Cardiac electrical responses to catecholamines are differentially mediated by β2-adrenoceptors in anesthetized dogs

European Journal ol'Pharmacoh)gy, 219 (19921 15 21 ~;~ 1992 Elsevier Science Publishers B.V. All rights reserved /){114-2999/92/$05.0(/

15

EJP 52566

Cardiac electrical responses to catecholamines are differentially mediated by/32-adrenoceptors in anesthetized dogs M a n a b u T a k c i , Y a s u y u k i F u r u k a w a , M a s a h i r o Narita, L e i - M i n g R e n and Shigetoshi Chiba D~7~artment ol" Pharmacology, Shinshu Unil,elwiO'School of Medicine, ~[atA'llllloto390, ,lapan Received 21 April 1992, accepted 12 May 1992

We investigated the /32-adrenoceptor-mcdiated effects of atrial and vcntricular effective rcfractory period (ERP), SA node paccmaker activity, and AV conductivity induccd by sympathetic nerve stimulation or epinephrine infusion in anesthetized dogs. A /3:-adrenoceptor antagonist, ICI 118,551 up to 100 ~tg/kg, i.v,, inhibited the positive chronotropic and dromotropic responses to sympathetic stimulation but did not shorten the atrial or ventricular ERP. ICI 118,551 also attenuated the positive chronotropic and dromotropic responses and the shortcning of atrial E R P in response to epinephrine but not the shortening of ventricular E R P . A selective ,~l-adrenoceptor antagonist, atenolol, inhibited each electrical cardiac response to sympathetic stimulation and epinephrine infusion in a similar manner. These results suggest that/3e-adrenoceptor-mediated electrical cardiac responses to endogenous catecholamines also exist in addition to the predominant /31-adrenoccptor-mediated responses, and that the order of the proportion o f / 3 : - a d r e n o c e p t o r - m c d i a t e d cardiac effects was SA node pacemaker activity >> AV conductivity = atrial E R P >> vcntricular E R P in the dog hear!.

Atrial effective refractory period; Atrioventricular conduction time; /3-Adrenoceptors; Ventricular effective refractory period; Sinoatrial pacemaker activity

1. Introduction

Both /31" and /32-adrenoceptors coexist in the heart, as determined by radioligand binding studies (Minneman et al., 1979; Hedberg et al., 1980; Brodde et at., 1982, 19861. The amount of /31- and /32-adrenoceptors has been determined in the right atrium and left ventricle of various mammalian hearts, and the proportion of /32-adrenoceptors in the right atrium is higher than that in the left ventricle (Hedberg et al., 1980; Brodde et al., 1982, 19861. Recently, an autoradiographic study has shown that the AV node contains both /3~- and /32-adrenoceptors, and the proportion of/32-adrenoceptors in the AV node (25%) is higher than that in the right atrium (18%) and in the left ventricle (12%) in the guinea-pig heart (Molenaar et al., 19901. /32-adrenoceptors mediate chronotropic and inotropic effects in isolated dog heart preparations, and the /32-adrenoceptor-mediated effects on the SA node are substantially greater than those on atrial muscle, whereas only small effects are elicited on ventricular

Correspondence to: S. Chiba. Department of Pharmacology, Shinshu University School of Medicine. Matsumoto 390, Japan.

muscle (Akahane et al., 1989). We recently observed in a preliminary study, that the /3e-adrenoceptor-mediated chronotropic response to sympathetic nerve stimulation was greater than the /32-adrenoceptor-mediated dromotropic response in anesthetized dogs. Ansa subclavial stimulation (Kralios and Millar, 1981; lnoue and Zipes, 1987) or catecholamine infusion (Morady et al., 19881 shortens the atrial and ventricular effective refractory periods (ERPs). The catecholamine-mediated shortening of action potential duration is mediated by/32-adrenoceptors as well as by /3j-adrenoceptors in isolated dog atrial muscle (Liang et al., 19851. In the present study, we investigated whether the shortening of atrial or ventricular ERP in response to sympathetic nerve stimulation is mediated by /32adrenoceptors in the anesthetized dog heart and whether cardiac electrical responses, i.e., sinus node pacemaker activity, AV conductivity and excitability, to catecholamines arc diffcrentially mediated by /32adrenoceptors. To achieve these aims, we studied the effects of a selective /3j-adrenoceptor antagonist, atenolol, and a selective /32-adrenoceptor antagonist, ICI 118,55l, on positive chronotropic and dromotropic responses and on the shortening of atrial and ventricu-

16 lar ERPs during stimulation of the ansa subclavia or intravenous infusion of epinephrine in the anesthetized, open-chest dog.

2. Materials and methods

2.1. Preparations Twenty-two mongrel dogs of either sex weighing between 10-30 kg were anesthetized with sodium pentobarbital (30 m g / k g i.v.). A tracheal cannula was inserted and intermittent positive-pressure ventilation was started. The chest was opened transversely at the fifth intercostal space. Each cervical vagus nerve was crushed with a tight ligature and each stellate ganglion was ligated tightly at its junction with the ansa subclavia. These maneuvers have been shown to remove virtually all tonic neural activity to the heart (Levy el al., 1966). A bipolar electrode was placed on the base of the epicardial surface of the right atrium near the sinoatrial (SA) node to record electrical activity. Another bipolar electrode was placed on the epicardial surface of the right atrial free wall to determine the atrial effective refractory period (ERP). A quadripolar electrode was placed on the apical site of the epicardial surface of the left ventricle to record electrical activity and to determine the ventricular ERP. The heart rate (HR) and atrioventricular conduction time (AVCT) were measured and displayed on a thermo-writing rectigraph (Nihon Kohden WT685T, Tokyo, Japan). AVCT was measured at a fixed cycle length (300 or 4(1(I ms) in electrically paced hearts. The basic pacing cycle length was consistent for each dog. Two iridium bipolar hook electrodes were placed on the cardiac side of the bilateral stellate ganglia and connected to an electrical stimulator (Nihon Kohden MSE-3). We used a steady stimulation of l0 V, 1-ms pulse duration and a frequency of 1-4 Hz. The left femoral vein was cannulated for drug injection and for physiological saline infusion to adjust for spontaneous fluid losses. The right femoral vein was also cannulated for epinephrine infusion.

2.2. Measurement of effectit'e refractoo: period E R P was determined at each test site by the extrastimulus technique using an electrical stimulator (Nihon Kohden SEN 71(131. Each test site was driven with a 2-ms rectangular stimulus at 1.5 times the diastolic voltage threshold for activation. A train of 8 stimuli (S L) at a constant cycle length of 400 or 300 ms was followed by a prematurc stimulus ($2). The atrial or ventricular response to S, was recorded as the atrial deflection, which was obtained from the bipolar elec-

trode at the right atrium near the SA node, or as thc ventricular deflection, which was obtained from the quadripolar electrode at the apical site of the left ventricle. The S~-S 2 interval was shortened in steps of 2 ms until S~ failed to produce a propagated rcsponse. The S~-S 2 interval was then increased by 4 ms and shortened in l-ms increments until S, failed to capture.

2.3. Experimental protocols We carried out two series of experiments. Wc used 12 dogs in the first series. We investigated the effects of ICI 118,551 ( 0 . 3 - 3 0 0 / x g / k g i.v., n = 6) and atenolol (0.03-100 / x g / k g i.v., n 6) on the positive chronotropic and dromotropic responses and on the shortening of right atrial ERP and left ventricu[ar ERP in response to stimulation of bilateral ansae subclaviae. Before we studied the cardiac responses to sympathetic stimulation, the dog was given atropine sulfate (0.2 m g / k g i.v.), and 0.1 m g / k g i.v., of atropine was given each hour thereafter to block the response mediated by muscarinic receptors. The level of bilateral ansac subclaviae stimulation was determined to increase the HR by more than 30% of its control level. Basal control HR, AVCT, atrial ERP and ventricular ERP were determined 5 min before the start of sympathetic stimulation. The effects of sympathetic stimulation on cardiac electrical responses werc determined 1 min after the HR became stable. The order of determination of each response to sympathetic stimulation was randomized. ICI 118,551 or atenolol at each dosc was injected 2 min before sympathetic stimulation. Each nerve stimulation was followed by a recovery, period of at least 10 rain. In the second series of experiments, we studied thc effects of ICI 118,551 (1(I-30(I # g / k g i.v., n = 5) and atenolol (1-100 /.tg/kg i.v., n - 5 ) on the positivc chronotropic and dromotropic responses and on the shortening of right atrial E R P and left ventricular ERP in response to infusion of epinephrine. The epinephrine infusion rate was determined to increase the HR by more than 30% of its control level. Basal responses were determined 5 rain before epinephrine infusion. Electrophysiological variables were determined every 5 rain during epinephrine infusion in preliminary experiments. These variables reached a steady state 10 rain after the start of epinephrine infusion, and our results were consistent with the plasma epinephrine concentrations recorded by Glutter et al. (198(1) during epinephrine infusion. We therefore determined control changes in cardiac responses I(1 min after the start of the epinephrine infusion. The effects of a drug on the changes in cardiac responses to epinephrine infusion were determined 2 min after ICI 118,551.

17

2.4. Statistical analysis All data are expressed as a percentage change in the respective control value of each stimulation obtained just before treatment with /3-adrenoceptor antagonists. These data are expressed as means 4- S.E. Fifty percent inhibition doses (IC5¢,) were determined for each dose-inhibition curve. The ERPs obtained during each stimulation were compared with the respective control values. The data were analyzed by means of a one-way analysis of variance, and Bonferroni's test was used for comparisons of mean values. Student's t-test for paired and unpaired data was used for comparisons between the two groups. P values of less than 0.05 were considered statistically significant.

3. Results

3.1. Direct cardiac effects of 1C1 118,551 and atenolol In the first series of experiments, the basal heart rate (HR), atrioventricular conduction time (AVCT), right atrial E R P and left ventricular E R P in six neurally decentralized, anesthetized open-chest dogs were 1 2 6 ± 8 b e a t s / m i n , 134_+ 10 ms, 147_+6 ms, 161_+4 ms, respectively. ICI 118,551 at doses of 0 . 3 - 1 0 0 / z g / k g i.v., did not change these basal cardiac electrical responses significantly. ICI 118,551 at a dose of 300 # g / k g i.v., significantly (P < 0.05) decreased H R and increased AVCT, atrial E R P and ventricular ERP. Atenolol at doses of 3-100 / z g / k g i.v., significantly (P < 0.05) decreased the basal H R and increased ventricular E R P in six anesthetized dogs. Atenolol at a dose of 100 / x g / k g i.v., significantly increased atrial E R P but did not change A V C T at any dose (0.3-100 / z g / k g i.v.). In the second series of experiments, ICI 118,551 and atenolol affected the basal electrical cardiac responses in the same way as they did the responses in the first series of experiments. The cardiac responses deter-

mined in the two series of experiments before administration of /3-adrenoceptor antagonists did not differ significantly.

3.2. Blocking effects" of IC1 118,551 and atenolol on the responses to sympathetic stimtdation When bilateral ansae subclaviae stimulation (sympathetic stimulation) increased H R by more than 30% of its control level, it decreased AVCT, atrial E R P and ventricular E R P (table 1). The responses to sympathetic stimulation before administration of either ICI 118,551 or atenolol did not differ significantly between the two experimental groups. ICI 118,551 at doses of 0.3-300 / z g / k g i.v., significantly (P < 0.05) inhibited the positive chronotropic response to sympathetic stimulation in a dose-dependent manner (fig. 1A). In contrast, the positive dromotropic response to the stimulation was significantly (P <0.05) attenuated by ICI 118,551 at doses of 100 and 300 /zg/kg, i.v. (fig. 1A). The shortening of atrial and ventricular ERPs in response to the stimulation was not significantly inhibited by 1CI 118,551 at doses of 1 0 0 / ~ g / k g i.v., or lower (fig. 1B). The inhibition by ICI 118,551 at doses of 30-300 # g / k g i.v., of the positive dromotropic response was significantly (P < 0.05) smaller than that of the positive chronotropic response (fig. 1A). The inhibitory effects of ICI 118,551 at doses of 30 and 1 0 0 / x g / k g i.v., on the shortening of right atrial and left ventricular ERPs tended to be smaller (0.05 < P < 0 . 1 ) than those on the positive chronotropic response. Atenolol at doses of 0 . 1 - 1 0 0 / z g / k g i.v., attenuated the positive chonotropic and dromotropic responses to sympathetic stimulation in a dose-dependent manner (P < 0.01, fig. 2A). The shortening of atrial and ventricular ERPs in response to stimulation was also significantly (P < 0.05) inhibited by atenolol in a dose-dependent manner (fig. 2B). The ICs0s of atenolol for the positive chronotropic and dromotropic responses and the shortening of right atrial E R P and left ventricular

TABLE 1 The changes in heart rate (HR), atrioventricular conduction time (AVCT), right atrial effective refractory period ( R A - E R P ) and left ventricular E R P (LV-ERP) induced by sympathetic stimulation or epinephrine infusion in each experimental group. Group 1: the effects of ICI 118,551 on the electrical cardiac responses induced by sympathetic stimulation; Group 2: the effects of atenolol on the electrical cardiac responses induced by sympathetic stimulation; Group 3: the effects of ICI 118,551 on the electrical cardiac responses induced by epinephrine infusion; Group 4: the effects of atenolol on the electrical cardiac responses induced by epinephrine infusion. Group

n

Increase in H R (beats/min)

Decrease in A V C T (ms)

Decrease in R A - E R P (ms)

Decrease in LV-ERP (ms)

1 2 3 4

6 6 5 5

4 6 + 10 40_+ 6 47_+ 8 56_+ 8

32_+7 38+4 33+6 42+6

14_+3 14+2 12+5 19+5

11 + 2 11_+2 19_+2 28+4

ERP in response to sympathetic stimulation were 2.1 _+ 1.1, 4.1_+ 1.3, 3.4_+2.0 and 3 . 1 + 2 . 2 /xg/kg i.v., respectively. These 1Cs0s of atcnolol were not significantly different.

A. 120 100 80

3.3. Blocking effects of ICI 118,551 and atenolol on the

C u) 0~ £E

Infusion of epinephrine at a rate of 1-3 # g / k g per min i.v., increased HR and decreased AVCT, atrial ERP and ventricular E R P (table 1). The responses to epinephrine infusion in the two experimental groups before administration of either ICI 118,551 or atenolol were not significantly different. ICI 118,551 also inhibited both positive chronotropic and dromotropic responses to epinephrine infusion in a dose-dependent manner (fig. 3A). The shortening of right atrial E R P in response to epinephrine infusion was significantly (P < 0.05) inhibited by ICI 118,551 at doses of 100 and 3 0 0 / . t g / k g i.v. (fig. 3B). The shortening of left ventricular ERP in response to epinephrine was not significantly inhibited by ICI 118,551 at doses

60

o

re,wonse to el)inephrine infttsion

40 20

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~, SA

OAV

1 C

100

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i

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Fig. 2. The effects ol atenolol a! doses of (L3 10l) # g / k g i.v. on the positive chonotropic (SA, c ) and dromotropic (AV, o) responses (panel A) and the shortening of atrial (RA, • ) and vcntricular (LV, [] ) ERPs in response (panel B) to ansae subclaviac stimulation in six anesthetized dogs. Vertical bars show S.V.

100

8o

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D o s e of Atenolol (pg/kg, tv)

120

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0.1

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60 40 o

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t

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1

3

10

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100

300

D o s e of ICI 1 1 8 , 5 5 1

(lag/kg, iV)

Fig. 1. The effects of ICI 118,551 at doses of 0.3-300 # g / k g i.v. on the positive chonotropic (SA, <:) and dromotropic (AV, o) responses (panel A) and the shortening of atrial (RA, • ) and vcntricular (LV, D) effective refractory periods (ERPs) in response (panel B) to ansae subclaviae stimulatkm in six anesthetized dogs. Vertical bars show S.E.

lower than 300 /xg/kg i.v. (fig. 3B). The inhibitory effects of ICI 118,551 at doses of 30-300 # g / k g i.v., on the increase in HR and shortening of right atrial ERP in response to epinephrine infusion were significantly (P < (t.05) greater than those on the shortening of left ventricular ERP. Atenolol (1-100 /xg/kg i.v.) inhibited the positive chronotropic and dromotropic responses to epinephrine infusion in a dose-dependent manner, but atenolol at doses of 1-30 /,tg/kg i.v., inhibited the dromotropic response less than it inhibited the chronotropic response (fig. 4A). The shortening of right atrial ERP and left vcntricular E R P was significantly (P < 0.05/ attenuated by atenolol in a dose-related manner at doses of 3-100 # g / k g i.v. (fig. 4B). The inhibition by atenolol (1-11)0 # g / k g i.v.) of the shortening of atrial ERP was not significantly different to that for the shortening of ventricular ERP at each dose. The 1Cs0s of atenolol for the chronotropic and dromotropic responses and the shortening of right atrial ERP and left ventricular ERP in response to epinephrine infusion were 7.8 _+ 1.6, 24.6_+ 5.9, 7.8 + 1.6 and 15.7 +_ 4.8 # g / k g i.v., respectively. The IC50 of atcnolol for the dromotropic response was significantly (P < 0.05)

19

greater than that for the chronotropic response and for the changes in right atrial ERP.

A. 120 100

4. D i s c u s s i o n

80

A selective/3~-adrenoceptor antagonist, atenolol, inhibited the shortening of atrial ERP induced by sympathetic nerve stimulation and epinephrine infusion to a similar extent whereas a selective /32-adrenoceptor antagonist, ICI 118,551, did not significantly attenuate the shortening of atrial ERP in response to sympathetic stimulation but did attenuate the shortening of atrial E R P in response to epinephrine. ICI 118,551 blocks /32-adrenoceptors selectively at doses of up to 100/~g/kg i.v., in anesthetized dogs (Bilski et al., 1983; Hohnloser et al., 1987). These results suggest that epinephrine partly elicits the shortening of atrial ERP by/32-adrenoceptors in addition to/31-adrenoceptors in anesthetized dogs. However, ICI 118,551 partly attenuated the positive chronotropic responses to both sympathetic stimulation and epinephrine infusion. This differential inhibition of ICI 118,551 on the chronotropic response and the shortening of atrial

r-0 Q. u~

60

40

n" 20 0

o SA • AV

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Dose of Atenolol (IJg/kg, iv) A.

Fig. 4. The effects of atenolol at doses of 1-100 ~ g / k g i.v. on the positive chronotropic (SA, o ) and dromotropic (AV, o) responses (panel A) and the shortening of atrial (RA, • ) and ventricular (LV, C5) ERPs in response (panel B) to epinephrine infusion in five anesthetized dogs. Vertical bars show S.E.

120 IO0

a~ ~" C 0 Q. a0 ®

80 60 40 20

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rr

40 20

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0

Dose

RA

of

ICI

1 18,551

\ 100

300

(l~g/kg,

iv)

Fig. 3. The effects of ICI 118,551 at doses of 10-300 p . g / k g i.v. on the positive chronotropic (SA, o ) and dromotropic (AV. o) responses (panel A) and the shortening of atrial (RA, • ) and ventricular (LV, []) E R P s in response (panel B) to epinephrine infusion in five anesthetized dogs. Vertical bars show S.E.

ERP in response to sympathetic stimulation may be induced by the different proportion of /32-adrenoce ptors in each tissue, i.e., the proportion of /32-adrenoceptors in the SA node (about 50%) is greater than that in the atrial muscle (about 25%) (Liang et al., 1985; Liang and Molinoff, 1986; Saito et al., 1989). Liang et al. (1985) reported that the proportion of /32-adrenoceptors in the atrium was 25%, but/32-adrenoceptors were responsible for 50% of the shortening of the atrial action. In the present study, ICI 118,551 attenuated both the chronotropic response and the shortening of atrial E R P in response to epinephrine to a similar extent. Thus, further studies, including studies of the postreceptor transduction mechanisms, need to clarify the /32-adrenoceptor-mediated shortening of atrial ERP induced by endogenous catecholamines, although the potency of norepinephrine in occupying /3~- and /32-adrenoceptors is similar to its potency in stimulating /3 l- and /32-adrenoceptor-mediated increases in adenylate cyclase activity (Liang and Molinoff, 1986). The shortening of ventricular E R P induced by sympathetic nerve stimulation or epinephrine infusion was not attenuated by ICI 118,551 at doses up to 100

20 /*g/kg i.v., although the shortening of ventricular ERP in response to catecholamines was inhibited by atenolol in a dose-dependent manner. Thus, we suggest that the shortening of ventricular E R P induced by endogenous catecholamines is mediated by /3~-adrenoceptors and hardly by/3a-adrenoceptors in normal dog hearts. ICI 118,551 at doses of up to 1011 # g / k g i.v., significantly attenuated the positive chronotropic response to cardiac sympathetic nerve stimulation or epinephrine infusion in a dose-dependent manner in the neurally decentralized, anesthetized dog (figs. 1 and 3). A t e n o H also inhibited the positive chronotropic response in a dose-related manner (figs. 2 and 4). These results confirmed previous reports in which the positive chronotropic responses to catecholamines were found to be partially mediated by /~2-adrenoceptors but predominantly by/3~-adrenoceptors in in vitro and in vivo (Caflsson et al., 1972; Bilski et at., 1983, Akahane et al., 1989; Hall et al., 1989; Motomura et al., 1990a). ICI 118,551 at doses of 30 and 100 /xg/kg i.v., attenuated the positive dromotropic response to epinephrine infusion dose dependently. Atenolol inhibited the positive dromotropic responses to endogenous catecholamines in a dose-dependent manner. These results suggest that the positive dromotropic response to epinephrine is partially mediated by ~2-adrenoceptors in the dog heart. However, the positive dromotropic response to sympathetic stimulation was inhibited by ICI 118,551 at doses of 100 and 3110 # g / k g i.v. It is therefore suggested that ~2-adrenoceptors play little or no part in sympathetic stimulation-induced changes in AVCT. The order of the ratio of/32//~-adrenoceptor-mediated electrical cardiac responses to sympathetic nerve stimulation in the anesthetized dog was SA node pacemaker activity >> AV conductivity = atrial E R P = ventricular ERP, and that for epinephrine infusion was SA node pacemaker activity > atrial ERP >/AV conductivity >> ventricular ERP. These results suggest that endogenous catecholamines can activate both /31- and /32-adrenoceptors in the heart. As epinephrine but not norepinephrine activates presynaptic /32-adrenoceptors (Majewski et al., 1980), this may be the cause of the discrepancy in the order of the ratio o f / 3 2 / ~ - a d r e n o ceptor-mediated electrical cardiac responses to neurally released norepinephrine and epinephrine infusion. In the present study, the rank order of the /J2adrenoceptor-mediated effect was sinus node pacemaker activity >> AV conductivity = atrial ERP >> ventricular ERP. This result corresponds well with the /~2//3~-adrenoceptor ratios, which are highest in the SA node region, lower in the right atrial muscle and AV node region, and lowest in the left ventricular muscle (Saito et al., 1988, 1989; Molenaar et al., 1990). The affinity of 1CI 118,551 for /3~-adrenoceptors is about 1 nM and the affinity of atenolol for/3~-adreno-

ceptors is about 40-100 nM in isolated mammalian cardiac tissues (Bilski et al., 1983; Lemoine et al., 1985, 1988; Liang and Molinoff, 19861, although it is difficult to compare directly data from experiments with the isolated mammalian cardiac tissues to those in anesthetized dogs. Thus, when taking into consideration the doses of ICI 118,551 and atenolol used in the presenl study and their affinities fl)r/3:- and /3~-adrenoccptors, respectively, the antagonistic potency of atenolol against sympathetic nerve stimulation as well as against epinephrine-induced effects is 5-10 times greater than that of ICI 118,551. Thus, these results can be explained by the involvement of /31-adrenoccptors only. It is therefore suggested that the electrical cardiac responses to endogenous catecholamines are predominantly mediated by /31-adrenoceptors in the normal dog heart. Chronic treatment with a /31-adrenoceptor antagonist sensitizes ~z-adrenoceptor-mediated function in the human heart (Hall et al., 1990: Motomura et al., 1990b). Therefore, even though the proportion of /3,adrenoceptors in the normal ventricle is about 10% (Hedberg et al., 1980; Brodde et al., 1982, 1986: Molenaar et al., 1990), the shortening of ventricular ERP induced by endogenous catecholamines may be partly mediated by /32-adrenoceptors in chronic /3radrcnoceptor antagonist-treated hearts and in hearts exposed to high concentrations of catecholamine. In the present study, wc demonstrated that the order of the ratio of /3y/31-adrenoceptor-mediatcd electrical cardiac responses to sympathetic nerve stimulation in the anesthetized dog was SA node pacemaker activity >> AV conductivity > atrial ERP = ventricular ERP, and that for epinephrine infusion was SA node pacemaker activity >~ atrial ERP >/AV conductivity >> ventricular ERP. These results suggest that the proportion of/32-adrenoceptor-mediated electrical cardiac responses is correlated with the proportion of ~:-adrenoceptors in each respective cardiac tissue, but postrcceptor transduction may relate partly to the different proportion of/32-adrenocepior-mediated electrical cardiac responses.

References

Akahanc, K., Y. Furukawa, Y. Ogiwara, M. Haniuda and S. ('hiba, 1989, Beta-2 adrenoeeptor-mediated effects on sinus rate and atrial and ventricular contractility on isolated, blood-perfused dog heart preparations, J. Pharmacol. Exp. Ther. 248, 1276. Bilski, A.J., S.E. ttalliday, J.D. Fitzgerald and J.L. Wale. 1983. The pharmacology of a /32-selective adrenoceptor antagonist (IC1 118,5511, J. Cardiovasc. Pharmacol. 5, 43/I. Brodde, O-E., F-J. Leifert and H-J. Krehl, 1982, Coexistence of /3Iand /32-adrenoceptors in the rabbil heart: Quantitative analysis of the regional distribution by (-)-3H-dihydroalprenolol binding, J. Cardiovasc. Pharmacol. 4.34. Brodde, O-E., S. Schuler, R. Kretsch, M. Brinkmann, tt.G. Borsl, R.

21 Hetzer, J.C. Reidemeister, H. Warnecke and H.R. Zerkowski, 1986, Regional distribution of /3-adrenoceptors in the h u m a n heart: Coexistence of functional /3K- and /32-adrenoceptors in both atria and ventricles in severe congestive cardiomyopathy, J. Cardiovasc. Pharmacol. 8, 1235. Carlsson, E., B. Ablad, A. Branstrom and B. Carlsson, 1972, Differentiated blockade of the chronotropic effects of various adrcnergic stimuli in the cat heart, Life Sci. 2, 953. Glutter, W.E., D.M. Bier, S.D. Shah and P.E. Cryer, 1980, Epinephrine plasma metabolic clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man, J. Clin. Invest. 66, 94. Hall, J.A., M.C. Petch and M.J. Brown, 1989, Intercorona~' injeclions of salbutamol demonstrate the presence of functional ~_~adrenoceptors in the h u m a n heart, Circ. Res. 65, 546. Hall, J.A., A.J. K a u m a n n and M.J. Brown, 1990, Selective /3a-adrenoceptor blockade enhances positive inotropic responses to endogenous catecholamines mediated through /32-adrenoceptors in h u m a n atrial myocardium, Circ. Res. 66, 1610. Hedberg, A.. K.P. M i n n e m a n and P.B. Molinoff, 1980, Differential distribution of beta-1 and beta-2 adrenergic receptors in cat and guinea-pig heart, J. Pharmacol. Exp. Ther. 213, 503. Hohnloser, S.H., R.L. Verrier and B. Lown, 1987, Influence of beta2-adrenoceptor stimulation and blockade on cardiac electrophysiologic properties and serum potassium concentration in the anesthetized dog, Am. Heart J. 113, 11166. lnoue, 1|. and D.P. Zipes, 1987, Changes in atrial and ventricular refactoriness and in atrioventricular nodal conduction produced by combination of vagal and sympathetic stimulation that result in a constant spontaneous sinus cycle length, Circ. Res. 6/1, 942. Kralios. F.A. and C.K. Millar, 1981, Sympathetic neural effects on regional atrial recover, properties and cardiac rhythm, Am. J. Physiol. 240, H590. Lemoine, H., B. Ehle and A.J. K a u m a n n , 1985, Direct labelling of /32-adrenoceptors. Comparison of binding potency of 3tt-IC1 118,551 and blocking potency of ICI 118,551, Naunyn-Schmiedeb. Arch. Pharmacol. 331.40. Lemoine, H.. H. SchSnell and A J . K a u m a n n , 1988, Contribution of /31- and /3z-adrenoceptors of h u m a n atrium and ventricle to the effects of noradrenaline and adrenaline as assessed with (-)atenolo[, Br. J. Pharmacol. 95, 55.

Levy, M.N., M.L. Ng and H. Zieske, 1966, Functional distribution of the peripheral cardiac sympathetic pathways, Circ. Res. 19, 650. Liang, B.T., L.H. Frame and P.B. Molinoff, 1985, /32-Adrenergic receptors contribute to catecholamine-stimulated shortening of action potential duration in dog atrial muscle, Proc. Natl. Acad. Sci. 82, 4521. Liang, B.T. and P.B. Molinoff, 1986, Beta adrenergic receptor subtypes in the atria: Evidence for close coupling of beta-I and beta-2 adrenergic receptors to adenylate cyclase, J. Pharamcol. Exp. Ther. 238. 886. Majewski, H, M.W. McCulloch, M.J. Rand and D.F. Story, 198(I, Adrenaline activation of prejuncfional /3-adrenoceptors in guinea-pig atria, Br. J. Pharmacol. 71,435. Minneman, K.P., L.R. Hegstrand and P.B. Molinoff, 1979, Simultaneous determination of beta-I and beta-2-adrenergic receptors in tissues containing both receptor subtypes, Mol. Pharmacol. 16, 34. Molenaar, P., J.J. Smolich, F.D. Russell, L.R. McMartin and R.J. Summers, 1990, Differential regulation of beta-1 and beta-2 adrenoceptors in guinea pig atrioventricular conducting system after chronic (-)-isoproterenol infusion, J. Pharmacol. Exp. Tiler. 255, 393. Morady, F., S.D. Nelson, W.H. Kou, R. Pratley, S. Schmaltz, M. De Buitleir and J.B. Halter, 1988, Electrophysiologic effects of epinephrine in humans, J. Am. Coll. Cardiol. 11. 1235. Motomura, S., H.-R. Zerkowski, A. Daul and O.-E. Broddc, 199(1a, On the physiologic role of beta-2 adrenoceptors in the human heart: In vitro and in vivo studies, Am. Heart J. 119, 6/18. Motomura, S., N.M. Deighton, H.-R. Zerkowski, N. Doetsch, M.C. Michel and O.-E. Brodde, 1990b, Chronic /31-adrenoceptor antagonist treatment sensitized /32-adrenoceptors. but desensitizes M~-muscarinic receptors in the h u m a n right atrium. Br. J. Pharmacol. 101, 363. Saito, K., M. Kurihara, R. Cruciani. W.Z. Potter and J.M. Saavedra. 1988, Characterization of /31- and /32-adrenoceptor subtypes in the rat atrioventricular node by quantitative autoradiography, Circ. Res. 62, 173. Saito, K., T. Torda, W.Z. Potter and J.M. Saavedra, 1989. Characterization of /3E- and /32-adrenoceptor subtypes in the rat sinoatrial node and stellate ganglia by quantitative autoradiograhpy, Neurosci. Lett. 96, 35.