Amrinone is a phosphodiesterase III inhibitor that has positive inotropic and vasodilating effects via increasing intracellular adenosine 3′,5′-cyclic monophosphate (cAMP; 1,2). It is widely used to treat patients with congestive heart failure (CHF; 3,4), especially those patients with secondary pulmonary hypertension (5-7). Although the effects of amrinone on the pulmonary and the systemic vascular resistance have been investigated (5,6,8,9), the contribution of its vasodilatory action to its beneficial effect on ventricular function in congestive heart failure is not fully understood.
Studies have shown that levels of some vasoconstrictive neurohormonal factors, such as endothelin-1 (10,11) and norepinephrine (12,13), are increased in patients with CHF. The contribution of these factors to increases in the pulmonary and the systemic vascular resistance in evolving CHF has not been elucidated.
We investigated the hemodynamic effects of amrinone on pulmonary and systemic circulations and assessed the influence of amrinone on concentrations of vasoconstrictive neurohormonal factors in patients with evolving CHF.
We investigated 15 patients (10 men and five women; mean age, 65 ± 11 years) with evolving CHF who were treated at emergency departments for acute onset of CHF or acute worsening of chronic CHF. The diagnosis was dilated cardiomyopathy in four patients, valvular heart disease in five patients, ischemic heart disease in three patients, and hypertensive heart disease in three patients. Nine of them were treated with diuretic drugs and digitalis, and five also received angiotensin-converting enzyme inhibitor until admission to emergency departments. All drugs were discontinued ≥6 h before the study. Oral informed consent for participation in the study was obtained from all patients.
After right-sided cardiac catheterization was performed by using a balloon-tipped thermodilution catheter (7F Swan-Ganz catheter), amrinone was administered intravenously with an initial loading dose of 1 mg/kg body weight followed by a 60-min infusion at a rate of 10 μg/kg/min. Blood samples for measurement of the plasma concentrations of norepinephrine, atrial natriueretic peptide angiotensin II, and endothelin-1 were obtained from the pulmonary capillary wedge region (PCWR) and the peripheral vein just before and 30 and 60 min after initiation of the amrinone infusion. Pulmonary and systemic vascular-resistance indices (PVRI and SVRI (Wood U × m2)) and right and left heart stroke-work indices (RVSWI and LVSWI (g × m/m2) were measured when blood samples were obtained. Plasma concentrations of endothelin-1 (14), atrial natriuretic peptide (15), and angiotensin II (16) were measured by radioimmunoassays, according to previously described methods. The plasma concentration of norepinephrine was measured by high-performance liquid chromatography. No other drugs, such as diuretics, positive inotropic agents, and vasodilating agents, were administered during the study.
Before amrinone infusion, we divided the subjects in three groups: group I (n = 6) had a PVRI ≥15 Wood U × m2, group II (n = 5) had a PVRI <15 Wood U × m2 and an SVRI ≥50 Wood U × m2, and group III (n = 4), who had a PVRI <15 Wood U × m2 and an SVRI <50 Wood U × m2.
Data are presented as the mean ± standard deviation. They were analyzed by one-way analysis of variance (ANOVA). Changes in concentrations of neurohormonal factors and hemodynamic parameters were assessed by the paired t test. Linear-regression analysis was used to determine the correlations between PVRI or SVRI and concentrations of neurohormonal factors. A p value <0.05 was accepted as the level of statistical significance.
Effects of amrinone on hemodynamics
The mean pulmonary artery pressure (mPA) and pulmonary capillary wedge pressure (PCWP) decreased significantly, and the cardiac index (CI) increased significantly 30 min after initiation or infusion of amrinone in the subjects (Table 1).
In group I, mPA, PCWP, and the mean right atrial pressure (mRA) decreased significantly, and CI increased significantly 60 min after the initiation. In group II, although mPA and mRA decreased mildly but not significantly within 60 min after the initiation, PCWP decreased and CI increased promptly and significantly after the initiation. In group III, only PCWP decreased significantly after the initiation. There was no significant change in heart rate and mean systemic blood pressure (Table 1).
Amrinone induced a prompt and significant reduction in PVRI in group I, a prompt and significant decrease in SVRI in association with a slight decrease in PVRI in group II, and had no discernible effects on PVRI and SVRI in group III (Figs. 1 and 2). Amrinone did not significantly increase RVSWI or LVSWI (Fig. 2).
Correlations between hemodynamic parameters and changes in neurohormonal factors
Plasma levels of norepinephrine, atrial natriuretic peptide, and endothelin-1 in the PCWR and the peripheral vein were markedly increased, and the level of angiotensin II was slightly increased before treatment. Plasma levels of norepinephrine, atrial natriuretic peptide, and endothelin-1 decreased rapidly after infusion of amrinone (Table 2). In the PCWR, the PVRI was correlated with the endothelin-1 level (r = 0.75) but not with norepinephrine level (Fig. 3). In the peripheral vein, the SVRI was correlated with the norepinephrine level (r = 0.70) but not with the endothelin-1 level (Fig. 4). Neither PVRI nor SVRI was correlated with levels of epinephrine and atrial natriuretic peptide. There was no change in the angiotensin II level throughout the study.
Hemodynamic effects of amrinone in patients with evolving CHF
Although amrinone is widely used to improve hemodynamics in patients with CHF and the vasodilating effects of amrinone are well known (1,2), its selective systemic and pulmonary vasodilating effects have not been determined except in children (6,17). Robinson et al. (6) reported that the selective pulmonary vasodilating effect of amrinone, depending on the pulmonary artery pressure and resistance before infusion, improved hemodynamics in children with left-to-right shunt. In our study, the selective hemodynamic effects of amrinone on systemic and pulmonary circulations in adult patients with evolving CHF were related to the subjects' pretreatment PVRIs and SVRIs. Amrinone reduced PVRI in patients with a PVRI ≥15 Wood U × m2 and reduced SVRI in patients with an SVRI ≥50 Wood U × m2 and a PVRI <15 Wood U × m2. Amrinone had few or no effects on the PVRI, SVRI, and CI in patients with a PVRI <15 Wood U × m2 and an SVRI <50 Wood U × m2(Figs. 1 and 2). In addition, amrinone increased the CI without significantly increasing RVSWI or LVSWI, in association with decreases in PVRI and SVRI (Fig. 2). We hypothesize that the marked decrease in PVRI or SVRI or both counteracted the additional loading caused by the inotropic effects of amrinone on the right or left ventricles or both. These findings suggested that amrinone improves left and right ventricular functions mainly because of its effects on pulmonary and systemic circulations in patients with evolving CHF and will be helpful to determine the optimal hemodynamic conditions of amrinone therapy in the patients with various hemodynamic states.
Changes in neurohormonal factors and pulmonary and systemic vascular resistance
The increases in pulmonary and systemic vascular resistance in patients with CHF are believed to be regulated in part by neurohormonal factors, such as endothelin-1 (11), norepinephrine (18), atrial natriuretic peptide (19), and angiotensin II (20). The mechanisms by which neurohormonal systems regulate pulmonary and systemic vascular resistance in evolving CHF are not fully understood.
Endothelin-1 is an autocrine and paracrine hormone that acts locally and is present mainly in the pulmonary circulation in patients with pulmonary hypertension (16,21,22). Thus to assess the contribution of endothelin-1 to pulmonary vascular tone, it is necessary to measure the concentration in the PCWR (16). We measured neurohormonal factors that affect pulmonary or systemic vessels or both in both the PCWR and the peripheral vein. Actually, the endothelin-1 level in patients with a high PVRI was lower in the peripheral vein than in the PCWR (7.8 ± 2.5 vs. 5.1 ± 2.0 pg/ml) and was not correlated with the PVRI in this study.
The decrease in endothelin-1 in the PCWR, but not in norepinephrine or atrial natriuretic peptide, was significantly correlated with the reduction in PVRI in this study (Fig. 4). The decrease in norepinephrine level in the peripheral vein but not in endothelin-1 or atrial natriuretic peptide, was significantly correlated with the reduction in SVRI (Fig. 3). The concentration of angiotensin II did not change during amrinone treatment (Table 2). These findings suggest that endothelin-1 and norepinephrine regulate pulmonary and systemic vascular tone, respectively, in patients with evolving CHF.
Treatments that increase intracellular cAMP relax vascular smooth muscle by decreasing intracellular Ca2+ concentration and by decreasing the Ca2+ sensitivity of myosin light chain (MLC) phosphorylation (23-25). Although the molecular mechanism of the vasodilating effect of cAMP in evolving CHF is unknown, amrinone may counteract the augmented effect of vasoconstrictive factors such as endothelin-1 and norepinephrine, which increase intracellular Ca2+ concentration, resulting in MLC phosphorylation via activating MLC kinase. We propose that, in patients with evolving CHF, the vasodilating effect of amrinone blocks a vicious cycle in which increased levels of vasoconstrictive factors, such as endothelin-1 and norepinephrine, cause unfavorable hemodynamic changes by inducing further pulmonary and systemic vasoconstriction.
Amrinone exhibited selective hemodynamic effects on pulmonary and systemic circulation according to PVRI and SVRI before infusion and reduced the PCWR level of endothelin-1 and the peripheral venous level of norepinephrine in patients with evolving CHF. Further studies are needed to elucidate the molecular mechanism of the vasodilating effect of cAMP and the decreases in the neurohormonal factors induced by amrinone therapy in patients with evolving CHF.
Acknowledgment: This study was supported in part by Research Grant for Cardiovascular Disease 5A-3 from the Ministry of Health and Welfare of Japan, Tokyo, in 1995. We acknowledge the help of Katsunori Nishimura, Kazumi Aisaka, and Yutaka Akimoto of Meiji Seika Kaisha Ltd. for their measurement of neurohormonal factors and valuable advice. We thank the nursing staff of the east ward on the fourth floor in the National Cardiovascular Center for their nursing assistance.
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