Histamine attenuates the arrhythmogenic effects of norepinephrine in hearts of spontaneously hypertensive rats

European Journal of Pharmacology. 169 (1989) 23 31

23

Eb,evicr ['LIP 5(1987

Histamine attenuates the arrhythmogenic effects of norepinephrine in hearts of spontaneously hypertensive rats J o h n S. C a m e r o n , D e b o r a h Katz. C a r r i e R. Swigart a n d A r t h u r L. Bassett Department of Biological Sciences. Welh,sh W ('olh'ge. lYelh,sl~% MA 02181. (_'.S.,4.

Received 16 February 1989, revised MS received 22 June 1989, accepted 18 July 1989

A potential physiological role for cardiac histamine and its interaction with norepinephrine were investigated in isolated left ventricles from spontaneously hypertensive rats (SHR). Prior to drug administration, left ventricle-to-body weight ratios and spontaneous firing rates (beats per mini were significantly increased in SHR ventricles vs. age- and sex-matched controls (WKY). Also. action potential duration was significantly prolonged in SHR at all levels of repolarization. In all hearts, norepinephrine (10 7-10 4 M) increased spontaneous rate and the percent incidence of arrhythmias. The Hz-reeeptor antagonist cimetidine (10 s M) potentiated the rate and arrhythmogcnic effects of norepinephrine in SHR and, to a lesser extent, in WKY preparations: propranolol (10 ~' M) reduced them. Histamine ( I 0 7 M) also inhibited the norepinephrine-induced increase in arrhythmias in SHR, but nc,t in WKY. The attenuation of adrenergically induced rhythm disturbances by histamine and their potentiation by cimetidine in hypertensive hearts support the hypothesis that histamine plays a role as a postjunctional modulator of adrenoccptor function in a setting of hypertension and myocardial hypertrophy. Histanaine: Cardiac arrhythmias: Hvpertension: Myocardial hypertrophy: Spontaneously hypertensive rat (St I R)

I. Introduction It has been recognized for s o m e time that substances released from injured or ischemic m y o c a r d i u m might c o n t r i b u t e to an increased p r o p e n s i t y for a r r h y t h m o g e n e s i s . H i s t a m i n e , for example, is readily released into the circulation from stores in the heart a n d is highly a r r h y t h m o g e n i c ( W o l f f and Levi, 19861. In a d d i t i o n , s y m p a t h e t i c m e c h a n i s m s involving the release of n o r e p i n e p h r i n e have been r e p e a t e d l y m e n t i o n e d as p o t e n t i a l factors in the d e v e l o p m e n t of c a r d i a c r h y t h m d i s t u r b a n c e s in

ischemic heart disease (Zipes ct al., 1981). Supp o r t i n g the view that these agents might bc particularly deleterious is the o b s e r v a t i o n that diseased hearts are m o r e susceptible to the development of h i s t a m i n e - i n d u c e d ( C a m e r o n et al.. 1985: Li et al., 19871 a n d a d r e n e r g i c a l l y derived ( C a m e r o n a n d Han. 19821 a r r h y t h m i a s than are n o r m a l hearts. C o m p l i c a t i n g the issue, however, is the suggestion that in n o r m a l hearts, i n t r a c a r d i a c histamine plays a physiological role as an a n t a g o n i s t of a d r e n e r g i c n e u r o t r a n s m i s s i o n ( G r o s s et al., 1984; G i a c o m i n i a n d Reis, 1986). If so, the s e p a r a t e a r r h y t h m o g e n i c influences of h i s t a m i n e a n d

i Address of A.I.. Bassett: Dept. of Pharmacology. Univ. of Miami Schcx~l of Medicine. P.O. Box 016189. Miami. FI,

norepinephrine would not be expected to be additive.

33101. U.S.A. Correspondence to: J.S. Camerc,n, Department of Biological Sciences, Wellesley College, Wellesley. MA 02181, U . S . A .

The purpose of the present study was to investigate the possibility that histamine serves as a postsynaptic modulator of adrenoceptor function

0014-2999/89/$03.50 ' 1989 Elsevier Science Publishers B.V. (Biomedical Division)

24 in the heart, and to learn whether this function is altered in hypertension and myocardial hypertrophy,

2. Materials and methods

2.1. Animal prepuration Spontaneously' hypertensive rats (SHR) and age-matched normotensive controls ( W K Y ) w e r e purchased from Charles River Laboratories (Wilmington, MA). Male rats weighing 232-345 g (mean = 315 + 14 g) were anesthetized with sodium pentobarbital (50 m g / k g i.p.). In some cases, an electrocardiogram was monitored for several minutes just prior to killing. Each heart was quickly excised and placed in Tyrode solution of the following composition (raM): Na('l 130; N a H C O 3 20: dextrose 5.5; KCI 4; Nal-12PO,~ 2.1; CaCI~ 1.8 and MgCI2 1.1. Upon removal of the atria and right ventricle, the left ventricle was first weighed rapidly, then opened by an incision through the free wall adjacent to the posterior papillary muscle. The resulting preparation was mounted endocardial surface upward in a tissue bath and superfused with Tyrode at a rate of 15 m l / m i n ; the solution was equilibrated with 95~ O~-5% C()~ and maintained at 37.0 + (1.5 ° ('. 2.2. Electrophysioh;gical measurements Fransmembrane action potentials were recorded from the most superficial layer of endocardial muscle fibers using conventional microelcctrode techniques. Glass microelectrodes filled with 3 M KCI had tip resistances in the range of 20-60 M~(J and were connected to dual differential preamplifiers with input impedance of 1() ~' M~'2 (WPi, KS 700). Amplifier output was monitored with a Tektronix oscilloscope, then stored and later analyzed using a digital oscilloscope (Northwest Instrument Systems) mounted in an Apple lie microcomputer. Spontaneous activity was monitored with a Gould two-channel chart recorder or FM tape recorder,

Following a 60 rain equilibration period, predrug action potential configuration vs.as recorded from five sites (~n the endocardial surface: these included two o n the left vcntricular free vs'all, two on the interventricular septum anti one on the papillary' muscle. No regional differences in action potential configuration or drug effects were observed. Spontaneous arrhythmias were monitored continuously throughout the experiment, beginning 30 rain prior to drug infusion. Arrhvthmias included premature depolarizations, transient graded rate increases of 50-150~ resembling ventricular tachycardia, irregular rhvthms and spontaneous burst of activity during which the rate increased bv as much as 400%. Rapid. repetitive activity was rarely sustained more than 5 s. I)elayed afterdepolarizations were observed in S t I R preparations. The percent incidence of rhvthm abnormalities for a given 3() rain drug exposure was determined from the chart record and calculated as the number of minutes during which arrhythmias were observed divided by lg (data vs'ere obtained during three equally spaced 6 mm intervals in each 30 mm period). Arrhvthmia~, were counted as "present' upon observation of at least three individual premature depolarb,.ations or a single burst of rapid ventricular activity during anv 1 rain period. In general, individual periods were readily, classified as containing m, disturbances in rh\:thm or as showing recurring episodes of premature depolarizations a n d / o r bursts of rapid activity. The mean percent incidence of arrhythmias for a given drug exposure was then expressed _+ 1 S.E. Following these initial observations, the tissue was superfused with norepinephrine (hydrochloride: Sigmal at four concentrations (10 "-10 4 M) for an additional 30 min each, during which action potential characteristics were continuously recorded. Ascorbic acid was added to norepinephrine solutions to retard oxidation. In some experiments, histamine (dihydrochloride: Sigma: 10 ~or 10 s M). cimetidine ( [ l _,-receptor antagonist: Sigma: 10 5 M), chh)rpheniramine maleate (H~antagonist: Smith Kline: 1() s M) or dl-propranolol hydrochh)ride (fl-adrenoceptor blocker, Sigma; 10 " M) vs'as given 30 rain prior to administration of norepinephrine, and then main-

25 tained throughout norepinephrine exposure. C i m e t i d i n e was dissolved in a dilute solution of lactic acid before being b r o u g h t to its final con-

3. Results

c e n t r a t i o n with T y r o d e solution. D r u g infusion was followed by at least 60 min w a s h o u t of n o r e p i n e p h r i n e a n d a n t a g o n i s t s with c o n t i n u e d monitoring.

3.1. Pre-drug characterization o / S H R

2.3. Data analysis D a t a are expressed as m e a n +_ 1 S.E. A n a l y s i s of variance ( A N O V A ) for unequal n was used to test for significant differences in d r u g response a m o n g the various groups. W h e n significance was established, c o m p a r i s o n s between specific m e a n s were carried out using a m o d i f i e d z-statistic ( W a l lenstein et al., 1980). In s o m e cases, the analysis of the relationship between e x p e r i m e n t a l p r o c e d u r e s a n d electrophysiological a b n o r m a l i t i e s was carried out using X 2 analysis with Y a t e ' s c o r r e c t i o n for each c a t e g o r y of data. Statistical significance was established at P < 0.05.

Several e l e c t r o p h y s i o l o g i c a l and m o r p h o l o g i c a l p a r a m e t e r s in left ventricles isolated from S H R a n d W K Y rats were significantly different prior to d r u g a d m i n i s t r a t i o n . Left v e n t r i c u l a r weight-tob o d y - w e i g h t ratios for S H R (n = 32) were signific a n t l y (P < 0.05) greater than those of age- and s e x - m a t c h e d W K Y s (n = 33) (table i). S p o n t a n e o u s rates ( b e a t s per min) also were significantly increased in S H R hearts relative to W K Y . C o n c o m i t a n t with the e n h a n c e d a u t o m a t i c ity, the S H R p r e p a r a t i o n s showed a consistently thought not significantly increased p r o p e n s i t y for the d e v e l o p m e n t of electrical r h y t h m d i s t u r b a n c e s of all types (fig. 1). T a b l e 1 illustrates that the p e r c e n t a g e of time d u r i n g which a r r h y t h m i a s (inc l u d i n g p r e m a t u r e beats, bursts of rapid, repetitive activity and d e l a y e d a f t e r d e p o l a r i z a t i o n s ) were te-

ib.

a.

"

NE (IO'~IA)

WKY ~) ms

I

50 mV

3s

3s

-

SHR

Fig. 1. Transmembrane action potentials recorded in left ventricular preparations from normotensive control rats (WKY, top) and age-matched spontaneously hypertensive rats (SHR, bottom) before drugs (a) and after administration of 10 ~' M norepinephrine (NE: b). Prior to drug application, action potential duration (APD) at all levels of repolarization and spontaneous firing rates were significantly increased in SHR preparations relative to WKY. At this concentration, NE raised spontaneous rates in both groups and significantly increased the incidence of arrhythmias in WKY. Time scale in (b) same as in (a) (at right).

26

rABLF I

3.2. Effects of norepmephrine

Differences in m o r p h o l o g i c a l and cardiac electrophysiological characteristics of W K Y and S I I R rat.,,. Values represent m e a n s ± S . E . " Significantly different from W K Y value. P < 0.05: h P<0.001.

SttR

spontaneously

hypertensive

rat~:

WKY.

W i s t a r - K y o m n o r m o t e n s i v e controls: bpm. beats per minute: LV. left ventricle: A P D . ventricular action potential d u r a t i o n at 50 and 907~: repolarization, W K Y (n = 33)

S H R (n = 32)

Bod> weight Ikg)

0.321T0.012

0.301_+0.015

LV weight (g) I,V , ~ e i g h t / b o d 5 ,,,eight

0.56 -0.09

0.94 ±0.n5 "

(g/kg) S p o n t a n e o u s heart rate (bpm)

1.8

3.2

Incidence of cardiac arrhvthmias tel) APD:~,, (ms) APl)~,(ms)

=0.2

+0.3b

41

-9

6s

±s"

28 19 28

•

6 -3 .5

37 25 3X

+6 +_2" ±4"

c o r d e d in S H R hearts was a u g m e n t e d relative to that in W K Y hearts. In addition, action potential d u r a t i o n at all levels of r e p o l a r i z a t i o n was significantly, (P < 0.05) p r o l o n g e d in the S H R hearts (fig. 1). However, resting potential, action potential a m p l i t u d e and m a x i m u m rate of u p s t r o k e velocity (~"...... ) were not significantly different in the two groups,

Automaticitv.

the

incidence

of

spontaneous

-'

a r r h y t h m i a s a n d action p o t e n t i a l c o n f i g u r a t i o n w e r e m o n i t o r e d in left ventricuhtr p r e p a r a t i o n s d u r i n g superfusion with n o r e p i n e p h r i n e o v e r a range of c o n c e n t r a t i o n s (10 q l 0 ' M). N o r e p i nephrine produced concentration-dependent increases in s p o n t a n e o u s firing rates in both W K Y (n = 8) a n d S H R (n = 8) p r e p a r a t i o n s (table 2): the percent increases are shown in fig. 2. N o r e p i n e p h r i n e also increased the overall incidence of s p o n t a n e o u s r h y t h m d i s t u r b a n c e s in W K Y and S I I R p r e p a r a t i o n s in a c o n c e n t r a t i o n d e p e n d e n t m a n n e r ( t a b l e 2). The c o n c e n t r a t i o n threshold at which a significant response was first o b s e r v e d was lower in the hearts of W K Y rats. S H R hearts were not significantly affected bv n o r e p i n e p h r i n e in terms of increased r h y t h m dist u r b a n c e s at a c o n c e n t r a t i o n of I0 " M, ~ h i l e a r r h v t h m i a s were significantly (P < 0.05) elevated in W K Y hearts at this c o n c e n t r a t i o n (table 2). Increased incidences of r h y t h m d i s t u r b a n c e s were reversed u p o n w a s h o u t of the d r u g (30 rain).

3.3. Ef/~'cts of receptor blockade on the response to m)repinephrme W h e n given ahme, neither timer±dine (10 ~ M), c h l o r p h e n i r a n m a e (10 ~ M) nor p r o p r a n o H 110 ~'

"I'A IH,E 2 Effects of n o r e p i n e p h r i n e on s p o n t a n e o u s firing rate and incidence o f arrh)thmia~, in W K Y and S H R isolated ,,entricular m v o c a r d i u m . Values represent means_+ S.I'. " Significantly different from pre-drug value. P < 0.05" h p <: 0.001. SHR. spontaneousl> h?,pertensi',e rats: W K Y . W i s t a r - K y o t o n o r m o t e n s i v e controls" bpm. beats per minute, n i m h c a t e d in parentheses. WKY

SHR

Rate ( b p m )

I ncidence o f

Rate ( b p m )

Incidence o f arrhvthmias (q)

68+ ~32)

37_- 6 {32)

a r r h y t h m i a s (c/) Pre-drugvalue Norepinephrine 10 : M 10 i ' M 10 " M 10

4 M

41+ (33)

9

83+ 15 "

28t 6 133} 38.-

4

8

101 ~ 36

26*

(8)

(8)

17)

(7)

119_.27" (8) 154±35" 18) 161 + 1'4 ' (8)

64+ 7 ~' (8) 89-10" (8) 94_-. q h (8)

140_+22' (8) 184-42 h (8) 223 t 31 ~' (8)

49. 8 (8) 60z 3" (8) 71 _~ lfl " (8)

27 WKY

20

I

.sol

a 1

1

i

1

SHR

~o

0 1

7

I

6

I

1

5

- log [Nomplnephrlne]

b

4 (M)

I:ig. 2. Effects of pretreatment with cimetidine (('im: 10 " M), propranolol (Pro: 10 ~' M) or histamine (His: 10 : M) on norepinephrine-mduced (10 :-10 "~ M) changes in spontaneous, rates in isolated normotensive control (a: WKY: n = g) and spomaneously hypertensive rat (b: St|R: n = g) ventricles. Absolute (table 2) and percent rate increases (relative to pre-drug control values) were observed in both groups. ('imetidine potentiated the rate increases in WKY at 10 : M norepinephrine and in SHR at the three lover concentrations; propranolol blocked them. Histamine inhibited the norepinephrine-induced rate increase in SHR, but not WKY. ¢~Significantlydifferent (P < 0.05) from pre-drug value. All values shown +_S.E. M) caused any significant change in the s p o n t a neous rate of either W K Y or S H R preparations, W h e n a d m i n i s t e r e d s i m u l t a n e o u s l y with norepin e p h r i n e at the three lower c o n c e n t r a t i o n s (10- " 10 5 M), cimetidine caused a significant potentiation of the n o r e p i n e p h r i n e - i n d u c e d rate increase in S H R hearts (fig. 2). In W K Y , the n o r e p i n e p h rine response was potentiated significantly only at the lowest c o n c e n t r a t i o n of the drug (10 ~ M). ( ' h l o r p h e n i r a m i n e did not significantly affect the response to any c o n c e n t r a t i o n of n o r e p i n e p h r i n e . Pretreatment with propranolol, however, blocked the adrenergically mediated rate increase in both groups. Similarly, s i m u l t a n e o u s infusion of cimetidine and n o r e p i n e p h r i n e (10 7 M) a u g m e n t e d the in-

crease in the m e a n incidence of r h y t h m irregularities which occurred in the presence of the carec h o l a m i n e alone. This was true for both groups, although the response was significant only at the lower c o n c e n t r a t i o n s of n o r e p i n e p h r i n e (10 7 and 10 " M) in the W K Y p r e p a r a t i o n s (fig. 3). Chlorp h e n i r a m i n e did not affect the response to n o r e p i n e p h r i n e , while p r o p r a n o l o l e l i m i n a t e d it in both groups.

,~.4. E//ects o/histamine on norepmephrine-induced changes W h e n given alone, histamine (10 ~' M) does not significantly affect s p o n t a n e o u s rate in S H R ventricles ( C a m e r o n et al., u n p u b l i s h e d observa-

28

WKY loo-

604020o-

~

a

i

S i

~00-

~

20-o-

b I

7

I

6

I

I

5

• log [Noreplnephrlne]

4

(M)

Fig. 3. |'ffects of pretreatment with cimetidin¢, propranolol or histamine on norepinephrine-induced arrtl?,thmogunesis m P,olated W K Y (a) and SHR (b) ventricles. Norepinephrine increased the mean percent of time during '.~.hich arrh~,'thmias (including premature beats, repetitive tachyarrhythmias and delayed afterdepolarizations) v, ere obser,.ed in both WKY and SHR preparations. The concentration threshold for increased catecholamine-induced arrhythmogenesis wa~ lowest in WKY ventricles: mean pre-drug incidence of arrhythmias is indicated by arrows at left (see table 2). The incidence of ,lrrh},thmia~ in response to norepinephrine ~as potentiated by cimetidine but decreased b~, propranolol. Histamine inhibited the NE-induced increases in SIIR but not WKY. Significant difference.,,: ~ from pre-drug value: * from re~,ponse to N I- alone at concentration sho~vn.

tion). Concurrent administration of norepinephrine and histamine attenuated the increases in rate and incidence of arrhythmias observed in SHR hearts with norepinephrine alone. The increases in W K Y hearts were not significantly affected, however (figs. 2, 3).

4. Discussion While prior investigators have reported a roodulatory effect of histamine on adrenergic responses in the heart, the interaction between histamine and norepinephrine in myocardial hypertrophy has not been described previously,

As in most animal models of hypertension and myocardial hypertrophy, StIR demonstrate prolonged ventricular action potential duration relatire to normotensive controls (WKY) (Hayashi and Shibata, 1974: table 1). Accompanying the abnormal action potential configuration in hypertensive rats is an increased propensity for the development of cardiac arrhythmias, including delayed afterdepolarizations (Aronson, 1981). The mechanism of the increased vulnerability to arrhythmogenesis is unclear (see below). In the present study, the tllreshold concentration for significant norepinephrine-induced increases in spontaneous rate (fig. 2) and the incidence of all arrhythmias (fig. 3) was lower (10 "

29 M) in WKY than in SHR. The data on percent rate increases, however, must be viewed in light of the fact that the initial rates for the two groups were significantly different (table 2). Alterations in adrenergic responsiveness associated with hypertension and myocardial hypertrophy have been reported previously; decreased reactivity to catecholamine is the usual finding (Vatner et al., 1984; Fouad et al., 1985). Altered responsiveness to histamine in cardiac hypertrophy has been examined far less often, While the marked arrhythmogenic effect of histamine in normal myocardium is widely appreciated (Wolff and Levi, 1986), there is also evidence that diseased hearts are more responsive to the adverse electrophysiologic effects of histamine than are normal hearts (Levi et al., 1979; Cameron et al., 1985; Li et al., 1987). We have recently confirmed this observation in hypertrophied hearts of SHR, and showed that by preventing the onset of hypertension, the enhanced propensity for development of cardiac arrhythmias was elimihated (Cameron and Antonik, 1988).

4.1. A rrhythmogenic mechanisms

Prolonged action potential duration in hypertension has been associated with alterations in Ca" + or K ' currents in the ventricular sarcolemma (Aronson, 1981; Kleiman and Houser, 1988; Cameron et al., 1988). Abnormal ion channel kinetics may arise in an environment of myocyte hypertrophy and global myocardial ischemia (Maron et al.. 1987) resulting from a drastic decline in capillary density (Engelman et al., 1987). In addition, focal ischemia in hypertrophied myocardium may come about via spasm of the microvasculature (Factor et al., 1982). The onset of ischemia, whether global or focal, is thought to increase sympathetic discharge and promote a rapid release of norepinephrine from neural and other stores (Zipes et al., 1981). Thus, plasma norepinephrine concentrations are significantly higher in SHR than in normal rats (Mukherjee et al., 1980). This increase in humoral catecholamine levels is thought to induce a 'down-regulation" of /3-adrenoceptors.

Similarly, there is a mean 10-fold increase in the histamine concentration of plasma in the coronary sinus in response to coronary occlusion in dogs; in the subsequent 30 min, the increase in the incidence of arrhythmias, the histamine level and infarct size are all positively correlated (Wolff and Levi, 1986; 1988). Further, Masini et al. (1988) have reported that plasma histamine significantly increases 10-72 h after coronary occlusion in dogs, and during acute coronary occlusion-reperfusion in isolated guinea pig heart. Although histamine has been reported to be without positive chronotropic effect in rat hearts (McNeill, 1984), there is similar evidence that histamine release from rat myocardium after acute coronary artery ligation contributes to the genesis of ventricular arrhythmias (Dai, 1987; Ko et al., 1988). Both histamine and norepinephrine have been shown to promote the slow inward current carried primarily by calcium (I~.) (Reuter, 1983; Hescheler et al., 1987). Wolff and Levi (1986) reviewed the evidence indicating that histamine exerts its arrhythmogenic influence in the ventricle by an H2-mediated potentiation of I~,. Thus, ischemia a n d / o r hypertrophy promote the availability of both norepinephrine and histamine in plasma, each of which may separately increase [Ca2*], in the myocardium. Increased Ca 2~ influx through the sarcolemma may cause elevated levels of intracellular calcium. On the other hand, enhanced vulnerability to histamine-induced arrythmogenesis in SHR (Cameron and Antonik, 1988) may reflect a reversible alteration of reticular Ca e'transport; a similar mechanism has been advanced to explain increased vascular reactivity to histamine in systemic hypertension (Thompson et al., 1987). Whatever the source of elevated [Ca 2'],. its presence may precipitate a variety of electrophysiologic abnormalities, including slow action potenrials, electrical uncoupling and afterdepolarizations and triggered activity(Wit and Rosen, 1983; Amerini et al., 1985). 4.2. Interaction of histamine and neurohumoral factors

We found that histamine attenuates the arrhythmogenic effects of norepinephrine in SHR but not WKY ventricles, a response apparently

3(/

mediated by H2-receptors (fig. 3). This suggests a postjunctional inhibitor.,,' effect of histamine in hypertrophied myocardium, a setting in which altered responsiveness to both histamine and norepinephrine have been demonstrated, The influence of catecholamines on histamine release has long been appreciated, both in cardiac systems and elsewhere (Giotti et al., 1966; Lichtenstein and Margolis, 1968). Conversely, histamine has been shown to reduce the positive chronotropic response to sympathetic nerve stimulation in dogs, although not to infusion of norepinephrine; the response was mediated by both H 1- and Hz-receptors (Lockhandwala, 1978: Kimura and Satoh, 1983). This would suggest a presynaptic mechanism. Giacomini and Reis (1986), however, found that histamine reduces the norepinephrine-induced rate increase in isolated guinea pig atria via H2-receptors, indicating a potential for postjunctional inhibition. Gross et al. (1984) found that histamine attenuated the heart rate increases caused by both sympathetic nerve stimulation and i n t r a c a r d i a c infusion of norepinephrine in guinea pig. They concluded that a postjunctional mechanism was involved in the modulation by histamine of adrenergic mechanisms, Dai (1987) distinguished between the chronotropic effects of histamine in ischemic rat myocardium on one hand, and its arrhythmogenic influence on the other, concluding that they arise via different mechanisms. Previous attempts to clarify the interaction between histamine and norepinephrine in terms of their arrhythmogenic effects have been few. Stowe et al. (1987) observed that histamine may promote ventricular rhythm disturbances caused by epinephrine in n o r m a l guinea pig hearts. In contrast, the arrhythmogenic effects of norepinephrine in WKY w e r e n o t increased by histamine in the present study; however, in SHR, adrenergically induced rhythm disturbances w e r e inhibited b y h i s t a m i n e . T h i s o b s e ~ ' a t i o n is in o n e sense not surprising, in that reactivity to the arrhythmogenic effects of catecholamines is reduced in hypertrophied hearts (sec above: table 2). On the other hand. the potential for development

of

histamine-induced

increased in hypertrophy.

arrhythmias

is

Clearb,'. then. the separate arrhythmogenic effects of histamine and norepincphrine are not additive. Recent voltage clamp studies in guinea pig vcntricular myocytes by Hescheler et al. (19871 may help to explain this observation. They showed that the effects of histamine and isoproterenol to promote inward Ca z " current also are not additive. It is possible, then, that these agents promote the development of potentially lethal arrhvthmias by identical mechanisms, invob,'ing an enhancement of sarcolemmal Ca:" influx. The precise mechanism by which histamine inhints the arrhythmogenic influence of catecholamines is unclear. Speculation as to the physiological significance of such an arrangement has centered on the existence of an l-!~-mediated negative feedback loop. such that sympathetically released histamine interacts with postsynaptic B-receptors to attenuate their response(Wolff and Levi. 1986). If so. lt,-blockade would be expected to enhance the incidence of arrhvthmias associated with ischemia, as recently demonstrated b\' Wolff and Levi (1988). Our data support thepossibilitv that this or a similar mechanism persists in hypertrophied myocardium. The widespread therapeutic use of fle-adrenoceptor blockade in ischemic heart disease, as well as the possibly dangerous potential for concomitant use of il:-antagonists, warrants further investigation of histamine-norepinephrine interactions in diseased myocardium.

Acknowledgements We would like to thank I)orothea A. Jackson-Burns for technical support. This work was supported b~ a grant-in-aid from the American Heart Association, Massachusetts Affiliate (13-527-867), by United Stales Public Health Service G r a m s HL-34672 and HL-19044 from the National Heart, Lung and Blood Institute, NIH, and by grants from Wellesly College. C.R.S. was supported in part by a Research Fellowship from the Charles A. Dana Foundation.

References Amerini. S.. F. Fusi and A. Mugelli, 1985. Role of oscillatory afterpotentials in the arrhythmogenic action of histamine. Agents Actions 16, 219.

31 Aronson, R.S.. 1981, Afterpotentials and triggered activity in hypertrophied myocardium, Circ. Res. 48, 720. Cameron. J.S. and L.J. Antonik, 1988, Prevention of hypertension is associated with reduced susceptibility to histamineinduced arrhythmias in SHR, Am. J. Hypert. 1. 34S. Cameron, J.S., M.S. Gaide, P.L. Goad, C.B. Airman, J. Cuevas, R.J. Myerburg and A.L. Bassett, 1985, Enhanced adverse electrophysiologic effects of histamine after myocardial infarction in guinea pigs, J. Pharmacol. Exp. Ther. 232, 480. Cameron, J.S. and J. Han. 1982. Effects of epinephrine on automaticity and the incidence of arrhythmias in Purkinje fibers surviving myocardial infarction, J. Pharmacol. Exp. Ther. 223, 573. Cameron, J.S., S. Kimura, D.A. Jackson-Burns. D.B. Smith and A.L. Bassett, 1988. ATP-sensitive K" channels are altered in hypertrophied ventricular myocytes, Am. J. Physiol. 255, H1254. Dai, S., 1987. Ventricular histarnme concentrations and arrhythmias during acute 6ayocardial ischaemia in rats, Agents Actions 21.66. Engelmann, G.L., J.C. Vitullo and R.G. Gerrity, 1987, Morphometric analysis of cardiac hypertrophy during development. maturation, and senescence in spontaneously hypertensive rats, Circ. Res. 60, 487. Factor, S.M., T. Minase, S. Cho, R. Dominitz and E.H. Sonnenblick, 1982. Microvascular spasm in the cardiomyopathic Syrian hamster: a preventable cau~ of focal myocardial necrosis. Circulation 66, 342. Found. F.M., K. Shimamatsu, M.M. Hanna, P.A. Khairallah and R,('. "l-arazi, 1985. Impaired inotropic responses to c~-adrenergic stimulation in experimental left ventricular hypertrophy. Circulation 71, 1023. Giacomini. V.A. and C.C.A. Reis, 1986, Antagonistic effect between histamine and norepinephrine on isolated guineapig right atrium, Gen. Pharmacol. 17, 219. Giotti, A., A. Guidotti, P.F. Mannaioni and L. Zilletti, 1966, l h c influences of adrenotropic drugs and noradrenaline on the histamine release in cardiac anaphylaxis in vitro, J. Physiol. 184, 924. Gross, S.S., Z.-G. Guo. R. I,evi. W.H. Bailey and A.A. Chcnouda. 1984, Release of histamine by sympathetic nerve stimulation in the guinea pig heart and modulation of adrenergic responses: A physiological role for cardiac histamine?, Circ. Res. 54, 516. Hayashi. H. and S. Shibata. 1974, Electrical property of cardiac cell membraneof spontaneously hypertensive rat. European J. Pharmacol. 27, 255. Hescheler. J., M. Tang, B. Jastorff and W. Trautwein, 1987, On the mechanism of histamine induced enhancement of the cardiac C a 2 " current, Pfliigers Arch. 410, 23. Kimura. T. and S. Satoh, 1983, Inhibition of cardiac sympathetic neurotransmission by histamine in the dog is mediated by I,i I receptors, Br. J. Pharmacol. 78, 733. Kleiman, R.B. and S.R. Houser, 1988, Calcium currents in normal and hypertrophied isolated feline ventricular myocytes. Am. J. Physiol. 255, H1434. Ko, W.W.-W., S. Dai and M.-Y. Chan, 1988, Ventricular histamine concentrations in naive and morphine-treated

rats during acute myocardial ischaemia, Agents Actions 24, 95. Levi, R., J.H. Zavecz, C.-H. Lee and G. Allan, 1979, Histamine-drug-disease interactions and cardiac function, in: Histamine Receptors, ed. T.O. Yellin (Spectrum Publications, Inc., New York) p. 99. Li, Y.-S.. S.-X. Fu and C.-G. Li, 1987, Arrhythmogenic effects of histamine on ischemic hearts of guinea pigs, Acta Pharmacol. Sin. 8. 536. Lichtenstein, L.M. and S. Margolis, 1968, Histamine release in vitro: inhibition by catecholamines and methylxanthines. Science 161,902. Lokhandwala. M.F., 1978, Inhibition of sympathetic nervous system by histamine: Studies with I-t~ and H~ receptor antagonists. J. Pharmacol. Exp. Ther. 206, 115. Maron, B.J., R.O. Bonow, R.O. Cannon 111, M.B. Leon and S.E. Epstein, 1987, Hypertrophic cardiomyopathy, lnterrelations of clinical manifestations, pathophysiology, and therapy, N. Engl. J. Med. 316. 780. Masini. E.. E. Giannella, S. Bianchi. B. Palmerani. A. Pistelli and P.F. Mannaioni. 1988. Histamine release in acute coronary occlusion-reperfusion in isolated guinea pig heart, Agents Action 23, 266. McNeill, J.H., 1984, Histamine and the heart, Can. J. Physiol. Pharmacol. 62. 720. Mukherjce, A., R.M. Graham, A.t,. Sagalowsky. W. Pettinger and K.E. McCoy, 1980, Myocardial beta-adrenergic receptors in the stroke-prone spontaneousl) hypertensive rat, J. Mol. (.'ell. Cardiol. 12, 1263. Reuter, |i., 1983, Calcium channel mc,dulation h~ neurotransmitters, enzymes and drugs, Nature 301. 569. Stowe. D.F., Z.J. Bosnjak, J. Marijic and J.P. Kampine, 1988, Effects of halothane with and without histamine and/or epinephrine in automaticity, intracardiac conduction times, and the development of dysrhythmias in the isolated guinea pig heart, Anesthesiology 68, 695. Thompson. L.P., C.A. Bruner, F.S. Lamb. ('.M. King and R.C. Webb, 1987. Calcium influx and vascular reactivity in systemic hypertension. Am. J. Cardiol. 59. 29A. Vatner, D.E., C.J. Homey, S.P. Sit, W.T. Manders and S.F. Vatner, 1984. Effects of pressure overload, left ventricular hypertrophy on /3-adrenergic receptors and responsiveness to catecholamines, J. Clin. Invest. 73, 1473. Wallenstcin. S,, C.L. Zucker and J.L. Fleiss, 1980. Some statistical methods useful in circulation research, Circ. Res. 47, 1. Wit, A.L. and M.R. Rosen, 1983, Pathophysiologic mechanisms of cardiac arrhythmias, Am. Heart J. 106, 798. Wolff, A.A. and R. Levi, 1986, tlistamine and cardiac arrhythmias, Circ. Res. 58, 1. Wolff, A.A. and R. Levi. 1988, Ventricular arrhythmias parallel cardiac histamine efflux after coronary artery occlusion in the dog, Agents Actions 25, 296. Zipes. D.P.. J.B. Martins. R. Ruffy. E.N. Prystowsky, V. Elhartar and R.F. Gilmour, Jr., 1981, Roles of autonomic innervation in the genesis of ventricular arrhythmias, in: Disturbances in Neurogenic Control of the Circulation, eds. F.M. Abboud, H.A. Foz.zard, J.P. Gilmore and D.J. Reis (Am. Physiological Soc., Bethesda) p. 225.