Hemodynamic and electrophysiologic effects of amlodipine, a new long-acting calcium antagonist:...

Hemodynamic and Electrophysiologic Effects of Verapamil And Nifedipine in Patients on Propranolol

MICHAEL D. WINNIFORD, MD, ROY V. MARKHAM, Jr., MD,

BRIAN G. FIRTH, MD, D Phil, PASCAL NICOD, MD, and L. DAVID HILLIS, MD

Because the combined use of a beta-adrenergic blocking agent and a calcium antagonist may be beneficial in patients with severe angina, we assessed the hemodynamic and electrophysiologic effects of verapamil or nifedipine in patients receiving oral propranolol. In 26 patients with stable angina receiving oral propranolol (234 f 230 mg/day, mean f standard deviation), cardiac catheterization was performed, and variables were measured at baseline and 5 to 10 minutes after (1) intravenous saline solution, 10 ml (n = 6); (2) intravenous verapamil, 0.15 mg/kg body weight to a maximal dose of 10 mg (n = 10); and (3) sublingual nifedipine, 10 mg (n = 10). Cardiac output (by thermodilution) was unchanged after saline solution and verapamil but increased with nifedipine (4.3 f 1.1 to 5.0 f 1.4 liters/min, p <O.OS). Mean arterial pressure did not change with saline solution or nifedipine but decreased with verapamil. Peak-positive dP/dt was reduced only by verapamil (from 1,066 f 175 to 926 f 167 mm Hg/s, p <O-05). Coronary sinus blood flow (by thermodilution) was

not altered by saline solution, nifedipine, or verapamil. Verapamil reduced the heart rate (from 63 f 8 to 60 f 9 beats/min, p <0.05) and increased the A-H interval (from 108 f 14 to 129 f 23 ms, p <0.05). In contrast, nifedipine increased the heart rate (from 65 f 8 to 71 f 8 beats/min, p <0.05) but did not change the A-H interval. Left ventricular ejection fraction (by radionuclide ventriculography) was unaltered by saline solution or verapamil but increased with nifedipine (from 0.52 f 0.13 to 0.57 f 0.13, p <O.OS). In summary, when administered to patients with normal or only mildly depressed left ventricular function who are receiving oral propranolol, nifedipine improves cardiac output and left ventricular ejection fraction without affecting intracardiac filling pressure or atrioventricular conduction. In contrast, verapamil diminishes left ventricular contractility and slows atrioventricular conduction. Thus, the combination of verapamil and propranolol must be used with caution in patients with underlying left ventricular dysfunction or conduction system disease.

The beta-adrenergic blocking agents are efficacious in the treatment of most patients with stable angina pectoris-s By reducing the heart rate, systolic arterial pressure, and left ventricular contractility, these agents diminish myocardial oxygen demands. More recently, the calcium antagonists, including verapamil and nifedipine, have been shown to exert a potent antianginal

From the Deoartment of Internal Medicine (Cardiovascular Division), the University of Texas Health Science Center, Dallas, Texas. This work was supported in part by the lschemic SCOR grant (HL-17669) from the National Institutes of Health, Bethesda, Maryland; the Harry S. MOSS Heart Fund, Dallas, Texas; and the Texas Affiliate of the American Heart Association, Dallas, Texas. Manuscript received January 18, 1982; revised manuscript received April 12, 1982, accepted May 26,

effect.*-s Like the beta-adrenergic blocking drugs, these agents reduce myocardial oxygen requirement&r2; in addition, they may diminish coronary vascular resistance and augment coronary blood flo~.*J~-~~ For the patient whose angina is not controlled by beta blockade or calcium blockade alone, a combination of these agents may be particularly effective because their mechanisms of action are, in some ways, complemen- tary. In fact, initial clinical studies have shown that nifedipine and propranololt6J7 as well as verapamil and propranololls are beneficial in patients with severe angina.

Although combined beta-adrenergic and calcium blockade is potentially beneficial to the patient with severe angina, only a few studies have attempted to define the hemodynamic and electrophysiologic con- sequences of such combination therapy.1g-22 These

1982. Address for reprints: L. David Hillis. MD, Room L5-134, University

of Texas Health Scrence Center, 5323 Harry Hines Boulevard, Dallas, Texas 75235.

704 October 1992 The American Journal of CARDIOLOGY Volume 50

PROPRANOLOL PLUS CALCIUM ANTAGONISTS-WINNIFORD ET AL

TABLE I Hemodynamic Variables Before and After Drug Administration __I- Saline Solution Verapamil Nifedipine

-

Variable Before After Before After Before After

Cardiac output (litersjmin) 4.2 f 1 2 42f12a 4.5 i 0.7 4.4 f 1.0 a 4.3 & 1 1 5.0 f 1.4’ b Coronary sinus blood flow (mUmin) 104 f 65 108f64a 123 f 30 131 f 61 a 127 f 71 146f95a

Pressures (mm Hg) Femoral arterial mean 95f 13 98* 14a 98 * 7 87f 10b 100 f 17 94f 12ab

Right atrial mean 6f2 5fZab 5f2 7f2”b 6*2 6f2a

Pulmonary capillary wedge mean lOf4 llf4a 10 f 2 13 f 3’ a llf2 llf3a

Resistances (dynes s cm- ) Systemic vascular 1.788 f 494 1,869 f 510 a 1,667 f 296 1,513 f 251’ab 1,881 f 704 1,505 f 474” b Pulmonary arteriofar 129 f 52 137 f 58 a 145 f 60 157f69a 148 f 61 157f42a

LV + dP/dt (mm Hg/s) 1,091 f 210 1,081 f 215 a 1,086 f 175 926 f 167’ b 1,092 f 190 1,109 f 185 a

* p (0.05 in comparison with the same pharmacologic agent in the baseline state. By analysis of variance, those figures marked with the same letter (a or b) are statistically indistinguishable at p = 0 05; those marked with different

letters are statistically distinguishable at p CO.05

TABLE II Electrophysiologic and Scintigraphic Variables Before and After Drug Administration

Salrne Solution Verapamil Nifedipine


Heart rate (beats/min) 60 f 8 60f9a 63 f 8 60f9’a 65 f 8 71 f 8’ b A-H interval (ms) 90 & 27 89*22a 108 f 14 129 k 23” b 113f24 115%23a H-V interval (ms) 59 f 9 51 f 15 LVEDVI (ml/m*)

57f8a 50f 12a 49 f 11 49f lla 106 f 45 106 f 38 a 102 f 29 105 f 32 a 85 YL

LVESVI (mllmz) 21 87 f 22 a

55 f 25 58 f 26 a 55f 19 54 f 20 a 45f 19 42 f 20’ a LVEF 0.51 f 0 06 0.49 f 0.09 a 0.49 f 0.10 0.50 ab f 0.09 052ztOo.13 0.57 f 0.13” b

See Table I for an explanation of statistical indicators LVEDVI = left ventricular end-diastolic volume index; LVEF = left ventricular ejection fraction: LVESVI = left ventricular end-systolrc volume

preliminary investigations have suggested that verapamil and nifedipine can be administered safely to the patient already receiving propranolol, but the effects of a verapamil-propranolol combination may differ substantially from those of combined nifedipine and propranolol. The present study was performed to compare the acute hemodynamic and electrophysiologic effects of intravenous verapamil with those of sublingual nifedipine in patients receiving oral propranolol.

Methods

Study patients: The study was performed in 26 consecutive persons (18 men and 8 women, mean age 54 years) referred for cardiac catheterization for the evaluation of chest pain, all of whom were receiving oral propranolol (mean dose 234 mg/day; range 40 to 1,280). In each patient data acquisition was performed 2 to 3 hours after a regularly scheduled dose of oral propranolol. Informed consent was obtained from all patients Patients with valvular or congenital heart disease, left bundle branch block, or previous coronary arterial bypass surgery were excluded.

Protocol: In each patient, hemodynamic, electrophysiologic, and (in 15 patients) radionuclide ventriculographic measurements were made (1) in the baseline state (that is, on propranolol alone), and (2) after random administration of 1 of 3 pharmacologic agents. All data acquisition was performed before angiography.

Control group (n = 6): In these subjects, baseline measurements were accomplished, after which 10 ml of normal saline solution was administered intravenously. Subsequently, all measurements were repeated 5 to 10 minutes later. This

group comprised 4 men and 2 women with an average age of 51 years. Their daily propranolol dosage was 177 f 92 mg (mean f standard deviation) (range 60 to 320). Coronary arteriography revealed single vessel coronary arterial disease (defined as 70% or greater luminal diameter narrowing) in 3 and triple vessel disease in 3.

Verapamil group (n = 10): In these patients, baseline measurements were made, then verapamil (Knoll Pharma- ceutical, Whippany, New Jersey), 0.15 mglkg to a maximal dose of 10 mg, was administered intravenously. All measurements were repeated 5 minutes after administration of verapamil. These 10 patients included 8 men and 2 women with a mean age of 54 years. Their daily propranolol dose was 298 f 352 mg (range 80 to 1,280). At coronary arteriography 3 had single vessel coronary arterial disease, 3 had double vessel disease, and 4 had triple vessel disease.

Nifeedipine group (n = 10): After baseline measurements were performed, nifedipine (Bayer Pharmaceutical, Munich, Germany) (10 mg) was administered sublingually, and all measurements were repeated 10 minutes later. Of these 10 patients, 6 were men and 4 were women, with an average age of 54 years. Their daily propranolol dose was 204 f 104 mg (range 40 to 360). Three had single vessel coronary artery disease, 1 had double vessel disease, and 6 had triple vessel disease.

Variables assessed: Hemodynamic measurements: Sys- temic arterial pressure was recorded through a percutaneous femoral arterial cannula. Left ventricular pressure was recorded with a high fidelity micromanometer-tipped pigtail catheter (Millar Instruments, Houston) advanced to the left ventricle from the femoral artery, and the maximal first de- rivative of left ventricular pressure (dP/dt) was electronically derived from this pressure trace. Right atrial, pulmonary ar-

October 1982 The American Journal of CARDIOLOGY Volume 50 705


terial, and pulmonary capillary wedge pressure as well as forward cardiac output were measured with a flow-directed, balloon-tipped thermodilution catheter (Electronics for Medicine, model 62 00 37) advanced from the femoral vein. An average of 3 to 4 thermodilution measurements of cardiac output was used for the final computations. The variability of thermodilution measurements in our laboratory is 54%. From these data, systemic and pulmonary arteriolar resistance was calculated.

Coronary blood flou measurements: In each patient, a thermodilution catheter (model CCS-7U-90B, Wilton Web- ster Laboratories, Altadena, California) was advanced to the coronary sinus from the right basilic vein, and its position was confirmed oximetrically and by the injection of 3 to 5 ml of contrast material. Coronary sinus blood flow was measured with the continuous thermodilution technique.2”

Electrophysiologic measurements: A tripolar pacing catheter was advanced from the femoral vein and positioned across the tricuspid valve, and atrio-His bundle (A-H) and His bundle-ventricular (H-V) conduction times were measured.z4

Radionuclide uentriculography: In 15 of the 26 patients, red blood cells were labeled with 30 mCi of technetium-99m sodium pertechnetate using a technique combining features of both in vitro and in vivo labeling.2s In the remaining 11 patients, radionuclide ventriculography was not performed because the necessary imaging equipment was not available. Scintigraphic data collection was performed with a portable gamma scintillation camera (Series Sigma 420, Ohio Nuclear, Solon, Ohio), as previously described.2e--:r0 Left ventricular volume and ejection fract,ion were estimated by a totally nongeometric technique developed and validated in our laboratory.z8~:~0 All volumes were normalized for body surface

area. The inter- and intraobserver variability of these volume measurements in our laboratory is 7.5 and 6%, respectively, and the reproducibility of these measurements over time has been substantiated.27

Statistical analysis: All data are reported as mean f 1 standard deviat,ion. For each variable in the baseline state, the 3 groups were compared with an analysis of variance. For each group (control, verapamil, and nifedipine), each variable at baseline and after drug administration was evaluated with a paired t test.:‘] This analysis of paired data was performed (1) for the complete groups (6 control subjects, 10 taking verapamil and 10 taking nifedipine) and (2) after excluding the 4 patients who were receiving either a small (less than 100 mg/day) or large (more than 500 mg/day) dose of propranolol (5 control subjects, 8 taking verapamil, and 9 taking nifedipine). In addition, for each variable in each patient, the dif- ference between the value of baseline and after drug administration was determined, and these differences were compared among the 3 groups by analysis of variance. For all analyses, a p value less than 0.05 was considered significant.

Results

In the baseline state, the 3 groups were similar with regard to age, severity of coronary artery disease, propranolol dosage, and all hemodynamic, electrophysiologic, and scintigraphic variables (Tables I and II). Three patients (1 from each group) were receiving less than 100 mg/day of propranolol, and 1 patient in the verapamil group was receiving an unusually large dose of propranolol (1,280 mg/day). With the exclusion of these 4 patients, the control group (n = 5) received a

TABLE III Hemodynamic Variables Before and After Drug Administration in the 22 Patients Receiving 100 to 360 mg/Day of Propranolol

Saline Verapamil Nifedipine


Cardiac output (liters/min) 4.4 f 1.3 4.4 f 1.2 4.7 f 0.5 4.7 f 0.8 4.2 f 1 0 4.0 f 1.2’ Coronary sinus blood flow (mllmin) 115f66 118f66 121 f 32 136 f 64 121 f 73 143 f 100 Pressures (mm Hg)

Femoral arterial mean 98f 11 102 f 11 99 f 7 90 f 7‘ 102 f 17 95f 12 Right atrial mean 6f2 6f2 5f2 7 f 2’ 653 6f2 Pulmonary capillary wedge mean 10 f 4 12f4 10 f 2 13 f 3’ 11 f3 10 f 3

Resistances (dynes s cm- ) Systemic vascular 1,796 f 552 1,873 f 570 1,608 f 257 1,455 f 236” 1,966 f 690 1,577 f 441’ Pulmonary arteriolar 136 f 55 140 f 64 136 f 49 133 f 37 154 f 63 165 f 33

LV dP/dt (mm Hgk) 1,092 f 243 1,081 f 248 1,132 f 163 980 f 129’ 1,104 f 198 1,123 f 191 -

l p <0.05 in comparison with the same pharmacologic agent in the baseline state

TABLE IV Electrophysiologic and Scintigraphic Variables Before and After Drug Administration in the 22 Patients Receiving 100 to 360 mg/Day of Propranolol

Variable

Saline Solution Verapamil Nifedipine

Before After Before After Before After

Heart rate (beatslmin) 60 k 9 61 f9 65 f 6 62 f 7 66 f 9 71 f9’ A-H Interval (ms) 80f 17 81 f 15 107 f 13 131 zk 24’ 117 f 23 118f23 H-V Interval (ms) 57 f 9 55 f 9 53* 17 53i 16 50f 11 50f 11 LVEDVI (ml/m’) 106 f 45 106 f 38 98 f 32 106 zk 35’ 85 f 21 87 f 22 LVESVI (ml/m*) 55 f 25 58 f 26 52 f 23 56 f 23 45% 19 42 f 20’ LVEF 0.51 f 0.06 0.49 f 0.09 0.50 f 0.11 0.50 zlz 0.10 0.52 f 0.13 0.57 f 0.13’

l p <0.05 in comparison with the same pharmacologic agent in the baseline state Abbreviations as in Table Il.



daily propranolol dose of 200 f 80 mg (range 120 to 320); the verapamil group (n = 8) received 203 f 66 mg (range 100 to 320); and the nifedipine group (n = 9) received 222 f 92 mg (range 120 to 360). For these 22 patients, the baseline characteristics of the 3 patient groups were similar (Tables III and IV).

Hemodynamic alterations: The hemodynamic alterations induced by saline solution, verapamil, and nifedipine for all 26 patients are shown in Table I. Cardiac output did not change with the administration of saline solution or verapamil. In contrast, nifedipine caused a significant increase in cardiac output (Fig. 1). Systemic arterial pressure was not altered by saline solution or nifedipine but was reduced by verapamil; however, the reduction in arterial pressure produced by verapamil did not differ statistically from that produced by nifedipine (Table I). Systemic vascular resistance did not change with saline solution but decreased with both calcium antagonists (Fig. 1).

Mean right atria1 pressure was unchanged with saline solution and nifedipine but increased slightly with verapamil, and pulmonary capillary wedge pressure behaved similarly. These changes in right atria1 and pulmonary capillary wedge pressure induced by verapamil were not significantly different from those pro-

SALINE VERAPAMIL NIFEDIPINE

I I BEFORE AFTERBEFORE AFTER BEFORE AFTER

FIGURE 1. Cardiac output, in liters/min (top panel), and systemic vascular resistance. in dynes-set-cm-+ (bottom panel), before and after the administration of saline solution (left), verapamil (middle), or nifedipine (right). Each line represents the data from 1 patient, and the means f 1 standard deviation are shown on either side of each set of lines. Cardiac output was unchanged by saline solution or verapamil but increased significantly with administration of nifedipine. Systemic vascular resistance was reduced by verapamil and nifedipine. Asterisks indicate p <0.05 in comparison with the values before drug administration.

duced by saline solution (Table I). Peak positive left ventricular dP/dt was not altered by saline solution or nifedipine but was reduced by verapamil (Fig. 2).

The results for the 22 patients receiving 100 to 360 mg/day of propranolol are shown in Table III. The hemodynamic changes induced by each of the 3 pharmacologic agents are similar to those described for the entire group.

Effects on coronary sinus blood flow: Coronary sinus blood flow was not altered by any pharmacologic agent (Tables I and III).

Electrophysiologic alterations: For the entire group of 26 patients, verapamil and nifedipine produced opposite effects on the heart rate: it decreased with verapamil and increased with nifedipine (Table Ii, Fig. 3). However, the reduction in heart rate produced by verapamil was not statistically different from that produced by saline solution. For the smaller group of 22 patients, the reduction in heart rate induced by verapamil did not achieve statistical significance (Table IV). The A-H interval was not altered by saline solution or nifedipine but was prolonged by verapamil (Tables II and IV, Fig. 3). None of the 3 agents altered the H-V interval.

Scintigraphic alterations: Left ventricular end- diastolic volume index was unchanged by the 3 agents (Tables II and IV). End-systolic volume index decreased

1600r SALINE VERAPAMIL NIFEDIPINE

;; 1400 -

f ‘, 7200- rL

1 1000-

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;;E 800-

2 a 600-

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0.80

I I I I

I I BEFORE AFTERBEFORE AFTERBEFORE AFTER

FIGURE 2. Left ventricular peak positive dP/dt, in mm l-lg/s (top panel), and left ventricular ejection fraction (bottom panel), before and after the administration of saline solution (left). verapamil (middle), or nifedipine (right). Each line represents the data from 1 patient, and the means f 1 standard deviation are shown on either side of each set of lines. Left ventricular dP/dt was reduced by verapamil; ejection fraction increased after administration of nifedipine. Asterisks indicate p <0.05 in comparison with the same pharmacologic agent before drug administration.

October 1982 The American Journal of CARDIOLOGY Volume 50 707


SAUNE VERAPAMIL NIFEDIPINE

160

r

50 b - 04- ’ I I I I I

BEFORE AFTER BEFORE AFTER BEFORE AFTER

FIGURE 3. Heart rate, in beats/min (top panel), and A-H interval, in milliseconds (ms) (bottom panel), before and after the administration of saline solution (teft), verapamil (middle), or nifedipine (right). Each line represents the data from 1 patient, and the means f 1 standard deviation are shown on either side of each set of lines. The heart rate was reduced by verapamil and increased by nifedipine. The A-H interval was lengthened only by verapamil Asterisks indicate p <0.05 in comparison with the same pharmacologic agent before drug administration.

with nifedipine. Left ventricular ejection fraction was not affected significantly by saline solution or verapamil but increased with nifedipine (Tables II and IV, Fig. 2).

Adverse effects: In one patient who received verapamil, mean systemic arterial pressure decreased from 93 to 68 mm Hg. The heart rate failed to increase, and cardiac output decreased from 3.1 liters/min to 2.4 liters/min. All values returned to baseline within 15 to 20 minutes. This patient was receiving a large daily dose of propranolol (1,280 mg). With this exception, all patients tolerated saline solution, verapamil, and nifedipine without difficulty.

Discussion

Preliminary clinical trials have suggested that the combination of a beta-adrenergic blocking agent and a calcium antagonist may be more effective than either agent alone in the treatment of patients with severe angina.l”-I* The beta-adrenergic blocking agents such as propranolol diminish myocardial oxygen demands by reducing the heart rate, systemic arterial pressure, and left ventricular contractility, but they do not increase the myocardial oxygen s~pply.“~J~ The calcium antagonists such as verapamil and nifedipine also reduce myocardial oxygen demands (primarily by di- minishing afterload); in addition, they augment coro-

nary blood flow by reducing coronary vascular resistance.“JzJ3 Because these agents exert their beneficial effects by different mechanisms, their combination may produce an especially salutary influence on the balance between myocardial oxygen supply and demand.

However, at the same time, combination beta- blocking calcium antagonist therapy could theoretically produce adverse effects. For example, in the patient not receiving a beta-blocking agent, verapamil’s negative inotropic and chronotropic influence is counteracted, at least in part, by a reflex increase in sympathetic tone.S4 In the presence of beta blockade this reflex response may be blunted, leading to a reduction in left ventricular performance and cardiac output. Alterna- tively, in the absence of a beta-blocking drug, nifedipine’s powerful effects as a peripheral arterial dilator are partially offset by a compensatory increase in heart rate. In the presence of a beta-blocking agent this reflex tachycardia could be prevented, leading to profound hypotension.“” Because it is unclear whether the potential beneficial effects of combined beta-blocking calcium antagonist therapy outweigh its potential adverse effects, the present study was performed to ex- plore the hemodynamic and electrophysiologic effects of verapamil and nifedipine in patients already receiving propranolol.

Hemodynamic alterations: In the absence of beta- adrenergic blockade, both verapamil and nifedipine reduce systemic arterial pressure and resistance.Y,1(~.1S,“‘Li:‘4 Because nifedipine is an especially potent vasodilator, it elicitas a strong reflex sympathetic response, which offsets its intrinsic negative inotropic effects, so that left ventricular dP/dt may even increase.Sfi As a result, nifedipine alone augments cardiac output and left ventricular ejection fraction, even in patients with underlying left ventricular dysfunction.1°J7 In contrast, verapamil causes a decrease in left ventricular dP/dtX8 and a modest increasea or no &ang$,f’” in cardiac output. Its effect on left ventricular ejection fraction is not clear: some studies have demonstrated a decrease,‘s others have shown no change,:373 and yet others have shown an increase in this variable.:<4

Although previous studies have attempted to assess the hemodynamic effects of verapamil or nifedipine in patients already receiving beta-adrenergic blocking agents, they have produced conflicting results. Packer et a1.z2 administered oral verapamil Cl20 mg) to patients receiving long-term propranolol therapy and noted a decrease in cardiac index and mean arterial pressure as well as an increase in pulmonary capillary wedge pressure. When this same dose of verapamil was readmin- istered after withdrawal of propranolol, the cardiac index and wedge pressure did not change. Leon et af.21 noted that a verapamil-propranolol combination produced a reduction in both left ventricular ejection fraction and ejection rate at rest, although verapamil alone produced a similar diminution in ejection fraction, In contrast, Kieval et al. 2o showed that a verapamil- propranolol combination caused no change in cardiac index, left ventricular end-diastolic pressure, left ven-

708 October 1982 The American Journal of CARDlOLOGY Volume 50

PROPRANOLOL PLUS CALCIUM ANTAGONISTS~WINNIFORD ET AL

tricular ejection fraction or maximal dP/dt. Finally, in 12 patients receiving atenolol, Joshi et al.lg observed no increase in left ventricular ejection fraction and a decrease in dP/dt after administration of nifedipine.

In our study, verapamil or nifedipine was administered on a short-term basis to patients already receiving long-term oral propranolol. Although we made no attempt to ensure full bet,a-adrenergic blockade in these patients, their dosages of propranolol were those com- monly used for the treatment of angina pectoris. Even in the presence of propranolol, nifedipine caused an increase in cardiac output and left ventricular ejection fraction as well as no change in left ventricular dP/dt or intracardiac filling pressure (Tables I and III, Fig. 1 and 2). In contrast, verapamil caused no change in cardiac output or ejection fraction and a decrease in left ventricular dP/dt. In 1 patient (who was taking 1,280 mg/day of propranolol), verapamil induced a sizeable decrease in cardiac output and systemic arterial pressure. Thus, the combination of verapamil and propranolol must be used cautiously, especially in persons who are taking particularly large doses of the latter agent.

Changes in coronary blood flow: The effect of verapamil or nifedipine on coronary blood flow represents a balance between direct coronary vasodilation and reflex vasoconstriction caused by a decrease in myocardial oxygen demands. In most studies verapamil or nifedipine administered alone has caused an increase in coronary blood flow, although Ferlinz et al.” demonstrated a slight decrease in coronary blood flow with verapamil. In the present study neither verapamil nor nifedipine caused a significant change in coronary sinus blood flow (Tables I and III).

Electrophysiologic changes: The negative chronotropic effect of nifedipine, like its negative inotropic effect, is offset in vivo by reflex mechanisms, so that nifedipine alone increases heart rate. Atrioven- tricular conduction is unaltered.4” In contradistinction, verapamil exerts a powerful negative chronotropic ef- feet, so that there is no reflex increase in heart rate despite a reduction in peripheral vascular resistance.“‘,:‘“,“s In addition, atrioventricular conduction is impaired.40 In the present study, the heart rat,e increased with nifedipine and decreased slightly with verapamil (Tables II and IV, Fig. 3). In addition, verapamil prolonged the A-H interval in all patients, whereas nifedipine exerted no effect on this variable. Thus, the combination of verapamil and propranolol must. be used cautiously in patients with underlying conduction system disease.

In short, the hemodynamic and electrophysiologic: alterations induced by verapamil and nifedipine in patients already receiving propranolol are similar to those induced by these agents in the absence of propranolol. Specifically, the alterations produced by verapamil in this study do not differ from those described by Singh and Roche”s in patients not receiving a beta-adrenergic blocking agent; similarly, the combination of nifedipine and propranolol caused hemodynamic and electrophysiologic changes resembling those induced by nifedipine alone.

Limitations of the present study: This study is limited in several ways. First, it examines the hemodynamic and electrophysiologic effects of a single dose of intravenous verapamil or sublingual nifedipine in patients already receiving long-term oral propranolol. It makes no attempt to assess these effects during the long-term administration of both a calcium antagonist, and a beta-adrenergic blocking agent. It is conceivable that the long-term administration of both agents may induce hemodynamic and electrophysiologic effects different from those described in our study. Second, both verapamil and nifedipine were administered in a standardized dose. Although the dosages of each were similar to those used in previous studies,4,‘:~.‘“,“s.4’ it is possible that different effects may be produced by different amounts of each agent. For example, it is possible that a larger dose of nifedipine (that is, 20 mg) could produce adverse effects not observed after 10 mg. Similarly, a smaller dose of verapamil (that is, 0.025 to 0.10 mg/kg) would be expected to exert a lesser effect on contract,ility and cardiac conduction. Third, most of the patients in the present st.udy had normal or only slightly impaired left ventricular function at rest (Ta- bles I to IV, Fig. 2); it is certainly possible that those with more severe left ventricular dysfunction may re- spond differently to the combination of propranolol and a calcium antagonist, either verapamil or nifedipine. Lastly, all variables were measured only in the resting state, and no attempt was made to assess the effects of combination therapy on hemodynamic or electrophysiologic variables during exercise.

Clinical implications: The combined use of a beta-adrenergic blocking agent and a calcium antagonist may be beneficial in patients with stable angina who continue to be symptomatic despite therapy with either agent alone. When administered to patients already receiving propranolol, verapamil and nifedipine produce hemodynamic and electrophysiologic changes similar to those produced in the absence of propranolol. Ni- fedipine improves left ventricular performance without affecting cardiac conduction. In contrast, verapamil diminishes left ventricular cont,ractility and slows atrioventricular conduction. Therefore, the combination of verapamil and propranolol must be used with great caution in patients with underlying left ventricular dysfunction or conduction system disease. Although administration of a nifedipine-propranolol combination is probably preferable in these patients, further studies are needed to establish the safety of this combination in patients with severe left ventricular dysfunction.

Acknowledgment

U’e acknowledge the technical assistance ot’ Sarah Hawkins, Randy Christian, Scott Lyons, and Nancy Smith, as well as the secretarial help of Juanita Alexander.

References 1. Amsterdam EA, Gorlin R, Wolison S. Evaluation of long-term use of pro-

pranolol tn anglna pectoris. JAMA 1969:210~103-106 2. Warren SG, Brewer DL, Orgain ES. Long-term propranolol therapy for

anglna pectoris Am J Cardlol 1976137 420-426 3. Shand DG. Propranolol N Engl J Med 1975,293 280-285

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4. Corbalan R, Gonzalez R, Chamorro G, Munoz M, Rodriguez JA, Casanegra P. Effect of a calcium Inhibitor. nifediprne, on exercise tolerance in patients with angina pectorrs A double-blind study Chest 1981;79.302-305 Johnsen SM, Mauritson DR, Corbett JR, Woodward W, Willerson JT, Hlllis LD. Double-blind randomized. q lacebo-controlled comoarrson of aropranolol

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