carvedilol for systemic hypertension

Carvedilol for Systemic Hypertension

MARY E. HEBER, MRCP, GEOFFREY S. BRIGDEN, MRCP, MICHAEL P. CARUANA, FRACP, AVIJIT LAHIRI, MB, BS, MSc,

and EDWARD B. RAFTERY, MD

Twenty-four-hour profiles of intraarterial ambulatory blood pressure (BP) and heart rate were signlficant- ly reduced by administration of carvedilol, a new & blocklng drug with vasodilating properties. Twelve patients were given carvedilol, 25 mg twice daily for 2 weeks; the dose was then increased to 50 mg twice daily if the target BP was not achieved. After 4 weeks of therapy, mean daytime reduction in BP was 25 f 3 mm Hg systolic and 19 f 3 mm Hg diastolic and mean reduction in heart rate was 22 f 3 beats/min. BP at the peak of isometric exer-

cise and during dynamic exercise was also significantly reduced. Radiormclide measurements showed that left ventricular ejection fraction was not affected by treatment, but there was a slgnlficant reduction in systolic and diastolic volumes. The drug was well tolerated. Thii clinical trial suggests that carvedild will be a useful first-line drug for treatment of essential hypertension, and its vasodilating action may have a more favorable effect on left ventricular function than conventional @blocking drugs- (Am J Cardiol 1987;59:400-405)

T he importance of both @-adrenoreceptor blockers and peripheral vasodilators for the treatment of systemic hypertension is well established,‘*2 but neither group of drugs is without disadvantages. Beta blockade may exacerbate any tendency to heart failure and of- ten causes complaints of excessive fatigue and cold extremities.3r4 Vasodilators tend to cause fluid retention and tachycardia, and may also produce headache and postural hypotension.5 The combination of a vasodilating and a p-blocking drug has a greater antihypertensive action than either agent used aloneS By reducing the afterload on the left ventricle, a vasodilator may also offset any negative inotropic effect of the @ blocker, which is potentially deleterious to patients with diminished left ventricular function. However, use of 2 separate medications complicates the treatment regimen and may tend to reduce patient compli-

From the Department of Cardiology and the Division of Clinical Sciences, Northwick Park Hospital and Clinical Research Cen- tre, Harrow, Middlesex, England. Manuscript received May 5, 1986; revised manuscript received August 8,1986, accepted Au- gust 11, 1986.

Address for reprints: Edward B. Raftery, MD, Department of Cardiology, Northwick Park Hospital and Clinical Research Centre, Watford Road, Harrow, Middlesex, England.

ante. Carvedilol is a noncardioselective p-blocking drug that also possesses vasodilating properties. Its ef- ficacy in the treatment of angina has already been reported.7J This study was designed to demonstrate its effect on .%&hour blood pressure (BP] in fully ambulant patients with essential hypertension. A secondary aim was to examine the effect of the drug on left ventricular function, assessed scintigraphically. We hoped to determine if the negative inotropic effects of /3 blockade are offset by the drug’s vasodilating properties and if either of its actions predominated acutely or after chronic administration. We also examined the effect of therapy on a program of isometric and dynamic exercise to determine how exercise-induced in- creases in BP and the left ventricular response to stress were influenced by the drug.

Methods Patients: Patients were recruited from the Harrow

Hypertension Clinic from among those whose untreated hypertension had recently been diagnosed or those whose hypertension was poorly controlled with their current therapy. They were considered for inclusion in the study if, when they had had no antihypertensive therapy for a minimum of 3 weeks, their routine clinic BP measured after 15 minutes of supine rest was greater than 160 mm Hg systolic or 100 mm Hg diastolic

400

February 15, 1987 THE AMERICAN JOURNAL OF CARDIOLOGY Volume 59 401

(Korotkoff phase V) on 3 consecutive clinic visits at least 1 week apart. Both men and women between the ages 20 and 65 years were selected for the study; however, women of childbearing potential were excluded. Other reasons for exclusion were a history of heart failure or of myocardial infarction within the last 3 months, secondary hypertension, conduction abnormality, obstructive airways disease, gastrointestinal disease, recent surgery or any other severe concomitant pathologic condition.

All patients gave informed written consent and the study was approved by the Harrow Health Authority Ethical Committee.

Study design: This was an open study; because no placebo effects were seen on intraarterial BP record- ingsg a placebo crossover was considered unnecessary and, in view of the invasive nature of the study, ethi- cally unwarranted.

On the first day, patients attended the hospital for commencement of intraarterial ambulatory BP recording. They then underwent a standard regimen of physiologic testing before leaving to resume their normal daily activities.

The next morning, after completion of 24 hours of recording, the patients returned to the hospital for rest and exercise gated equilibrium radionuclide ventriculography. When this was completed, they were given their first 25-mg dose of carvedilol and instructed to return 2 hours later for further rest and exercise gated ventriculography. The intraarterial cannula and recording equipment were then removed.

Each patient was then given carvedilol capsules at a starting dose of 25 mg to be taken twice daily, at 7 AM and 7 PM, before meals. At the end of 2 weeks they returned to the hospital for assessment of BP control as judged by recordings taken with a mercury-in-glass sphygmomanometer after 15 minutes of supine rest. If the diastolic BP had not decreased to less than 95 mm Hg (Korotkoff V), or to at least 20 mm Hg below the starting supine diastolic BP, the dose of carvedilol was increased to 50 mg twice daily for a further 2 weeks.

After 4 weeks of drug treatment, and therefore at least 2 weeks at a constant dose, the patients returned to the hospital for a second period of intraarterial BP monitoring and physiologic testing. Carvedilol was taken as usual that evening and the next morning. The patients then returned to the hospital and gated rest and exercise equilibrium radionuclide ventriculography was undertaken as before. The recording equipment was removed, blood samples were taken for routine hematologic and biochemical screening and a urine sample was obtained.

Patients were weighed at entry, at 2 weeks and at completion of the study. The occurrence of any adverse effects was noted, as was concomitant drug administration.

Intraarterial ambulatory blood pressure recording: The technique of ambulatory BP recording has been fully described previously.1° Briefly, patients were requested to attend the hospital for percutaneous

insertion of an intraarterial cannula into the brachial artery of the nondominant arm. The BP signal and the electrocardiogram from bipolar chest leads were re- corded using a specially designed uansducer/perfu- sion unit connected to a tape recorder (Medilog Mark I), which also incorporated a time channel with an event marker. The equipment was designed so that patients could be fully ambulant and able to carry out their normal daily activities.

After insertion of the cannula and fitting and cali- bration of the equipment, patients underwent a standard regimen of physiologic testing, comprising 20 minutes of supine rest, followed by head-up tilt to 60’ degrees maintained for 5 minutes. Isometric exercise was then performed using a handgrip dynanometer for 2 minutes at 50% maximal voluntary contraction. After recalibration of the equipment, the patients left the hospital to resume normal daily activities, returning in the evening for a further equipment check and recalibration,

Radionuclide angiography: Equilibrium radionu- elide ventriculography was performed with subj ects in the supine position. Blood was labeled in vivo by intravenous injection of 10 mg of stannous pyrophosphate, followed after 30 minutes by intravenous injection of 800 MBq of technetium-99m.

Imaging was performed using a mobile single-crys- tal digital cardiac gamma camera (Elscint model 215M) equipped with a low-energy, all-purpose, parallel- hole collimator. The camera was positioned in the 30° to 45” left anterior oblique (best septal) position with 10 to l5O caudal tilt to best isolate the left ventricle. Elec- trocardiographic gating was used to collect and orga- nize rest data of 5 million counts into a series of 32 frames for each cycle in order to obtain a high resolu- tion left ventricular time-activity curve. Patients then performed a symptom-limited dynamic exercise test with bicycle ergometry in the supine position, at work- loads increased by 25-W increments at 3-minute intervals. The patients were asked to indicate when they felt they were nearing the end of their exercise toler- ance, and a further gated acquisition of 3 million counts was then obtained and organized into a series of 24 frames for each cardiac cycle. Left ventricular ejection fraction, peak filling rate, end-systolic counts and end-diastolic counts were calculated on the El- stint computer using a preset semiautomatic program previously described.ll

Analysis of data: The ambulatory tape recordings were replayed and written out on a linear direct-writ- ing recorder to allow assessment of analog signal qual- ity, signal drift12 and of any artifact. Hourly sections were then analyzed on a hybrid computer to give mean levels of systolic and diastolic BP and heart rate (HR). Hourly mean values for all the patients were pooled, and curves to show the 24-hour profiles of BP and HR before and during treatment were constructed. The significance of differences in mean values for each hour were assessed using Student .&tailed paired t test.

The results of supine rest, tilt, isometric and dynamic exercise were computed using a standard digitizing

402 CARVEDILOL IN HYPERTENSION

n- 10 9 10 10 10 10 11 9 8 6 5 5

-z loo & (Y 90 5 r 80

lz 70 I

60J Systolic 200

p 180 E G 160

5 120 B 2 100 ’ : i

80

jjx , ,

10 20 30 40 50 60 70 80 90 100 110 120

Time (minutes)

FIGURE 1. Pooled blood pressure and heart rate trends In the 2 hours after the first dose of carvedilol, 25 mg, compared with the same 2 hours of the previous day. Dots, untreated; circles, after f&St dose. Solid line, p <0.005; broken line, p <g.g2; doffed fine, p <0.05.

program previously described.13 Results before and during therapy were again assessed using Student 2- tailed paired t test.

The BP and HR for the 2 hours immediately after the first dose of the drug were digitized in consecutive lo-minute intervals and compared with the same 2 hours of the previous day.

Scintigraphic left ventricular ejection fraction, end-systolic counts, end-diastolic counts and peak filling rate were calculated using a preset program on the Elscint computer. Peak filling rate was normalized to a HR of 70 beats/min using the formula: [(70 X peak filling rate)/HR], to produce a figure that was called the peak filling rate index. Values of these indexes for all patients were pooled, and the significance of any differences between pretreatment, first-dose response and chronic therapy was assessed using a Student 2- tailed paired t test.

Results Clinical course: Twelve patients (7 men, 5 women,

mean age 53 years [range 45 to 641) were studied. All patients underwent a full physical examination, routine hematologic and biochemical screening, electro- cardiography and chest x-ray before entry into the study. Three patients had evidence of left ventricular hypertrophy or “strain” on their preentry electrocar- diograms, 3 had evidence of cardiac enlargement on the chest x-ray, 6 had either grade I or II retinal hypertensive changes, and none had a blood urea level greater than 10 mmol/liter, or any other clinically significant hematologic or biochemical derangement.

-iz 100 is al 90 F r 80 E I 70

60

200

180

F E 160

H 140

2 120 z k 100 -8 i a m 80

60 p <o.oz ----- 401 p < 0.05 .......‘.

I I I I I I I I I I I III 09 11 13 15 17 19 21 23 01 03 05 07 09 11

Time of day (hours)

FIGURE 2. Circadian variatlon of blood pressure and heart rates. Dots, untreated; c/rc/es, after 4 weeks treatment with carvedllol.

All patients completed the study in accordance with the protocol. None had to be withdrawn.because of adverse effects or because their BP was believed to be dangerously elevated at the 2-week follow-up visit. In 5 patients the second period of intraarterial BP assessment was delayed because of the holidays for 2 weeks beyond the 4 weeks stated in the protocol.

In 10 of the 12 patients the dose of carvedilol was increased to 50 mg twice daily after 2 weeks. In the remaining 2 patients, BP appeared adequately controlled with 25 mg twice daily. One of these patients had had a very high initial 24-hour mean BP (1W129 mm Hg), whereas other patients with a lower initial BP required an increased dose.

No significant change in body weight occurred in any patient during therapy, nor did anyone complain of swollen ankles or other symptoms of fluid retention. Except for slight nausea on the first day of medication in 1 patient, no adverse effects were noted. In the 9 patients for whom full biochemical and hematologic screening results were available, no significant change or abnormality was found at completion of the study.

Intraarterial blood pressure: Technically ade- quate BP recordings were obtained before and during treatment in all patients. In 3 of the 24 recordings a significant (greater than 5 mm Hg) linear signal drift was seen for which a correction was made before analysis.12

A significant reduction in both systolic and diastolic BP was detected 30 minutes after the first dose (Fig, 1). This continued to a maximal reduction of 30/16 mm Hg 90 minutes after administration, and continued at


this level until the scan and exercise test were begun 2 hours later. This level of BP was similar to the reduction in mean daytime BP noted at 4 weeks (25/19 mm Hg). A small but significant reduction in HR was seen 70 minutes after administration of the first dose; however, this was significantly less than the reduction in mean daytime HR seen after 4 weeks of therapy (22 beats/min, p <O.OOl).

The %-hour profiles, plotted from consecutive mean hourly BP and HRs before and during therapy, are shown in Figure 2. The slope of the circadian curve was not altered by therapy, but a significant reduction was seen in systolic BP for 21 of the 24 hours and in diastolic BP for 20 of the 24 hours. HR was reduced throughout. The trend toward reduction was maintained in the hours that did not reach conventional levels of significance, and the drug maintained a significant hypotensive action during the early morning increase in BP. Mean reduction in daytime BP was 25 f 3 mm Hg systolic and 19 f 3 mm Hg diastolic. HR was reduced by a mean of 22 f 3 beats/min. During the night there was a mean reduction in systolic BP of 13 f 5 mm Hg, diastolic BP of 8 f 4 mm Hg and HR of 7 f 2 beats/min.

BP and HR during supine rest, 60' head-up tilt and at peak of isometric exercise are shown in Table I. A significant reduction in BP and HR occurred during therapy with the patient in the supine and 60' head-up tilt positions: no postural decrease occurred on tilt- ing. Peak values of systolic and diastolic BP during isometric exercise were significantly reduced by therapy, although the magnitude of the response was un- altered.

During dynamic exercise 2 hours after the first dose of carvedilol, BP was significantly reduced up to the ninth minute, when 8 of the patients were still exercis- ing. No additional change occurred after 4 weeks of treatment. However, HR was reduced only slightly by the first dose, but decreased significantly after 4 weeks of treatment (Fig. 3).

Radionuclide angiography: Mean rest ejection fraction in this group of patients was within normal

FIGURE 3. Blood pressure and heart rate response to exercise. Dofs, untreated; triangles, after first dose: circles, afler 4 weeks treatment with carve- $ dilol. Solid line, p <0.#5; broken Ilne, p X0.02; 2 _ dotted /he, p <0.05. Pre Ex = before exercise; Post ex = after exercise.

2

E I a F _C m

TABLE I intraarterial Blood Pressure During Physiologic Tests

Blood Pressure (mm Hg)

Before Treatment After Treatment p Value

Supine rest (end of 30 min)

Systolic 177 f 8 161 f 8 <0.02 Diastolic 100 f 5 88 f 4 <0.005 Heart rate 76 f 3 60 f 2 <O.OOl

Head-up tilt (60°) 15 seconds

Systolic 180 f 7 157 f 9 co.01 Diastolic 104 f 4 88 f 4 x0.002 Heart rate 83 f 5 67 f 4 -co.005

30 seconds Systolic 185 f 7 159 f 8 <O.OOl Diastolic 104 f 5 88 f 3 <0.005 Heart rate 80 f 5 65 f 3 <0.002

60 seconds Systolic 182 f 8 161 f 9 <0.005 Diastolic 106 f 5 91 f 4 <0.005 Heart rate 78 f 4 65 f 4 <0.02

Peak isometric exercise Systolic 231 f 9 205 f 6 <O.OOl Diastolic 135 f 6 119 f 6 <0.005 Heart rate 95 f 8 72 f 3 <0.005

limits before treatment (64% f 3), and did not change significantly with exercise (65% f 3). Although no significant change in rest ejection fraction occurred either after the first dose or after 4 weeks of treatment, a significant increase in ejection fraction with exercise occurred after the first dose, an effect that was lost after long-term therapy [Table II).

Diastolic function was assessed from the peak filling rate index. No significant change in rest peak filling rate index occurred, but a significant increase occurred during exercise both before treatment and after the first dose, which was lost after long-term treatment (Table II).

Rest end-systolic counts and end-diastolic counts were not altered significantly by the first dose, but were markedly decreased after 4 weeks (Fig. 4).

Pre Ex Exercise Pnst Ex Pre Ex Exercise Pnst Ex

60 40

Svstollc 240

I

220 200 180 160 140 Diastolic

:z 2 - y&q 80 60 40 nn-rnm

12 246 810 135

1 Systolic

2% 4%

Diastolic

i-r-mm :2 24 681013 5

Time (minutes)

Pre Ex Exercise Pnst Ex

1

Systdic

Diastolic

-In rr-rnm 12 246810135

404 CARVEDILOL IN HYPERTENSION

TABLE II Ejection Fraction and Peak Filling Rate Index at Rest and Peak Exercise

Ejection fraction (%) Rest Exercise Significance

of effect of exercise

Peak filling rate index Rest Exercise Significance

of effect of exercise

Before After Treatment 1st Dose

64 f 3 62 f 3 65 f 4 66 f 4

NS p <0.02

2.4 f 0.2 2.1 f 0.3 3.0 f 0.2 3.2 f 0.2 p <0.002 p <o.ooi

After 4 Weeks Treatment

62 f 2 62 f 3

NS

2.7 f 0.2 2.7 f 0.2

NS

NS = not significant.

Discussion Although the causes of essential hypertension are

not fully understood, the consistent hemodynamic abnormality found in patients with this condition is increased peripheral vascular resistance due to arteriolar vasoconstriction.14J5 The antihypertensive action of ,&blocking drugs is mediated at least in part by a reduction in cardiac output; peripheral vascular resistance actually tends to increase initially,ls decreasing after longer duration of treatment. Thus, although the effectiveness of P-blocking drugs in reducing BP is undisputed, their mode of action may not be ideal, and this may account for the slow onset of antihypertensive action. By reducing HR and contractility, /3 blockers may precipitate heart failure in patients with diminished left ventricular function: patients with normal cardiac function may complain of fatigue and reduced exercise capacity.

Peripheral vasodilators have a mode of action that is theoretically more appropriate in correcting the raised peripheral vascular resistance2; moreover, by unloading the heart, they may be beneficial to left ventricular function. The high incidence of adverse effects reduces the acceptability of these drugs; however, by combining vasodilating properties with /3 blockade, we anticipated that carvedilol would have the antihypertensive actions of both, and the unwant- ed effects of p blockade would be offset by the vasodilatation. Similarly, the p blockade would offset the adverse effects of vasodilatation.

In this study carvedilol brought about an appreciable reduction in systolic and diastolic BP similar to the reduction achieved by other P-blocking drugs; this effect was maintained over 24 hours by a twice-daily dosage. There were no appreciable adverse effects, even when patients were questioned directly. This was a significant observation because 6 of the patients were intolerant of previous antihypertensive medication, or had new adverse effects when therapy was changed at the end of the study period.

The early reports of 24-hour ambulatory intraarterial BP monitoring led to the appreciation of the rapid

160000.

120000~ 3

z 100000'

80000.

Systolic

cl untreated l--r -

Ti 1

I

I fiRi acute

Diastolic 400000 1 350000

300000 Ln E

s

250000

200000 1

0 1

R chronic

r

x l

l

a

* p < 0.05 **p < o.o2***p < 0.005 FIGURE 4. End-systolic and end-diastolic isotopic counts at rest, before treatment, after first dose and after 4 weeks treatment wlth carvedilol.

increase in BP in the morning; control of this increase was suggested to have important clinical and thera- peutic implications, since many of the serious cardio- vascular complications of hypertension tend to occur at this time.17 Twenty-four-hour BP profiles of patients treated with conventional P-blocking drugs showed that, although they produce effective reduction in BP during the daytime, they fail to control the early morning increase.18Jg This increase was believed to be due to circadian variation in sympathetic activity, which increased around the time of arousal and was unop- posed by /3 blockade. 2o This theory was supported by evidence that labetalol, a combined (Y- and P-blocking drug, greatly reduced the early morning increase in BP.21 The calcium channel antagonists, which act as vasodilators by causing direct relaxation of the smooth muscle in the arteriolar wall, were shown to modify the absolute BP at this time, but did not alter the rate of increase.20J2 It is not known how the vasodilating com- ponent of carvedilol is achieved, although it has been well demonstrated that the drug does not possess cy- blocking properties. 23 However, the early morning increase was controlled but not abolished by the drug, a result consistent with the theory that early morning BP increase is mediated with cx adrenoreceptors.

The antihypertensive effect of carvedilol appeared within 10 minutes of oral administration, and reached sustained maximal levels 96 minutes after administra-


tion. HR decreased only slightly during this period, but was significantly slower after 4 weeks of therapy. These findings suggest an early predominance of the drug’s vasodilating properties, making it useful for acute reduction in BP, but a more gradual onset of its p- blocking activity.

Scintigraphic end-systolic and end-diastolic counts were not altered acutely, but were markedly and significantly reduced at 4 weeks. The preset gamma-camera program ensured that the number of counts in each frame was constant in all rest studies. Thus, the number of counts from the left ventricle reflects the size of the blood pool within it. Although the counts cannot be used to calculate the absolute left ventricular volume, a reduction in counts from the left ventricle in repeat studies on the same patient does represent a relative reduction in size of the left ventricle. Thus, the reduction in relative end-diastolic counts at a slower HR may imply venodilation in addition to arteriolar dila- tion, sufficient to counteract the effect of /3 blockade, which usually causes the ventricle to dilate. This beneficial effect on left ventricular function may confer on the drug an advantage over other @ blockers, even if they possess similar antihypertensive properties.

References 1. Prichard BN, Gillam PM. Treatment of hypertension with propronold. Br Med r l969;1:7-16. 2. Koch-Weser J, Vosodilotor drugs in treatment of hypertension. Arch Intern Med 1974;133:1017-1027. 3. Kincaid-Smith P. Beta-adrenergic blocking drugs in hypertension. Am J Cardiol 1984;53:12A-15A 4. Bulpitt LJ, Hoffbrand BI, Dollery CT. Contribution of drug treatment to symptoms of hypertensive patients. In: Mild Hypertension: Natural History and Management, Gross F, Strasser T. eds. London; Pitman Medical Publish- ing 1979;291-302. 5. Kincaid-Smith P. Vasodilator drugs in the treatment of hypertension. Med r Aust 1985;142:450-453.

6. Gould BA, Hornung RS, Kieso HA, Cashman PM, Raftery EB. Prazosin alone and in combination with a beto-adrenoreceptor blocker in treatment of hypertension. J Cardiovasc Phormacol 1983;5.4:678-684. 7. Rodrigues EA. Kohli RS. Lahiri A. Raftery EB. An objective evaluation of corvedilol. a new vasodilating beta blocker, in angina pectoris (obstr). Clin Sci 1986;suppl 13:54-55. 8. Kaski JK, Rodriguez-Plaza L, Brown J, Maseri A. EfficacyofCorvedilol(BM 14,190), o new beta-blocking drug with vosodilating properties, in exercise- induced ischemia. Am J Cardiol 1985;56:35-40. 9. Gould BA. Mann S, Davies AB. Altman DG. Raftery EB. Can placebo therapy influence arterial blood pressure? Clin Sci 1981:61:478-490, 10. Millar-Craig MW. Hawes D. Whittington J, New system for recording ambulatory blood pressure in man. Med Biol Eng Comput 1978;16:727- 231. 11. Rodrigues EA. Lahiri A, Raftery EB. Improvement in diastolic dysfunction in ischaemic heart disease after treatment with calcium antagonists (abstr]. Clin Sci 1986;7O:suppl 13. GP. 12. Cashman PM, Stott ED, Millar-Craig MW. Hybrid system for fast data reduction of long term blood pressure recordings. Med Biol Eng Comput 1978;17:629-635. 13. Hornung RS. Gould BA, Jones RI, Sonecha TN, Raftery EB. Nifedipine tablets for systemic hypertension: a study using continuous ambulatory intraarterial recording. Am J Cardiol 1983:51:1323-1327. 14. Frohlich ED, Tarazi RC, Dustan HP. Re-examination of the hemodynam- its of hypertension. Am [ Med Sci 1969;257:9-23. 15. Lund-Johansen P. Haemodynamics in early essential hypertension. Acta Med Stand 1967;181:suppf 482:1-99. 16. Frohlich ED, Tarazi RC, Dustan HP, Page IM. The paradox of beta- odrenergic blockade in hypertension. Circulation 1968;37:417-423. 17. Millar-Craig MW. Bishop CN, Raftery EB. Circadian variation of blood pressure. Lancet 1978;1:795-797. 18. Millar-Craig MW, Kenny D. Mann S, Balasubramanian V, Raftery EB. Effect of once daily atenolol on ambulatory blood pressure. Br Med J 1979;1:237-238. 19. Mann S, Millar-Craig MW, Balasubramanian V, Raftery EB. Once daily B-adrenergic blockade in hypertension: an ambulatory assessment. Br J Clin Pharmacol 1981;12:223-228. 20. Beilin LJ. Juel-Jensen BE. Alpha and beta adrenergic blockade in hypertension. Lancet 1972:1:979-98X 21. Balasubramanian V, Mann S. Raftery EB, Millar-Craig MW, Altman D. The effects of labetalol on continuous ambulatory blood pressure. Br J Clin Pharm 1979;8:suppl 12:119S-1235. 22. Jones RI, Hornung RS. Sonecha T, Raftery EB. The effect of a new cahum channel blocker nicardipine on 24 ambulatory blood pressure and the pressure response to isometric and dynamic exercise. J Hypertens 1983;1:85-89. 23. Sponer G, Muller-Beckmann B. Studies on the mechanism of the vasodilating activity of BM 14.190 (abstr]. Naunyn Schmiedebergs Arch Pharmacol 1983;322:suppf R45.

carvedilol for systemic hypertension

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