Rest and exercise hemodynamic effects of sequential alpha-I-adrenoceptor (trimazosin) and beta-adrenoceptor (propranolol) antagonism in essential hypertension

The efficacy of acute beta blockade in essential hypertension is limited by reflex

vasoconstriction. The aim of this study was to determine whether the latter response was modified by prior selective alpha-1-adrenoceptor blockade. A single-blind, within-patient,

placebo-controlled evaluation of the immediate hemodynamic effects of sequential alpha-l

(trimarosin)- and beta (propranolol)-adrenoceptor blockade was undertaken in 10 men (34 to 58 years) with previously untreated essential hypertension. The study commenced with a 4-minute

control period of constant-load (600 to 900 kpm/min) upright bicycle exercise, and measurements were made before (control) and 30 minutes after intravenous trimarosin (2mg/kg)

and exercise was then repeated; measurements at rest were again made 4 minutes after intravenous propranolol (0.2 mg/kg) before a final exercise period. Trimazosin at rest reduced

systolic and diastolic arterial pressure and systemic vascular resistance without change in heart

rate, cardiac output, or left ventricular (LV) filling pressure. During upright bicycle exercise the reductions in blood pressure were sustained without change in their rest-to-exercise increments.

Other circulatory variables did not differ from control values. At rest the addition of propranolol further reduced systolic arterial pressure. Heart rate and cardiac output fell and systemic

vascular resistance increased to its pretreatment control value. During exercise the changes at

rest were sustained and the rest-to-exercise increments in blood pressure, heart rate, and cardiac output were reduced. LV filling pressure was significantly increased. In conclusion, alpha-1-adrenoceptor blockade modified the adverse effects of acute beta blockade at rest but

not during exercise. (AM HEART J 108:124, 1984.)

Gregory I. C. Nelson, Bernard Silke, Musharaf Hussain, Satya P. Verma, and Stanley H. Taylor. Leeds, England

The high blood pressure in stable essential hyper- tension is determined by raised systemic vascular resistance1-4 with a normally maintained cardiac output.5-7 Simultaneous reduction of both of these hemodynamic variables by combined blockade of the sympathetic efferent pathways can thus be expected to reduce the blood pressure more effi- ciently than selective blockade of either pathway alone.3**.g Moreover, such comprehensive blockade could be expected to have distinct circulatory

From the University Department of Cardiovascular Studies, and the

Department of Medical Cardiology, The General Infirmary.

Supported by the West Riding Medical Research Trust, the Yorkshire

Regional Health Authority, and Pfizer Central Research.

Received for publication Oct. 15, 1983; accepted Nov. 1, 1983.

Reprint requests: Dr. S. H. Taylor, Department of Medical Cardiology, The General Infirmary, Great George Street, Leeds LSl 3EX, England.

advantages. Any reflex stimulation of the heart rate and contractility due to the vasodilator-induced fall in blood pressure should be attenuated by beta blockade; conversely, the reflex increased in system- ic vasoconstriction secondary to the beta blocker- induced reduction in cardiac output should be mod- ified by alpha blockade. Relatively few reports are available of the hemodynamic synergism of the addition of beta blockade to selective alpha-l- adrenoceptor blockade in patients with essential hypertension, particularly during exercise in the upright posture. As a preliminary to a more extend- ed pragmatic clinical trial, the following study was designed to examine the hemodynamic conse- quences of the addition of beta blockade with pro- pranolol to alpha-l-adrenoceptor blockade with tri- mazosin in patients with stable essential hyperten- sion.

124

Volume 108

Number 1 Trimazosin plus propranolol in hypertension 125

Table I. Patient characteristics

Duration Clinic

of blood pressure Echocardiographic measurements hyper- (mm Hd

Age tension PLVWT IVST L VISD L VIDD

(range) (yr) Lying Standing CTR LAIA (cm) (cm) (cm) (cm)

(2:-!6) (0.3-6.1) 3.2 174(155-200) 164(140-200) 0.48 1.04 1.25 1.41 3.27 5.05 109(103-136) lll( 98-150) (0.39-0.57) (0.81-1.31) (1.10-1.64) (1.06-1.75) (2.45-4.48) (4.24-6.06)

Abbreviations: CTR = cardiotboracic ratio from standing B-foot posteroanterior radiograph; LA/A = left atrial/aortic root ratio; PLVWT = posterior left ventricular wall thickness; IVST = interventricular septal thickness; LVISD = left ventricular internal systolic dimension; LVIDD = left ventricular internal diastolic dimension.

METHODS

Patients (Table I). Ten male patients, aged 28 to 56 years, with uncomplicated and previously untreated essential hypertension of between 0.3 and 6.1 years’ duration, were studied. None had symptoms related to their high blood pressure; all were referred following its detection during routine medical examination. None had a history of angina of effort, myocardial infarction, or cerebrovascular accident, and none had received sustained antihypertensive treatment. One patient had radiographic cardiac enlargement (cardiothoracic ratio 0.57), and the same patient had ECG evidence of left ventricular (LV) hypertrophy. However, in eight patients, the echocardio- graphic thickness of the posterior LV wall and interventri- cular septum exceeded 11.0 mm. In the latter patients, asymmetric septal hypertrophy was present in two, and in two there was evidence of left atria1 enlargement. All patients were in sinus rhythm, none had retinal hemor- rhages or exudates, and renal function tests were normal in all. None had abnormal serum biochemistry. The details of the investigation were explained to all patients and the study was approved by the hospital ethics com- mittee.

Study design. The study design comprised two treat- ment phases, first with the selective alpha-l-adrenocep- tor-blocking drug, trimazosin, alone and then with the addition of the beta-blocking drug, propranolol. In both phases hemodynamic observations were made in patients sitting at rest and during upright bicycle exercise. Patients were familiarized with the technique of bicycle exercise beforehand, and the maximum workload which each could sustain for 4 minutes was determined. On another day, they were studied fasting and without premeditation. Intravascular cannulation followed a brief warm-up/exer- cise period at 50% of the previously determined workload. The study commenced with a 4-minute period of upright bicycle exercise at the predetermined workload (600 to 900 kpm/min) during which measurements were made at minute intervals. After exercise and when heart rate, blood pressure, and cardiac output had returned to stable levels, five control measurements at rest were made at 5-minute intervals over a period of 25 minutes. Without delay an intravenous bolus of trimazosin (2 mg/kg) was then given, and blood pressure and heart rate were

monitored for 30 minutes. Five groups of hemodynamic measurements were then made at 2-minute intervals with the patients sitting at rest. At the end of this period patients were immediately reexercised at the same bicycle workload as previously for 4 minutes and hemodynamic variables were recorded at minute intervals.

After a further sitting rest period of 15 to 20 minutes, an intravenous bolus of propranolol (0.2 mg/kg) was given. Five minutes later five consecutive periods of hemody- namic measurements were made at 2-minute intervals at rest. At the end of this period patients were immediately reexercised at the same bicycle workload as previously and minute-by-minute measurements were made for 4 minutes. Systemic arterial and pulmonary venous blood samples for the measurement of oxygen content and derivation of total body oxygen uptake were taken during each resting period and also during the last minute of exercise in both phases of the study. Venous blood samples for the measurement of plasma trimazosin and its chief metabolite were taken 30 minutes after its intrave- nous injection. Venous samples for the measurement of both propranolol and trimazosin were taken 12 minutes after the intravenous injection of propranolol.

The design of the study in terms of the time of hemodynamic measurements after the intravenous injec- tion of each drug was based on the following considera- tions. The maximum antihypertensive effect of trimazosin is delayed approximately 30 minutes after its intravenous administration,‘O while its plasma half-life and duration of hemodynamic effects exceed 3 hours.” Conversely, ade- quate beta blockade with propranolol is achieved within 5 minutes of the drug’s intravenous injection.‘?

Hemodynamic techniques. Heart rate was measured from the ECG and systemic arterial pressure through a brachial artery catheter. Pulmonary vascular pressures were measured through a balloon-tipped thermodilution catheter positioned radiographically so that inflation of the balloon resulted in replacement of the pulmonary artery pressure record by a typical pulmonary wedge tracing (pulmonary artery occluded pressure - PAOP). Pressures were externally transduced with strain gauges and recorded together with heart rate on an ultraviolet recorder. Zero reference point for transduced pressures was 10 cm below the horizontal plane of the sternal angle.

126 Nelson et al.

Control

July, 1984

American Heart Journal

Tnmazosln & Propwdd

Tnmazosin

\

\

\ -NS-

I’1 -1-1

Tnmazostn & Propranotot

I T= SEM I I

l * pco .Ol

I NS IlO. Slg. dlft.

u,I’ mln L 1~ I f ? : mn Y ,1 mn Rest Exercise Rest Exercise Rest Exercise

Fig. 1. Effects of intravenous trimazosin and propranolol on systemic arterial pressure and vascular resistance at rest and during 4 minutes of exercise in 10 patients with essential hypertension. Significance levels relate to comparison with control values *p < 0.05; **p < 0.01.

Mean pressures were integrated electronically, and heart rate and pressures were averaged over two respiratory cycles. Cardiac output was measured in triplicate by thermodilution and automatically computed (Gould Sta- tham Computer SP 1435fRecorder SP 2009). A gas- operated, constant-speed injector (OMP Model 3700) was used with 10 ml of dextrose-saline solution at 0” C as indicator. Systemic vascular resistance was calculated according to the following formula and corrected for body surface area: systemic vascular resistance (mean systemic arterial pressure X 80/cardiac output). Total body oxygen uptake was calculated from the Fick equation. Blood oxygen saturation was measured by a hemoreflector and oxygen capacity by a spectrophotometric method as previ- ously described.13

Drug plasma concentration measurements Trimazosin and its metabolite. The plasma concentra-

tions of trimazosin and its alkyl hydroxylated metabolite were measured by high-pressure liquid chromatography,

employing fluorimetric detection. The assay is specific for the drug and its metabolite and is linear over the range 0.1 to 20 rg/ml. The lower limit of sensitivity of this method is 2 pg/ml trimazosin and the variability of the technique over the range of sensitivity is less than 10%.

Propranolol The plasma concentration of propranolol was measured by means of high-performance liquid chro- matography with fluorimetric detection. The assay was specific for unchanged drug, linear over the range 10 to 1000 PgL (coefficient of variation 7.2 %), and with a lower limit of sensitivity of 2.5 pg/L.14

Statistical methods and graphic presentation. Statis- tical analysis of results involved four procedures. First, the probability of statistical differences between control data and both single and then combination drug data was tested by analysis of variance of repeated measures.15 Second, the differences between the values immediately before and then after propranolol, both at rest and during exercise, were tested by analysis of variance of repeated

Volume 100

Number 1 Trimazosin plus propranolol in hypertension 127

Rest Exercise

Trimazosin Trimazosin & Propranolol

+i Mean

3 T SEM

Aesl Exzse FGt EL& Fig. 2. Effects of trimazosin and propranolol on cardiac output and pulmonary artery occluded pressure at rest and at the fourth minute of exercise in 10 patients with essential hypertension. Data presented are for each patient as well as the group mean f SEM. Significance levels are in Table II.

measures. In the latter analysis, the values at rest after the second exercise period were used as controls. Third, the incremental differences from control values, minute by minute during exercise, were analyzed by means of Dun- nett’s test.16 Differences were considered significant at the conventional level of confidence of 95%. Fourth, the variability of measurements in the control period was determined from the coefficient of variation and expressed as a percentage of the mean. For clarity of presentation measurements and derived data in the con- trol period were averaged. Hemodynamic measurements during the last minute of exercise are given in tabular form (Table II). Minute-by-minute variables are present- ed graphically.

M-mode echocardiography. Measurements were made with the patient in a standard 15-degree left lateral position and 15-degree cranial elevation, using an Ekoline 20A ultrasonoscope and Honeywell recorder. Traces were analyzed in a blinded fashion by an independent observer and dimensions measured according to leading-edge methodology. I7 The average (and range) of variability in

echocardiographic measurements were: left atria1 size 3.2% (1.2% to 6.6%), aortic root size 2.5% (0.8% to 5.9%), posterior LV wall thickness 5.4% (0.3% to 9.5% ), intraventricular septal thickness 7.0% (1.8% to 15.6%), LV internal systolic dimension 4.3 % (1.0% to 10.8% ), and LV internal diastolic dimension 2.8% (0.4% to 6.9%).

RESULTS

Clinical observations (Figs. 1 to 3; Table II). The studies were completed without untoward incident in any patient. No patient complained of symptoms of palpitation, headache, facial flushing, or postural hypotension after trimazosin. Four of the 10 patients complained of leg fatigue during exercise after propranolol.

Plasma concentrations of trimazosin and its metabo- Iite. The plasma trimazosin concentrations (mean f SEM) at the end of the rest periods and immediately before the second and third exercise tests (i.e., 30

120 Nelson et al. July, 1984

American Heart Journal

Table II. Hemodynamic effects of trimazosin and propranolol in essential hypertension.

Systemic arterial pressures Heart Cardiac (mm Hg) PAOP rate output

Systolic Diastolic Mean (mm HR) (bpm) (Llminlm2)

Control 163 + 7 98 k 3 121 zk 4 7+1 81 2 5 3.3 t 0.1

Trimazosin 147 f 6** 84 f 3** 104 + 3** 6-cl 84 f 5 3.4 k 0.2

Trimazosin and 136 k 6** 83 k 3** 102 f 4** 8+1 72 k 4** 2.7 + 0.1**

propranolol

2% I Control 225 f 7 109 + 5 149 + 6 12 k 2 138 f 8 8.1 + 0.4

.M ‘2 Trimazosin 216 -t 8* 98 t 4** 134 T!L 5** 12 i- 1 141 + 8 8.2 +- 0.4

izs Trimazosin and 170 t 7** 89 t 4** 120 -r- 5** 20 * 2** 108 +- 4** 6.6 Ifr 0.3** 3w propranolol

Results are presented as mean + SEM. Control values at rest represent the average of five measurements. Values during exercise are from the fourth minute. Significance levels relate to comparison with control values *p < 0.05; **p < 0.01. PAOP = pulmonary artery occluded pressure; trimazosin (2mg/kg); propranolol (0.2mg/kg).

and 45 minutes after injection) were 13.6 f 1.0 pg/ml (range 5.3 to 16.8) and 10.2 t- 1.0 pg/ml (range 3.2 to 14.0), respectively. The plasma concen- trations of the trimazosin metabolite CP 23445 at the same times were 5.2 + 0.3 Fg/ml (range 3.1 to 5.6) and 5.3 & 0.4 pug/ml (range 3.2 to 7.1), respec- tively.

Plasma concentrations of propranolol. The plasma propranolol concentration (average f SEM) at the time of the third exercise period was 87 f 7 pg/L (range 56 to 134).

Hemodynamic measurements in the control studies at rest. The variability of all hemodynamic measure- ments in the control rest period was small. The average coefficients of variation (range) for the 10 patients were: systolic blood pressure 1.8% (0.2 to 6.0), diastolic blood pressure 1.5% (0.3 to 3.8), heart rate 3.5% (0.6 to 4.8), cardiac output 5.2% (1.6 to ll.l), and PAOP 7.0% (1.1 to 16.6). There was no significant trend to change during the 20-minute control period.

Hemodynamic effects of trimarosin. At rest, the intravenous injection of trimazosin was followed by significant reductions in systolic (p < O.Ol), diastolic (p < O.Ol), and mean (p < 0.01) systemic arterial pressure and vascular resistance (p < 0.01). Pulse pressure was unchanged. The increases in heart rate and cardiac output were not statistically significant. Stroke volume, PAOP, and total body oxygen uptake were unchanged.

During upright bicycle exercise, the reduction in the absolute level of the systemic arterial pressure (p < 0.01) was maintained throughout the 4 minutes of exercise but the rest-to-exercise increment was unchanged. During the first 2 minutes of exercise the increases in cardiac output 0, < 0.05), stroke

volume (p < 0.05), and PAOP (p < 0.05) were signif- icantly less than those measured in the control exercise studies. However, during the final 2 minutes of exercise, these variables were not signifi- cantly different from those measured during the control exercise period. There was no significant differences in the rest-to-exercise changes in any variable with the exception of systemic vascular resistance. The absolute values of systemic vascular resistance during exercise before and after trimaxo- sin were not significantly different, but the rest- to-exercise decrement was significantly less (p < 0.05) after trimazosin than in the control study. The increment in diastolic arterial pressure (+12 mm Hg) in the control period, however, was unchanged after trimaxosin.

Hemodynamic effects of the addition of propranoloi.

At rest the addition of propranolol to trimazosin resulted in a significant reduction in systolic arterial pressure (p < 0.05), heart rate (p < O.Ol), and cardi- ac output 0, < 0.01). Systemic vascular resistance increased to pretreatment control values (p < 0.05) while there was no further reduction in the systemic arterial mean and diastolic pressures, PAOP, or the total body oxygen uptake.

In contrast, during exercise the effects of the added beta blockade were conspicuous. At the same upright bicycle workload and total body oxygen uptake, there were reductions in heart rate (p < 0.01) and cardiac output (p < 0.01) compared with the control and post-trimazosin values. There was a small increase in the systemic vascular resis- tance (p < 0.05), but this was insufficient to main- tain the systemic arterial pressure (p < 0.01). The addition of propranolol to trimaxosin was also accompanied by a substantial increase in the exer-

Volume 108

Number 1 Trimazosin plus propranolol in hypertension 129

Stroke Systemic vascular volume resistance

(mllmz) (dynes . set cm-*/m’)

Total body

oxygen consumption (ml 02/minlm2)

42 + 2 2950 k 235 189 k 9

41 * 3 2490 xk 195** 199 f 8

38 k 3 3025 k 185 188 f 4

60 k 3 1475 * 105 748 f 62

58 f 2 1320 k 90 782 + 8 61 k 2 1450 -t 115 695 f 68

cise PAOP, compared to both the control (p < 0.01) and post-trimazosin 0, < 0.01) studies. There were significant differences in the rest-to-exercise changes. The increments in systolic, diastolic, and mean systemic arterial pressure, together with those in the heart rate and cardiac output, were all significantly less after propranolol compared with those in both the control and post-trimazosin stud- ies. The increments in PAOP and stroke volume were significantly greater after propranolol.

Relationship between LV filling pressure and cardiac output at rest and during exercise. At rest, the rela- tionship between PAOP and cardiac output was unchanged after trimazosin but shifted downward and to the right after the addition of propranolol. Similar qualitative changes occurred during exer- cise, although the magnitude of the increase in PAOP after propranolol was significantly greater than that which occurred at rest.

DISCUSSION

Trimazosin plus propranolol. Our results confirm that the selective alpha-1-adrenoceptor-blocking drug, trimazosin, effectively lowers the resting blood pressure without altering the reflex circulatory response to dynamic exercise. In this regard trima- zosin is similar to prazosin7T 18* lg and distinctly differ- ent from the nonselective alpha-adrenoceptor antag- onist, phentolamine. s, 20, 21 The addition of proprano- 101 resulted in a further small lowering of the systolic arterial pressure at rest, but its effects were most marked during dynamic exercise. Propranolol signif- icantly reduced the increment in both systolic and diastolic arterial pressure during dynamic exertion. These results are similar to those described with the combination of prazosin and propranolol or tolamo- 101~9~~ but differ from those in which the alpha- adrenoceptor antagonist, phentolamine, was used.g In this latter instance, intravenous phentolamine

/* x

Trimazc ’ 1’ /’ ,’ Trimazosln & Propranolol

S.E.M. =T

Control - Trimazow -. -

Trimazosin 8 Propranolol e - - a

Fig. 3. Effects of trimazosin and propranolol on the relationship between PAOP and cardiac output at rest and during exercise in 10 patients with essential hyperten- sion.

was associated with substantial increases in heart rate and cardiac output, particularly at rest. Our results support the thesis that blockade of beta adrenoceptors enhances the blood pressure-lower- ing effects of blockade of the peripheral arteriolar alpha adrenoceptors.

LV hypertrophy. Before considering the possible mechanisms and clinical usefulness of this informa- tion, it is important to comment on the extent of the hypertensive heart disease present in our patients, as this may have modified their hemodynamic response to physical activity.23-25 This may be deduced from two separate aspects. Although only one patient had definite ECG evidence of LV hyper- trophy, the majority had clear-cut evidence of such by echocardiography. From the physiologic view- point, the major hemodynamic abnormality in our patients at rest was the increase in their systemic vascular resistance; LV filling pressure and output were normal.

Study design. The authors are aware of the many limitations in interpreting the findings of such short-term, single-dose studies. There is an obvious order effect in giving a drug after control observa- tions, but in view of the extended pharmacodynamic activity of trimazosin, this design was dictated by laboratory convenience. The reason for carrying out the control resting measurements after a period of dynamic exercise also requires explanation. Mea- surements made following a short period of nonfa- tiguing exercise are frequently more stable and nearer to what may be assumed basal levels than those measured immediately following cannula-

130 Nelson et al.

tion.26 In this regard, the hemodynamic stability in our patients sitting at rest was confirmed by the relatively small coefficient of variation in all hemo- dynamic measurements during the control period.

Synergistic effects of combined sympathetic block-

ade. A number of points deserve comment. There have been numerous reports of the hemodynamic effects of alpha- and beta-adrenoceptor-blocking drugs, alone and in combination, at rest and during exercise, in hypertensive patients.7-g*27+2g However, few studies have been carried out with these drugs in patients in the upright posture, which is essential for their full hemodynamic evaluation. In this regard, none of our patients developed symptomatic hypo- tension, either at rest or after exercise, following trimazosin, although such reactions have been described with both prazosin and trimazosin.10*30*31 Intravenous propranolol countered the fall in vascu- lar resistance at rest, which followed trimazosin, but the latter variable did not exceed control values. Accordingly, the immediate fall in cardiac output after beta blockade was followed by a further reduc- tion in systolic arterial pressure. Previous studies have failed to show any acute reduction in blood pressure after intravenous beta blockade with pro- prano10132s34 because of the compensatory increase in vascular resistance. The effects of simultaneous alpha- and beta-adrenoceptor blockade on the dia- stolic arterial pressure were intriguing. Increases in the latter variable during exercise confirmed previ- ous observations in similar hypertensive pa- tients.g*35*36 Neither selective alpha blockade (trima- zosin)lO nor beta blockade alone35s36 reduced the increment in diastolic pressure, whereas their com- bination in our patients was followed by a 50% reduction in the response. The explanation for this observation is purely speculative but may relate to the synergistic effects of combined sympathetic blockade on systolic arterial pressure and LV after- load.

Exercise evaluation. Few studies have been con- cerned with the effects of selective or combined blockade of the sympathetic pathways on the hemo- dynamic performance of the left ventricle during exercise. In this regard we were surprised that trimazosin did not prevent the profound reduction in LV pumping ability in terms of the relationship between LV filling pressure and cardiac output. In a previous report,37 selective postsynaptic alpha-l- adrenoceptor blockade (prazosin) also failed to mod- ify the depression of LV function induced by meto- pro101 in hypertensive patients observed during iso- metric handgrip. Although previous studies with alpha- and beta-blocking drugs have usually been

1.

6.

7

8.

9.

10.

11.

12.

13.

Constantine JW, Hess H-J: The cardiovascular effects of trimazosin. Eur J Pharmacol 74:227, 1981. Lochan R, Silke B, Taylor SH: Speed of onset of pharmaco- dynamic activity of propranolol, practolol, oxprenolol and metoprolol after intravenous injection in man. Br J Clin Pharmacol 12:721, 1981. Sharma B, Majid PA, Meeran MK, Whitaker W, Taylor SH: Clinical, electrocardiographic and haemodynamic effects of digitalis (ouabain) in angina pectoris. Br Heart J 34:631. 1972.

Taylor SH, Donald KW, Bishop JM: Circulatory studies in hypertensive patients at rest and during exercise, with a note on the Starling relationship in the left ventricle in essential hypertension. Clin Sci 16:351, 1957. Freis ED: Hemodynamics of hypertension. Physiol Rev 40~21, 1960. Lund-Johansen P: Hemodynamics in essential hypertension. Clin Sci 59(Suppl 6):343S, 1980. Korner P: Mechanisms of hypertension. The Sixth Volhard Lecture, Clin Sci 63(Suppl 8):269, 1982. Ibrahim MM, Tarazi RC, Dustan MP, Bravo EL: Cardioad- renergic factors in essential hypertension. AM HEART J 88:724, 1974. Tarazi RC, Ibrahim MM, Dustan HP, Ferrario CM: Cardiac factors in hypertension. Circ Res 34(Suppl 1):213, 1974. Lund-Johansen P: Hemodynamic changes in hypertension and their modification by beta-blockers and prazosin. J Cardiovasc Pharmacol 2:S339, 1980. Beilin LJ, Juel-Jensen BE: Alpha- and beta-adrenergic blockade in hypertension. Lancet 1:979, 1972. Majid PA, Meeran MK, Benaim ME, Sharma B, Taylor SH: Alpha- and beta-adrenergic receptor blockade in the treat- ment of hypertension. Br Heart J 36:588, 1974. Nelson GIC, Hussain M, Forsyth D, Wilson J, Silke B, Taylor SH: Haemodynamic effects of selective alpha-l blockade (trimazosin) in essential hypertension. J Cardiovasc Pharma- co1 6:176, 1984.

July, 1994

American Heart Journal

carried out in the supine posture, the single stud9 in which LV filling pressure was measured at rest and during exercise with phentolamine did not show similar depression in cardiac function after the combination with the beta-blocking drug, oxpreno- 101. This may have been due to the additional cardiac stimulation resulting from alpha-2-adreno- ceptor blockade as well as the possession of intrinsic sympathomimetic activity by oxprenolol. But what- ever the truth of these latter speculations, it would appear that selective alpha-l blockade does not entirely offset the depression in LV pumping activi- ty occasioned by nonselective beta blockade.

Long-term efficacy. It should be emphasized that these single-dose intravenous studies with these drugs in no way predict their antihypertensive effi- cacy during long-term oral treatment. However, they do give confidence that this combination of drugs is an effective antihypertensive prescription in the short term, but longer term studies are clearly essential to establish the clinical efficacy of such a regimen.

We thank the nursing staff of the Department of Medical Cardiology and Mr. S. Bird for his technical assistance with these

studies and Mrs. A. Richmond, B.Sc., for statistical advice.

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Volume 108 Number 1 Trimazosin plus propranolol in hypertension 131

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