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Hemodynamic effects of molsidomine vasodilator therapy in acute myocardial infarction
American Founded
April
CLINICAL
Heart
Journal
in 1925
1981 Volume
101,
Number
4
INVESTIGATIONS
Hemodynamic effects of molsidomine vasodilator therapy in acute myocardial infarction The hemodynamic effects and duration of action of 4 mg of intravenous molsidomine (M), a new peripheral vasodilatlor antianginal agent, were evaluated and compared to those of 10 mg sublingual isosorbide dinitrate (ISDN) in 12 patients with uncomplicated acute myocardial infarction (AMI). Both M and ISDN produced marked decreases in mean right atrial pressure (RAP), mean pulmonary capillary wedge pressure (WI’), and mean pulmonary arterial pressure. The maximal decreases in RAP (-56%) and WP (-35%) witlh intravenous M intended to be more pronounced than with sublingual ISDN (RAP -35% and WP -29%). Physiologic modest declines in systemic vascular resistance, cardiac output, and arterial pressurs were similar with both drugs. The duration of action of M was longer (average 5 hours) than that of IISDN (2 hours). No patient experienced hypotension, tachycardia, or other adverse responses following M, suggesting that M is well tolerated by patients with normotensive AMI. (AM HEART J 101:369, 1981.)
Moises Aptecar, M.D., Carlos A. Otero y Garzon, M.D., Albert0 Vasquez, M.D., Sergio Varini, M.D., Luis Collia, M.D., Alfred0 Esteguy, M.D., and Salvador Caruso, M.D. Buenos Aires, Argentina
Nitroglycerin and other organic nitrates are frequently used for the treatment of angina and pump failure in patients with acute myocardial infarction (AMI), and the beneficial hemodynamic and clinical effects have been documented.*-j Since the duration of action of nonparenteral nitroglycerin and nitrates is relatively short, 6-11their frequent administration is necessary to maintain a sustained response. Molsidomine (M), a new antianginal vasodilator drug,l?I9 has been shown to produce hemodynamic responsessimilar in nature to those of nitroglycerin in patients with chronic stable angina,‘u and the duration of M action appears to be considerably ~onger~lt.li-19The hemodynamic effects of M, however, need to be evaluated in patients with AM1 to assess its potential role for treatment of postinfarction angin,a and for pump failure. The purpose From Received
the Cardiovascular for publication
Division, July
Institutes
14, 1980;
Reprint requests: Moises Aptecar, M.D., Coronary Care Unit, Institutos Medicaos 1424 Buenos Aires, Argentina.
0002-8703/81/040369
+ 05$00.50/O
Medicos
accepted
Nov.
Antartida. 26, 1980.
Chief, Cardiology Dept. and Antartida, Rivadavia 4980,
0 19181 The
C. V. Mosby
Co.
of this study, therefore, was to determine the hemodynamic effects and duration of action of this new vasodilator agent, molsidomine, in patients with AMI. METHODS Patients. Twelve patients, nine men and three women, aged 43 to 76 years (mean 63 years) formed the patient population. All patients had AM1 confirmed by clinical, ECG, and enzymatic criteria; seven had anterior and five had inferior myocardial infarction. None of these patients had clinical evidence of heart failure at the time of the study. All patients were studied within 48 hours of symptom onset. A triple-lumen flow-directed balloon flotation catheter was inserted through an anticubital vein cutdown to measure right heart (RAP), pulmonary arterial, and left ventricular filling (WP) pressures?l; cardiac output was determined in triplicate by thermodilution technique using the same catheter.Z1 Arterial pressure was obtained by sphygmomanometer. Calculated hemodynamic variables. Derived hemodynamic variables were calculated as follows: cardiac index (CI) L/min/m2 = cardiac output/body surface area;
389
370
Aptecar
et al.
Table 1. Hemodynamic with AM1
American
effects and duration
of action Minutes
x
RR
MABP (mm Hd PAMP (mm Hd MRAP (mm W WP (mm Hd Cl (L/m&m’)
SEM ss 70 x SEM ss % x SEM SS 5% x SEM ss % R SEM ss % x SEM ss
B
15
80.1
82.3 3.9
3.8
124.4
SI (ml/b/m’)
SEM ss
LVSWI gmm/b/m”)
SEM ss
RVSWI (gmm/b/m’)
SEM ss
SVR (u)
SEM SS
PVR (4
SEM ss %
*p < 0.05; * ‘p < 0.01; ***p < B = basal; HR = heart rate; work index; SVR = systemic R = average value for the 12
stroke min); (SBP DBP gm/m’ PADP temic
12.3
1.7
1.5 ***
-9.4 11.8 1.2 ***:
-27 2.8
-26.2 3.0
1.1 ***
1.0 *
4.4 1.1
-34.6 7.0
Minutes
77.8 3.5
79.0
80.4 5.4
Cl.5
-14.0 16.4
-10.6
1.1
1.0 ***
+2.5 5.0 1.1
-28.0 2.5
10.2
1.5 **
1.2 **
0.9
3.0 0.2
-28.6 2.8 0.2 *
-27.5 2.8
38.3 2.6
-6.7 34.2 1.7 *
1.8
-10.7
80.3
77.7 3.1
4.1
+ 3.2
+ 0.8 102.8 7.0
-0.1
105.4 10.0 **
98.6 7.5 **
-10.6 12.4 0.9 **X
-1.5
-7.8 14.0 0.8 ***
-24.4 3.6 0.9 **
-14.6
1.1 ***
-24.4 2.2 1.3 *** -56 6.8 0.6 ***
-28
-30
6.6 0.6 ***
11.8
-50
12.4 1.6 **
78.4 3.7
-3.9 17.2 1.2 + 4.9
3.5 I.2 **
0.9 *
7.7 0.7 ***
7.1
5.1
1-4 +2 10.3 0.8
-24.5 2.8 0.2
4-l
-6.7 34.6 1.7 c
-3.3 34.8 2.7 *
-6.9 33.7 3.4
-6.9 32.6 3.3
-3.4 35.0 2.8
-3.4 35.5 2.9
-6.9
-9.7 49.7 5.6 *
-9.1 51.2
-3.2 45.4 5.0 a
-6.3 43.7 4.7 *
+0.6 46.0 4.0
+2 48.0 3.0
-0.8 47.3 3.3
-6.2 4.9 0.7
-7.6 5.4 1.0
+4.1
9.1
-15.6
-33.3 37.3
-31.7 41.0 4.6
4.9 -13
4.3 0.5 ***
-2.1
-11.3
4.2 0.8 ***
5.0 0.9
-20.6 41.8
5.4 -0.2
-16
40.2 5.0 * -3.8
-16 40.3 5.1
-14 29.0 4.8 *
-2 40.8 5.0
+8
-3.6
-6.7
-2.4 1.3 0.2
+0.2 1.4 0.2
0
+ 7.7
4.3 0.7
1.0
1.3
1.1
1.2
1.2
0.2
0.1
0.2
0.3
0.2
0.2
0.3
+ 8.3
-15.4
0.001 compared to basal value prior to drug administration. LVSWI = left ventricular stroke work index; PVR = pulmonary vascular vascular resistance; WP = pulmonary capillary wedge pressure. patients; SEM = + standard error of mean; SS = statistical significance;
volume index (SVI) ml/m’ = CI/heart rate (beats/ mean blood pressure (MBP) (mm Hg) = 0.8 - DBP), where SBP = systolic blood pressure and = diastolic blood pressure; stroke work index (SWI) = SVI X (MBP - PADP) X 0.0136, where = mean pulmonary artery diastolic pressure; sysvascular resistance (SVR) (u) = MBP/CI expressed
34.5 1.4
-10.1
1.0
-16.7
2.7 0.1
-14.6 4.2 0.7 *
1.2
-16.7
360
-30.4 2.8 0.2
-23.2 4.2 0.6 ***
-11
300
-33.3 2.7 0.2
6.3 0.7
4.1 *
+ 3.3 95.7 8.7 ***
post-M 180
-35.3 2.7 0.2 **
45.2 5.5 **
4.8
95.7 7.8 ***
(M) in patients
2.9 0.2
58.9 4.7
41.9
4.5
-2.9 107.0 8.5
+ 13.6
-31.8
and molsidomine
60
7.1
9.8
70
x
12.4 *t 11.6
%
x
112.7
-16.1
%
x
+ 0.6
(ISDN)
15
4.1
104.4
dinitrate
120
80.6
16.0
%
x
post-ISDN 60
+2.7 11.3
%
x
of isosorbide
Aprii fS31 HearI Journal
-7.7
resistance; % = percent
-7.7
RVSWI change
= right from
41.9
5.1
ventricular
basal
stroke
value.
in hybride resistance units as mm Hg/L/min/m’; and pulmonary vascular resistance (PVR) (u) = (PAMP - WP)/CO, where PAMP = mean pulmonary artery pressure, WP = mean pulmonary capillary wedge pressure, and CO = cardiac output. Vasodilators which predominantly reduce peripheral venous tone tend to cause marked reduction in pulmonary capillary wedge
Volume Number
101 4
Molsidomine
pressureand lessde’crease in systemic vascular resistance. To assesswhether rnolsidomineis predominantly a venodilator or an arteriolar dilator, we determined the change in the ratio of systemic vascular resistance and wedge pressure (SVR/WP) as an index of relative changes in preload and afterload.2z Study protocol. On the day of study all patients received 10 mg of sublingual isosorbide dinitrate (ISDN) first and the hemodynamic response was determined at 15, 60, and 120 minutes. At that time, hemodynamics returned to control in all patients. Molsidomine, 4 mg, was then injected intravenously as a bolus and the hemodynamic determinations were repeated at 15, 60, 180, 300, and 360 minutes. During hemodynamic evaluation, the patients received only analgesics if needed. Statistical
evaluation was based on analysis of variance and Student’s t test for paired data, comparing corresponding basal control.
each value
of its
f r
PULMONARY
The hemodynamic changes and duration of action following isosorbide dinitrate and molsidomine are summarized in Table I. Heart rate, MBP, and PAMP. Heart rate did not change significantly with either drug. At 15 minutes after administration of sublingual ISDN, mean arterial pressure decreased significantly, and ,by 60 minutes it returned to the contra! level. M, however, caused less (average 10%) but more prolonged fall in MBP up to five hours. PAMP fell an average of 25% after ISDN and at 2 hours it returned to control. The magnitude of decrease in P.AMP following M was similar, but at persistent decrease was observed for at least five hIours. RAP and WP. Both ISDN and M caused significant decreasesin mean RAP and mean WP (Fig. 1). The maximum decrease in RAP and WP following ISDN was 35% and 29%, respectively, and occurred at 15 minutes. At two hours both RAP and WP returned to control. With :M, the declines in RAP (56%) and WP (35%) were more pronounced and these decreases persisted for 5 hours. CO, SWI, SVR, PVW, and SVRIWP. There was a slight decrease in CO with both drugs (Fig. 2). Right and left ventricular SW1 also decreased slightly following ISDN and M (Fig. 2). Although stroke volume decreased with both drugs, the decrease following M was not statistically significant. Both drugs caused a modest but statistically significant decrease in SVR (Fig. 2) but PVR remained unchanged. The ratio of SVR/WP increased following ISDN and M; the magnitude of increase following M was greater than post-ISDN. Adverse effects. Only one of the 12 patients com-
ARTERY
DIASTOLIC
infarction
PRESSURE
371
f&EMl
13-
r2II _ 1 I lo-
/I
:
/I
,’
9 --- ’ ’ gi ~=I ~1 i 12
WEDGE PRESSURE
(“TSEH)
lo l~~~~~&
:
;;I mm
.l 6-
RESULTS
in acute myocardial
x0
xi
“ml
RIGHT
I
==
ATRIAL
MEAN
PRESSURE
(X+SEH>
T
L/A----i: Fig. 1, Effects of sublingual ISDN and intravenous M on pulmonary artery diastolic pressure, WP, and RAP.
plained of mild headache with molsidomine. No patient developed hypotension or tachycardia. The maximum average decrease in MBP was 13 mm Hg with molsidomine. DISCUSSION
Molsidomine (N-ethoxycarbonyl-3-morpholinosydnonimine), a recently synthesized sydnonimine derivative with a mesoionic ring, has been reported to relieve angina and increase angina threshold in patients with chronic ischemic heart disease.?O Since post-infarction angina is not an infrequent complication during the early phase of AMI, M may have a potential role in the management of such episodes. However, before such therapy is advocated, it is desirable to deterrnine the agent’s safety and potential beneficial effects in patients with AMI. The present study indicates that patients with uncompli-
372
Aptecar et al.
Fig. 2. Effects of sublingual ISDN and intravenous M on
(20, left ventricular SWI, and SVR. cated AM1 tolerate M well without experiencing clinically important untoward effects. Principal preload reduction action of M. The principal hemodynamic effect of intravenous M appears to be reduction of pulmonary venous pressure. Thus, in almost all patients in this study there were marked decreasesin WP and RAP. The reduction of ventricular filling pressure is likely the result of decreased venous return to the heart and concomitant reduction of intracardiac volumes. Although, in this study, changes in volume of the capacitance bed directly determined, experimental were not studies23.2’ suggest that M increases limb blood volume, decreases cardiac venous return, and reduces ventricular end-diastolic volume. It is likely, therefore, that the decrease in left ventricular filling pressure observed in our patients was associated with decreases in left ventricular diastolic pressure
and volume. There was also some reduction in arterial pressure without significant increase in heart rate. These hemodynamic responsesare potentially beneficial in reducing myocardial oxygen demand and relieving manifestations of myocardial iscbemia. In the present study, intravenous M caused only a slight decrease in SVR, suggesting that it is a relatively weak arteriolar dilator. Alterations in arteriolar and venous tone were not directly determined in this study. However, the ratio of SVR/WP increased markedly following M, principally because of a fall in wedge pressure rather than a change in systemic vascular resistance. These findings indirectly suggest that M is a more potent systemic venodilator than peripheral arteriolar dilator. Molsidomine caused slight decreasesin CO, stroke volume, and SWI, along with the faalf in NT, indicating lack of improvement in pump performance in these patients. Since the patients in this study had normal WP pressures initially, their hearts were probably operating on the steep ascending portion of the left ventricular function curve. The further decrease in filling pressure with M thereby decreased stroke volume by the FrankStarling mechanism. In patients with left ventricular failure and elevated WP, considerable decreases in CO and stroke volume are lesslikely to occur with M. Principal preload reduction action of ISDN. The hemodynamic effects of sublingual ISDN were also evaluated in the present study, and the results were similar to those reported previously.“. -IReduction of WP was the major hemodynamic response. In the absence of left ventricular failure, there is usually no change or slight decrease in CO and stroke volume, and SVR remains unchanged or decreases slightly. Similar hemodynamic changes were observed in the present study following ISDN in patients with uncomplicated AMI. Marked reduction of pulmonary venous pressure with ISDN is probably relate to its pronounced systemic venodilator effect.18. ?Comparison
of degree
of M and ISDN actions.
In t
present study, the hemodynamic effects of and ISDN were compared in the same patients and the results indicated that both drugs produce qualitatively similar hemodynamic responses Both ISDN and M caused marked reductions in RAP and WP with only slight decreasesin SVR, arterial pressure, CO, stroke volume, and SWI. Heart rate was not altered by either agent. One potential difference between ISDN and M was that the magnitude of reductions of RAP and WP with M was significantly greater than with ISDN. However, disparate
Volume Number
101
4
dosages and routes of administration of the two drugs may have largely accounted for the different magnitude of hemodynamic rlesponses observed between M and ISDN. Comparison of duration of M and ISDN actions. The duration of action of intravenous M appeared to be considerably longer than that of sublingual ISDN in the doses given in the present study. Following the single intravenous dose of M, the hemodynamic effects persisted in most patients for over 5 hours. The decrease in WP post-M was observed within 15 minutes and persisted for 5 hours. While the onset of action of sublingual ISDN was also 15 minutes, the duration of hemodynamic response was 90 minutes. Such duration of action of ISDN administered sublingually has been reported previously.” Despite the aforementioned difficulties in making valid comparisons, M may offer an advantage over ISDN in duration of action and less frequent administration to maintain a sustained beneficial hemodynamic response. Similar prolonged duration of action has been reported after pul administration by oral and sublingual routes.14,Ii-l9 Conclusions. In conclusion, M appears to be a potent vasodilator agent and produces hemodynamic effects similar to those of nitrates. Reductions of WP and RAP constitute the agent’s principal hemodynamic effects which persist for several hours after a single dose. Since the drug did not produce adverse effects herein in patients with uncomplicated AMI, M may afford a potentially useful modality in the management of complicated AM1 in appropriate subsets of patients with this condition.
Molsidomine
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19. The authors express their gratitude to Dr. Kanu Chatterjee for his professional assistance and to Mrs. Kathleen Hecker and Ms. Mary Hurtado for their editorial assistance.
20.
REFERENCES
1.
2.
3.
4.
5.
6.
Gold HK, Leinbach RC, Sanders CA: Use of sublingual nitroglycerin in congestive heart failure following acute myocardial infarction. Circulation 46:839, 1972. Mantle JA, Russell RO, Moraski RE, Rackley CE: Isosorbide dinitrate for the relief of severe heart failure after myocardial infarction. Am J Cardiol37:263, 1976. Williams DO, Amsterdam EA, Mason DT: Hemodynamic effects of nitrogl.ycerin in acute myocardial infarction. Circulation 51:421, 1975. Bussmann WD, Lohner H, Kaltenbach M: Orally administered isosorbide dinitrate in patients with and without left ventricular failure due to acute myocardial infarction. Am J Cardiol 39:91, 1977. Armstrong PW, Matthew MT, Boroomand K, Parker JO: Nitroglycerin ointment in acute myocardial infarction. Am J Cardiol 38:474, 1976. Needleman P, Blehm DJ, Rot&off KS: Relationship between glutathione-dependent den&ration and the vasodil-
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in acute myocardial
infarction
373
ator effectiveness of organic nitrates. J Pharmacol Exp Ther 11X286, 1969. Needleman P, Lang S, Johnson EM, Jr: Organic nitrates: Relationship between bio-transformation and rational angina pectoris therapy. J Pharmacol Exp Ther 181:489, 1972. Kovick RB, Tillisch JH, Berens SC, Bramowitz AD, Shine KI: Vasodilator therapy for chronic left ventricular failure. Circulation 53:322, 1976. Taylor WR, Forrester JS, Magnusson P, Takano T, Chatterjee K, Swan HJC: Hemodynamic effects of nitroglycerin ointment in congestive heart failure. Am J Cardiol 38:469, 1976. Bussman WD, Schupp D: Effect of sublingual nitroglycerin in emergency treatment of severe pulmonary edema. Am J Cardiol 41:931, 1978. Gray R, Chatterjee K, Vyden JK, Ganz W, Forrester JS, Swan HJC: Hemodynamic and metabolic effects of isosorbide dinitrate in chronic congestive heart failure. AM HEART J 90:346, 1975. Tanayama S, Fujita T, Shirakawa Y, Suzuoki 2: Metabolic fate of 5-ethoxy-carbonyl-3-morpholinosydnonimine (Sin19). I. Absorption, excretion and tissue distribution in rats and mice. Jpn J Pharmacol 20:413, 1970. Tanayama S, Nakai Y, Fugita T, Suzuoki Z, Imashiro Y, Masuda K: Biotransformation of Molsydomine (N-ethoxycarbonyl-3-morpholinosydnonimine), a new antianginal agent in rats. Zenobiotica 4:175, 1974. Slony J, Mosslacher H, Schmoliner R, Kronik G: Einfuss von Molsidomin auf Hamodinamik und Arbeitstoleranz bei Patienten mit Angina Pectoris. Med Welt 27:2396, 1976. Karsch KR, Rentrop KP, Blanke H, Kreuzer H: Haemodynamic effects of molsidomin. Eur J Clin Pharmacol 13:241, 1978. Blazek G, Heeger H, Kubieek F: Zur Verbesserung der Arbeitsbelastung Koronarkrankeri: Wirkung von Molsidomin auf die ergometrisch gemessene Arbeitstoleranz. Dtsch Med Wochenschr 102:81, 1977. Jansen E, Klepzig H: Untersuchungen uber den Einfluss von Molsidomin auf die Belastungskoronarinsuffizienz. Med Klin 71:2072, 1976. Takeshita A, Nakamura M, Tajima T, Matsuguchi H, Kuroiwa A, Tanaka S, Kikuchi Y: Long-lasting effect of oral molsidomine on exercise performance. Circulation 55:401, 1977. Gurchicoff S, Vasquez A, Kunik H, Drajer S, Diaz F: Acute double-blind trial of a new anti-ansinal drug: Molsidomine. Eur J Clin Pharmacol13:247, 1978: Majid PA, DeFeyter PJF, Van der Wall EE, Wardeh R, Roos JP: Molsidomine in the treatment of patients with angina pectoris. Acute hemodynamic effects and clinical efficacy. N Engl J Med 302:1, 1980. Forrester JS, Ganz W, Diamond G, McHugh T, Chonette DW, Swan HJC: Thermodilution cardiac output determination with a single flow directed catheter. AM HEART J 83:306, 1972. Armstrong PW, Walker DC, Burton JR, Parker JO: Vasodilator therapy in acute myocardial infarction. A comparison of sodium nitroprusside and nitroglycerin. Circulation 52:1118, 1975. Takenaka F, Takeya N, Ishihara T, Inoue S, Tsutsumi E, Nakamura R, Mitsufuji Y, Sumie M: Effects of N-ethoxycarbonyl-3-morpholinosydnonimine (Sin-lo) on the cardiovascular system. Jpn J Pharmacol 20:253, 1970. Kikuchi K, Hirata M, Nagaoka A: Hypotensive action of N-ethoxycarbonyl-3-morpholinosydnonimine (Sin-lo). Jpn J Pharmacol 20~102, 1970. Mason DT, Braunwald E: The effects of nitroglycerin and amyl nitrite on arterial and venous tone in the human forearm. Circulation 32:755, 1965.
April
CLINICAL
Heart
Journal
in 1925
1981 Volume
101,
Number
4
INVESTIGATIONS
Hemodynamic effects of molsidomine vasodilator therapy in acute myocardial infarction The hemodynamic effects and duration of action of 4 mg of intravenous molsidomine (M), a new peripheral vasodilatlor antianginal agent, were evaluated and compared to those of 10 mg sublingual isosorbide dinitrate (ISDN) in 12 patients with uncomplicated acute myocardial infarction (AMI). Both M and ISDN produced marked decreases in mean right atrial pressure (RAP), mean pulmonary capillary wedge pressure (WI’), and mean pulmonary arterial pressure. The maximal decreases in RAP (-56%) and WP (-35%) witlh intravenous M intended to be more pronounced than with sublingual ISDN (RAP -35% and WP -29%). Physiologic modest declines in systemic vascular resistance, cardiac output, and arterial pressurs were similar with both drugs. The duration of action of M was longer (average 5 hours) than that of IISDN (2 hours). No patient experienced hypotension, tachycardia, or other adverse responses following M, suggesting that M is well tolerated by patients with normotensive AMI. (AM HEART J 101:369, 1981.)
Moises Aptecar, M.D., Carlos A. Otero y Garzon, M.D., Albert0 Vasquez, M.D., Sergio Varini, M.D., Luis Collia, M.D., Alfred0 Esteguy, M.D., and Salvador Caruso, M.D. Buenos Aires, Argentina
Nitroglycerin and other organic nitrates are frequently used for the treatment of angina and pump failure in patients with acute myocardial infarction (AMI), and the beneficial hemodynamic and clinical effects have been documented.*-j Since the duration of action of nonparenteral nitroglycerin and nitrates is relatively short, 6-11their frequent administration is necessary to maintain a sustained response. Molsidomine (M), a new antianginal vasodilator drug,l?I9 has been shown to produce hemodynamic responsessimilar in nature to those of nitroglycerin in patients with chronic stable angina,‘u and the duration of M action appears to be considerably ~onger~lt.li-19The hemodynamic effects of M, however, need to be evaluated in patients with AM1 to assess its potential role for treatment of postinfarction angin,a and for pump failure. The purpose From Received
the Cardiovascular for publication
Division, July
Institutes
14, 1980;
Reprint requests: Moises Aptecar, M.D., Coronary Care Unit, Institutos Medicaos 1424 Buenos Aires, Argentina.
0002-8703/81/040369
+ 05$00.50/O
Medicos
accepted
Nov.
Antartida. 26, 1980.
Chief, Cardiology Dept. and Antartida, Rivadavia 4980,
0 19181 The
C. V. Mosby
Co.
of this study, therefore, was to determine the hemodynamic effects and duration of action of this new vasodilator agent, molsidomine, in patients with AMI. METHODS Patients. Twelve patients, nine men and three women, aged 43 to 76 years (mean 63 years) formed the patient population. All patients had AM1 confirmed by clinical, ECG, and enzymatic criteria; seven had anterior and five had inferior myocardial infarction. None of these patients had clinical evidence of heart failure at the time of the study. All patients were studied within 48 hours of symptom onset. A triple-lumen flow-directed balloon flotation catheter was inserted through an anticubital vein cutdown to measure right heart (RAP), pulmonary arterial, and left ventricular filling (WP) pressures?l; cardiac output was determined in triplicate by thermodilution technique using the same catheter.Z1 Arterial pressure was obtained by sphygmomanometer. Calculated hemodynamic variables. Derived hemodynamic variables were calculated as follows: cardiac index (CI) L/min/m2 = cardiac output/body surface area;
389
370
Aptecar
et al.
Table 1. Hemodynamic with AM1
American
effects and duration
of action Minutes
x
RR
MABP (mm Hd PAMP (mm Hd MRAP (mm W WP (mm Hd Cl (L/m&m’)
SEM ss 70 x SEM ss % x SEM SS 5% x SEM ss % R SEM ss % x SEM ss
B
15
80.1
82.3 3.9
3.8
124.4
SI (ml/b/m’)
SEM ss
LVSWI gmm/b/m”)
SEM ss
RVSWI (gmm/b/m’)
SEM ss
SVR (u)
SEM SS
PVR (4
SEM ss %
*p < 0.05; * ‘p < 0.01; ***p < B = basal; HR = heart rate; work index; SVR = systemic R = average value for the 12
stroke min); (SBP DBP gm/m’ PADP temic
12.3
1.7
1.5 ***
-9.4 11.8 1.2 ***:
-27 2.8
-26.2 3.0
1.1 ***
1.0 *
4.4 1.1
-34.6 7.0
Minutes
77.8 3.5
79.0
80.4 5.4
Cl.5
-14.0 16.4
-10.6
1.1
1.0 ***
+2.5 5.0 1.1
-28.0 2.5
10.2
1.5 **
1.2 **
0.9
3.0 0.2
-28.6 2.8 0.2 *
-27.5 2.8
38.3 2.6
-6.7 34.2 1.7 *
1.8
-10.7
80.3
77.7 3.1
4.1
+ 3.2
+ 0.8 102.8 7.0
-0.1
105.4 10.0 **
98.6 7.5 **
-10.6 12.4 0.9 **X
-1.5
-7.8 14.0 0.8 ***
-24.4 3.6 0.9 **
-14.6
1.1 ***
-24.4 2.2 1.3 *** -56 6.8 0.6 ***
-28
-30
6.6 0.6 ***
11.8
-50
12.4 1.6 **
78.4 3.7
-3.9 17.2 1.2 + 4.9
3.5 I.2 **
0.9 *
7.7 0.7 ***
7.1
5.1
1-4 +2 10.3 0.8
-24.5 2.8 0.2
4-l
-6.7 34.6 1.7 c
-3.3 34.8 2.7 *
-6.9 33.7 3.4
-6.9 32.6 3.3
-3.4 35.0 2.8
-3.4 35.5 2.9
-6.9
-9.7 49.7 5.6 *
-9.1 51.2
-3.2 45.4 5.0 a
-6.3 43.7 4.7 *
+0.6 46.0 4.0
+2 48.0 3.0
-0.8 47.3 3.3
-6.2 4.9 0.7
-7.6 5.4 1.0
+4.1
9.1
-15.6
-33.3 37.3
-31.7 41.0 4.6
4.9 -13
4.3 0.5 ***
-2.1
-11.3
4.2 0.8 ***
5.0 0.9
-20.6 41.8
5.4 -0.2
-16
40.2 5.0 * -3.8
-16 40.3 5.1
-14 29.0 4.8 *
-2 40.8 5.0
+8
-3.6
-6.7
-2.4 1.3 0.2
+0.2 1.4 0.2
0
+ 7.7
4.3 0.7
1.0
1.3
1.1
1.2
1.2
0.2
0.1
0.2
0.3
0.2
0.2
0.3
+ 8.3
-15.4
0.001 compared to basal value prior to drug administration. LVSWI = left ventricular stroke work index; PVR = pulmonary vascular vascular resistance; WP = pulmonary capillary wedge pressure. patients; SEM = + standard error of mean; SS = statistical significance;
volume index (SVI) ml/m’ = CI/heart rate (beats/ mean blood pressure (MBP) (mm Hg) = 0.8 - DBP), where SBP = systolic blood pressure and = diastolic blood pressure; stroke work index (SWI) = SVI X (MBP - PADP) X 0.0136, where = mean pulmonary artery diastolic pressure; sysvascular resistance (SVR) (u) = MBP/CI expressed
34.5 1.4
-10.1
1.0
-16.7
2.7 0.1
-14.6 4.2 0.7 *
1.2
-16.7
360
-30.4 2.8 0.2
-23.2 4.2 0.6 ***
-11
300
-33.3 2.7 0.2
6.3 0.7
4.1 *
+ 3.3 95.7 8.7 ***
post-M 180
-35.3 2.7 0.2 **
45.2 5.5 **
4.8
95.7 7.8 ***
(M) in patients
2.9 0.2
58.9 4.7
41.9
4.5
-2.9 107.0 8.5
+ 13.6
-31.8
and molsidomine
60
7.1
9.8
70
x
12.4 *t 11.6
%
x
112.7
-16.1
%
x
+ 0.6
(ISDN)
15
4.1
104.4
dinitrate
120
80.6
16.0
%
x
post-ISDN 60
+2.7 11.3
%
x
of isosorbide
Aprii fS31 HearI Journal
-7.7
resistance; % = percent
-7.7
RVSWI change
= right from
41.9
5.1
ventricular
basal
stroke
value.
in hybride resistance units as mm Hg/L/min/m’; and pulmonary vascular resistance (PVR) (u) = (PAMP - WP)/CO, where PAMP = mean pulmonary artery pressure, WP = mean pulmonary capillary wedge pressure, and CO = cardiac output. Vasodilators which predominantly reduce peripheral venous tone tend to cause marked reduction in pulmonary capillary wedge
Volume Number
101 4
Molsidomine
pressureand lessde’crease in systemic vascular resistance. To assesswhether rnolsidomineis predominantly a venodilator or an arteriolar dilator, we determined the change in the ratio of systemic vascular resistance and wedge pressure (SVR/WP) as an index of relative changes in preload and afterload.2z Study protocol. On the day of study all patients received 10 mg of sublingual isosorbide dinitrate (ISDN) first and the hemodynamic response was determined at 15, 60, and 120 minutes. At that time, hemodynamics returned to control in all patients. Molsidomine, 4 mg, was then injected intravenously as a bolus and the hemodynamic determinations were repeated at 15, 60, 180, 300, and 360 minutes. During hemodynamic evaluation, the patients received only analgesics if needed. Statistical
evaluation was based on analysis of variance and Student’s t test for paired data, comparing corresponding basal control.
each value
of its
f r
PULMONARY
The hemodynamic changes and duration of action following isosorbide dinitrate and molsidomine are summarized in Table I. Heart rate, MBP, and PAMP. Heart rate did not change significantly with either drug. At 15 minutes after administration of sublingual ISDN, mean arterial pressure decreased significantly, and ,by 60 minutes it returned to the contra! level. M, however, caused less (average 10%) but more prolonged fall in MBP up to five hours. PAMP fell an average of 25% after ISDN and at 2 hours it returned to control. The magnitude of decrease in P.AMP following M was similar, but at persistent decrease was observed for at least five hIours. RAP and WP. Both ISDN and M caused significant decreasesin mean RAP and mean WP (Fig. 1). The maximum decrease in RAP and WP following ISDN was 35% and 29%, respectively, and occurred at 15 minutes. At two hours both RAP and WP returned to control. With :M, the declines in RAP (56%) and WP (35%) were more pronounced and these decreases persisted for 5 hours. CO, SWI, SVR, PVW, and SVRIWP. There was a slight decrease in CO with both drugs (Fig. 2). Right and left ventricular SW1 also decreased slightly following ISDN and M (Fig. 2). Although stroke volume decreased with both drugs, the decrease following M was not statistically significant. Both drugs caused a modest but statistically significant decrease in SVR (Fig. 2) but PVR remained unchanged. The ratio of SVR/WP increased following ISDN and M; the magnitude of increase following M was greater than post-ISDN. Adverse effects. Only one of the 12 patients com-
ARTERY
DIASTOLIC
infarction
PRESSURE
371
f&EMl
13-
r2II _ 1 I lo-
/I
:
/I
,’
9 --- ’ ’ gi ~=I ~1 i 12
WEDGE PRESSURE
(“TSEH)
lo l~~~~~&
:
;;I mm
.l 6-
RESULTS
in acute myocardial
x0
xi
“ml
RIGHT
I
==
ATRIAL
MEAN
PRESSURE
(X+SEH>
T
L/A----i: Fig. 1, Effects of sublingual ISDN and intravenous M on pulmonary artery diastolic pressure, WP, and RAP.
plained of mild headache with molsidomine. No patient developed hypotension or tachycardia. The maximum average decrease in MBP was 13 mm Hg with molsidomine. DISCUSSION
Molsidomine (N-ethoxycarbonyl-3-morpholinosydnonimine), a recently synthesized sydnonimine derivative with a mesoionic ring, has been reported to relieve angina and increase angina threshold in patients with chronic ischemic heart disease.?O Since post-infarction angina is not an infrequent complication during the early phase of AMI, M may have a potential role in the management of such episodes. However, before such therapy is advocated, it is desirable to deterrnine the agent’s safety and potential beneficial effects in patients with AMI. The present study indicates that patients with uncompli-
372
Aptecar et al.
Fig. 2. Effects of sublingual ISDN and intravenous M on
(20, left ventricular SWI, and SVR. cated AM1 tolerate M well without experiencing clinically important untoward effects. Principal preload reduction action of M. The principal hemodynamic effect of intravenous M appears to be reduction of pulmonary venous pressure. Thus, in almost all patients in this study there were marked decreasesin WP and RAP. The reduction of ventricular filling pressure is likely the result of decreased venous return to the heart and concomitant reduction of intracardiac volumes. Although, in this study, changes in volume of the capacitance bed directly determined, experimental were not studies23.2’ suggest that M increases limb blood volume, decreases cardiac venous return, and reduces ventricular end-diastolic volume. It is likely, therefore, that the decrease in left ventricular filling pressure observed in our patients was associated with decreases in left ventricular diastolic pressure
and volume. There was also some reduction in arterial pressure without significant increase in heart rate. These hemodynamic responsesare potentially beneficial in reducing myocardial oxygen demand and relieving manifestations of myocardial iscbemia. In the present study, intravenous M caused only a slight decrease in SVR, suggesting that it is a relatively weak arteriolar dilator. Alterations in arteriolar and venous tone were not directly determined in this study. However, the ratio of SVR/WP increased markedly following M, principally because of a fall in wedge pressure rather than a change in systemic vascular resistance. These findings indirectly suggest that M is a more potent systemic venodilator than peripheral arteriolar dilator. Molsidomine caused slight decreasesin CO, stroke volume, and SWI, along with the faalf in NT, indicating lack of improvement in pump performance in these patients. Since the patients in this study had normal WP pressures initially, their hearts were probably operating on the steep ascending portion of the left ventricular function curve. The further decrease in filling pressure with M thereby decreased stroke volume by the FrankStarling mechanism. In patients with left ventricular failure and elevated WP, considerable decreases in CO and stroke volume are lesslikely to occur with M. Principal preload reduction action of ISDN. The hemodynamic effects of sublingual ISDN were also evaluated in the present study, and the results were similar to those reported previously.“. -IReduction of WP was the major hemodynamic response. In the absence of left ventricular failure, there is usually no change or slight decrease in CO and stroke volume, and SVR remains unchanged or decreases slightly. Similar hemodynamic changes were observed in the present study following ISDN in patients with uncomplicated AMI. Marked reduction of pulmonary venous pressure with ISDN is probably relate to its pronounced systemic venodilator effect.18. ?Comparison
of degree
of M and ISDN actions.
In t
present study, the hemodynamic effects of and ISDN were compared in the same patients and the results indicated that both drugs produce qualitatively similar hemodynamic responses Both ISDN and M caused marked reductions in RAP and WP with only slight decreasesin SVR, arterial pressure, CO, stroke volume, and SWI. Heart rate was not altered by either agent. One potential difference between ISDN and M was that the magnitude of reductions of RAP and WP with M was significantly greater than with ISDN. However, disparate
Volume Number
101
4
dosages and routes of administration of the two drugs may have largely accounted for the different magnitude of hemodynamic rlesponses observed between M and ISDN. Comparison of duration of M and ISDN actions. The duration of action of intravenous M appeared to be considerably longer than that of sublingual ISDN in the doses given in the present study. Following the single intravenous dose of M, the hemodynamic effects persisted in most patients for over 5 hours. The decrease in WP post-M was observed within 15 minutes and persisted for 5 hours. While the onset of action of sublingual ISDN was also 15 minutes, the duration of hemodynamic response was 90 minutes. Such duration of action of ISDN administered sublingually has been reported previously.” Despite the aforementioned difficulties in making valid comparisons, M may offer an advantage over ISDN in duration of action and less frequent administration to maintain a sustained beneficial hemodynamic response. Similar prolonged duration of action has been reported after pul administration by oral and sublingual routes.14,Ii-l9 Conclusions. In conclusion, M appears to be a potent vasodilator agent and produces hemodynamic effects similar to those of nitrates. Reductions of WP and RAP constitute the agent’s principal hemodynamic effects which persist for several hours after a single dose. Since the drug did not produce adverse effects herein in patients with uncomplicated AMI, M may afford a potentially useful modality in the management of complicated AM1 in appropriate subsets of patients with this condition.
Molsidomine
7.
8.
9.
10.
11.
12.
13.
14.
15.
16.
17.
18.
19. The authors express their gratitude to Dr. Kanu Chatterjee for his professional assistance and to Mrs. Kathleen Hecker and Ms. Mary Hurtado for their editorial assistance.
20.
REFERENCES
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