Experimental and laboratory reports

Acute hemodynamic effects of an alpha- and beta-receptor blocking agent (AH 5158) on the systemic and pulmonary circulation at rest and during exercise in hypertensive patients

Gfinter Koch Karlskrona, Sweden, and Berlin, Germany

Adrenergic beta- receptor blocking agents have increasingly been used and proved effective in the t r e a t m e n t of hypertensive disease during the last yearsJ Thei r blood-pressure-lowering effect appears mainly, if not entirely, due to a decrease of cardiac output , while the systemic vascular resistance has been shown to increase or to be unchanged: -~

Constr ict ion of the peripheral resistance vessels is media ted by adrenergic alpha receptors; thus a lpha-receptor blocking agents should lower systemic blood pressure, and have been shown to do so, ~ by decreasing peripheral vascular resis- tance, as do other peripheral vasodilators, i.e., hydralazine2 The pressure decrease induced by peripheral vasodilation, however, activates the baroreceptors ' homeosta t ic mechanisms, thus causing an unwanted increase in hear t ra te and cardiac output .

Studies in both the exper imental animal 5 and man 3 ~ - have shown that the homeosta t ic reflex mechanism elicited by peripheral vasodilation can be efficiently counterac ted by the simulta- neous adminis t ra t ion of a beta-receptor blocking agent. An agent combining the properties of efficiently blocking both the beta-1 receptors in the hear t and the alpha-receptors of the resis- tance vessels can be ant icipated ~o lower blood pressure by decreasing not only cardiac ou tpu t bu t even the peripheral vascular resistance and would thus represent a par t icular ly a t t rac t ive

From the Department of Clinical Physiology, Central Hospital, Karls- krona, Sweden. and Department of Physiology, Free University, Berlin, Germany (GFR~

Received for publication Nov. 19. 1975.

Reprint requests: Prof G. Koch. Department of Physiology, Free University, Arnimallee 22. D-1 Berlin 33 (West-Berlink Germany.

ant ihyper tensive agent from the hemodynamic point of view. Using the combinat ion of the beta- receptor antagonist oxprenolol and the alpha- receptor antagonis t phentolamine, Majid and associates ~ not only demons t ra ted this pa t t e rn of hemodynamic adapta t ion actual ly "to occur, at least in the acute experiment, bu t they also showed t h a t the combinat ion had a more potent ant ihyper tensive effect t han each drug alone.

The recent ly developed agent AH 5158 (Allen & Hanburys Research. Ltd., England) has been shown to be a competi t ive adrenergic blocking agent at both beta and alpha sites in bo th the exper imental animal s and in man. 9-~ In the exper- imental animal it is 5 to 18 times less po ten t than propranolol in blocking beta receptors and 2 to 7 times less potent than phentolamine in blocking alpha receptors2 In man the relative potencies of the alpha- and beta-receptor blocking properties are approximate ly 1:32~ hence the compound has relatively less alpha- than beta-receptor blocking effects. Like propranolol it is unselective with respect to beta receptors and lacks intrinsic sympathomimet ic properties.

The present s tudy reports the acute hemody- namic effects of in t ravenously administered AH 5158 on the systemic and the pu lmonary circula- tion during rest in bo th supine and upright posi- tions and during exercise in pat ients with essen- tial hypertension.

Patients

Thi r teen hypertensive patients, 12 men and one woman, mean age 52.0 < 6.3, range 37.0 to 57.2 years, who were referred to the depar tmen t for investigation, gave their informed consent to par t ic ipate in this study. In five, hypertension

May, 1977, Vol. 93, No. 5, pp. 585-591 American Heart Journal 585

K o c h

Table I . Patient da ta t

Range

Age (yr.) 13 52.0 6.3 37.0-57.2 Length (cm.) 13 173 l0 153-185 Weight (Kg.) 13 82.2 1 2 . 6 58-107 Blood vol. (L.) 13 6.18 1.31 3.74-8.59 THb (Gin.) 13 807 226 429-1,044 Heart vol. (ml.) 13 1,027 280 670-1,480 HV/THb 13 1.30 0.25 0.99-1.73 Total work 10 10,230 2 . 9 6 5 6.300-15.600

(k.p.m./min.) Renin activity 12 2.95 2.48 1.14-8.46

~ng./ml.)

tTHb, Total amount of hemoglobin: HV, heart volume: total work as determined during ergometer exercise test prior to the hemodynamic examination.

had been recently discovered and antihyperten- sive treatment had been initiated in one of these. Eight patients had suffered from hypertension for between 1 and 14 years and all but one had been receiving antihypertensive treatment. In all patients, however, all antihypertensive therapy had been discontinued at least 6 weeks prior to the hemodynamic examination. Blood pressures when measured by the Riva-Rocci cuff method ranged between 155/115 and 240/140 ram. Hg at rest and 220/120 and 290/150 mm. Hg during exercise.

The clinical evaluation indicated that all had essential hypertension; blood counts, serum elec- trolytes, serum creatinine, liver and renal func- tion tests were normal. Fundoscopic examination revealed no abnormaility in one subject; 11 had non-exudative Grade 1 to 2 hypertensive changes, one had Grade 3 exudative changes. None had evidence of ischemic heart disease as evaluated by exercise electrocardiogram (ECG) (maximal work load between 600 and 1,200 kpm per minute} dr of significant cardiac enlargement (relative heart volume 521 __+ 117, range 350 to 700 ml. per square meter of body surface area). Chest radiographs and spirometry gave no indication of lung disease. Some relevant patient data including blood volume, heart volume, total amount O f hemoglo- bin, and renin activity (in blood sampled immedi- ately after exercise) are given in Table I.

Methods

Prior to the hemodynamic study all the patients underwent a clinical examination includ- ing blood and urine analysis, an isotope renogram, determination of blood volume by means of

radioiodinated (1~'~I) human serum albumin (RIHSA) and of heart volume 12 and a number of cardiopulmonary function tests: ECG and blood pressure recording at rest in the supine and upright position, an exercise test with simulta- neous ECG and blood pressure recording, and spirometric determination of lung volumes, venti- lation capacity, and gas distribution. Hemodynamic investigation. Hemodynamics were studied at rest in both the supine and the upright positions, and during steady-state exer- cise at two different work loads in the sitting position on an electrically braked bicycle ergom- eter as previously described. 13 Both the ortho- static test and exercise on each work load lasted for 6 minutes. Work loads were 358 _+ 81 (Wl) and 723 _+ 159 k.p.m, per minute (W2), W~ corre- sponding to about 70 to 80 per cent of the patient's maximal O5 uptake.

Having fasted overnight, the patients came to the laboratory at about 8 A.M. Polyvinyl cathe- ters were inserted percutaneously TM in a brachial artery and in an antecubital vein; the tip of the vein catheter was then placed into the main pulmonary artery with the use of a spiral guide wire and fluoroscopy. Twenty minutes were allowed to elapse before the first (predrug) series of measurements wasstarted.

On completion of the predrug study and after 15 minutes' rest 5 ml. (50 mg.) of AH 5158 were administered intravenously over 5 minutes. Arterial blood pressure was Continuously re- corded from the beginning of injection until 30 minutes after the end of injection at which time the second (postdrug) series of measurements was taken under exactly identical conditions as during the predrug series.

Blood pressures were recorded by means of an Elema 82 multichannel direct recorder using the Elema strain gauge transducers, together with the ECG. In the supine position the midaxillary line, in the erect and sitting position the sternal angle was taken as zero pressure levels. Pressure recordings were made after 4 minutes' standing and exercise, respectively.

Cardiac output was determined accOrding to the direct Fick principle. Oxygen uptake was measured with the Douglas bag technique. Expired air was collected during 5 minutes at rest in the supine and during 3 minutes at rest in the erect posture and during exercise, starting 3 minutes after the onset of standing and exercise,

586 May, 1977, Vol. 93, No. 5

Table II. Means, standard deviations (S.D.) and ranges of blood pressures and vascular resistances before and their mean (D) and percentage (D %) changes after intravenous administration of 50 mg. of AH 5158, at rest in the supine (R) and the upright (O) position and during exercise at two different work loads (W~ and Wz)

Brachial artery: Systolic pressure R 174 32 0 179 35 Wl 202 34 W: 241 34 Diastolic pressure R 97 15 O 108 19 Wl 101 16 W~ 113 24 Mean pressure R 126 18 O 136 23 W1 143 20 Wz 163 28

Pulmonary artery(n= 12): Systolic pressure R 23 7 0 19 6 Wa 31 7 W~ 39 10 Diastolic pressure R 4.3 0 2.8 W, 7.9 W,, 13.3 Mean pressure R 12.3 O 8.7 Wl 16.8 W2 23.9

SVR I: R 48.2 O 58.9 W~ 25.3

PVR I: R 3.0 O 2.6 W2 1.6

Range 1) %

144-247 -33*** -19.0"** 148-247 -60*** -33.5*** 157-261 --61"** --30.2*** 177-294 --85*** --35.3***

87-115 --14"** -14.4"** 88-123 -35*** -32.4*** 87-126 -24*** -23.8*** 85-144 -36*** -31.9 '**

112-144 -22*** --17.5"** 116-162 -42*** --30.9*** 106-165 --40*** --28.0*** 131-209 -52*** -31 .9"**

9-36 -4** -17.4"* 13-31 --4** -21 .1 '* 21-42 -3* --9.7* 19-58 1 2.6

3.6 1-9 --1.4 --32.6 2.8 --3-6 --0.8 --28.4 3.3 3-14 0.7 8.9 6.5 3-27 2.1 15.8

4.4 6-20 --2.3** --18.7"* 4.1 0-14 --1.5"* --17.2"* 5.9 10-25 0.7 4.2 8.5 11-38 2.2 9.2

12.1 25.6-65.5 --5.2 --10.8 15.4 40.7-82.0 --10.3" --17.5" 6.3 14.9-38.6 --5.1"* --20.2**

1.2 1.1-4.5 --0.4 --13.3 1.3 1.1-5.1 0.2 7.7 0.7 0.8-2.6 0.3* 18.8"

*p < 0.05; **p < 0.01; ***p < 0.001.

respectively. Arterial and mixed venous blood samples were taken simultaneously during the collection of expired air. Because of the occurrence of marked postural hypotension the orthostatic test had to be shortened in two instances; two patients had to be examined in the sitting rather than in the standing position.

H e m o d y n a m i c effects of blocking agent

Table I I I . Means, standard deviations (S.D.) and ranges o f some hemodynamic variables before and their mean (D) and percentage (D %) changes after intravenous administration of 50 mg. of AH 5158 at rest in the supine (R) and upright (O) position and during exercise at work load W2 (723 _+ 159 k . p � 9

Mean S.D. Range 1) D %

Heart rate: R 73 8 60-84 - 3 -4.1 O 87 15 60-104 -14"* -16.1"*

�9 W2 146 23 90-174 -37*** -25.3*** V o 2 (ml./min.):

R 269 48 219-375 - 6 -2.2 O 351 79 233-513 - 2 8 -8.0 W~ 1,776 290 1,006-2,117 - 1 1 8 ' -6.6*

A Vo2, diff. (ml./L.): R 51 12 30-68 2 3.9 O 75 10 54-90 8** 10.7"* W~ 138 13 113-162 17"** 12.3"**

C.O. (L./min.): R 5.49 1.45 3.86-8.87 -0.50 -9.1 O . 4.77 1.34 3.38-7.16 -0.87* -18.2" W2 12.94 2,12 8.89-15.45 -2.11"** -16.4"**

C.I.(L./min./M.2): R 2.86 0.98 1.76-4.85 -0.29 -10.1 O 2.46 0.66 1.67-3.27 -0.46* -18.7" W2 6.70 1.30 4.56-9.47 -1.11"** -16.6"**

SV (ml.): R 75 19 52-106 0 0 O 58 23 32-102 - 2 -3 .5 W2 95 26 57-109 11' 11.6"

*p < 0.05; **p < 0.01; ***p < 0.001.

Calculations�9 T h e s y s t e m i c ( p e r i p h e r a l ) v a s c u -

l a r r e s i s t a n c e i n d e x ( S V R I ) a n d t h e p u l m o n a r y

v a s c u l a r r e s i s t a n c e i n d e x ( P V R I ) w e r e c a l c u l a t e d

a c c o r d i n g t o t h e e q u a t i o n s

PBA - - PRa S V R I =

C I

and PVRI = PPA -- P~iast. PA CI

where PBA, P~A, and PpA are the mean pressures in the brachial artery, right atrium (resting value), and pulmonary artery, respectively, Pdla~t. PA the diastolic pressure in the pulmonary artery, and ' CI the cardiac index. It is well established 1~ that in the absence of significant pulmonary hyperten- sion the pulmonary artery diastolic pressure reflects the pulmonary wedge pressure.

Dead space was calculated from Bohr's equa- tion and the alveolar O2 tensions from the

Amer i can Hear t Jou r n a l 5 8 7

Koch

alveolar gas equation, assuming arterial Pco2 to equal mean alveolar Pco2.1~ This assumption appears justified in view of the very low anatomic right to left shunts present in these patients.

Blood and gas analyses. The volume of expired air was measured in a gasometer, O2 and CO~ were determined according to Scholander, 17 the O2 saturation and the hemoglobin concentration with a spectrophotometric method 18 using a Beckman B photometer; pH, Po2 and Pco2 were measured with microelectrodes using Radiome- ter's PMH 72, lactic acid was determined enzy- matically. 19 Blood gas analyses were performed within 30 minutes after sampling. Methodological details, including the analytical accuracy, are given elsewhere. 2~

S t a t i s t i c a l methods. Current statistical meth- ods were used for calculation of standard devia- tions (S.D.), mean differences (D) and t analysis. ~1 Comparison of data obtained before and after the administration of AH 5158 was always based on paired samples.

Results

Mean values and standard deviations of some relevant hemodynamic parameters as measured prior to, as well as the changes observed after the administration of AH 5158, are given in Tables II and III.

The pre-treatment average systemic blood pressure was 174/97 (mean 125) mm. Hg at rest in the supine and 179/108 (mean 136) mm. Hg in the upright position. It increased to 241/113 (mean 163) mm. Hg during exercise (W~). The adminis- tration of AH 5158 resulted in a marked (by 14 to 35 per cent) and statistically significant (p < 0.001) reduction of blood pressures under all conditions, the effect being most pronounced in the upright position and during exercise. Systolic, mean, and diastolic pressures were similarily affected.

Blood pressures in the pulmonary circulation were within normal limits both before and after the administration of AH 5158. At rest in the supine and the upright position AH 5158 resulted in a statistically significant decrease (between 17 and 21 per cent) of the systolic and mean pres- sure. During exercise pressures were not signifi- cantly affected.

The heart rate was significantly reduced at rest in the upright position (by 16 per cent, p < 0.01) and particularly during exercise (by 25 per cent,

p < 0.001) but not at rest in the supine posi- tion.

Oxygen uptake (~'o~) was slightly decreased (p < 0,05) during exercise, ventilation (~'E) was not affected.

Mean cardiac output was 9 per cent lower at rest in the supine position, but this change was not statistically significant. It was significantly lower in the erect posture (18 per cent, p < 0.05) and during exercise (16 per cent, p < 0.001). This decrease was entirely due to a decrease in heart rate, since stroke volume was not affected at rest, and during exercise increased by 12 per cent (p < 0.05). The arterial-mixed venous oxygen difference was increased in the erect posture and during exercise.

The mean systemic vascular resistance index was 11 per cent lower at rest in the supine position, but this change was not statistically significant. I t was significantly lower in the erect posture (17 per cent, p < 0.05) and during exer- cise (20 per cent, p < 0.01). The mean pulmonary vascular resistance index was unchanged at rest but slightly higher (p < 0.05) during exercise.

Table IV summarizes the most relevant data concerning pulmonary ventilation, gas exchange, and acid base balance. Only minimal changes occurred after AH 5158: at rest in the supine position tidal volume (VT) and alveolar ventila- tion (~'A) were slightly increased and the respira- tory exchange ratio (R) slightly decreased. No changes occurred during rest in the erect posture. During exercise (W~) tidal volume (VT) and oxygen uptake (Vow) were slightly lower, while the respiratory rate and the alveolar ventilation in relation to cardiac output (~rA/Q) were slightly higher. Not any significant change was observed concerning the alveolar-arterial oxygen tension difference, arterial blood gases, acid-base balance, or arterial lactate concentrations.

Discussion

AH 5158 administered intravenously in a dose of 50 mg. had a marked antihypertensive effect, inducing a fall in systemic systolic, diastolic, and mean pressures by between 14 per cent (diastolic pressure at rest in the supine position) and 35 per cent (systolic pressure during exercise) at rest both in the supine and upright position and during exercise. The main pressure fall occurred within the first 10 minutes following the onset of injection.

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Table IV. Means and standard deviations (S.D.) of some variables concerning pulmonary ventilation, gas exchange, and acid base balance, before, and their mean changes (D) after intravenous administration of 50 mg. of AH 5158, at rest in the supine and upright position and during exercise at work load W2 (723 _+ 159 k.p.m./min.)

Rest supine

L Rest upright

Exercise W2 (723 +_ 159 k.p.m./min.)

I Mean S.D. Mean S.D. D Mean S.D. I D

B

Resp. ra te (br . /min. ) 14:8 2.4 1.0 17.5 3.9 1.4 23.0 4.9 3.5* VT, 1 B T P S 0.78 0.31 0.10"* 0.91 0.36 0 2.42 0.61 -0 .3* VE, 1 B T P S 11.01 4.15 -0 .64 15.31 5.00 0.14 54.67 13:95 0.21 Vo._,, 1 S T P D 0.27 0.05 -0 .01 0.35 0.79 -0 .03 1.78 0.29 -0 .12" R 0.85 0.15 -0 .06** 0.81 0.13 0.04 0.93 0.09 0.04 yE/Vo~ 41.4 14.5 --2.3 43.4 10.5 4.6 30.6 5.4 3.2 VA, .1 B T P S 6.19 2.82 -0 .45* 8.86 3.99 0.01 43.58 10.58 0.68 VA/Vo~ 21.5 9.0 --1.4 23.3 7.8 2.2 25.6 6.2 2.6 VD/VT 38.7 7.2 0.2 38.6 9.4 --0.1 17.8 8.1 0.2 PAO -Pao2 (ram. Hg) 23.0 5.9 2.3 19.1 4.6 -0 .1 24.5 8.1 -1 .2 Pao~ (mm. Hg) 87.0 10.6 -4 .1 94.2 12.1 1.7 90.7 9.7 2.7 PacQ ~ (mm. Hg) 34.5 4.4 -0 .3 30.4 4.3 0.3 34.1 3.5 -2 .3 VA/Q 1.20 0.67 --0.06 1.88 0.76 0.37 3.35 0.54 0.9* pHa 7.45 0.06 -0 .01 7.46 0.05 -0 .01 7.37 0.03 -0 .01 S tand . bic. (mMol . /L . ) 24.0 2.3 - 0 .5 23.1 1.1 -0 .6 2i.4 4.4 -2 .2 Lac ta t e (mMol . /L . ) 1.08 0.43 0.42 1.27 0.62 0.24 3.75 1.49 0.39 L a c t a t e t (mMol . /L . ) 4.07 1.22 0.59

tValues 4 min. a.w. *P < 0.05; **p < 0.01.

The mode of antihypertensive action was similar at rest and during exercise: blood pressure was lowered by a reduction of both cardiac output and the systemic vascular resistance. These effects were particularly evident in the upright position and during exercise. During exer- cise the relative decrease of the vascular resist- ance was more important than that of cardiac output. The reduction of cardiac output was entirely due to a decrease of heart rate and not of stroke volume; during exercise stroke volume even increased by 12 per cent after AH 5158 (p < 0.05). These changes toward a slightly more hypokinetic circulation in the upright position and during exercise were accompanied by an increase of the arterial-mixed venous oxygen difference by 11 and 12 per cent during standing in the upright position (p < 0.01) and during exercise (p < 0.001), respectively.

There are slight differences in the hemody- namic effects between different beta blockers due to the presence or lack of intrinsic sympathomi- metic activity ~. 53; moreover, the hemodynamic effect is somewhat dependent on the degree and the stage of the hypertensive disease. 24 Regardless of these minor differences the acute hemody-

namic effect of parenteral administration of a beta-adrenergic blocking agent consists princi- pally in a reduction of cardiac output and an increase of systemic vascular resistance. Cardiac output is reduced by a decrease of heart rate, but also by a reduction of stroke volume. The net result of this adaptation is a virtually unchanged or only slightly decreased arterial blood pres- sure. 22-24 The oxygen-carrying capacity of the decreased circulating blood volume is maintained by a substantial increase of the arterial-mixed venous oxygen difference, total oxygen uptake being unchanged.

Due to the additional alpha-receptor blocking properties the acute hemodynamic effect of AH 5158 is, as could be anticipated, s ignif icantly different from that of an agent which exclusively blocks the adrenergic beta receptors. By blocking the (dilator) beta-2 receptors in the resistance vessels the beta-receptor blockers increase the relative effect of the (constrictor) alpha-receptors thus inducing an increase in systemic vascular resistance which inhibits the antihypertensive effect anticipated from the decrease of cardiac output. The additonal alpha-recepto r blocking effect of AH 5158 inversely induces a decrease of

American Heart Journal 589

K o c h

the systemic vascular resistance and probably even attenuates the cardiac-output-lowering effect of the beta-blocking component. The alpha-receptor blocking component, however, also increases the probability of postural hypo- tension to occur. Four of the patients in this group actually experienced marked postural hypotension necessitating a minor modification or shortening of the investigation procedure in the erect posture.

A similar effect on blood pressure and on systemic vascular resistance has been shown to occur after the acute administration of a periph- eral vasodilator such as hydralazine ~ or phento- lamine ~ when supplemented by a beta blocker. On the other hand, clonidine, an antihypertensive agent which mainly inhibits the sympathetic vasomotor center, has been shown to have hemo- dynamic effects at rest and during exercise more similar to those of beta-receptor blockers, with- out, however, increasing the systemic vascular resistance. '-'~

The effect of AH 5158 on the pulmonary circu- lation is especially noteworthy: at rest, both in the supine and in the upright positions, there was a reduction (p < 0.01) of systolic and mean pres- sures while the changes of diastolic pressures under all conditions and of systolic and mean pressures during exercise were inconsistent. De- spite these hemodynamic effects on the pulmo- nary circulation, pulmonary ventilation was only minimally affected and intrapulmonary gas exchange and acid base balance were not at all affected.

The pulmonary artery diastolic pressure has been shown (see Forsberg ~ and Koch, unpub- lished data) to reflect pulmonary wedge and thus left ventricular filling pressure in the absence of significant increase of pulmonary vascular resis- tance. The absence of any rise of the diastolic pressure at rest and during exercise clearly demonstrates that AH 5158, at least in the acute experiment and with the dose used, lacks signifi- cant negative inotropic effects on the left heart, which is further suggested by the absence of any reduction in stroke volume; on the contrary, stroke volume increased by 12 per cent during exercise. A similar reduction of pulmonary artery pressures has been shown to occur after cloni- dine ~ whereas a rise has been reported for beta- receptor blockers, especially propranolol. ~

Due to its particular hemodynamic effects,

comprising both a reduction of cardiac output and especially of systemic vascular resistance without indication of significant negative inotrop- ic cardiac action, At-t 5158 appears to be a partic- ularly attractive antihypertensive drug, at least in the management of acute hypertensive crisis. It has already been shown that the antihypertensive effect persists during long-term oral treatment (see Prichard and associates 11 and Koch, unpub- lished data); there are, however, still no data available indicating tha t the favorable hemody- namic pattern of adaptation induced by the intravenous administration of the drug does persist during long-term oral treatment. For the combination of oxprenolol plus hydralazine given orally for several months it has recently been shown 7 tha t the vasodilator effect of hydralazine is largely overshadowed by the hemodynamic effects of the beta-receptor antagonist. It will thus be of considerable interest to determine the hemodynamic effects of AH 5158 after long-term oral treatment.

Summary The acute hemodynamic effects of 50 mg. of the

alpha- and beta-receptor blocking agent AH 5158, administered intravenously, on the systemic and pulmonary circulation were studied in 13 hypertensive patients at rest in the supine and erect positions, and during exercise, with right heart and brachial artery catheterization.

AH 5158 induced a signficant fall of systemic blood pressures under all conditions, whereas the pulmonary systolic and mean pressures were lower at rest and unaltered during exercise. The left ventricular filling pressure largely remained unchanged.

Blood pressure was lowered predominantly by a reduction in systemic vascular resistance to- gether with a reduction in cardiac output. These effects were particularly pronounced in the erect position and during exercise. Cardiac output was lowered solely by the reduction of heart rate; stroke volume was unchanged or even increased. The arterial-mixed venous oxygen difference increased in the erect position and during exer- cise.

The pattern of AH 5158-induced hemodynamic adaptation comprising a reduction of both vascular resistance and cardiac output, without evidence of significant negative inotropic action, offers a novel basis for treating hypertension with

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Hemodynamic effects of blocking agent

a s i n g l e d r u g . I t s p h a r m a c o l o g i c a l a n d h e m o d y -

n a m i c p r o f i l e s u g g e s t s c o n s i d e r a b l e p o t e n t i a l i n

t h e t r e a t m e n t o f h y p e r t e n s i v e p a t i e n t s .

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