antihypertensive effects of nifedipine combined with cardioselective beta-adrenergic receptor...

Rich et al. September, 1982

American Heart Journal

images is sufficient to permit analysis. In addition, it should be kept in mind that we are overlooking the shortening of the ventricle in the major axis, which on the average contributes 3% to 7% to the actual EF.? The method would also be unreliable in patients with large discrete ventricular aneurysms that are not included in the short-axis view of the ventricle. Our experience in patients with coronary artery disease in general, however, is that the method is useful and reliable.

Conclusions. We found that the percent area reduction of the LV as viewed in the short axis with 2DE closely approximates the actual LVEF, and that this percent change can be reliably estimated by trained echocardiographers. This method obvi- ates the need for planimetry, digitizers, or calcula- tions. In addition, by making the estimates during real-time viewing, an instantaneous assessment of LV function can be made and image quality is preserved, making this technique applicable to most patients who are studied. REFERENCES

1. Carr KW, Engler RL, Forsythe JR, Johnson AD, Gosink B: Measurement of left ventricular ejection fraction by mechan-

2.

3.

4.

5.

6.

7.

ical cross-sectional echocardiography. Circulation 59:1196, 1979. Folland ED, Paris AF, Moynihan PF, Jones DR, Feldman CL, Tow DE: Assessment of left ventricular ejection fraction and volumes by real-time, two-dimensional echocardiography. Circulation 60:760, 1979. Gueret P, Meerbaum S, Wyatt HL, Uchiyama T, Lang T-W, Corday E: Two-dimensional echocardiographic determination of left ventricular volumes and ejection fraction. Circu- lation 62:1309, 1980. Pave1 DG, Zimmer AM, Patterson UN: In vivo labeling of red blood cells with 99m Tc: A new approach to blood pool visualization. J Nucl Med l&305, 1977. Pave1 DG, Byrom E, Ayres B, Pietras PJ, Bianco JA, Kanakis C: Multifaceted evaluation of left ventricular function by the first transit technique using Anger type cameras and an optimized protocol: Correlation with biplane roentgen angiography. In Sorenson JA, editor: Nuclear cardiology: Select- ed computer abstracts. Atlanta, 1978, Society of Nuclear Medicine, pp 129-138. Dodge HT:-Determination of left ventricular volume and mass. Radio1 Clin North Am 9:459. 1971. Quinones MA, Waggoner AD, Reduto LA, Nelson JG, Young JB, Winters WL, Ribeiro LG, Miller RR: A new, simplified and accurate method for determining ejection fraction with two-dimensional echocardiography. Circulation 64:744, 1981.

The calcium-channel blocker, nifediplne, was used as addltional oral therapy to betaudrenergic receptor blockade by the cardtoselective agent, atenolol, in the therapy of 31 pattents with hypertension. Initial studies were directed towards control of assoctated angina pectoris In 15 of the patients, but no effects were found on angina except in two pattents. However, artertal blood pressure was condstently reduced In all pattents. Further studies on 16 patients were therefore directed towards the use of nifedlpine as an antthyperten8ive agent In addttton to atenolol and a thlazide dhtretfc. Nifedtpine (10 mg subtlngualty) acutely dropped blood pressure by about 30120 mm HI) (systolic/diastolic) wlthin 20 minutes. Follow-up studks made after 4 to 8 weeks showed that the lnltlal acute response to nifedipine predlcted the long-term response to oral ntfedtpfne, 10 mg twice daily. Of 31 hypertensive patients tested, only one failed to respond to nlfedtplne. (Au HEART J 104:606, 1982.)

L. H. Opie, L. Jee, and D. White. Cape Town, South Africa

From the Hypertension Clinic, Department of Medicine, Groote Schuur Nifedipine is a calcium antagonist drug which has Hospital and University of Cape Town. been used primarily in the treatment of angina Received for publication Dec. 28, 1981; revision received Apr. 29, 1982; pectoris. The recently described clinical efficacy of accepted May 18, 1982. Reprint requests: Lionel H. Opie, M.D., Dept. of Medicine, Hypertension

n&&pine as an antihypertenaive agent can be

Clinic, Univereity of Cape Town, Medical School, Obeervatmy 7925, Cape ascribed to its direct vascular effect which is medi- Town, South Africa. ated by a decrease in systemic vascular resistance,

606 0002-8703/82/090606 + 07$00.70/O 0 1982 The C. V. Mosby Co.

Volume 104

Number 3 Antihypertensive therapy with combined atenolol-nifedipine 607

with consequent reduction of cardiac afterload.1*2 Beta-blockade, on the other hand, is an established therapy for hypertension, with a complex mode of actidn which does not involve direct arteriolar effect. The effect of nifedipine in decreasing systemic vascular resistance may be accompanied by cate- cholamine release and mild tachycardia.’ The properties of nifedipine and of beta-blockade are complementary, and the combination becomes logical therapy for hypertension. In the therapy of angina of effort, nifedipine and beta-blockade also have contrasting effects. Thus nifedipine has a major effect on vascular tissue and hence reduces cardiac afterload, and despite an increase in heart rate, exercise tolerance is increased.3 Beta-blockade, on the other hand, acts to reduce heart rate, blood pressure, and cardiac contractility while not increasing or possibly decreasing blood supply to ischemic myocardium. Because ventricular afterload is reduced in different ways by nifedipine and beta- blockade, these two agents are additive in their beneficial effects on angina of effort>J

Such considerations led us to add nifedipine to therapy with the be&-selective agent, atenolol, in patients with hypertension and persisting angina of effort. Atenolol was selected as the beta-antagonist agent of choice because of its cardioselectivity, its prolonged clinical effectiveness over 24 hours, and its “flat” dose-response curve whereby a fixed dose of 100 mg/day is usually the dose of choice. After an initial period of observation, 15 patients were given nifedipine placebo and then active nifedipine before returning to the nifedipine placebo. Because angina was so severe in some patients, we felt that a single-blind study was ethically preferable to a double-blind trial. The severity of angina was monitored both subjectively and by repetitive treadmill exercise tests. The first part of our study showed that in such patients nifedipine added to beta- blockade was a more effective antihypertensive than antianginal agent, and the remainder of this report deals predominantly with its antihypertensive effects. Because of the consistent hypotensive effects of nifedipine when so used, a second part of our study was aimed at assessing whether the hypotensive effect of nifedipine could also be found when added to atenolol in the therapy of hypertensive patients without angina.

METHODS

Hypertensive patients with angina pectoris. After an initial run-in period of 2 to 6 weeks, nifedipine placebo (one capsule twice daily) was added to the preexisting therapy of 15 patients for a period of 6 weeks, with all

blood pressure (BP) measurements repeated three times at a-week intervals. For purposes of calculation, the mean of the three BP values was taken as a single reading. Thereafter active oral nifedipine (10 mg, every 12 hours) was substituted for placebo nifedipine (10 mg) for a further 6 weeks and all the above measurements were repeated. Again the mean of all series of BP readings (2,4, and 6 weeks) was taken for purpose of calculation. Finally, active nifedipine was replaced by an equivalent dose of nifedipine placebo and all BP readings were repeated after 2 weeks and 1 month, as was the exercise test. Two treadmill exercise tests were undertaken during the initial placebo period (after 2 and 4 weeks) with the Naughton protocol at a constant speed of 2 mph and an increasing elevation. End-points were ECG ST depression, fatigue, onset of chest pain, or ventricular arrhythmias. A further treadmill test was undertaken between 2 and 4 weeks of active nifedipine.

Fifteen outpatients with established hypertension and stable exertional angina (one patient also had angina at rest) were studied. Early emphasis in our studies was biased more towards the possible antianginal effects of nifedipine, so that in six patients when active nifedipine was substituted for placebo and the BP fell, other changes were also effected in the patient’s drug regime, in order that this fall might not be too great. Thus one patient stopped taking rauwolfia and five stopped prazosin. Despite these changes, a significant fall in BP was seen. These findings prompted a closer look at the antihypertensive effects of nifedipine under conditions where any changes seen could be more confidently interpreted. Thus in the nine patients with hypertension and angina pectoris studied thereafter, no changes in regime occurred other than those involving nifedipine. Of the 15 patients, 12 were treated with atenolol, 100 mg once daily, and the remaining three were treated with 50 mg daily, in addition to thiazide diuretic therapy (usually hydrochlorothiaxide plus amiloride); in eight patients prazosin (mean total daily dose 15 mg) was also required. One patient received clonidine, 75 kg three times daily, in addition to atenolol, and another rauwolfia, 50 mg twice daily. Intermittent sublingual nitroglycerin (0.5 mg tablets) was given as required. The patients had been attending the Hyperten- sion Clinic for several montlhs or years. They were all of Caucasian or mixed (mulatto) ethnic origin.

After an initial run-in period of 2 to 6 weeks to establish compliance, initial control BP readings were done in the sitting (mean of two BP values 2 minutes apart after 10 minutes rest), standing after 30 seconds, standing just after walking a measured distance of 60 meters, during hand-grip of 60 seconds to half maximal pressure (using a Medicon dynamometer graduated in arbitrary units), and after 30 seconds of cold immersion (left hand up to mid-arm in bucket of ice-cold water) with BP measured while hand still immersed. BP was taken on the right arm with a standard mercury sphygmomanometer, with a cuff with bladder 24 cm in length and 13 cm in width, and disappearance of sounds (Korotkoff sound 5) was taken as the diastolic value, always using the same machine and

888 Opie, Jee, and White

0 10 20 30 443 50 00 T#me fMmteQl

Fig. 1. Pilot study of acute BP response to sublingual nifedipine in patients receiving atenolol. Mean values of 14 patients are shown, seven of whom continued with the oral nifedipine plus atenolol study.

same cuff throughout. Readings were taken at about 10:00 A.M. to 11:00 A.M., i.e., 3 to 4 hours after the morning dose of drugs.

Two unexpected reactions led to deviations from trial design. In one patient reported elsewhere: severe hypotension developing on combined atenolol and nifedipine led to inability to undertake the exercise test during the nifedipine period. Another patient, described in more detail in the second paragraph of the Results section, did not complete the second placebo period because of striking improvement from unstable angina and effort-induced ST elevation in response to nifedipine.

Hypertensive patients wlthout angina. Having established the hypotensive efficacy of nifedipine for patients with both hypertension and angina, it was logical next to explore the effect of nifedipine added to beta-blockade in the therapy of patients with hypertension but without angina. The hypotensive effect of sublingual nifedipine is claimed to be rapid, with peak effects being reached within 20 minutes.’ We confirmed these findings in a pilot dose-response study, during which a random group of hypertensive patients already receiving atenolol, 100 mg/ day, were given nifedipine, 10 mg sublingually, and were then monitored with BP readings taken at lo-mirmte intervals over 1 hour (Fig. 1).

Having established that sublingual nifedipine exerted its full hypotensive effect within 20 minutes, we proceeded with a comparison between acute and chronic hypotensive

September, 1982


effects as follows. Sixteen hypertensive patients, already treated with beta-blockade (atenolol, 100 mg daily) were given sublingual nifedipine placebo, and 20 minutes later were given active nifedipine, 10 mg sublingually. BP and heart rate were recorded 10 and 20 minutes after placebo, and then after active nifedipine. Two patients who did not respond to 10 mg after 20 minutes were given a further 10 mg. The response to this added therapy was monitored for a further 20 minutes. Patients given acute nifedipine were then given oral nifedipine 10 mg (or 20 mg in two patients) every 12 hours and followed for a further 4 to 8 weeks to establish a chronic hypotensive response.

Statistical methods. For both parts of this investiga- tion, results are expressed as mean values + standard errors of the mean (SEM). The p values were calculated by Student’s t test, using paired values and a two-tailed test; p values over 0.05 were regarded as not significant W).

RESULTS

Hypertension with angina. The addition of nifedipine placebo to atenolol and diuretic therapy in 15 patients produced virtually no effect on BP, but replacement of placebo by active nifedipine produced decreases in the sitting, standing, and post exercise BPS, as well as during isometric exercise (hand-grip) (Table I). However, during cold exposure, significance was not consistently reached although mean BP values fell. The initial placebo sitting BP of 165 f 9/102 -t- 5 mm Hg (mean -+ SEM) fell with active nifedipine to 148 + 8194 + 4 mm Hg, and then reverted to 164 + 9/105 f 4 mm Hg on nifedipine placebo. In those patients whose only regime change was nifedipine, heart rates were not changed (Table II). In one patient with an initially normal BP on atenolol, unacceptable hypotension developed when active nifedipine was added.

In one of the above patients, nifedipine had dramatic effects. While receiving atenolol 100 mg/ day, the patient developed ST segment elevation during and immediately after exercise as well as ventricular arrhythmias, including one run of ventricular tachycardia (three beats). The ST elevation occurred maximally in the inferior leads (II, III, aV,), but at coronary angiography the right coronary artery was disease-free, and the major lesion was in the left anterior descending coronary artery with 60% to 70% narrowing of the circumflex artery. According to Lahiri et al.,’ the transmural ischemia indicated by the raised ST segment usually develops in zones supplied by the diseased coronary artery. We therefore postulated exercise-induced coronary spasm in a site remote from the anatomic coronary artery disease, although lesser degrees of atheroma of the arteries supplying the inferior zone

Volume 104


Table I. Effect of nifedipine added to atenolol on blood pressures in patients with hypertension and angina pectoris

Sitting Standing blood pressure blood pressure

(mm Ha) (mm Hd

Blood pressure

after walking (mm Hg)

Blood pressure during isometric

exercise

(mm Hg)

Blood pressure during cold

exposure

(mm fk)

First placebo 165 -t 11/102 f 7 160 f lo/104 rfr 6 157 + lo/100 ? 6 189 +- 12/125 _+ 6 183 + 15/119 & 7

period (n = 15)

P <0.005 <O.OOl -Co.02 <0.005 <0.02 <0.02 <O.Ol <O.Ol <0.02 NS Nifedipine (n = 15) 148 + 8194 f 4 146 f 6196 + 3 143 + 6187 + 3 174 f 71116 -t 3 166 f 7/111 +- 4

P <0.02 <0.005 -Co.02 <0.005 NS <0.03 <0.05 <0.02 NS NS Second placebo 164 + 9/105 f 3 162 f 9/108 f 4 162 f 8198 + 4 188 + 91125 I? 4 179 f 8/121 + 3

period (n = 14)

Mean values c SEM for number of patients in brackets. p values calculated by Student’s t test; each value refers to the figures directly above and below it. NS = not significant.

of the heart could have been overlooked. A similar discrepancy between the site of presumed spasm and maximal arterial disease has been reported in some variant angina patients.* When given nifedipine, the patient entirely lost all chest pain at rest, the exercise time improved, the nitroglycerin con- sumption fell, and there was no longer any exercise- induced ST elevation nor ventricular arrhythmias (Fig. 2). In this patient, the final nifedipine placebo study was not undertaken because it would have been unethical to revert her to a situation predispos- ing to exercise-induced ventricular tachycardia.

Hypertension without angina. In 16 patients, nifedipine (10 mg sublingually in 14, 20 mg in two) decreased mean systolic BP by about 30 mm Hg and mean diastolic BP by about 20 mm Hg within 20 minutes. The heart rate increased slightly from 59 + 3 bpm (initial value on beta-bldckade; same value with added placebo) to 64 + 3 bpm (p < 0.0001). Follow-up studies on these patients were made 4 to 8 weeks later (Table III). It was striking that the mean arterial BP of all 16 patients after 4 to 8 weeks of therapy corresponded well to the acute reduction at 20 minutes. In one patient who did not respond to acute nifedipine, there was also no response for several weeks.

DISCUSSION

Antihypertensive action of nifedipine added to ateno- loI. Nifedipine was an active hypotensive agent when added in a relatively low dose (usually 10 mg twice daily) to atenolol in our patienta with hypertension and angina. Nifedipine reduced sitting, lying, and standing BPS, as well as the response to walking, hand-grip, and to cold. An important reservation is that the BP measurements were taken about 3 to 4 hours after the dose of nifedipine, and there is no guarantee that low BPS were maintained throughout

Table II. Effect of nifedipine on heart rate (bpm) (mean + SEM)

After During isotonic isometric

Sitting exercise exercise

Active nifedipine 62.8 f 3.0 66.6 rf: 3.3 67.6 k 3.0 (n = 9)

Second placebo period 65.2 & 2.4 69.2 & 2.4 72.6 ? 2.4 (n = 8)

p values for comparison between nifedipine and placebo period = not significant.

24 hours. However, the combination of atenolol and nifedipine should reduce BP for 24 hours, as can be expected from the prolonged hypotensive effect of atenolol and the hypotensive effect of nifedipine by itself, which lasts for 8 to 12 hours.2 There was no reason to suppose that nifedipine would be any less effective when added to atenolol in nonangind hypertensive patients than it was in our anginal hypertensive patients; the acute and chronic studies on such patients confirm that nifedipine is as active in hypertensive patienti without angina as in those with angina.

Two patients had an unusual reaction to nifedipine which allows certain specific conclusions. In one patient, fully documented elsewhere,6 with a very well-controlled initial BP (admission reading, sitting 130/90 mm Hg), nifedipine was added and symptomatic hypotension developed. In another patient, exercise-induced ST elevation and arrhythmias were found during the atenolol period. Of interest is the remarkable response to nifedipine in this patient, described above under the Results section, which further support the hypothesis that the mechanism of the exercise-induced ECG changes was vasospasm.

610 Opie, Jee, and White September, 1082


torftg b.d

lmim4Wraawcisrr

,.: . .i.

Fig. 2. Exercise-induced ST elevation in patient with hypertension and angina pectoris (top panel). Note development of multiple ventricular premature systoles. After addition of nifedipine to atenolol (bottom panel), the ECG abnormalities reverted to normal.

Vasodepressor mechanism of nifedipine and beta- blockade combination. Theoretically, beta-blockade and nifedipine have some complementary qualities. Thus, in addition to strong coronary and peripheral arteriolar dilatation, nifedipine slows depolarization in the sinoatrial node.s The combination of this property and the tendency to develop a compensato- ry tachycardia in response to vasodilatation resolves into a slight rise in heart rate, in contrast to the well known tachycardia which follows the administration of other vasodilators, particularly hydralazine. Here similar vasodilating properties are not accompanied by the modifying effect on the sinoatrial node. These actions make nifedipine theoretically a sound additive to beta-blockade, which exerts its effects by slowing atrioventricular conduction and causing a negative inotropic change in ventricular contraction, thus decreasing the oxygen demands of the myocardium.

It is of interest to reexamine the cases of adverse effects in response to nifedipine, thusfar reported, because the combination of nifedipine and beta- blockade has apparently caused a frequent inci- dence of complications, judged by reports in the literature,lO~ll including a report from our group.‘j

The patients of Brooks et aLI had severe cardiac failure, not receiving beta-blockade. In one patient in whom the cardiac output fell, the pre-nifedipine BP values were low (mean value of 80 mm Hg), while the other patient who deteriorated had been given a relatively large dose of nifedipine (30 mg). Doses of 20 mg have been given with apparent safety to patients with mean arterial BP of below 80 mm Hg13 with improvement in the cardiac index, but such patients were hemodynamically monitored. Blood pressures were not reported in the patients of Gill- mer and Kark.‘” In the latter study, the patient had severe aortic stenosis, usually considered to be a contraindication to vasodilator therapy. Thus when adding nifedipine to beta-blockade for hypertension or angina, it must be assessed whether an additional drop of arterial pressure can be tolerated, especially by a potentially ischemic myocardium, and aortic stenosis must be excluded.

Acute effects of nifedipine. Our studies show that sublingual nifedipine produces its acute fall in BP within 20 minutes (Fig. 1). Therefore, in cases of doubt, nifedipine may be added to beta-blockade and the BP and clinical picture monitored for 20 minutes; lack of adverse reaction is very likely to

Volume 104


Table III. Effects of acute administration of nifedipine, 10 mg sublingually, and chronic nifedipine orally to hypertensive patients already receiving atenolol

Patient Control blood pressure 20 minutes later After 4-8 weeks

(mm Hd (mm Hd (mm Hd

J.de V. 170/108 144184 130174

AL 169/103 166/101 182194

HT 190/115 155/100 145195

LA 1781128 140/104 149197

FP 194/108 160196 178/100 MJ 1441100 128194 126/98 JL 2201136 1781104 146/104 MW 210/110 176196 175184 PJ 170/130 162/106 140/104

RA 1861124 1741108 152/100 CP 1721122 158/110 156/110 RB 184/130 154198 156/110 LB 2501126 210/110 186196 M vN 210/110 180/96 166/90 FL (20 mg) 2421’136 156198 150195

CA (20 mg) 200/140 1751114 138/106

Mean SEM p vs control

193/120 k7 k3

164/101 155197 25 k2 k5 +2

<O.OOOl <O.OOOl

predict lack of long-term negative interaction. This property has practical application because it is possible for the physician to know whether or not the patient will respond to nifedipine within minutes of administration. Furthermore, it can be predicted with reasonable confidence that the magnitude of the acute response will predict the long- term response over weeks (Table III). Such a response removes much of the usual uncertainty as to whether an added hypotensive agent will be effective in a given patient or not.

Conclusions. Our study appears to be the first report on the effects of addition of the calcium- channel blocker, nifedipine, to therapy with the beta-receptor antagonist, atenolol, in patients with hypertension, or hypertension with angina. It also appears to be the first report of combination therapy of hypertension with nifedipine, a beta-blocker, and a thiaxide diuretic. We show that in such patients: (1) nifedipine is an effective additional antihypertensive agent and (2) nifedipine can be strikingly effective in the unusual condition of angina of effort associated with exercise-induced ST elevation and ventricular arrhythmias. In patients with hypertension, nifedipine is a valuable hypotensive agent when added to preexisting beta-blockade therapy with atenolol and a thiaxide diuretic. The hypotensive effect of sublingual nifedipine is acutely mani- fest within 20 minutes, which result we have used as a test for the safety of combined therapy with nifedipine and beta-blockade. The magnitude of the

acute hypotensive effect predicts well the further response when therapy with oral nifedipine is sus- tained for a further 4 to 8 weeks. It is noteworthy that in all 31 patients except one, nifedipine was an effective and powerful hypotensive agent, in a dose of 10 mg or 20 mg sublingually or orally.

We thank Bayer AG, Leverkusen, W. Germany, for a supply of nifedipine (Adalat) and matching placebos.

REFERENCES

1.

2.

3.

4.

5.

6.

7.

8.

9.

Pedersen OL, Mikkelsen E: Acute and chronic effects of nifedipine in arterial hypertension. Eur J Clin Pharmacol 14:375, 1978. Olivari MT, Bartorelli C, Polese A, Fiorentini C, Moruzzi P, Guazzi MD: Treatment of hypertension with nifedipine, a calcium antagonist agent. Circulation 59~1056, 1979. Atterhijg J-H, Ekelund L-G, Melin A-L: Effect of nifedipine on exercise tolerance in patients with angina pectoris. Eur J Clin Pharmacol 8:125, 1975. Ekelund L-G, OrS L: Antianginal efficiency of nifedipine with and without a beta-blocker, studied with exercise test. A double-blind, randomized subacute study. Clin Cardiol2:203, 1979. Lynch P, Dargie H, Krikler S, Krikler D: Objective assessment of antianginal treatment: A double-blind comparison of propranolol, nifedipine, and their combination. Br Med J 2:184, 1980. Opie LH, White D: Adverse interaction between nifedipine and &blockade. Br Med J 281:1462, 1980. Lahiri A, Subramanian B, Millar-Craig M, Crawley J, Raftery EB: Exercise-induced S-T segment elevation in variant angina. Am J Cardiol 45:887, 1980. Maseri A, Severi S, De Nes M et al: ‘Variant’ angina: One aspect of a continuous spectrum of vasospastic myocardial ischemia. Am J Cardiol 42:1019, 1978. Kawai C, Konishi T, Matsuyama E, Okazaki H: Comparative

Opie, Jee, and White September, IS82


effects of three calcium antagonists diltiazem, verapamil and nifedipine, on the sino-atria1 and atrioventricular nodes. Circulation 63:1035, 1981.

10. Anastassiades CJ: Nifedipine and beta-blocker durgs. Br Med J 261:1251, 1980.

11. Staffurth JS, Emery P: Adverse interaction between nifedipine and beta-blockade. Br Med J 282:225, 1981.

12. Brooks N, Cattell M, Pidgeon J, Balcon R: Unpredictable response to nifedipine in severe cardiac failure (Letter). Br Med J 281:1324, 1980.

13. Klugmann S, Salvi A, Camerini F: Haemcdynamic effects of nifedipine in heart failure. Br Heart J 43:440, 1980.

14. Gillmer DJ, Kark P: Pulmonary oedema precipitated by nifedipine. Br Med J 260~1420, 1980.

15. Guazzi M, Olivari MT, Polese A, Fiorentini C, Margrini F, Moruzzi P: Nifedipine, a new hypertensive with rapid action. Clin Pharmacol Ther 22:528, 1977.

Ebctrophysialogic ts of pb loI on sinus node function in c

Little is known regarding the effects of propranotoi (P) on sinus node function in children. in this study, corrected sinus node recovery time (CSNRT) and estimated sinoarttai conduction time @ACT) were measured in 10 children (ages 3 to 16 years; mean 8.3 years) without clinical evidence of sinus node dysfunction before and after intravenous P. The spontaneous sinus cycle length (SCL) increased after P(O.l mg/kg) in ail patients. Mean SCL increaeed 13.4% from 636 + 200 msec (+SD) to 720 2 202 msec (P < 0.01). Maximum CSNRT increased in nine patients after P and mean CSNRT increased 63% from 2D3 * 61 msec to 330 + 190 msec (p < 0.05). SACT changed in a random fashion after P. Mean SACT did not change significantly. We conclude that P significantly suppresses sinus node automaticlty in chit&en with normal sinus node function but has iittie or no effect on sinoatrfai conduction. (AM kieart~ J 104~612, 1962.)

Steven M. Yabek, M.D., William Berman, Jr., M.D., and Terrence Dillon, M.D. Albuquerque, N.M.

Sinus node dysfunction may occur in children with congenital heart disease both prior to and following surgical correction. I4 Since many of these children receive cardiac medications, it is important to know how these pharmacologic agents affect the sinus node. The electrophysiologic effects of digitalis on sinus node function in children have heen reported previously.5 Propranolol is used in children to treat arrhythmias, hypertension, and dynamic right and left ventricular outflow obstruction. Although the effects of propranolol on the sinus node in adults with normal and abnormal sinus node function have been evaluated, those studies have yielded conflict- ing data.6p7 In this report, we describe how propran- 0101 affected three parameters of sinus node function

From the Department of Pediatrics, University of New Mexico, School of Medicine.

Received for publication Apr. 1, 1981; revision received May 20, 1981; accepted June 2, 1981.

Reprint requests: Steven M. Yahek, M.D., Dept. of Pediatrics, University of New Mexico, School of Medicine, Albuquerque, NM 87131.

612 0002-8703/82/090612 + 05$00.50/O o 1982 The C. V. Mosby Co.

in 10 children with clinically and electrocardio- graphically normal sinus node function.

METHODS

Study pattents. Electrophysiologic evaluation of sinus node function prior to and folIowing intravenous propran- 0101 was conducted in 10 children undergoing routine cardiac catheterization. Informed consent was obtained from the parents. The age and diagnosis of each patient are listed in Table I. In each patient, sinus node function was considered to be normal on the basis of clinical and ECG data. Specifically, each patient had at least two X&lead ECGs which failed to show evidence for inappro- priate sinus bradycardia for age,8 sinus arrest, xinue node exit block,’ abnormal P wave morphology, or bradyt&by- arrhythmias. Only one patient bad undergone prior cardiac surgery and no patients were receiving cardiotonic or antiarrhytbmic medications it the time of study.

Eiectrophyatobgic proc6durer. Each patient was studied in the postabxorbtive state 60 minutes following sedation with intrar.&m&r meperidi& (1.5 mg/kg) and droperidol (0.03 m&g). The el~hysinl&ic studies were performed prior to angiography. Sinus node function

antihypertensive effects of nifedipine combined with cardioselective beta-adrenergic receptor...

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