Journal Logo

Article

Hemodynamic Effect of Amrinone Depends on Pretreatment Vascular Resistance in Patients with Evolving Congestive Heart Failure: Correlation Between Vascular Resistance and Neurohormonal Activity

Sasaki, Tatsuya; Tomimoto, Shigehiro; Noguchi, Teruo; Baba, Takeshi; Komamura, Kazuo; Ohmori, Fumio; Miyatake, Kunio

Author Information
Journal of Cardiovascular Pharmacology: January 1998 - Volume 31 - Issue 1 - p 80-84
  • Free

Abstract

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.

METHODS

Study subjects

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.

Study protocol

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.

Statistical analysis

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.

RESULTS

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).

TABLE 1
TABLE 1:
Effects of amrinone on hemodynamic parameters in patients classified according to PVRI and SVRI levels before treatment

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).

FIG. 1
FIG. 1:
Changes in pulmonary vascular-resistance index (PVRI) and systemic vascular-resistance index (SVRI) induced by amrinone in patients classified according to PVRI and SVRI levels before treatment. Solid circles, before amrinone infusion; open circles, 30 and 60 min after initiation of amrinone.
FIG. 2
FIG. 2:
Changes in hemodynamic parameters induced by amrinone in patients classified according to PVRI and SVRI levels before treatment. PVRI, pulmonary vascular-resistance index; RVSWI, right ventricular stroke-work index; SVRI, systemic vascular-resistance index; LVSWI, left ventricular stroke-work index. Solid circles, group I; solid squares, group II; open circles, group III. *p < 0.05 versus before therapy.

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.

TABLE 2
TABLE 2:
Changes in neurohormonal factors induced by amrinone
FIG. 3
FIG. 3:
Correlations between systemic vascular-resistance index (SVRI) and neurohormonal factors in patients with evolving congestive heart failure (CHF). Correlations between SVRI and NE (a), ET-1 (b), and ANP (c) in the peripheral vein in patients with evolving CHF treated with amrinone. NE, norepinephrine; ET-1, endothelin-1; ANP, atrial natriuretic peptide; solid circles, before treatment; open circles, during treatment.
FIG. 4
FIG. 4:
Correlations between pulmonary vascular-resistance index (PVRI) and neurohormonal factors in patients with evolving congestive heart failure (CHF). Correlations between PVRI and NE (a), ET-1 (b), and ANP (c) in the pulmonary capillary wedge region (PCWR) in patients with evolving CHF treated with amrinone. NE, norepinephrine; ET-1, endothelin-1; ANP, atrial natriuretic peptide; solid circles, before treatment; open circles, during treatment.

DISCUSSION

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.

CONCLUSIONS

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.

REFERENCES

1. Firth BG, Ratner AV, Frassman ED, Winniford MD, Nicod P, Hillis LD. Assessment of the inotropic and vasodilator effects of amrinone versus isoproterenol. Am J Cardiol 1984;54:1331-6.
2. Konstam MA, Cohen SR, Weiland DS, et al. Relative contribution of inotropic and vasodilator effects to amrinone-induced hemodynamic improvement in congestive heart failure. Am J Cardiol 1986;57:242-8.
3. Mancini D, LeJemtel T, Sonnenblick E. Intravenous use of amrinone for the treatment of the failing heart. Am J Cardiol 1985;56:8-15B.
4. DiBianco R. Acute positive inotropic intervention: the phosphodiesterase inhibitors. Am Heart J 1991;21(6 Pt 1):1871-5.
5. Deeb GM, Bolling SF, Guynn TP, Nicklas JM. Amrinone versus conventional therapy in pulmonary hypertensive patients awaiting cardiac transplantation. Ann Thorac Surg 1989;48:665-9.
6. Robinson BW, Gelband H, Mas MS. Selective pulmonary and systemic vasodilator effects of amrinone in children: new therapeutic implications. J Am Coll Cardiol 1993;21:1461-5.
7. Cheng DC, Asokumar B, Nakagawa T. Amrinone therapy for severe pulmonary hypertension and biventricular failure after complicated valvular heart surgery. Chest 1993;104:1618-20.
8. Levy JH, Bailey JM. Amrinone: pharmacokinetics and pharmacodynamics. J Cardiothorac Anesth 1989;3:10-4.
9. Nyhan DP, Pribble CG, Peterson WP, et al. Amrinone and the pulmonary vascular pressure-flow relationship in conscious control dogs and following left lung autotransplantation. Anesthesiology 1993;78:1166-77.
10. McMurray JJ, Ray SG, Abdullah I, Dargie HL, Morton JJ. Plasma endothelin in chronic heart failure. Circulation 1992;85:1374-9.
11. Cody RJ, Haas GJ, Binkley PF, Capers Q, Kelley R. Plasma endothelin correlates with the extent of pulmonary hypertension with chronic congestive heart failure. Circulation 1992;85:504-9.
12. Thomas JA, Marks BH. Plasma norepinephrine in congestive heart failure. Am J Cardiol 1978;41:233-43.
13. The SOLVD Investigators. Comparative neurohormonal responses in patients with preserved and impaired left ventricular ejection fraction: results of the Studies of Left Ventricular Dysfunction (SOLVD) Registry. J Am Coll Cardiol 1993;22:146-53A.
14. Ando K, Hirata Y, Shiichiri M, Emori T, Marumo F. Presence of immunoreactive endothelin in human plasma. FEBS Lett 1989;245:164-6.
15. Hama N, Nakao K, Mukoyama M, et al. Fundamental and clinical evaluation of Shionoria ANP, human atrial natriuretic peptide IRMA kit. Clin Rep 1991;25:455-62.
16. Tsutamoto T, Wada A, Maeda Y, Adachi T, Kinoshita M. Relation between endothelin-1 spillover in the lungs and pulmonary vascular resistance in patients with chronic heart failure. J Am Coll Cardiol 1994;23:1427-33.
17. Coe JY, Olley PM, Vella G, Coceani F. Bipyridine derivatives lower arteriolar resistance and improve left ventricular function in newborn lambs. Pediatr Res 1987;22:422-8.
18. Francis GS, Goldsmith RS, Levine TB, Olivari MT, Cohn JN. The neurohormonal axis in congestive heart failure. Ann Intern Med 1984;101:370-7.
19. Bolli P, Muller FB, Linder L, et al. The vasodilator potency of atrial natriuretic peptide in man. Circulation 1987;75:221-8.
20. Packer M. Neurohormonal interactions and adaptations in congestive heart failure. Circulation 1988;77:721-30.
21. Yoshibayashi M, Nishioka K, Nakao K, et al. Plasma endothelin concentrations in patients with pulmonary hypertension associated with congestive heart failure. Circulation 1991;84:2280-5.
22. Giaid A. Expression of endothelin-1 in lungs of patients with pulmonary hypertension. N Engl J Med 1993;328:1732-9.
23. McDaniel NL, Rembold HM, Richard HM, Murphy RA. Cyclic AMP relaxes swine arterial smooth muscle predominantly by decreasing cell Ca2+ concentration. J Physiol (Lond) 1991;439:147-60.
24. Tang DC, Stull JT, Kubota Y, Kamm KE. Regulation of the Ca2+ dependence of smooth muscle contraction. J Biol Chem 1992;267:11839-45.
25. Van Riper DA, Weaver BA, Stull JT, Rembold CM. Myosin light chain kinase phosphorylation in swine carotid artery contraction and relaxation. Am J Physiol 1995;268(6 Pt 2):H2466-75.
Keywords:

Congestive heart failure; Amrinone; Vascular resistance; Neurohormone

© Lippincott-Raven Publishers