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Impaired Vasodilatation Response to Amrinone in the Forearm of Patients with Congestive Heart Failure: Role of Endothelium-Derived Nitric Oxide

Sakane, Takeshi; Ishibashi, Yutaka; Shimada, Toshio; Takahashi, Nobuyuki; Sugamori, Takashi; Hirano, Yoshifumi; Ohata, Shuzo; Inoue, Shin-ichi; Nakamura, Ko; Murakami, Yo

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Journal of Cardiovascular Pharmacology: August 2000 - Volume 36 - Issue 2 - p 188-195
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Abstract

Amrinone, a specific type III phosphodiesterase (PDE-III) inhibitor, has positive inotropic (1,2) and potent direct vasodilating properties (3,4) and has been found to have favorable hemodynamic effects in the treatment of congestive heart failure (CHF) (5,6) and pulmonary hypertension (7-9). It acts directly on the myocardium and peripheral vessels through the intracellular accumulation of adenosine 3′:5′-cyclic monophosphate (cAMP) by selectively blocking its hydrolysis (10).

Recent in vitro experiments have shown that amrinone enhances the release of nitric oxide (NO) from the endothelium and induces NO mediated vasodilatation (11). The purpose of this in vivo study was to examine whether, in healthy human subjects, amrinone causes vasodilatation mediated by endothelium-derived NO, and whether these effects are attenuated in patients with CHF whose endothelial function has been reported to be impaired (12).

METHODS

Study population

The study population consisted of eight patients with CHF (six men and two women; mean age, 60 ± 10 years) and 17 healthy control subjects who volunteered for the study (10 men and seven women; mean age, 56 ± 17 years). There were no significant differences between the two study groups. The proposal was approved by Medical Ethics Committee of the Shimane Medical University Hospital. After a detailed explanation of the protocol, written informed consent was obtained from each study participant.

Among the eight patients with CHF, six had dilated cardiomyopathy and two had valvular heart disease with moderate or severe left ventricular dysfunction, confirmed by echocardiography and cardiac catheterization (Table 1). No patient had hypertension, hyperlipidemia, diabetes mellitus, or peripheral vascular disease. All were mildly or moderately symptomatic, in New York Heart Association functional class II or III. They were instructed to discontinue all vasodilating medications, anticoagulation, and digitalis 3 days before the day of the study, and to discontinue diuretics on the day of the study. During that period, the patients were closely monitored for any sign of decompensated heart failure.

TABLE 1
TABLE 1:
Clinical and hemodynamic characteristics of patients with congestive heart failure

Each normal volunteer was screened by history, physical examination, electrocardiogram, chest roentgenogram, echocardiogram, and routine chemical analysis. None had current or past hypertension, hyperlipidemia, diabetes mellitus, cardiovascular disease, or any other systemic illness, and none was taking medications at the time of the study. Smokers, whether in the patient or in the control group, were excluded from this study.

Study procedures

All participants were instructed to abstain from eating food and from drinking caffeinated beverages for ≥12 h before the study, which was performed in the supine position in an air-conditioned room at a temperature of 25-26°C. Under local anesthesia with 1% lidocaine, the left brachial artery was cannulated with a 22-gauge intravascular over-the-needle polycatheter (RA-4122; Arrow International Inc., Reading, PA, U.S.A.) for drug infusion, and the catheter was connected by a three-way stopcock to a pressure transducer for direct measurement of arterial pressure. The arterial line was kept open by infusing heparinized saline (0.1 ml/min) when no drug was administered. The antecubital veins of both arms were cannulated with a 22-gauge cannula (Angiocath; Becton Dickinson Inc., Sandy, UT, U.S.A.) to collect blood samples for measurement of amrinone plasma concentration. Heart rate was measured by continuous electrocardiographic monitoring.

Measurements of forearm blood flow

Forearm blood flow (FBF) was measured with mercury-in-Silastic strain gauge plethysmography (EC-5; Hokanson Inc., Bellevue, WA, U.S.A.) by a venous occlusion technique. The strain gauge was placed ∼5 cm below the antecubital crease. The arm was slightly elevated above the level of the right atrium, and the mercury-in-Silastic strain gauge was connected to the plethysmograph calibrated to measure the percentage change in volume, and interfaced with a chart recorder to record the flow measurements. FBF (ml/min/100 ml forearm tissue) was calculated from the rate of increase in forearm volume while venous return from the forearm was prevented by inflating a cuff placed on the arm proximally. For each measurement, the proximal cuff was inflated to 40 mm Hg with a rapid cuff inflator (E-10; Hokanson Inc.) to occlude venous outflow from the extremity. Circulation to the hand was arrested by a cuff inflated around the wrist. The wrist cuff was inflated to suprasystolic pressures 1 min before each measurement of FBF and continuously throughout the measurements. Flow measurements were performed for 5 s every 15 s. Forearm vascular resistance (FVR), expressed as mm Hg/ml/min/100 ml forearm tissue, was calculated by dividing the mean arterial pressure (diastolic pressure plus one third of the pulse pressure) by the FBF. An average of four flow measurements made at 15-s intervals, calculated independently by two of the authors, was used for the analysis.

Study protocol

After placements of the cannulas and strain gauge, ∼30 min was allowed for the participants to become accustomed to the study conditions before the experiments began.

Vascular responses to acetylcholine, amrinone, and nitroglycerin. FBF responses to intraarterial infusions of acetylcholine, amrinone, and nitroglycerin were examined in eight patients with CHF and 10 age- and sex-matched control subjects. Baseline measurements were performed before the intraarterial infusion of drugs and were repeated during infusions of acetylcholine, amrinone, and nitroglycerin. Acetylcholine was infused in doses of 3.75, 7.5, 15, and 30 μg/min, amrinone in doses of 12.5, 25, 50, 100, and 200 μg/min, and nitroglycerin in doses of 12.5, 25, and 50 μg/min. Each dose was infused for 4 min, and FBF was measured during the last 2 min. The order of drug was randomized to eliminate biases related to the sequence of drug infusion, and the study participants were blinded to the drug being infused. Blood pressure was recorded directly from the intraarterial catheter after each flow measurement.

After completion of the measurements made during incremental infusion of the first drug, the study participants rested until FBF had returned to baseline (∼40 min), after which the next drug was tested. After the completion of FBF measurements at each dose of the second drug, an ∼40-min resting period was allowed again for the return of FBF to baseline. Thereafter, FBF response to third drug was tested. Sixty minutes after the completion of these measurements, 100 μmol of NG-monomethyl-L-arginine (L-NMMA; Clinalfa Co., Läufelfingen, Switzerland), a blocker of endogenous NO synthesis, was infused intraarterially over a period of 5 min. Five minutes later, measurements of FBF were repeated, followed by measurements of FBF during administration of amrinone in incremental doses, as described earlier.

Degree and duration of inhibition of NO synthesis by L-NMMA. The magnitude of L-NMMA as an NO synthesis inhibitor was assessed in seven control subjects. For this purpose, we measured the increases in FBF produced by intraarterial infusion of acetylcholine (3.75, 7.5, and 15 μg/min). After completion of this measurements, L-NMMA was administered intraarterially in an dose of 100 μmol over a period of 5 min. Five minutes later, FBF response to intraarterial infusion of acetylcholine (3.75-15 μg/min) was repeated. To establish the duration of blocking effect of NO synthesis by L-NMMA, we repeatedly examined FBF response to intraarterial infusion of 15 μg/min of acetylcholine before and 5, 10, 20, 30, and 40 min after the administration of 100 μmol of L-NMMA in five control subjects on a different day.

Measurements of plasma amrinone concentration

In all study participants, 4-5 ml of blood was collected from the antecubital vein of both forearms for measurements of amrinone plasma concentration before and during infusion of amrinone in doses of 12.5-200 μg/min. Blood was immediately centrifuged, frozen, and later measured by a commercial laboratory (Health Sciences Research Institute Inc., Yokohama, Japan).

Solution of drugs and infusion

Acetylcholine (Daiichi Pharmaceutical Co., Tokyo, Japan), nitroglycerin (Nihonkayaku Co., Tokyo, Japan), and amrinone (Meiji Pharmaceutical Co., Tokyo, Japan) were dissolved in 0.9% saline. The dose of drug infusion was altered by changing infusion volume. The maximal infusion volume for the maximal dose of each drug was 0.5 ml/min. We confirmed in preliminary experiments that infusion of saline at 0.5 ml/min did not affect forearm blood flow (not shown).

Statistical analysis

Changes in FBF and FVR were expressed as percentage changes from baseline values. The unpaired Student's t test was used to compare the changes in FBF in control subjects versus patients with CHF. Within-group responses before and after L-NMMA were compared by paired Student's t test. The effect of drug on the relation between two variable was analyzed by analysis of covariance (ANCOVA). All data are expressed as mean ± standard deviation. A p value <0.05 was considered statistically significant.

RESULTS

Degree and duration of NO inhibition by L-NMMA

FBF increased from 3.12 ± 1.12 ml/min/100 ml at baseline to 18.68 ± 5.42 ml/min/100 ml during infusion of acetylcholine at a dose of 15 μg/min (Fig. 1, left). After L-NMMA, The basal FBF significantly decreased to 2.46 ± 0.98 ml/min/100 ml, and this dose of acetylcholine increased FBF to 9.23 ± 2.56 ml/min/100 ml, representing 51 ± 5% inhibition of the response to acetylcholine. The significant depression of increase in FBF response to intraarterial infusion of 15 μg/min of acetylcholine by L-NMMA lasted until ≥30 min after the administration of L-NMMA (Fig. 1, right).

FIG. 1
FIG. 1:
Effects of NO synthesis blockade on the increase in forearm blood flow produced by intraarterial infusion of acetylcholine in seven control subjects, and the duration of blocking effect in five control subjects. Shown are the dose-response curves before (open circles) and after (solid circles) the administration ofNG-monomethyl-L-arginine (L-NMMA; left), and forearm blood flow responses to intraarterial infusion of 15 μg/min of acetylcholine (Ach; arrow) before (open circles) and 5, 10, 20, 30, and 40 min after (solid circles) the administration of L-NMMA (right). Data are expressed as mean ± SD. *p < 0.01 versus before L-NMMA with ANCOVA; †p < 0.01 versus before L-NMMA with paired t test.

Amrinone plasma concentration before and after L-NMMA

Infusion of incremental doses of amrinone caused a progressive increase in amrinone plasma concentration at the ipsilateral forearm in both groups (Fig. 2), reaching 1.0 μg/ml at infusion rates >100 μg/min. Significant differences in amrinone plasma concentrations were found between neither control subjects and patients nor before and after infusion of L-NMMA.

FIG. 2
FIG. 2:
Amrinone plasma concentrations before (open circles) and after (solid circles)NG-monomethyl-L-arginine (L-NMMA) in control subjects (Control; left) and in patients with congestive heart failure (CHF; right) during intraarterial infusions of incremental doses of amrinone. Data are expressed as mean ± SD.

Amrinone plasma concentrations obtained from the contralateral forearm vein were <0.01 μg/ml at the maximal infusion rate of 200 μg/min in all study participants, which suggests that the infusion rates used in this study had no influence on systemic hemodynamics.

Vascular responses to acetylcholine and nitroglycerin

Baseline FBF was comparable in control subjects versus patients (3.2 ± 0.79 vs. 2.91 ± 0.79 ml/min/100 ml, respectively; p = 0.43). None of the drugs infused produced changes in systemic blood pressure or heart rate.

In both groups, FBF increased progressively in response to increasing of acetylcholine and nitroglycerin (Fig. 3). The magnitude of increase in FBF in response to acetylcholine was less in patients than in control subjects. During infusion of the highest dose of acetylcholine, FBF in control subjects and patients were 24.87 ± 8.65 and 9.75 ± 2.69 ml/min/100 ml, respectively (p < 0.01). In contrast, the magnitude of increase in FBF in response to nitroglycerin did not differ between the two groups. During infusion of the highest dose of nitroglycerin, FBF was 12.58 ± 4.76 ml/min/100 ml in control subjects versus 11.25 ± 3.49 ml/min/100 ml in patients (p = 0.51).

FIG. 3
FIG. 3:
Increases in forearm blood flow in response to intraarterial infusions of incremental doses of acetylcholine(left) and nitroglycerin (right) in control subjects (open circles) and patients with congestive heart failure (solid circles). Data are expressed as mean ± SD. *p < 0.01 versus Control with ANCOVA.

Vascular responses to amrinone before and after L-NMMA

Amrinone affected systemic blood pressure or heart rate in neither group. Incremental doses of amrinone caused increases in FBF and decreases in FVR. In control subjects, amrinone significantly increased FBF from 3.06 ± 1.24 ml/min/100 ml at baseline to 7.15 ± 2.06 ml/min/100 ml during the infusion of 200 μg/min (p < 0.001). In patients, amrinone increased FBF from 2.29 ± 1.07 ml/min/100 ml at baseline to 3.79 ± 1.21 ml/min/100 ml during infusion of the highest dose (p < 0.001). The percentage increase in FBF between baseline and infusion of the highest dose of amrinone was less in patients than in control subjects (65 ± 40% vs. 134 ± 27%, respectively; p < 0.05). These findings indicate that the vasodilating effect of amrinone was blunted in patients with CHF.

Infusion of L-NMMA did not change systemic blood pressure or heart rate in either control subjects or patients. L-NMMA significantly decreased baseline FBF to 2.44 ± 0.85 ml/min/100 ml in control subjects (p < 0.01) and to 1.61 ± 0.74 ml/min/100 ml in patients with CHF (p < 0.01). The percentage decreases in FBF by L-NMMA were larger in patients with CHF (29.7%) than in control subjects (20.3%). The increase in FBF in response to the infusion of incremental doses of amrinone was significantly depressed by L-NMMA in control subjects (Fig. 4, left). In patients, however, although L-NMMA tended to blunt the response to amrinone infusion, its effect was not statistically significant (Fig. 4, right). Figure 5 shows the amrinone-induced percentage increases from baseline in FBF, before and after L-NMMA, in control subjects and in patients. In controls, the percentage increases in FBF were significantly depressed by L-NMMA at the lower doses of amrinone, whereas at the highest dose, the difference was not statistically significant (Fig. 5, left). In contrast, in patients, comparisons of the differences in amrinone-induced percentage increases in FBF measured before and after L-NMMA were insignificant (Fig. 5, right).

FIG. 4
FIG. 4:
Increases in forearm blood flow in response to intraarterial infusions of incremental doses of amrinone before (open circles) and after (solid circles)NG-monomethyl-L-arginine (L-NMMA) in control subjects (Control; left) and patients with congestive heart failure (CHF; right). Data are expressed as mean ± SD. *p < 0.05 versus before L-NMMA with ANCOVA.
FIG. 5
FIG. 5:
Percentage changes in forearm blood flow (FBF) in response to intraarterial infusions of incremental doses of amrinone before (open bars) and after (solid bars)NG-monomethyl-L-arginine (L-NMMA) in control subjects (Control; left) and patients with congestive heart failure (CHF; right). Data are expressed as mean ± SD. *p < 0.01 versus before L-NMMA with paired t test.

DISCUSSION

This study demonstrates that, although amrinone had vasodilating effects in both control subjects and patients with CHF, this effect is depressed in patients. NO synthesis inhibition by L-NMMA attenuated significantly the increase in FBF produced by amrinone in control subjects, whereas it had little effect in patients, whose response to acetylcholine was impaired. These observations are in support of an endothelium-derived NO-mediated vasodilating effect of amrinone, as opposed to its small or absent effect in patients with endothelial dysfunction.

Methodologic considerations

In this study, L-NMMA was used to inhibit endogenous NO synthesis. L-NMMA in a dose of 100 μmol caused ∼50% inhibition of the vasodilator response to the endothelium-dependent vasodilator acetylcholine. This is consistent with previous studies in the human forearm that L-NMMA caused 25-60% inhibition of the response to acetylcholine (13-16). The degree of blockade persisted 30 min after the administration of L-NMMA. In our study, vasodilator response to amrinone was repeated after the administration of L-NMMA. This measurement required ∼30 min to complete. Thus, NO-mediated vasodilation would have been adequately blocked until completion of this protocol.

Vasodilating effect of amrinone: NO mediated or not?

This study indicates that the vasodilating effect of amrinone in human vessels involves the pathway of endothelium-derived NO. However, whether the vasodilating effect of amrinone is NO mediated remains controversial. Table 2 summarizes previous in vitro and in vivo studies that have examined the contribution of endothelium-derived NO to the vasodilating effect of amrinone. In 1987, Kauffman et al. (17) suggested a modulation of NO release from the endothelium by PDE inhibitors. Later, Clarke and Soltow (18) first demonstrated in an in vitro study of rat pulmonary arteries, with and without endothelium, that amrinone caused vasodilatation by both endothelium-dependent and -independent mechanisms. Thereafter, Mori et al. (11) found that the relaxation of rat aortic ring produced by amrinone was reversed by the NO synthesis inhibitor, NG-nitro-L-arginine (L-NNA), and further documented the production of NO in ring segments of aorta with NO-selective electrodes and the electron paramagnetic resonance spin-trapping method. These investigations are in support of our results.

TABLE 2
TABLE 2:
Role of endothelium-derived NO in amrinone-induced vasodilatation in previous studies

Conversely, Lee and Hou (19) showed that amrinone caused marked vasodilatation of isolated rabbit aorta and pulmonary arteries contracted by norepinephrine or potassium chloride, although the vasodilating response did not differ in the presence versus the absence of endothelium. Furthermore, an in vitro study in human vessels found that, although vasodilatation by milrinone, another PDE inhibitor, was partially endothelium dependent, that of amrinone was not (20). Hemida et al. (21) examined the effects of amrinone on systemic hemodynamics in anesthetized rats, before and after NO synthesis inhibition by NG-nitro-L-arginine methyl ester (L-NAME). In that study, the decrease in systemic vascular resistance caused by amrinone was not prevented by L-NAME. These observations are not consistent with our results. However, a close examination of the in vivo study by Hemida et al. (21) reveals that the lowering effect of low dose of amrinone on systemic vascular resistance was significantly diminished by L-NAME, from −24 ± 1% to −9 ± 4%, suggesting that the vasodilating effects of amrinone in low doses might have been mediated by endothelium-derived NO. In our study, the blocking effects on amrinone-induced vasodilatation by L-NMMA were observed at the lower doses (≤100 μg/min), a finding consistent with the observations of Hemida et al.

The mechanism of NO-mediated vasodilatation of amrinone is difficult to ascertain from our results. Putative mechanisms of NO release include elevated shear stress by increased FBF during amrinone infusion, and direct production of NO induced by amrinone. The observation of a lesser increase in FBF by NO synthesis inhibition at the lower doses, but not at the highest dose of amrinone, suggests that NO release secondary to flow-dependent vasodilatation is not the main mechanism. However, the possibility that NO-mediated vasodilatation was masked by a direct effect of amrinone on vascular smooth muscle cannot be excluded, because an increase in FBF tended to be depressed after L-NMMA, even at the highest dose. As an alternate mechanism, an increase in endothelial cAMP induced by amrinone could enhance NO production, although the functional role of cAMP in vascular endothelial cells remains controversial (22-24). Mori et al. (11), using a electron paramagnetic response spintrapping method, have demonstrated the direct production of NO by increased cAMP induced by forskolin, a stimulator of adenylate cyclase.

From this review, we believe that amrinone has both endothelium-derived NO-mediated, and endothelium-independent vasodilating properties in human vessels in vivo, although further studies are in order.

Impaired vasodilatation in patients with CHF

In this study, the vasodilating response to amrinone was impaired in patients with CHF compared with healthy volunteers. In these patients, endothelium-dependent vasodilatation stimulated by acetylcholine also was depressed, as previously reported (25-28). Conversely, the percentage decreases in FBF by L-NMMA at baseline were larger in patients with CHF than in control subjects. These data indicated that the contribution of NO on basal tone in patients with CHF was greater compared with that in control subjects. This results were similar to the previous reports (29,30).

We showed that amrinone has in part endothelium-dependent vasodilating effects in control subjects. Thus, the impaired amrinone-induced vasodilatation in patients with CHF may be due to impaired endothelial function, resulting in the reduced vasodilatory reverse, because the endothelium-independent vasodilatation induced by nitroglycerin was not different in patients versus control subjects. The finding that NO synthesis inhibition did not attenuate the amrinone-induced vasodilatation in patients is in support of this possibility.

Although vasoactive drugs were discontinued 3 days before the study, residual effects of these drugs may have played a role in the attenuated amrinone-induced vasodilatation in patients with CHF. Jondeau et al. (6) reported that digitalis glycosides decrease the direct vasodilating effect induced by PDE-III inhibition with amrinone in superficial femoral arteries of patients with CHF. Inhibition of the Na,K-ATPase pump by digitalis glycosides may cause an increase in intracellular calcium concentration, which offsets the lower affinity of myosin light-chain kinase for the calcium-calmodulin complex and/or the decrease in intracellular calcium concentration induced by PDE-III inhibition.

Finally, it is possible that a defect at the receptor and postreceptor levels of adenylate cyclase decreases the effectiveness of cAMP-increasing agents in patients with CHF. Reithmann et al. (31) demonstrated that β-adrenoceptor-stimulated adenylate cyclase activity was decreased by 65% in patients with severe heart failure in comparison to patients with no or mild heart failure. In addition, receptor-independent adenylate cyclase stimulation by forskolin was reduced by 52% in patients with severe heart failure.

This study did not identify the predominant cause of the decreased vasodilating effect of amrinone in patients with CHF.

Clinical implications

This study showed both endothelium-dependent and -independent vasodilating effects of amrinone on peripheral vessels, as well as a lesser increase in blood flow in response to amrinone in patients with endothelial dysfunction. Impaired endothelium-derived NO-mediated vasodilator responses have been observed in patients with hypertension (32,33), hypercholesterolemia (14), or diabetes (34). Our findings suggest that the beneficial effects of amrinone could be reduced in such patients.

The plasma concentrations of amrinone at which beneficial hemodynamic effects may be expected in the treatment of heart failure have been proposed to be >1.0 μg/ml (35). Our results, however, showed a dose-dependent drug-induced vascular relaxation, apparent even at the lowest concentration, suggesting efficacy of amrinone as a vasodilator, as well as, in addition to the drug's direct effects, an important role played by the endothelium in vascular relaxation caused by low doses of amrinone. Endothelial function may, therefore, have to be considered when treating patients with risk factors for atherosclerosis, particularly ischemic heart failure.

In conclusion, the selective PDE-III inhibitor, amrinone, has endothelium-derived NO-mediated vasodilating effects in addition to its direct effects. This beneficial property may be impaired in patients with CHF.

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Keywords:

Amrinone; Congestive heart failure; Vasodilatation; Endothelium; Nitric oxide

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