Metabolic and hemodynamic effects of nicardipine during pacing-induced angina pectoris

Metabolic and HemodynamicEffects of Nicardipine During Pacing-InducedAngina Pectoris ANNE THOMASSEN,

MD, JENS P. BAGGER, MD, TORSTEN T. NIELSEN, MD, and PER HENNINGSEN, MD

metabolic signs of ischemia included release of lactate across the heart in 7 patients, decreased mean free fatty acid and glutamate uptake and alanfne release during pacing, together with increased glucose uptake and citrate release during recovery. After nicardipine lactate release decreased in 5 of the 7 patients, pacing no longer changed free fatty acid, glutamate and alanine uptake/release from the level at rest. During recovery glucose uptake was reduced and citrate release was unaffected. The hemodynamic data indicate that nicardipine is a systemic and coronary vasodilator, increasing oxygen supply to the ischemic myocardium. The metabolic results indicate a change in substrate UtiliZation toward that of normal heart, suggesting improved aerobic energy supply. (Am J Cardiol 1967;59:219-224)

During repeat exercise testing in 10 patients wtth stable angina, individual optimal doses of nkardipine were determined. Hemodynamic values and cardiac metabolism were studied during 2 pacing periods carried out before and after this dose (mean 5.3 mg). Postpacing ST-segment depression diminished (1 mm) after nicardipine administration (p <0.05), whereas pacing time to onset of angina did not change. Nicardipine administration increased heart rate 16% (p
N

icardipine is a new dihydropyridine calcium entry blocking drug that has been reported effective in the treatment of vasospasticl and chronic effort angina.2J Individual dose titration is important to ensure maximal antianginal benefit.4 Several studies confirm that nicardipine is a potent systemic and coronary vasodilator without cardiodepressant effects.5-7 Rousseau et al8 reported a nicardipine-induced decrease in myocardial lactate production and decreased uptake of tracer lactate,

suggesting reduced anaerobic as well as aerobic carbohydrate utilization. This may be secondary to decreased cardiac energy requirements or, alternatively, caused by a shift toward free fatty acids (FFA] as the preferred fuel, as suggested for verapamilg and nifedipine.*O To examine the mechanisms of the metabolic effects of nicardipine in patients with stable angina, we measured myocardial exchanges of FFA, lactate, glucose, citrate, glutamate and alanine during coronary sinus (CS) pacing before and after administration of individually titrated optimal doses of the drug.

From the Department of Cardiology, Aarhus Kommunehospital, Aarhus, Denmark. This study was supported by grants from Syntex Clinical Research Europe and from the Danish Heart Foundation. Manuscript received June 24, 1986; revised manuscript received August 25, 1986, accepted August 26, 1986. Address for reprints: Anne Thomassen, MD, Department of Cardiology, Aarhus Kommunehospital. 8000 Aarhus C, Denmark.

Methods Subjects: The study included 9 men and 1 women, aged 55 f 6 years, with stable effort angina and a positive exercise test response with chest pain and more than 1 mm of ST-segment depression. Seven patients had had a myocardial infarction more than 6 months before the study. Coronary angiography re219

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vealed a more than 50% proximal fixed diameter reduction of 1 vessel in 4 patients, 2 vessels in 2 patients and 3 vessels in 4 patients. All had a diseased left anterior descending artery, and collateral flow to this region was assessed as good in 5 patients and absent in 5. Left ventricular end-diastolic pressure was 15 f 7 mm Hg and ejection fraction was 57 f 14%. None of the patients had spontaneous angina1 attacks, additional heart disease, hypertension or metabolic disorders. Dose-titration study: Patients gave informed consent. Antianginal medication except for glyceryl trinitrate was stopped a week before the study. Individual optimal dose of nicardipine was assessed in each patient during 4 upright bicycle exercise tests on 4 subsequent days and performed 15 minutes after intravenous infusion of 0, 2.5, 5.0 and 7.5 mg of nicardipine, respectively.4 The initial workload was 50 W and was increased by 50 W every 3 minutes to the point of angina, fatigue or dyspnea. Nicardipine improved exercise tolerance in all but 1 patient. Maximal benefit was achieved after 7.5 mg in 4 patients, 5.0 mg in 4 and after 2.5 mg in 2. Improvement after the optimal dose compared with the control state was indicated by prolonged exercise capacity (98 f 52 seconds, p
resistance was calculated from mean aortic blood pressure divided by CS blood flow. Net substrate exchange across the heart was calculated as aorto-CS concentration difference multiplied by CS blood flow for whole blood determinations and further multiplied with l-hematocrit for plasma measurements. Values are mean f standard deviation unless otherwise stated. The paired t test, Wilcoxon signed rank test and linear regression analysis were used for statistics.

Results Adverse effects, angina1 threshoId and plasma nicardipine: One patient with 3-vessel disease, who was to receive 5.0 mg nicardipine, showed 2 mm of STsegment depression and tachycardia at a rate of 120 beats/min after infusion of 2.5 mg. He felt no pain. The infusion was stopped, the electrocardiogram normalized within a few minutes, heart rate decreased to 80 beats/min and the second pacing period was carried out as planned. Mean pacing duration was 332 f 161 seconds. Pacing time to onset of angina or to termination of pacing without angina (1 patient] was not significantly changed after nicardipine administration (249 f 172 vs 273 f 185 seconds), but postpacing ST-segment depression was reduced from 1.5 f 1.7 to 0.7 f 1.3 mm (p <0.05). Arterial plasma concentrations of nicardipine at the start of the second pacing session ranged from 8 to 64 rig/ml (mean 39 f 22) and was closely related to the infused dose [r = 0.90, p
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TABLE

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Rest HR (beatslmin) SAP (mm Hg) DAP (mm Hg) MAP (mm W HR X SAP (beats/min X mm Hg X IO-*) CSBF (mllmin) CVR (mm Hg/min/ml) 02 A-CS (ml1100 ml) O2 MV (mllmin)

C N C N C N C N C N C N C N C N C N

70f 84 f 147 f 132 f 78 f 76 f 101 f 94 f 101 f 111 f 105 f 146 f 1.2 f 0.8 f 12.4 f 10.4 f 12.9 f 15.1 f

Pacing 12 1511 21 1511 IO IO 12 10% 14 20 41 6511 0.7 0.511 1.2 I.211 5.1 6.7

146 f 146 f 142 f 123 f 97 f 83 f 112 f 98 f 206 f 184 f 165 f 178 f 0.8 f 0.6 f 11.5 f 11.4 f 18.7 f 19.9 f

7' 7’ 20 195 16’ 13117 177 1411 26' 28’9 58’ 73 0.2$ 0.211 I.17 0.7t 6.1' 7.9t

1 min 76f 17 84 f 179 154 f 19 137 f 1911 83 i6t 77 rt 811 100 l IO 97 f 111 116 f 24$ 114 f 23 117 l 53 135 f 635 1.2 f 0.6 0.9 f 0.45 11.1 f I.27 10.8 f 1.1 12.7 f 5.2 14.6 f 6.7

Difference from respective rest values: ‘p
pacing. The reduction in mean aorto-CS oxygen was balanced by the opposite changes in CS blood flow, leaving myocardial net oxygen consumption unchanged despite a decreased rate-pressure product during pacing. Metabolic results (Fig. 1) Free fatty acids: Mean arterial FFA concentration increased from 0.78 f 0.22 mmol/liter before to 0.89 f 0.21 mmol/liter after nicardipine treatment (p
3 min 73f 85 149 135 82 76 104 96 108 114 116 128 1.1 0.9 11.2 10.3 12.6 12.8

f f f f f f f f f f f f f f f f f

18 1611 24 185 8% 911 13 1111 26 24 49 52 0.6 0.35 I.37 1.15 4.5 5.1

5 min 74 f 88 f 147 f 135 f 81 f 76 f 103 f 96 f 108 f 118 f 110 f 1249~ 1.2 f 0.9 f 11.5 f 10.3 f 12.7 f 12.6 f

17 1411 21 l8$ 7$ 811 11 129 24 22 46 47$ 0.6 0.39 I.27 I.211 4.8 4.4$

7 min 75 84 145i 134 80 76 102 95 108 113 110 121 1.1 0.9 11.6 10.4 12.3 12.7

f i

16 1411 18 * 2011 zk 7 ck 9!j l 10 f 129 f 22 f 23 f 47 l 47$ f 0.8 f 0.35 f I.27 f 1.211 f 4.5 f 4.7$

pacing means of 2 determinations. sinus blood flow; CVR = coronary vascular resistance; DAP = uptake; N = after nicardipine; SAP = systolic aortic pressure.

glucose decreased throughout the study from an average of 0.20 f 0.11 mmol/liter to 0.14 f 0.09 mmol/liter (p
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ery [Fig. 1). Nicardipine reduced this pacing-induced decrease of aorto-CS glutamate (13 f 7 vs 6 f 10 pmol/ liter, p
Discussion In the present study, antiischemic properties of nicardipine were manifest as improved exercise tolerance and decreased ‘postpacing ST-segment depression, whereas chest pain during pacing was not significantly affected by the drug. Similar disagreements between antianginal efficacy during exercise

and pacing-induced angina have been suggested.1°J4 Hemodynamic results support the concept that nicardipine is a potent systemic vasodilator that reduces arterial blood pressure and causes reflex tachycardia.4-7 Despite the decreased coronary perfusion pressure, CS blood flow was increased, presumably because of coronary vasodilatation.5r7J The pronounced increase in CS blood flow at rest was far above the increase expected from reflex tachycardia. Further, it appeared to be near the maximum, as pacing did not increase flow further or above the flow found during control pacing.15 The decreased aorto-CS oxygen differences at rest suggest that global myocardial perfusion is in excess of that required to meet oxygen demand. Such “luxury” perfusion could be caused by a preferential dilation of normal coronary vessels at the expense of diseased vessels, a coronary steal phenomenon. The lack of correlation between increase of coronary blood flow both vs the number of vessels stenosed and the degree of collateral vascularization gave, however, no evidence for this. On the contrary, the finding that net myocardial oxygen consumption was unchanged despite the significant reduction of rate-pressure product during 0.30-

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pacing suggests an improved supply to the ischemic areas. Similar discrepancies between changes in estimated myocardial oxygen demand and measured consumption after nicardipine administration have been reported.5v7J The metabolic pattern during the control study was characteristic for ischemic heart disease. Pacing reduced myocardial FFA uptake and increased anaerobic carbohydrate utilization.16 The amount of lactate produced during pacing exceeded that of exogenous glucose taken up, indicating glucogen breakdown. Repletion of glycogen stores during recovery was suggested from accelerated uptake of exogenous glucose17 together with increased release of citrate, as the latter implies inhibition of the glycolytic pathway.l* Myocardial uptake of glutamate and release of alanine were elevated in the resting state and decreased during pacing.lz Myocardial exchange of these amino acids is closely related to aerobic carbohydrate breakdown.*2Jg Nicardipine improved several of these ischemic metabolic responses. FFA consumption was no longer reduced by pacing, suggesting an increased capacity for aerobic energy supply at the expense of glycolytic substrates as fuel. In the anaerobic state during and immediately after pacing, nicardipine diminished lactate release in lactate producers and reduced lactate extraction in the lactate-nonproducers, leaving mean grouped values unchanged. These findings are not contradictory, as they both indicate lessened myocardial carbohydrate utilization. Rousseau et a15J found reduced myocardial production of lactate together with decreased uptake and oxygenation of tracer lactate during pacing after nicardipine. In our study myocardial glucose uptake tended to decrease in the resting state, and pacing no longer induced an ischemic or a postischemic increase in myocardial glucose consumption. The latter finding, together with decreased lactate production during pacing, may be taken indirectly as evidence for a glycogen-sparing drug effect. At rest, myocardial exchange of alanine decreased and that of glutamate tended to do so, confirming earlier reports5p* and probably reflecting a lowered carbohydrate utilization.lg Abolishment of the decrease of myocardial amino acid exchange during pacing after the drug may be taken as evidence of normalization of myocardial energy metabolism. Several mechanisms may lie behind the metabolic changes induced by nicardipine administration. One is altered substrate competition caused by changed arterial FFA and lactate levels. Increased oxygen sup ply to ischemic areas may in itself change substrate preference toward FFA. 16~1gHowever, similar metabolic responses have been reported after verapamilg and nifedipine1°v20 treatment despite unchanged levels of arterial FFA and myocardial oxygen consumption. Together, these results suggest that calcium antagonists, apart from peripheral effects, also have a direct myocardial metabolic effect. Such an effect may be a combination of inhibited cellular carbohydrate uptake21s22and increased mitochondrial oxidative capacity,23 but the mechanisms need further study.

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18. Bagger JP. Nielsen TT, Henningsen P, Thomsen PEB, Eyjolfsson K. Myocardial release of citrate and lactate during atrial pacing-induced angina pectoris. &and 1 Clin Lab Invest 1981:4X:431-439, 19. Thomassen A, Nielsen ‘IT, Bagger JP, Thuesen L. Myocardial glutamate and alanine exchanges related to carbohydrate metabolism in patients with normal and stenotic coronary arteries. CJin Physiol 1984;4:425-434. 20. Thomassen A, Nielsen ‘IT. Bagger JP, Alterations in myocardial uptake of glutamate and release of alanine after propranolol, nifedipine, and glyceryl trinitrate in coronary artery disease. 1 Cardiavasc Pharmacol 1985:7:394400. 21. Ishibashi

F. Kubo K. Calcium antagonist inhibition of insulin action on rat odipocyte hexose transport (abstr]. Diabetes 1982;31:suppJ 2:127A. 22. Dow Rj. Baty J. Isles TE. The effect of nicardipine on glucose and drugstimulated insulin secretion in normal volunteers. Br J CJin Pharmacol 1985;20:758-838. 23. Nayler WG, Ferrari R, Williams A. Protective effect of pretreatment with verapamil, nifedipine and propranolol on mitochondrial function in the ischemic and reperfused myocardium. Am 1 Cardiol 1980;46:242-248,