Actu pharmacol. et toxicol. 1975, 36, suppl. V, 85-95.

From the Department of Pharmacology and Medicine, AB Hassle, Fack, S-431 20 Molndal, Sweden

Effects of metoprolol and propranolol on some metabolic responses to catecholamines in the anaesthetized dog by Bengt Ablad, Inger Borjesson, Enar Carlsson and Gillis Johnsson

Abstract: The effects of metoprolol (0.5 mg/kg i.v.) and propranolol (0.2 mg/ kg i.v.) on the plasma FFA response to i.v. infused adrenaline and noradrenaline and on the blood glucose and lactate responses to adrenaline were studied in anaesthetized dogs. Both !-blockers markedly reduced the plasma FFA response to noradrenaline. Metoprolol differed from propranolol by inhibiting the plasma FFA response to adrenaline significantly less than that to noradrenaline. The lactacidemic effect of adrenaline was somewhat reduced by metoprolol and abolished by propranolol. The slight increase of blood glucose concentration produced by adrenaline was not significantly affected by either blocker. Adrenaline elicited a marked increase of the arterial blood pressure after propranolol treatment, whereas a slight hypotensive effect was observed after administration of metoprulol or in control experiments. It is suggested that the effects of metoprolol could be ascribed to inhibition of adrenergic Pi-receptor mediated actions, while those of propranolol were due to combined and P2-receptor blockade.

Key-words: !-blockade - metoprolol bolic effects.

- propranolol - catecholamines - meta-

Adrenergic lJ-receptor blockers have been shown to influence many of the metabolic effects of adrenaline and noradrenaline (review by Himms-Hagen 1967). In vitro experiments with adrenergic agonists and antagonists have given results indicating that 8-adrenergic receptors are involved in the mediation of e.g. adrenergically induced lipolysis in adipose tissue (review by Fain 1973), glycogenolysis in skeletal muscle (review by Lundholm et al. 1968) and insulin release from pancreatic beta cells (review by Porte & Robertson

1973).

B. ABLAD et al.

It is at present less clear whether and how 8-receptor mediated metabolic effects will fit into the /31-/12 subclassification suggested by Lands et al. (1967) (cf. e.g. Lands et al. 1967 and Harms et al. 1974), or into the modification of the concept of Lands et al. suggested by Carlsson et .al. (1972). In view of this we found it of interest to make an exploratory comparison of how the two adrenergic J?-receptor blockers metoprolol" and propranolol influenced the effects of adrenaline or noradrenaline on the plasma concentration of free fatty acids and the effects of adrenaline on the blood levels of glucose and lactate in the anaesthetized dog. Metoprolol differs from propranolol in producing more marked inhibition of the cardiac stimulant than of the bronchial and vascular smooth muscle relaxant responses to isoprenaline (Ablad et al. 1973). Metoprolol may therefore be classified as a selective !-receptor antagonist according to the concept of Lands et al. (1967).

Methods The experiments were carried out on dogs of mixed breed, weighing 9-16 kg. After 12 hours fasting the dogs were anaesthetized with sodium pentobarbital (30 mg/kg i.v.) . Catheters were placed in a femoral artery and a femoral vein. They were kept open by frequent flushes with 0.9 % ealine. The arterial catheter was connected to a Stabham pressure transducer, and the arterial blood pressure was recorded on a Beckman Dynograph. The heart rate was registered with a Beckman cardiotachometer triggered by the ECG. Two series oi experiments were carried out. I n the fimt series the interaction of metoprolol or propranolol and adrenaline was studied. I n each experiment two intravenous infusions of adrenaline were given a t a n interval of 110 minutes. Each infusion was given by a constant infusion pump for 20 minutes and the dose was 0.2 pg lev0 adrenaline tartrate per kg body weight and minute. Twenty minutes before the second infusion of adrenaline, metoprolol (as the tartrate salt) or propranolol (as the chloride salt) was injected intravenously over 2 minutes in a dose of 0.5 mg/kg or 0.2 mg/kg respectively. In addition, control experiments were performed, i n which physiological saline was administered instead of a &blocker. Arterial blood samples were taken in pre-chilled heparinized tubes for analyses of plasma FFA (Friedberg et al. 1963), blood glucose (Levin & Linde 1962) and blood lactate (Hohorst et al. 1959). Blood samples were taken at times indicated in figures 1 and 2. I n the second series of experiments h e interaction of the two &blockers and noradrenaline was studied. The time schedule of bhese experiments was the same as in the first series. A dose of 0.2 pg levo noradrenaline tartrate per kg body weight and minute was given. The &blockers were given in the same doses as in the first series and the corresponding control experiments were carried out. In the second series only plasma FFA concentrations were analyzed. The statistical evaluation of the results was made using Student's t-test.

*

(

* ) -1- (isopropylamino) -3- [p- (2-methoxyethyl) phenoxy] -2-propanol

METABOLIC EFFECTS OF METOPROLOL

a7

Results Free fatty acids Interaction with adrenaline. The effects obtained are shown in figure 1 and table 1. Administration of adrenaline caused a significant increase of the plasma FFA concentration as measured at the end of the 20 minutes infusion. The level of plasma FFA had declined markedly 10 minutes later and returned to near basal values after an additional 75 minutes. In the control experiments the second adrenaline infusion elicited an increase of the plasma FFA concentration of about the same magnitude as that produced by the first infusion. After administration of the &blockers, the basal plasma FFA levels were not significantly affected but the response to adrenaline was reduced compared to the initial response. After metoprolol (0.5 mg/kg) the response, measured at the end of the adrenaline infusion, was blocked by 4% 14.4 % (pO.O5).

+

FFA

&/I

-1 1500-

W-

500-

0-

Time min

Fig. 1. Effects of adrenaline (0.2 pg/kg/rnin i.v.) on plasma FFA concentration before and after treatment with metoprolol (0.5 mg/kg i.v.), propranolol (0.2 mgfkg i.v.) or in saline control experiments. Mean values from 6 experiments with metoprolol and 4 experiments with propranolol and saline control respectively.

Blood lactate mg/100ml Mean arte. rialblood pressure mm H g Heart rate beats/min

M P C M P C

C

P

C M

P

M

P C

131f12.8 138k19.6 1212 5.9 102f 5.2 1042 3.8 113*11.8

123* 9.6 160224.4 1 1 5 e 5.9 1182 5.2 8 7 k 8.5 175k10.0

*

-6*5.6 623.2 -9k2.1 58 6.3 66k8.5 63k5.1

-823.4 +22+6.8 -6k1.5 16k3.0 -1725.3 62 f6.0

2 f5.6 -2829.2 -3 f2.2 42f 5.5 83 2 16.5 l f 3.5

126f10.4 129k15.8 1192 6.9 165* 8.3 1572 7.4 172k12.4

132k12.4 135218.6 1282 6.5 107* 6.2 9 1 k 3.4 109k13.3

133*12.9 141219.7 121k 5.5 1122 9.5 109k 3.3 114k12.0

6.0k0.57 7.1k0.60 7.2k1.41

14.2k2.89 19.3a0.90 18.320.30

10.0+1.59 6.6k0.55 17.1k2.52

2.821.1 10.3k0.25 -0.3*0.09

5.0k1.43 O.lkO.70 9.42 1.31

5.0k0.20 6.520.15 7.7k1.67

535k162.3 11072138.8 1342 78.8 3 -+ 3.2 023.7 O k 1.4

548f144.8 1602 91.0 13222 98.5 11 k2.9 720.6 10'2.1 1083k64.9 1267k84.3 1456k81.1 1424.3 7 -C 2.3 1023.5 7.8k2.39 10.420.45 9.1 k 1.22

7502142.7 588+ 66.8 16912164.6 76 f 6.4 7322.9 77k4.3

202k27.9 428250.0 369269.7 651* 2.9 6622.3 67 f4.2

242254.9 421k54.9 410f51.1 62 2 2.5 65k1.5 67k4.1

1228k 72.0 1471k106.0 1804k141.4 78k8.6 68* 1.3 74 -c 3.9

145228.3 204k45.3 348k62.8 6424.6 61k2.9 64k3.5 6.420.88 8.9k0.45 9.220.97

M

Plasma FFA PEI~ Blood glucose mg/100ml

Adr. at end of infusion

Second infusion

Basal

j?blocker

Parameter

First infusion

Difference between responses to 1st and 2nd adr. infusion

Adr. at end of infusion

Effect of adrenaline

Basal 15 min after &blockade

After @-blocker Basal 85 min after adr. infusion

Before &blocker

Table 1. Effects of intravenously infused adrenaline (0.2 Fg/kg/min) on plasma FFA, glucose and lactate and on mean arterial blood pressure and heart rate before and after administration of metoprolol (0.5 mg/kg i.v.) or propranolol (0.2 mg/kg i.v.). Mean values k SEM from 6 experiments with metoprolol ( M ) and 4 experiments with propranolol ( P ) and saline control (C) respectively.

p

2

1 ?j

89

METABOLIC EFFECTS OF METOPROLOL

I n the dogs given propranolol, the plasma levels of FFA showed an increase instead of the expected decline during the 10 minutes after the end of the adrenaline infusion. The increase was small but statistically significant ( 134 50.4 pE/1, p