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Hemodynamic action of nicorandil in chronic congestive heart failure
Hemodynamic Action of Nicorandil in Chronic Congestive Heart Failure Alain Cohen Solal, MD, Philippe Jaeger, MD, Jean Bouthier, MD, Jean-Michel Juliard, MD, Michel Dahan, MD, and Ret@ Gourgon, MD
Nicorandil is a new compound that has shown potent vasodilator activities on venous and arterial beds in experimental pharmacology. This study was designed to evaluate the magnitude and the time course of hemodynamic effects of different doses of nicorandil in congestive heart failure. Eleven patients with severe congestive heart failure (New York Heart Association class III or IV), with a cardiac index <3 liters/min/m2 and a pulmonary wedge pressure >15 mm Hg were enrolled in the study. Three patients had ischemic dilated cardiomyopathy and 8 had idiopathic dilated cardiomyopathy. Hemodynamic assessments were performed by right-sided cardiac catheterization (Swan-Ganz catheter) with cardiac output determination (thermodilution) at baseline and from 30 mintues to 12 hours after single oral administration of nicorandil; 3 patients were given 40 mg, 6 patients 60 mg, and 2 patients 60 mg. Maximal hemodynamic changes were observed 30 minutes after dosing and remained statistically significant at 3 hours. Thirty minutes after drug administration, pulmonary wedge pressure decreased 34 f 6%, cardiac index increased by 55 f 13% and diastolic and mean arterial pressures decreased by 15 f 3% and 9 f 2%, respectively, from baseline values. The decrease in systolic blood pressure was slight (5 f 2%) and not statistically significant. Calculated systemic vascular resistances decreased by 36 f 6% and heart rate did not significantly change. Nicorandil was well tolerated. Thus, the results of this first study of nicorandil in congestive heart failure demonstrated the unloading action of this compound on the failing heart, leading to an improvement in cardiac function; further investigation of nicorandil in this therapeutic area is needed. (Am J Cardiol lSSSt63:44J-481)
From the Service de Cardiologie, HBpital Bichat, 46 rue Henri Huchard, 75018 Paris, France. Address for reprints: Alain Cohen Solal, MD, Service de Cardiologie, HBpital Bichat, 46 rue Henri Huchard, 75018 Paris, France.
44J
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63
N
icorandil, a nicotinamide derivative, is a new potent coronary vasodilator with pharmacologic properties differing from those of conventional antianginal drugs. l Although the hemodynamic actions of nicorandil have been studied in animal& and in normal volunteers,4~5no hemodynamic study has been undertaken in patients with congestive heart failure. The present study investigates the magnitude and the time course of the acute hemodynamic effects of a single oral administration of nicorandil in patients with chronic heart failure. AND METHODS The study group consisted of 11 patients with severe congestive heart failure (New York Heart Association class III or IV). There were 9 men and 2 women, aged 25 to 74 years (mean 52). Based on history, electrocardiograms and echocardiograms, 3 patients had an ischemic dilated cardiomyopathy and 8 patients an idiopathic dilated cardiomyopathy. Patients with organic valvular disease, hypertension, unstable angina or recent myocardial infarction, were excluded. All had sinus rhythm except 1 who had a fixed paced heart rate. All had a cardiac index of less than 3 and more than 1.5 literpmin - 1. m-* and a mean pulmonary wedge pressure higher than 15 mm Hg (19 to 38 mm Hg). Digitalis and diuretics, when used, were withheld the morning of the study. Vasodilator therapy was discontinued at least 48 hours before the study. One patient was given a constant infusion of dobutamine at a rate of 5 pg/kg/min. After informed consent was obtained, right-sided cardiac catheterization was performed under fluoroscopic guidance with a triple lumen thermodilution flow-directed Swan-Ganz catheter inserted the evening before or the morning of the study. To ensure a stable baseline, measurements were repeated every 15 minutes during 2 hours; baseline was assumed to exist only if 2 measurements differed by less than 10%. To minimize spontaneous hemodynamic variations, patients were kept in the supine position in a special room in the intensive care unit, and remained fasting all during the study.6 Right atrial, pulmonary arterial and pulmonary wedge pressures were recorded directly on a Siemens Mingograph Elema recorder. Heart rate was monitored from a precordial electrocardiographic lead (the patient with a cardiac pacemaker was not considered for the study of this parameter). Humeral systolic, diastolic and mean arterial pressures were recorded by a continuous automatic device (Automatic Device-Dynamap 845, oscillometric PATIENTS
I
Pulmonary Wedge Pressure
Cardiac
1
Mean Blood Pressure
Index
130-
FIGURE 1. Hemedynamic reqenee of pulcardiac index -w we&z -, amlmeambloodpressurebftfomand30 minutes after nicorandil administration (40-, so- and 8omg do!ms).
120-
\
IlOloo-
\
gokI 70 6oI
s
60-
technic). Thermodilution cardiac output was determinated in triplicate (variation of 10% or less). Cardiac, systemic vascular resistance and stroke volume indexes were calculated by standard formulas. Three patients received 40 mg, 6 patients 60 mg and 2 patients 80 mg of nicorandil orally. Measurements were repeated at 30 minutes and 1, 2, 3, 6 and 12 hours after administration. Statistical analysis used paired t tests with a Bonferroni Holm adjustment for repeated measurements.
Systolic
RESULTS The effects of nicorandil on pulmonary wedge pressure, cardiac index and mean arterial pressure are summarized in Figure 1. Nicorandil administration resulted in a decrease in mean arterial and pulmonary wedge pressures and an increase in cardiac index, suggesting a potent vasodilation. Diastolic arterial pressure decreased by 15% at 30 minutes; the decrease in systolic arterial pressure was less pronounced (5%) and not statistically significant (Fig. 2); mean arterial pressure decreased by
Blood
Pressure
mmHg
140
T
1
loo’ Diastolic
Blood
Pressure
mmHg FfGURE 2. Changes in systolic and diastollc arterial presswe after nicorandil adminishtion. SEM = standard ewer of the mean.
go-
Hours -+ 1 SEM
after
Nicorandil * p<
0.05
administration (Bonferronl
Helm
Adjustment)
THE AMERICAN JOURNAL OF CARDIOLOGY JUNE 20,1989
451
A SYMPOSIUM:
Cardiac 4
FOCUS ON NICORANDIL
Index
l.mn-'.rn-* 1 * FIGURE 3. Changes in cardiac index after nicorandil administration. SEM = standard error of the mean.
fl
Hours after
Nicorandil
SEM
p
*
Administration
(Bonferroni
Helm
adjustment)
9% (p <0.05). Nicorandil caused an important increase in cardiac index, reaching 55% at 30 minutes (Fig. 3), and the calculated systemic vascular resistance index decreased by 36% (Fig. 4). Increase in cardiac index was entirely due to an increase in stroke volume; heart rate did not significantly change (Fig. 5). Finally, nicorandil administration resulted in a marked decrease in right atria1 (35%) and pulmonary wedge pressures (34%) (Fig. 5). Maximal hemodynamic changes were observed at 30 minutes for all parameters and remained statistically significant only for 2 hours.
Systemic
Vascular
Resistance
dynes.sec.cm-5.m 4000
2
3000
-
Index
-*
FIGURE 4. Changes in systemic vascular resistance index after nicorandil administratlen. SEM = standard errar of the mean.
oh!/*/
*/
o/’
Hours after Nicorandil 21 SEM
46J
DISCUSSION Nicorandil is a new potent vasodilator with anti-ischemic properties. 2,3,7-9This study is the first to characterize the hemodynamic action of nicorandil in patients with congestive heart failure. Nicorandil administration resulted in a pronounced vasodilatory action leading to a marked improvement in cardiac function. The decrease in systemic vascular resistances and in diastolic and mean arterial pressures are consistent with the previous data, showing a potent vasodilatory action of nicorandil on the arterial bed.‘y3J Sys-
$7 p
.a/’
administration (Sonfsrronl
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63
Helm
Adjustment)
Right Atrial ‘51
Heart Rate 110
Pressure
mmHg
b.mn-’
1
Stroke
Volume index
Pulmonary
Wedge
Pressure
40 7 ml.me2 h
,oJ . . . . . o~u*I d Hours after fl
SEM
Pulmonary
Wedge
Nicorandil
2 p
FIGURE 5. Changer in hart rate, stroke volume index, right atrial pressure and pulmonary ministration. SEM = standard error of the mean.
j (Bonierroni
J
4
administration Helm
Adjustment)
wedge pressure aflw
Pressure
nicorandil
ad-
(Means)
mmHg
FIGURE 6. f%~lmonary wedge pressure (means). Magnitude and time course of the change in pudmonary wedge pressure after administration of 40 mg (n = 3), 50 mg (n = 6) and 66 mg (n = 2) of nicorandil.
Hours l
40mg
after dose
Nicorandil v 60mg
administration dose
l
80mg
THE AMERICAN JOURNAL OF CARDIOLOGY JUNE 20.1989
dose
47J
A SYMPOSIUM:
FOCUS ON NICORANDIL
tolic arterial pressure did not significantly change proba- ry patients because of the hypotensive risk. Finally, the bly because of a large increase in stroke volume.1o duration of action of nicorandil, whatever the dose, was The magnitude of the increase in stroke volume is short, always lesser than 3 hours (Fig. 6), suggesting probably related to the marked left ventricular dilation multiple daily dosing for an effective treatment; this conand the depressed contractility in our patients. A decrease trasts with pharmacokinetic data obtained in patients in afterload after nicorandil administration can result in a without heart failure in which plasma half-life of eliminamarked decrease in end-systolic volume and an important tion was longer.’ Further studies with pharmacokinetic increase in stroke volume; this differs with the situation in data are necessary to assessthe best schedule dosing in the normal heart in which stroke volume did not or only ambulatory patients with congestive heart failure. moderately increased after administration of an arterial In conclusion, nicorandil appears to be a promising dilator.‘O and potent vasodilator leading to a marked improvement Despite the decrease in diastolic pressure, heart rate in ventricular function, justifying further investigations in did not significantly change. This is not an uncommon congestive heart failure. finding in patients with severe congestive heart failure Acknowledgment: We thank RhBne Poulenc Sante because of the blunting of the baroreflex response] 1 and Laboratories for the supply of nicorandil tablets and VCthe desensitization of the p myocardial receptors.‘* Anronique Foulon for her expert secretarial assistance. other explanation could be that nicorandil also has a dilatory action on large arteries; an increase in the arterial diameter could counteract the decrease in blood pressure, resulting in an absence or decrease in arterial wall REFERENCES 1. Sakai K, Nakano H, Nagano H, Uchida Y. Nicorandil. In: Scriabine A, ed. stress.i3 New Drugs Annual: Cardiovascular Drugs. New York: Raven Press, 1983;227Nicorandil administration resulted in a marked de- 242. crease in right atria1 and pulmonary wedge pressures. 2. Preuss KC, Gross GJ, Brooks HL, Warltier DC. Hemodynamic actions of nicorandil, a new antianginal agent, in the conscious dog. J Cardiouasc PharmaThis decrease was probably due to a reduction in ventriccd 1985;:7:709-714. ular volumes. A first mechanism that can account for the 3. Sakai K, Shiraki Y, Nabata H. Cardiovascular effects of a new coronary reduction in ventricular preload is that nicorandil has vasodilator N-(2-hydroxyethyl) nicotinamide nitrate (SG-75): comparison with and diltiazem. J Cardiouasc Pharmacol 198/;3:139-150. balanced properties, dilating both the arterial and the nitroglycerin 4. Belz GG, Matthews JH, Beck A, Wagner G, Schneider B. Hemodynamic venous bed.3J A second mechanism could be that, be- effects of nicorandil, isosorbide dinitrate and dihydralazine in healthy volunteers. cause of the marked arterial dilation with nicorandil, the J Cardiovasc Pharmacol 1985;7:1107-1112. 5. Signy M, Crowther A, Coltard DJ. Hemodynamic effects of oral and sublindecrease in end-systolic volume was more pronounced gual nicorandil. Proceedings of the Xth World Congress ofcardiology; Washingthan the increase in stroke volume, resulting in a decrease ton, 1986:45. 6. Packer M, Medina N, Yushak H. Hemcdynamic changes mimicking a vasodiin end-diastolic volume. However, in our patients with later drug response in the absence of drug therapy after right heart catheterization frequent biventricular dilation, ventricular interaction in patients with chronic heart failure. Circulation 1985:71:761-766. 7. Gross GJ, Warltier DC, Hardman HF. Lamping KA. Enhanced subendocardicannot be ignored, and part of the decrease in filling perfusion distal to a flow-limiting coronary artery stenosis in dogs: comparative pressures could only be secondary to an improvement in aleffects of nicorandil, a potential new antianginal agent and nitroglycerin. J Carventricular chamber compliance. Finally, an improve- diouasc Pharmacol 1985:7:977-982. ment in load-dependent ventricular relaxation cannot be 6. Kobayashi K, Kobayashi H, Yoshimura H, Hakuta T, Kaneko Y. Effects of nicorandil on coronary hemodynamics in ischemic heart disease: comparison with excluded, accounting in part for a better diastolic filling. nitroglycerin, nifedipine and propranolol (abstr). Circulation 1985:72:suppl lli:11I-276. Further studies including measurements of ventricular 9. Thormann J, Schlepper H, Kramer W, Gottwik M, Kindler M. Effectiveness of volumes, measurements with venous plethysmography, nicorandil (SG-75). a new long-acting drug with nitroglycerin effects, in patients or comparisons of the hemodynamic action of nicorandil with coronary artery disease: improved left ventricular function and regional wall motion and abolition of pacing-induced angina. J Cardiouasc Pharmacol with that of a pure arteriolar dilator (such as hydrala1983:5:371&377. zine) are necessary. 10. MCrillon JP, Fontenier G, Lerallut JF, Jaffrin MY, Chastre J, Assayag P, Nicorandil administration resulted in a potent and Motte G, Gourgon R. Aortic input impedance in heart failure: comparison with interesting action in our patients, leading to a marked normal subjects and its changes during vasodilator therapy. Eur Heart J 1984;5:447-455. increase in systemic output and a decrease in congestive 11. Higgins CB, Vatner SF, Eckerg DL, Braunwald E. Alterations in the baroresigns. However, high doses were used and the 40-mg ceptor reflex in conscious dogs with heart failure. J Clin Invest 1972;52:715-722. 12. Bristow HR. Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie dose-usually effective in patients with myocardial ische- K, Billingham ME, Harrison DC, Stinson EB. Decreased catecholamine sensitivmia or hypertension-had only a weak effect. Although ity and betaadrenergic receptor density in failing human heart. N Engl J Med high dosesof 60 and 80 mg have been well tolerated in our 1982;207:205-21 I. 13. Simon AC, &far ME, Levenson JA, London GM, Levy Bl, Chau NP. An patients with cardiac dilation, in the supine position, ex- evaluation of large arteries compliance in man. Am J Physiol 1979;237:H550treme caution is warranted with these doses in ambulatoH554.
48J
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63
Nicorandil is a new compound that has shown potent vasodilator activities on venous and arterial beds in experimental pharmacology. This study was designed to evaluate the magnitude and the time course of hemodynamic effects of different doses of nicorandil in congestive heart failure. Eleven patients with severe congestive heart failure (New York Heart Association class III or IV), with a cardiac index <3 liters/min/m2 and a pulmonary wedge pressure >15 mm Hg were enrolled in the study. Three patients had ischemic dilated cardiomyopathy and 8 had idiopathic dilated cardiomyopathy. Hemodynamic assessments were performed by right-sided cardiac catheterization (Swan-Ganz catheter) with cardiac output determination (thermodilution) at baseline and from 30 mintues to 12 hours after single oral administration of nicorandil; 3 patients were given 40 mg, 6 patients 60 mg, and 2 patients 60 mg. Maximal hemodynamic changes were observed 30 minutes after dosing and remained statistically significant at 3 hours. Thirty minutes after drug administration, pulmonary wedge pressure decreased 34 f 6%, cardiac index increased by 55 f 13% and diastolic and mean arterial pressures decreased by 15 f 3% and 9 f 2%, respectively, from baseline values. The decrease in systolic blood pressure was slight (5 f 2%) and not statistically significant. Calculated systemic vascular resistances decreased by 36 f 6% and heart rate did not significantly change. Nicorandil was well tolerated. Thus, the results of this first study of nicorandil in congestive heart failure demonstrated the unloading action of this compound on the failing heart, leading to an improvement in cardiac function; further investigation of nicorandil in this therapeutic area is needed. (Am J Cardiol lSSSt63:44J-481)
From the Service de Cardiologie, HBpital Bichat, 46 rue Henri Huchard, 75018 Paris, France. Address for reprints: Alain Cohen Solal, MD, Service de Cardiologie, HBpital Bichat, 46 rue Henri Huchard, 75018 Paris, France.
44J
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63
N
icorandil, a nicotinamide derivative, is a new potent coronary vasodilator with pharmacologic properties differing from those of conventional antianginal drugs. l Although the hemodynamic actions of nicorandil have been studied in animal& and in normal volunteers,4~5no hemodynamic study has been undertaken in patients with congestive heart failure. The present study investigates the magnitude and the time course of the acute hemodynamic effects of a single oral administration of nicorandil in patients with chronic heart failure. AND METHODS The study group consisted of 11 patients with severe congestive heart failure (New York Heart Association class III or IV). There were 9 men and 2 women, aged 25 to 74 years (mean 52). Based on history, electrocardiograms and echocardiograms, 3 patients had an ischemic dilated cardiomyopathy and 8 patients an idiopathic dilated cardiomyopathy. Patients with organic valvular disease, hypertension, unstable angina or recent myocardial infarction, were excluded. All had sinus rhythm except 1 who had a fixed paced heart rate. All had a cardiac index of less than 3 and more than 1.5 literpmin - 1. m-* and a mean pulmonary wedge pressure higher than 15 mm Hg (19 to 38 mm Hg). Digitalis and diuretics, when used, were withheld the morning of the study. Vasodilator therapy was discontinued at least 48 hours before the study. One patient was given a constant infusion of dobutamine at a rate of 5 pg/kg/min. After informed consent was obtained, right-sided cardiac catheterization was performed under fluoroscopic guidance with a triple lumen thermodilution flow-directed Swan-Ganz catheter inserted the evening before or the morning of the study. To ensure a stable baseline, measurements were repeated every 15 minutes during 2 hours; baseline was assumed to exist only if 2 measurements differed by less than 10%. To minimize spontaneous hemodynamic variations, patients were kept in the supine position in a special room in the intensive care unit, and remained fasting all during the study.6 Right atrial, pulmonary arterial and pulmonary wedge pressures were recorded directly on a Siemens Mingograph Elema recorder. Heart rate was monitored from a precordial electrocardiographic lead (the patient with a cardiac pacemaker was not considered for the study of this parameter). Humeral systolic, diastolic and mean arterial pressures were recorded by a continuous automatic device (Automatic Device-Dynamap 845, oscillometric PATIENTS
I
Pulmonary Wedge Pressure
Cardiac
1
Mean Blood Pressure
Index
130-
FIGURE 1. Hemedynamic reqenee of pulcardiac index -w we&z -, amlmeambloodpressurebftfomand30 minutes after nicorandil administration (40-, so- and 8omg do!ms).
120-
\
IlOloo-
\
gokI 70 6oI
s
60-
technic). Thermodilution cardiac output was determinated in triplicate (variation of 10% or less). Cardiac, systemic vascular resistance and stroke volume indexes were calculated by standard formulas. Three patients received 40 mg, 6 patients 60 mg and 2 patients 80 mg of nicorandil orally. Measurements were repeated at 30 minutes and 1, 2, 3, 6 and 12 hours after administration. Statistical analysis used paired t tests with a Bonferroni Holm adjustment for repeated measurements.
Systolic
RESULTS The effects of nicorandil on pulmonary wedge pressure, cardiac index and mean arterial pressure are summarized in Figure 1. Nicorandil administration resulted in a decrease in mean arterial and pulmonary wedge pressures and an increase in cardiac index, suggesting a potent vasodilation. Diastolic arterial pressure decreased by 15% at 30 minutes; the decrease in systolic arterial pressure was less pronounced (5%) and not statistically significant (Fig. 2); mean arterial pressure decreased by
Blood
Pressure
mmHg
140
T
1
loo’ Diastolic
Blood
Pressure
mmHg FfGURE 2. Changes in systolic and diastollc arterial presswe after nicorandil adminishtion. SEM = standard ewer of the mean.
go-
Hours -+ 1 SEM
after
Nicorandil * p<
0.05
administration (Bonferronl
Helm
Adjustment)
THE AMERICAN JOURNAL OF CARDIOLOGY JUNE 20,1989
451
A SYMPOSIUM:
Cardiac 4
FOCUS ON NICORANDIL
Index
l.mn-'.rn-* 1 * FIGURE 3. Changes in cardiac index after nicorandil administration. SEM = standard error of the mean.
fl
Hours after
Nicorandil
SEM
p
*
Administration
(Bonferroni
Helm
adjustment)
9% (p <0.05). Nicorandil caused an important increase in cardiac index, reaching 55% at 30 minutes (Fig. 3), and the calculated systemic vascular resistance index decreased by 36% (Fig. 4). Increase in cardiac index was entirely due to an increase in stroke volume; heart rate did not significantly change (Fig. 5). Finally, nicorandil administration resulted in a marked decrease in right atria1 (35%) and pulmonary wedge pressures (34%) (Fig. 5). Maximal hemodynamic changes were observed at 30 minutes for all parameters and remained statistically significant only for 2 hours.
Systemic
Vascular
Resistance
dynes.sec.cm-5.m 4000
2
3000
-
Index
-*
FIGURE 4. Changes in systemic vascular resistance index after nicorandil administratlen. SEM = standard errar of the mean.
oh!/*/
*/
o/’
Hours after Nicorandil 21 SEM
46J
DISCUSSION Nicorandil is a new potent vasodilator with anti-ischemic properties. 2,3,7-9This study is the first to characterize the hemodynamic action of nicorandil in patients with congestive heart failure. Nicorandil administration resulted in a pronounced vasodilatory action leading to a marked improvement in cardiac function. The decrease in systemic vascular resistances and in diastolic and mean arterial pressures are consistent with the previous data, showing a potent vasodilatory action of nicorandil on the arterial bed.‘y3J Sys-
$7 p
.a/’
administration (Sonfsrronl
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63
Helm
Adjustment)
Right Atrial ‘51
Heart Rate 110
Pressure
mmHg
b.mn-’
1
Stroke
Volume index
Pulmonary
Wedge
Pressure
40 7 ml.me2 h
,oJ . . . . . o~u*I d Hours after fl
SEM
Pulmonary
Wedge
Nicorandil
2 p
FIGURE 5. Changer in hart rate, stroke volume index, right atrial pressure and pulmonary ministration. SEM = standard error of the mean.
j (Bonierroni
J
4
administration Helm
Adjustment)
wedge pressure aflw
Pressure
nicorandil
ad-
(Means)
mmHg
FIGURE 6. f%~lmonary wedge pressure (means). Magnitude and time course of the change in pudmonary wedge pressure after administration of 40 mg (n = 3), 50 mg (n = 6) and 66 mg (n = 2) of nicorandil.
Hours l
40mg
after dose
Nicorandil v 60mg
administration dose
l
80mg
THE AMERICAN JOURNAL OF CARDIOLOGY JUNE 20.1989
dose
47J
A SYMPOSIUM:
FOCUS ON NICORANDIL
tolic arterial pressure did not significantly change proba- ry patients because of the hypotensive risk. Finally, the bly because of a large increase in stroke volume.1o duration of action of nicorandil, whatever the dose, was The magnitude of the increase in stroke volume is short, always lesser than 3 hours (Fig. 6), suggesting probably related to the marked left ventricular dilation multiple daily dosing for an effective treatment; this conand the depressed contractility in our patients. A decrease trasts with pharmacokinetic data obtained in patients in afterload after nicorandil administration can result in a without heart failure in which plasma half-life of eliminamarked decrease in end-systolic volume and an important tion was longer.’ Further studies with pharmacokinetic increase in stroke volume; this differs with the situation in data are necessary to assessthe best schedule dosing in the normal heart in which stroke volume did not or only ambulatory patients with congestive heart failure. moderately increased after administration of an arterial In conclusion, nicorandil appears to be a promising dilator.‘O and potent vasodilator leading to a marked improvement Despite the decrease in diastolic pressure, heart rate in ventricular function, justifying further investigations in did not significantly change. This is not an uncommon congestive heart failure. finding in patients with severe congestive heart failure Acknowledgment: We thank RhBne Poulenc Sante because of the blunting of the baroreflex response] 1 and Laboratories for the supply of nicorandil tablets and VCthe desensitization of the p myocardial receptors.‘* Anronique Foulon for her expert secretarial assistance. other explanation could be that nicorandil also has a dilatory action on large arteries; an increase in the arterial diameter could counteract the decrease in blood pressure, resulting in an absence or decrease in arterial wall REFERENCES 1. Sakai K, Nakano H, Nagano H, Uchida Y. Nicorandil. In: Scriabine A, ed. stress.i3 New Drugs Annual: Cardiovascular Drugs. New York: Raven Press, 1983;227Nicorandil administration resulted in a marked de- 242. crease in right atria1 and pulmonary wedge pressures. 2. Preuss KC, Gross GJ, Brooks HL, Warltier DC. Hemodynamic actions of nicorandil, a new antianginal agent, in the conscious dog. J Cardiouasc PharmaThis decrease was probably due to a reduction in ventriccd 1985;:7:709-714. ular volumes. A first mechanism that can account for the 3. Sakai K, Shiraki Y, Nabata H. Cardiovascular effects of a new coronary reduction in ventricular preload is that nicorandil has vasodilator N-(2-hydroxyethyl) nicotinamide nitrate (SG-75): comparison with and diltiazem. J Cardiouasc Pharmacol 198/;3:139-150. balanced properties, dilating both the arterial and the nitroglycerin 4. Belz GG, Matthews JH, Beck A, Wagner G, Schneider B. Hemodynamic venous bed.3J A second mechanism could be that, be- effects of nicorandil, isosorbide dinitrate and dihydralazine in healthy volunteers. cause of the marked arterial dilation with nicorandil, the J Cardiovasc Pharmacol 1985;7:1107-1112. 5. Signy M, Crowther A, Coltard DJ. Hemodynamic effects of oral and sublindecrease in end-systolic volume was more pronounced gual nicorandil. Proceedings of the Xth World Congress ofcardiology; Washingthan the increase in stroke volume, resulting in a decrease ton, 1986:45. 6. Packer M, Medina N, Yushak H. Hemcdynamic changes mimicking a vasodiin end-diastolic volume. However, in our patients with later drug response in the absence of drug therapy after right heart catheterization frequent biventricular dilation, ventricular interaction in patients with chronic heart failure. Circulation 1985:71:761-766. 7. Gross GJ, Warltier DC, Hardman HF. Lamping KA. Enhanced subendocardicannot be ignored, and part of the decrease in filling perfusion distal to a flow-limiting coronary artery stenosis in dogs: comparative pressures could only be secondary to an improvement in aleffects of nicorandil, a potential new antianginal agent and nitroglycerin. J Carventricular chamber compliance. Finally, an improve- diouasc Pharmacol 1985:7:977-982. ment in load-dependent ventricular relaxation cannot be 6. Kobayashi K, Kobayashi H, Yoshimura H, Hakuta T, Kaneko Y. Effects of nicorandil on coronary hemodynamics in ischemic heart disease: comparison with excluded, accounting in part for a better diastolic filling. nitroglycerin, nifedipine and propranolol (abstr). Circulation 1985:72:suppl lli:11I-276. Further studies including measurements of ventricular 9. Thormann J, Schlepper H, Kramer W, Gottwik M, Kindler M. Effectiveness of volumes, measurements with venous plethysmography, nicorandil (SG-75). a new long-acting drug with nitroglycerin effects, in patients or comparisons of the hemodynamic action of nicorandil with coronary artery disease: improved left ventricular function and regional wall motion and abolition of pacing-induced angina. J Cardiouasc Pharmacol with that of a pure arteriolar dilator (such as hydrala1983:5:371&377. zine) are necessary. 10. MCrillon JP, Fontenier G, Lerallut JF, Jaffrin MY, Chastre J, Assayag P, Nicorandil administration resulted in a potent and Motte G, Gourgon R. Aortic input impedance in heart failure: comparison with interesting action in our patients, leading to a marked normal subjects and its changes during vasodilator therapy. Eur Heart J 1984;5:447-455. increase in systemic output and a decrease in congestive 11. Higgins CB, Vatner SF, Eckerg DL, Braunwald E. Alterations in the baroresigns. However, high doses were used and the 40-mg ceptor reflex in conscious dogs with heart failure. J Clin Invest 1972;52:715-722. 12. Bristow HR. Ginsburg R, Minobe W, Cubicciotti RS, Sageman WS, Lurie dose-usually effective in patients with myocardial ische- K, Billingham ME, Harrison DC, Stinson EB. Decreased catecholamine sensitivmia or hypertension-had only a weak effect. Although ity and betaadrenergic receptor density in failing human heart. N Engl J Med high dosesof 60 and 80 mg have been well tolerated in our 1982;207:205-21 I. 13. Simon AC, &far ME, Levenson JA, London GM, Levy Bl, Chau NP. An patients with cardiac dilation, in the supine position, ex- evaluation of large arteries compliance in man. Am J Physiol 1979;237:H550treme caution is warranted with these doses in ambulatoH554.
48J
THE AMERICAN JOURNAL OF CARDIOLOGY VOLUME 63