a direct action on the heart. Furthermore, intrarenal arterial infusion of ADM increases renal blood flow or glomerular filtration rate, causing diuresis and natriuresis in dogs.33 34 Considered in conjunction with the present findings, these observations suggest that ADM may have a unique biological nature involving a combination of potent vasodilatory effects, positive inotropic action, and a renal excretory effect. In addition, several recent reports have shown abundant expression of ADM mRNA and immunoreactivity in cultured vascular smooth muscle tissues, failing human heart, and kidney.3 4 5 7 8 9 35 The production of ADM from cultured smooth muscle cells is stimulated by cytokines such as interleukin-1ß and tumor necrosis factor-
.7 8 Indeed, it has been reported that plasma cytokine levels are elevated in patients with CHF,36 37 a condition characterized by elevated circulating levels of ADM.10 11 12 We therefore hypothesize that although the vasodilatory potency of ADM is blunted in the peripheral vascular bed of patients with CHF, this peptide may be an important paracrine factor in the regulation of cardiovascular and renal function in this pathophysiological condition.
Conclusions
We have found that picomolar doses of ADM induce potent and prolonged increases in skeletal muscle blood flow in human peripheral vasculature. Given the potent vasorelaxing action of this peptide, we suggest that ADM may be involved in the regulation of vascular tone in humans and that there may be impairment of ADM-mediated vasomotor control in the limb resistance vessels of patients with CHF. These observations may provide new information contributing to the clarification of the pathophysiology of heightened afterload in CHF and may have important implications in the quest for a new therapeutic approach to the regulation of local metabolism or circulating levels of the peptide.
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Acknowledgments |
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This study was supported in part by a grant-in-aid for general scientific research from the Japanese Ministry of Education, Science and Culture (No. 07670802) and by a grant from Keiryoukai Research Foundation (No. 57). We thank Dr Yoshihiro Inoue (Critical Care and Emergency Center, Iwate Medical University) for his kind advice regarding the use of the laser Doppler flowmeter.
Received August 28, 1996; revision received October 17, 1996; accepted October 23, 1996.
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