Failure of Captopril to Prevent Nitrate Tolerance in Congestivh Heart Failure Secondary to Coronary Artery Disease Nader Dakak, MD, Nabeel Makhoul, MD, Moshe Y. Flugelman, MD, Amnon Merdler, MD, Habib Shehadeh, MD, Adam Schneeweiss, MD, David A. Halon, MB, ChB, and Basil S. Lewis, MD, MRCP(UK), FCP(SA)
The possible role of angiotensin-converting enzyme inhibition in preventing or minimizing tolerance to intravenous nitroglycerin in severe congestive heart failure (CHF) was studied by quantitating the degree of tolerance in 12 patients receiving nitroglycerin (group 1) and in 9 patients (group 2) receiving nitroglycerin and concurrent treatment with captopril (66 f 29 mg/day). At peak effect, nitroglycerin produced almost identical hemodynamic changes in both groups, with significant decreases in right atrial and pulmonary arterial wedge pressure, systolic blood pressure and systemic and pulmonary vascular resistances. Cardiac index increased. The extent of nitrate tolerance was calculated for each hemodynamic parameter as the percentage loss of the peak effect achieved by the drug. At 24 hours, 98 f 60% of the benefit achieved with respect to right atrial pressure was lost in group 1 and 61 f 74% in group 2 (group 1 vs 2, difference not significant). For pulmonary arterial wedge pressure, 51 f 31% (group 1) and 85 f 53% (group 2) (difference not significant) of the effect was lost, and for cardiac index, 53 f 66% (group 1) and 64 f 44% (group 2) (difference not significant). Tolerance was also almost identical regarding systolic blood pressure and systemic and pulmonary vascular resistance. Thus, the extent of tolerance to high-dose intravenous nitroglycerin in CHF was unaltered by administration of captopril, indicating that in clinical dosage, counter-regulatory neurohumoral mechanisms involving the renin-angiotensin system appear to be unimportant in its development. (Am J Cardiol 1990;66608-613)
From the Department of Cardiology, Lady Davis Carmel Hospital, Haifa, Israel. Manuscript received January 16, 1990; revised manuscript received April 27, 1990, and accepted April 29. Address for reprints: Basil S. Lewis, MD, Department of Cardiology, Lady Davis Carmel Hospital, 7 Michal Street, Haifa, 34362 Israel.
608
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
66
he beneficial effect of nitrate therapy in patients with congestive heart failure (CHF) may be rapidly offset by the development of tolerance to the drug within 24 to 48 hours.1-4 Two primary mechanisms have been proposed4m6: (1) a cellular mechanism, in which depletion of sulfhydryl groups or alteration of the guanylate cyclase pathway is followed by attenuation of the effect of nitrates,5*7-10 and (2) a systemic mechanism, in which hemodynamic changes produced by nitroglycerin trigger a counter-regulatory neurohumoral response,’ iJ2 with stimulation of the renin-angiotensin pathway, fluid retention and a secondary deterioration in hemodynamics. In keeping with the cellular mechanism is the evidence that administration of the sulfhydryl donor N-acetyl cysteine may ameliorate nitrate tolerance,4J3 while in keeping with the neurohumoral mechanism is the increase in plasma renin activity and body weight that has been observed during nitrate administration4 and the rebound vasoconstrictive changes that occur in some patients on withdrawal of nitrate therapy. *I The present study examined in more detail the role of the renin-angiotensin pathway in the development of nitrate tolerance. We quantitated the extent of tolerance to intravenous nitrates in patients with CHF, and compared the data with those of patients concurrently receiving the angiotensin-converting enzyme inhibitor captopril.
T
METHODS Study patients:
The study involved 21 patients (18 men, 3 women) with severe (New York Heart Association functional class IV) CHF in sinus rhythm, who required hemodynamic monitoring as part of their clinical management. Their age ranged from 38 to 78 years. The etiology of CHF was advanced coronary artery disease with extensive regional and global left ventricular dysfunction. In all, the pulmonary arterial wedge pressure was 216 mm Hg and systolic blood pressure 190 mm Hg. Long-acting nitrate and other vasodilator therapy was discontinued at least 48 hours before the study. Baseline drug therapy with digoxin (10 patients) and furosemide (21 patients, dose 40 to 160 mg/day) was continued at a constant dosage schedule throughout the study period. Diuretic was administered at the same time each day, 6 hours after commencement of the nitroglycerin infusion.
T
TABLE I Peak Hemodynamic RAP mm Hg
Group 1 1 2 3 4 5 6 7 8 9 10 11 12
Mean SD
Mean SD
Pvalue
Cl
SBP mm Hg
Ilters/min/m7
SVR dyne.
PVR s. cm-’
HR
dyne.
s. cm-j
mln-’
N
C
N
C
N
C
N
C
N
C
N
3 22 6 13 11 2
0 1 1 6 3 0 5 0 2 1 1 2 2
25 30 20 28 27 32 28 34 29 34 18 18 27 6
5 9 11 19 15 14 16 16 11 13 7 8 12 4
2.3 2.2 2.0 1.4 2.6 2.9 1.9 2.0 2.6 2.2 1.8 1.7 2.1 0.4
3.2 3.3 2.0 2.2 3.1 2.9 3.2 3.1 3.1 2.7 2.7 2.6 2.8 0.4
129 124 167 152 118 102 127 127 171 170 113 100 133 25
The possible role of angiotensin-converting enzyme inhibition in preventing or minimizing tolerance to intravenous nitroglycerin in severe congestive heart failure (CHF) was studied by quantitating the degree of tolerance in 12 patients receiving nitroglycerin (group 1) and in 9 patients (group 2) receiving nitroglycerin and concurrent treatment with captopril (66 f 29 mg/day). At peak effect, nitroglycerin produced almost identical hemodynamic changes in both groups, with significant decreases in right atrial and pulmonary arterial wedge pressure, systolic blood pressure and systemic and pulmonary vascular resistances. Cardiac index increased. The extent of nitrate tolerance was calculated for each hemodynamic parameter as the percentage loss of the peak effect achieved by the drug. At 24 hours, 98 f 60% of the benefit achieved with respect to right atrial pressure was lost in group 1 and 61 f 74% in group 2 (group 1 vs 2, difference not significant). For pulmonary arterial wedge pressure, 51 f 31% (group 1) and 85 f 53% (group 2) (difference not significant) of the effect was lost, and for cardiac index, 53 f 66% (group 1) and 64 f 44% (group 2) (difference not significant). Tolerance was also almost identical regarding systolic blood pressure and systemic and pulmonary vascular resistance. Thus, the extent of tolerance to high-dose intravenous nitroglycerin in CHF was unaltered by administration of captopril, indicating that in clinical dosage, counter-regulatory neurohumoral mechanisms involving the renin-angiotensin system appear to be unimportant in its development. (Am J Cardiol 1990;66608-613)
From the Department of Cardiology, Lady Davis Carmel Hospital, Haifa, Israel. Manuscript received January 16, 1990; revised manuscript received April 27, 1990, and accepted April 29. Address for reprints: Basil S. Lewis, MD, Department of Cardiology, Lady Davis Carmel Hospital, 7 Michal Street, Haifa, 34362 Israel.
608
THE AMERICAN
JOURNAL
OF CARDIOLOGY
VOLUME
66
he beneficial effect of nitrate therapy in patients with congestive heart failure (CHF) may be rapidly offset by the development of tolerance to the drug within 24 to 48 hours.1-4 Two primary mechanisms have been proposed4m6: (1) a cellular mechanism, in which depletion of sulfhydryl groups or alteration of the guanylate cyclase pathway is followed by attenuation of the effect of nitrates,5*7-10 and (2) a systemic mechanism, in which hemodynamic changes produced by nitroglycerin trigger a counter-regulatory neurohumoral response,’ iJ2 with stimulation of the renin-angiotensin pathway, fluid retention and a secondary deterioration in hemodynamics. In keeping with the cellular mechanism is the evidence that administration of the sulfhydryl donor N-acetyl cysteine may ameliorate nitrate tolerance,4J3 while in keeping with the neurohumoral mechanism is the increase in plasma renin activity and body weight that has been observed during nitrate administration4 and the rebound vasoconstrictive changes that occur in some patients on withdrawal of nitrate therapy. *I The present study examined in more detail the role of the renin-angiotensin pathway in the development of nitrate tolerance. We quantitated the extent of tolerance to intravenous nitrates in patients with CHF, and compared the data with those of patients concurrently receiving the angiotensin-converting enzyme inhibitor captopril.
T
METHODS Study patients:
The study involved 21 patients (18 men, 3 women) with severe (New York Heart Association functional class IV) CHF in sinus rhythm, who required hemodynamic monitoring as part of their clinical management. Their age ranged from 38 to 78 years. The etiology of CHF was advanced coronary artery disease with extensive regional and global left ventricular dysfunction. In all, the pulmonary arterial wedge pressure was 216 mm Hg and systolic blood pressure 190 mm Hg. Long-acting nitrate and other vasodilator therapy was discontinued at least 48 hours before the study. Baseline drug therapy with digoxin (10 patients) and furosemide (21 patients, dose 40 to 160 mg/day) was continued at a constant dosage schedule throughout the study period. Diuretic was administered at the same time each day, 6 hours after commencement of the nitroglycerin infusion.
T
TABLE I Peak Hemodynamic RAP mm Hg
Group 1 1 2 3 4 5 6 7 8 9 10 11 12
Mean SD
Mean SD
Pvalue
Cl
SBP mm Hg
Ilters/min/m7
SVR dyne.
PVR s. cm-’
HR
dyne.
s. cm-j
mln-’
N
C
N
C
N
C
N
C
N
C
N
3 22 6 13 11 2
0 1 1 6 3 0 5 0 2 1 1 2 2
25 30 20 28 27 32 28 34 29 34 18 18 27 6
5 9 11 19 15 14 16 16 11 13 7 8 12 4
2.3 2.2 2.0 1.4 2.6 2.9 1.9 2.0 2.6 2.2 1.8 1.7 2.1 0.4
3.2 3.3 2.0 2.2 3.1 2.9 3.2 3.1 3.1 2.7 2.7 2.6 2.8 0.4
129 124 167 152 118 102 127 127 171 170 113 100 133 25
