- Email: [email protected]
Adenosine in the mammalian heart: nothing to get excited about
VIEWPOINT
Adenosine in the mammalian heart: nothing to get excited about Amir Pelleg and Steven P. Kutalek Until quite recently, adenosine
the cardiodepressant
were widely
produces
negative
adenosine,
accepted.
chronotropic
A nucleoside and ionotropic
has been used clinically
choice for terminating (atrioventricular an important this, recent
part in regulating
a paradoxical
that effects,
as the drug of
experimental
and is likely to play
arrhythmogenic
antiarrhythmic
from in vitro studies
of
supraventricular
node) tachycardia
as an endogenous
actions
metabolite.
data, particularly
using animal models,
excitable
action of adenosine
activity Despite
resulting have shown in the
heart. In this article,
Amir Pelleg and Steven Kutalek
present
why they continue
the reasons
any excitatory clinically
actions
of adenosine
to believe that
in the heart are
irrelevant.
Several in vitro studies summarized in a recent review by Hernandez and Ribeiroi, which is similar to their earlier review on the same subject*, claim that adenosine exerts an excitatory effect on ventricular automaticity. Automaticity of excitable cells is their ability to depolarize spontaneously, which in the heart is manifested in the repetitive cyclical activity of normal and abnormal pacemakers. Another form of repetitive activity is triggered activity (TA) associated with early (EADs) and/or delayed (DADS) afterdepolarizations. Thus, Hemandez and Ribeiro imply explicitly that adenosine excites ventricular pacemakers and implicitly, enhances TA (Ref. 1). However, the opposite appears to be the case, that is, the suppression of both ventricular pacemaker activity and TA by adenosine has been demonstrated in numerous studies, none of which is cited in that review.
In vitro studies A. Pslleg. Professor. and S. P.Kutalek. Allegheny University of Health Sciences, Likoff Cardiovascular Institute. Department of Medicine, Philadelphia. PA 19102-1192,USA.
2 3 6
The depressant effects of adenosine on ventricular automaticity have been observed in several experimental models in vitro including dog Purkinje fibers, rat ventricular preparation and perfused guinea-pig heart~ia. In fact, adenosine is 30 times more effective in suppressing ventricular than sinoatrial (SA) pacemakerss. This differential sensitivity was documented also in vim (see below). In an experimental model similar to that used by Hemandez and Ribeirol, HeIler et al.73found no evidence for increased ventricular automatic@ by adenosine; on the
~2’s -July
1997 (Vol. 18)
contrary, adenosine caused a concentration-dependent inhibition of ventricular automaticity. Specifically, ventricular automaticity was not affected by low concentrations (i.e. l-10On~) of adenosine but was significantly inhibited by higher concentrations of the nucleosidea. In addition, Heller and 01sson7demonstrated that this effect of adenosine was mediated by adenosine A, receptors of the pacemaker cells, and not by the modulation of neurotransmitter release. These findings are in agreement with results obtained with canine I’urkinje fibers4and a guinea-pig ventricular preparation3 as well as Hemandez and Ribeiro’s own data, which demonstrated that the inhibitory effect of diazepam on ventricular automaticity is mediated by adenosine, the transport of which is blocked by the drugli. Furthermore, there is compelling evidence for the mediation by adenosine of the inhibitory effect of hypoxia and ischaemia on atria1and ventricular automaticivl2. Moreover, data obtained by Hemandez and Ribeiro, which are the basis for their hypothesis, are problematic. In particular, the finding that very low concentrations of adenosine (i.e. O.l-10nM) increased ventricular automaticity’a. These concentrations of adenosine are several-fold lower than either 79m4, which is the rat plasma level of adenosine under unstressed conditions, or 100-300I-W,which is the estimated guinea-pig myocardial interstitial adenosine level. Thus, these results of Hemandez and Ribeirol imply that physiological levels of extracellular adenosine should exert a tonic excitatory effect on ventricular automaticity and consequently either adenosine antagonists or adenosine deaminase should exert a negative chronotropic effect on ventricular pacemakers. Importantly, there are no data supporting either the latter conclusion or a constitutive action of adenosine in the heart. On the contrary, adenosine antagonists are devoid of any electrophysiological effect unless endogenous levels of adenosine are elevated6,8.Furthermore, Hemandez and Ribeiro’s observation that at low concentrations, adenosine enhances ventricular automaticity and at high concentrations depresses itI3is also inconsistent with relevant observations in the clinical setting. That is, in patients with myocardial ischaemia adenosine’s plasma levels are elevated to the micromolar range, therefore, adenosine should suppress ventricular automaticity and not enhance it.
ln vivo studies Several studies in uivo have established the negative chronotropic action of adenosine on junctional and ventricular pacemakers. In dogs with complete atrioventricular (AV) nodal conduction block and stable ventricular escape rhythm, adenosine exerts a dose-dependent slowing of heart rate 14Js.In addition, adenosine slowed junctional rhythms in the canine heart. Moreover, the sensitivity of cardiac pacemakers (in viva and in vitro) to adenosine follows the order of: venticuIar>junctior&SA (Refs 5,15,16). Furthermore, the negative chronotropic action of adenosine was attenuated and enhanced by aminophyIline and dipyridamole, respectively, suggesting a mediation of this action by a cell surface receptor14.Because the A, recep-
0 1997, Elsevier Science Ltd
PII:SOl65-6147(97)01084-5
VIEWPOINT
tar antagonist, NO861 (N6-endonorbornan-Z-yl-9methyladenine) (Ref. li’), attenuated overdrive suppression of ventricular pacemakers in vim, it can be concluded that the A, receptor mediates the negative chronotropic action of adenosine on ventricular pacemaker+Js. Adenosine and ventricular arrhythmias Regarding other ventricular rhythms, Hemandez and Ribeiror apparently favour the view that adenosine exerts arrhythmogenic effects in the ventricular myocardium. However, there are considerable data to the contrary (for review see Ref. 18). First, it was recently shown that adenosine can suppress digoxin-induced triggered activity in the guinea-pig heart iti vivo and that this action is mediated by the anti-a-adrenergic action of the nucleoside19. The latter action is probably respon-sible also for the antiarrhythmic effect of adenosine on non-re-entrant ventricular tachycardia which was demonstrated in both animals and human patients’2 (for review see Ref. 18). In addition, several studies have demonstrated that adenosine can exert beneficial effects on ventricular rhythms, the mechanism of which is not fully elucidatedls. For example, adenosine reduced the incidence of arrhythmias in the isolated perfused rat heart as well as anesthetized rats subjected to acute myocardial In another in viva rat model ischaemiarx. with bilateral cervical vagotomy, adenosine prevented the decrease in ventricular fibrillation threshold induced by coronary artery ligationrs. Moreover, adenosine and the A, receptor agonist, R-PIA [R(-)N6(2-phenylisopropyl)adenosine], decreased the rate of ventricular tachycardia 24 h after acute regional myocardial ischaemia. Similar results were obtained in the pig heart in viva. Finally, PD81723, an allosteric enhancer of the cardiac A, receptor, exerted an antiarrhythmic effect in the acutely ischaemic rabbit hearPa. Clinical studies Hernandez and Ribeiro cited several reports on cardiac arrhythmias associated with the use of adenosine in the clinical setting to support their hypothesis that adenosine enhances ventricular automaticity in the mammalian heart’. It seems, however, that selective citation and misinterpretation of published data have led to the authors’ conclusion. Specifically, regarding adenosine-induced ventricular ectopic activity, several studies have shown that the incidence of adenosine (as well as ATP) induced premature contractions (WCs) and nonsustained ventricular tachycardia (VT) is similar to that of verapamil (in the same patient population). In view of the different electrophysiological mechanisms of action of adenosine and verapamil, it is highly likely that the ventricular ectopic activity induced by both compounds was due to indirect action mediated by a sympathetic reflex. The latter can be triggered by the transient asystole following termination of paroxysmal supraventricular tachycardia by adenosine or verapamil. In addition, adenosine can directly elicit sympathetic afferent traffic by stimulating chemosensitive nerve terminals within and without the hearPI. Indeed, adenosine
induced a transient increase in heart rate, blood pressure and skeletal muscle sympathetic nerve activity in healthy adults=-2”. The acceleration of ventricular response to an underlying atria1 tachyarrhythmia following adenosine is well describedzs-29. This has occurred in patients with sustained atria1 flutter in generaPJ7, and children with congenital heart disease in particula+. This phenomenon could also be explained by adenosine’s stimulation of the sympathetic limb of the autonomic nervous system. Acceleration of the ventricular rate following the administration of adenosine has been observed in patients with accessory pathways, including left lateral and atria1 dextro fascicular pathways. In addition, venas well as atria1 tachycardia tricular fibrillatiorPJ*J0 with rapid AV conduction29 have also been observed in patients with accessory pathways following the administration of adenosine. These arrhythmias are likely to be due to enhanced sympathetic input to the heart concomitant with the complete AV nodal conduction block induced by adenosine. Finally, Hernandez and Ribeirol mention the induction of torsades de pointes (TdP) by intravenous adenosine31J2 as a manifestation of adenosine’s induced enhanced ventricular automaticity. However, the mechanism of this type of arrhythmia is thought to be associated with EADs-dependent triggered activity bradycardia, and the prolongation of the action potential plateau and the QT intervaP3. Thus, the induction of TdP by adenosine in this case was probably secondary to the slowing of the heart rate and prolongation of the QT interval, and not due to acceleration of ventricular pacemakers as proposed by Hernandez and Ribeiro. It can be concluded that the few cases of ventricular tachyarrhythmias observed in patients following the administration of adenosine were due to other mechanisms than adenosine’s induced enhancement of ventricular automaticity. In summary, adenosine not only does not exert a direct excitatory effect on the ventricular myocardium, but it exerts a direct negative chronotropic action on the His-Purkinje fibers and indirect anti-adrenergic action on the ventricular myocardium. References 1 Hemandez,J. and Ribeiro,J. A. (1996) Trends Phurtwol. Sci. 17,141-144 2 Hemandez, J. and Ribeiro J. A. (1995) Life Sci. 57,1393-1399 3 Szentmiklosi, A. J., Nemeth, M., Szegi, J., Papp Gy and Szekeres, L. (1980) Nuunyn-Schmiedeberg’s Arch. Pharmacol. 311,147-149 4 Rosen, M. R., Danilo I’., Jr and Weiss R. M. (1983) Am. 1, Physiol 244, H715-H721 5 Belardinelli, L., West, A., Crampton, R. and Beme, R. M. (1983) in Reg. uhtory Functm $Adenosine (Beme, R. M., RaU, T. W. and Rubio, R., eds), pp. 377-398, Martinus Nijhoff Publishers 6 Wesley, R. C., Jr and Belardinelli, L. (1985) Circ. Res. 57,517-531 7 Heller, L. J. and Olsson, R. A. (1985) Am. 1, Physiol. 248, H907-H913 8 Heller, L. J., Dewitt, D. F. and Sparks, H. V. (1987) Curdiounsc. Rts. 21, 391-398 9 Lerman, B. B., Belardinelli, L., West, G. A., Beme, R. M. and DiMarco, J. I’. (1986) Circulation 74,271-280 10 Belardinelli, L., Shryock, J. C., Song, Y., Wang, D. and Srinivas, M. (1995) FASEB I. 9,359-365 11 Ruiz, F., Hemandez, J. and Ribeiro, A. J. (1988) Eur. \. Phumracol. 155,
TiPS
- July 19Y7
(Vol. 18)
2
3 7
VIEWPOINT
Acknowledgements We thank Drs Belardmelll
tub
and Bruce B
Lerman far their helpful comments and Mrs Dwendolyn Dtllard and MS Chelyl A Courm for their awstance
I” the
preparation of this manu-
scriptorIgInal work was supported I” part by NIH grant HL43006IAPl
205-209 12 Kobayashi, Y. et al. (1994) PACE 17,377-385 13 Laorden, M. L., Hemandez, J. and Ribeiro, J. A. (1986) Arch. Int. Pharmacodyn. 279,258-267 14 PeBeg, A., Mitamura, H., Mitsuoka, T., Michelson, E. L. and Dreifus, L. S. (1986) J. Am. Co2l.Cnrdiol. 8,1145-1151 15 Pelleg, A., Hurt, C., Miyagawa, A., Michelson, E. L. and Dreifus, L. S. (1990) Am. J Physiol. 258, H1815-H1822 16 Pelleg, A., Hurt, C. M. and Michelson, E. L. (1990) Ann. Neul YorkAcud. Sci. 603,19-30 17 PeUeg, A. and Hurt, C. M. (1992) Can. J. Physiol. Pharmucol. 70, 1450-1457 18 Pelleg, A. and Xu, J. (1996) in Purines and Myocardiul Protection (Abd-Elfattah, A. S. and Wecbsler, A. S., eds), pp. 373-382, Kluwer Academic Publishers 19 Xu, J., Hurt, C. M. and Pelleg, A. (1995) Heart Vessels 10,119-127 20 Xu, J., Wang, L., Belardinelli, L. and Pelleg, A. (1994) Drug Dezt Ra. 31, 335 21 Pelleg, A., Katchanov, G., and Xu, J. Am. J Curdiol. (in press) 22 Watt, A. H. and Routledge, P. A. (1986) Br. J. Clin. Pharmacol. 21, 533-536 23 Biaggioni, I., O&son, B., Robertson, R. M., Hollister, A. S. and Robertson, D. (1987) Circ. Res. 61,779-786 24 Biaggioni, I., Killian, T. J., Mosqueda-Garcia, R., Robertson, R. M. and
Robertson, D. (1991) Circuhtion 83,1668-1675 25 Slade, A. K. B. and Garratt, C. J. (1993) Br. Hem?J 70,91-92 26 Rankin, A. C., Rae, A. P. and Houston, A. (1993) Br. Heart J69,263-265 27 Cowell, R. I? W., Paul, V. E. and Bsley, C. D. J. (1994) Br. Heart [, 71, 569-571 28 Garratt, C. J., O’Nunain, S., Griffith, M. J. and Connelly, D. T. (1994) Am. 1. Curdiol. 74,401-404 29 Exner, D. V., Muzyka, T. and Gillis, A. M. (1995) Ann. Intern. Med. 122, 351-352 30 Ben-Sorek, E. S. W. and Wiesel, J. (1993) Intern. Med. 53, 2701-2702 31 Wesley, R. C., Jr and Turnquest, P. (1992) Am. Henrf 1. 123, 794-796 32 Harrington, G. R. and Froelich, E. G. (1993) Chesst103,1299-1301 33 Guideri, F. et al. (1995) Int. J. Cnrdiol. 48,67-73
I
I
Chymical name
1
PD81723: (2-ammo-4,5-drmethyl-3-threnyl)-[3-(trrfluromethyl)phenyl]methanone.
In the September issue.... The Trends Guide to the Internet (1997) Feeling left behind? Worried about time-wasting? through those all-important effectively.
This free guide will lead you
first steps towards using the Internet efficiently and
Written by an international
panel of experts, the guide will tell you
what to expect and where to find it. Articles include:
l
Key terms: the jargon explained
l
l
The origins of the Internet
Basic Internet facilities and how to connect l
l
USENET: setting up and joining newsgroups l
l
The World Wide Web
Creating your own home page
FTP: how to retrieve files from around the world l
What’s new in online journals l
Where to go next for help
Also including a poster listing useful sites to visit. For further information [email protected];
2 3 8
‘i-d’s -July
1997 (Vol. 18)
concerning bulk sales, contact Thelma Reid: e-mail,
Tel, +44 1223 311114; Fax, +44 1223 321410.
1
Adenosine in the mammalian heart: nothing to get excited about Amir Pelleg and Steven P. Kutalek Until quite recently, adenosine
the cardiodepressant
were widely
produces
negative
adenosine,
accepted.
chronotropic
A nucleoside and ionotropic
has been used clinically
choice for terminating (atrioventricular an important this, recent
part in regulating
a paradoxical
that effects,
as the drug of
experimental
and is likely to play
arrhythmogenic
antiarrhythmic
from in vitro studies
of
supraventricular
node) tachycardia
as an endogenous
actions
metabolite.
data, particularly
using animal models,
excitable
action of adenosine
activity Despite
resulting have shown in the
heart. In this article,
Amir Pelleg and Steven Kutalek
present
why they continue
the reasons
any excitatory clinically
actions
of adenosine
to believe that
in the heart are
irrelevant.
Several in vitro studies summarized in a recent review by Hernandez and Ribeiroi, which is similar to their earlier review on the same subject*, claim that adenosine exerts an excitatory effect on ventricular automaticity. Automaticity of excitable cells is their ability to depolarize spontaneously, which in the heart is manifested in the repetitive cyclical activity of normal and abnormal pacemakers. Another form of repetitive activity is triggered activity (TA) associated with early (EADs) and/or delayed (DADS) afterdepolarizations. Thus, Hemandez and Ribeiro imply explicitly that adenosine excites ventricular pacemakers and implicitly, enhances TA (Ref. 1). However, the opposite appears to be the case, that is, the suppression of both ventricular pacemaker activity and TA by adenosine has been demonstrated in numerous studies, none of which is cited in that review.
In vitro studies A. Pslleg. Professor. and S. P.Kutalek. Allegheny University of Health Sciences, Likoff Cardiovascular Institute. Department of Medicine, Philadelphia. PA 19102-1192,USA.
2 3 6
The depressant effects of adenosine on ventricular automaticity have been observed in several experimental models in vitro including dog Purkinje fibers, rat ventricular preparation and perfused guinea-pig heart~ia. In fact, adenosine is 30 times more effective in suppressing ventricular than sinoatrial (SA) pacemakerss. This differential sensitivity was documented also in vim (see below). In an experimental model similar to that used by Hemandez and Ribeirol, HeIler et al.73found no evidence for increased ventricular automatic@ by adenosine; on the
~2’s -July
1997 (Vol. 18)
contrary, adenosine caused a concentration-dependent inhibition of ventricular automaticity. Specifically, ventricular automaticity was not affected by low concentrations (i.e. l-10On~) of adenosine but was significantly inhibited by higher concentrations of the nucleosidea. In addition, Heller and 01sson7demonstrated that this effect of adenosine was mediated by adenosine A, receptors of the pacemaker cells, and not by the modulation of neurotransmitter release. These findings are in agreement with results obtained with canine I’urkinje fibers4and a guinea-pig ventricular preparation3 as well as Hemandez and Ribeiro’s own data, which demonstrated that the inhibitory effect of diazepam on ventricular automaticity is mediated by adenosine, the transport of which is blocked by the drugli. Furthermore, there is compelling evidence for the mediation by adenosine of the inhibitory effect of hypoxia and ischaemia on atria1and ventricular automaticivl2. Moreover, data obtained by Hemandez and Ribeiro, which are the basis for their hypothesis, are problematic. In particular, the finding that very low concentrations of adenosine (i.e. O.l-10nM) increased ventricular automaticity’a. These concentrations of adenosine are several-fold lower than either 79m4, which is the rat plasma level of adenosine under unstressed conditions, or 100-300I-W,which is the estimated guinea-pig myocardial interstitial adenosine level. Thus, these results of Hemandez and Ribeirol imply that physiological levels of extracellular adenosine should exert a tonic excitatory effect on ventricular automaticity and consequently either adenosine antagonists or adenosine deaminase should exert a negative chronotropic effect on ventricular pacemakers. Importantly, there are no data supporting either the latter conclusion or a constitutive action of adenosine in the heart. On the contrary, adenosine antagonists are devoid of any electrophysiological effect unless endogenous levels of adenosine are elevated6,8.Furthermore, Hemandez and Ribeiro’s observation that at low concentrations, adenosine enhances ventricular automaticity and at high concentrations depresses itI3is also inconsistent with relevant observations in the clinical setting. That is, in patients with myocardial ischaemia adenosine’s plasma levels are elevated to the micromolar range, therefore, adenosine should suppress ventricular automaticity and not enhance it.
ln vivo studies Several studies in uivo have established the negative chronotropic action of adenosine on junctional and ventricular pacemakers. In dogs with complete atrioventricular (AV) nodal conduction block and stable ventricular escape rhythm, adenosine exerts a dose-dependent slowing of heart rate 14Js.In addition, adenosine slowed junctional rhythms in the canine heart. Moreover, the sensitivity of cardiac pacemakers (in viva and in vitro) to adenosine follows the order of: venticuIar>junctior&SA (Refs 5,15,16). Furthermore, the negative chronotropic action of adenosine was attenuated and enhanced by aminophyIline and dipyridamole, respectively, suggesting a mediation of this action by a cell surface receptor14.Because the A, recep-
0 1997, Elsevier Science Ltd
PII:SOl65-6147(97)01084-5
VIEWPOINT
tar antagonist, NO861 (N6-endonorbornan-Z-yl-9methyladenine) (Ref. li’), attenuated overdrive suppression of ventricular pacemakers in vim, it can be concluded that the A, receptor mediates the negative chronotropic action of adenosine on ventricular pacemaker+Js. Adenosine and ventricular arrhythmias Regarding other ventricular rhythms, Hemandez and Ribeiror apparently favour the view that adenosine exerts arrhythmogenic effects in the ventricular myocardium. However, there are considerable data to the contrary (for review see Ref. 18). First, it was recently shown that adenosine can suppress digoxin-induced triggered activity in the guinea-pig heart iti vivo and that this action is mediated by the anti-a-adrenergic action of the nucleoside19. The latter action is probably respon-sible also for the antiarrhythmic effect of adenosine on non-re-entrant ventricular tachycardia which was demonstrated in both animals and human patients’2 (for review see Ref. 18). In addition, several studies have demonstrated that adenosine can exert beneficial effects on ventricular rhythms, the mechanism of which is not fully elucidatedls. For example, adenosine reduced the incidence of arrhythmias in the isolated perfused rat heart as well as anesthetized rats subjected to acute myocardial In another in viva rat model ischaemiarx. with bilateral cervical vagotomy, adenosine prevented the decrease in ventricular fibrillation threshold induced by coronary artery ligationrs. Moreover, adenosine and the A, receptor agonist, R-PIA [R(-)N6(2-phenylisopropyl)adenosine], decreased the rate of ventricular tachycardia 24 h after acute regional myocardial ischaemia. Similar results were obtained in the pig heart in viva. Finally, PD81723, an allosteric enhancer of the cardiac A, receptor, exerted an antiarrhythmic effect in the acutely ischaemic rabbit hearPa. Clinical studies Hernandez and Ribeiro cited several reports on cardiac arrhythmias associated with the use of adenosine in the clinical setting to support their hypothesis that adenosine enhances ventricular automaticity in the mammalian heart’. It seems, however, that selective citation and misinterpretation of published data have led to the authors’ conclusion. Specifically, regarding adenosine-induced ventricular ectopic activity, several studies have shown that the incidence of adenosine (as well as ATP) induced premature contractions (WCs) and nonsustained ventricular tachycardia (VT) is similar to that of verapamil (in the same patient population). In view of the different electrophysiological mechanisms of action of adenosine and verapamil, it is highly likely that the ventricular ectopic activity induced by both compounds was due to indirect action mediated by a sympathetic reflex. The latter can be triggered by the transient asystole following termination of paroxysmal supraventricular tachycardia by adenosine or verapamil. In addition, adenosine can directly elicit sympathetic afferent traffic by stimulating chemosensitive nerve terminals within and without the hearPI. Indeed, adenosine
induced a transient increase in heart rate, blood pressure and skeletal muscle sympathetic nerve activity in healthy adults=-2”. The acceleration of ventricular response to an underlying atria1 tachyarrhythmia following adenosine is well describedzs-29. This has occurred in patients with sustained atria1 flutter in generaPJ7, and children with congenital heart disease in particula+. This phenomenon could also be explained by adenosine’s stimulation of the sympathetic limb of the autonomic nervous system. Acceleration of the ventricular rate following the administration of adenosine has been observed in patients with accessory pathways, including left lateral and atria1 dextro fascicular pathways. In addition, venas well as atria1 tachycardia tricular fibrillatiorPJ*J0 with rapid AV conduction29 have also been observed in patients with accessory pathways following the administration of adenosine. These arrhythmias are likely to be due to enhanced sympathetic input to the heart concomitant with the complete AV nodal conduction block induced by adenosine. Finally, Hernandez and Ribeirol mention the induction of torsades de pointes (TdP) by intravenous adenosine31J2 as a manifestation of adenosine’s induced enhanced ventricular automaticity. However, the mechanism of this type of arrhythmia is thought to be associated with EADs-dependent triggered activity bradycardia, and the prolongation of the action potential plateau and the QT intervaP3. Thus, the induction of TdP by adenosine in this case was probably secondary to the slowing of the heart rate and prolongation of the QT interval, and not due to acceleration of ventricular pacemakers as proposed by Hernandez and Ribeiro. It can be concluded that the few cases of ventricular tachyarrhythmias observed in patients following the administration of adenosine were due to other mechanisms than adenosine’s induced enhancement of ventricular automaticity. In summary, adenosine not only does not exert a direct excitatory effect on the ventricular myocardium, but it exerts a direct negative chronotropic action on the His-Purkinje fibers and indirect anti-adrenergic action on the ventricular myocardium. References 1 Hemandez,J. and Ribeiro,J. A. (1996) Trends Phurtwol. Sci. 17,141-144 2 Hemandez, J. and Ribeiro J. A. (1995) Life Sci. 57,1393-1399 3 Szentmiklosi, A. J., Nemeth, M., Szegi, J., Papp Gy and Szekeres, L. (1980) Nuunyn-Schmiedeberg’s Arch. Pharmacol. 311,147-149 4 Rosen, M. R., Danilo I’., Jr and Weiss R. M. (1983) Am. 1, Physiol 244, H715-H721 5 Belardinelli, L., West, A., Crampton, R. and Beme, R. M. (1983) in Reg. uhtory Functm $Adenosine (Beme, R. M., RaU, T. W. and Rubio, R., eds), pp. 377-398, Martinus Nijhoff Publishers 6 Wesley, R. C., Jr and Belardinelli, L. (1985) Circ. Res. 57,517-531 7 Heller, L. J. and Olsson, R. A. (1985) Am. 1, Physiol. 248, H907-H913 8 Heller, L. J., Dewitt, D. F. and Sparks, H. V. (1987) Curdiounsc. Rts. 21, 391-398 9 Lerman, B. B., Belardinelli, L., West, G. A., Beme, R. M. and DiMarco, J. I’. (1986) Circulation 74,271-280 10 Belardinelli, L., Shryock, J. C., Song, Y., Wang, D. and Srinivas, M. (1995) FASEB I. 9,359-365 11 Ruiz, F., Hemandez, J. and Ribeiro, A. J. (1988) Eur. \. Phumracol. 155,
TiPS
- July 19Y7
(Vol. 18)
2
3 7
VIEWPOINT
Acknowledgements We thank Drs Belardmelll
tub
and Bruce B
Lerman far their helpful comments and Mrs Dwendolyn Dtllard and MS Chelyl A Courm for their awstance
I” the
preparation of this manu-
scriptorIgInal work was supported I” part by NIH grant HL43006IAPl
205-209 12 Kobayashi, Y. et al. (1994) PACE 17,377-385 13 Laorden, M. L., Hemandez, J. and Ribeiro, J. A. (1986) Arch. Int. Pharmacodyn. 279,258-267 14 PeBeg, A., Mitamura, H., Mitsuoka, T., Michelson, E. L. and Dreifus, L. S. (1986) J. Am. Co2l.Cnrdiol. 8,1145-1151 15 Pelleg, A., Hurt, C., Miyagawa, A., Michelson, E. L. and Dreifus, L. S. (1990) Am. J Physiol. 258, H1815-H1822 16 Pelleg, A., Hurt, C. M. and Michelson, E. L. (1990) Ann. Neul YorkAcud. Sci. 603,19-30 17 PeUeg, A. and Hurt, C. M. (1992) Can. J. Physiol. Pharmucol. 70, 1450-1457 18 Pelleg, A. and Xu, J. (1996) in Purines and Myocardiul Protection (Abd-Elfattah, A. S. and Wecbsler, A. S., eds), pp. 373-382, Kluwer Academic Publishers 19 Xu, J., Hurt, C. M. and Pelleg, A. (1995) Heart Vessels 10,119-127 20 Xu, J., Wang, L., Belardinelli, L. and Pelleg, A. (1994) Drug Dezt Ra. 31, 335 21 Pelleg, A., Katchanov, G., and Xu, J. Am. J Curdiol. (in press) 22 Watt, A. H. and Routledge, P. A. (1986) Br. J. Clin. Pharmacol. 21, 533-536 23 Biaggioni, I., O&son, B., Robertson, R. M., Hollister, A. S. and Robertson, D. (1987) Circ. Res. 61,779-786 24 Biaggioni, I., Killian, T. J., Mosqueda-Garcia, R., Robertson, R. M. and
Robertson, D. (1991) Circuhtion 83,1668-1675 25 Slade, A. K. B. and Garratt, C. J. (1993) Br. Hem?J 70,91-92 26 Rankin, A. C., Rae, A. P. and Houston, A. (1993) Br. Heart J69,263-265 27 Cowell, R. I? W., Paul, V. E. and Bsley, C. D. J. (1994) Br. Heart [, 71, 569-571 28 Garratt, C. J., O’Nunain, S., Griffith, M. J. and Connelly, D. T. (1994) Am. 1. Curdiol. 74,401-404 29 Exner, D. V., Muzyka, T. and Gillis, A. M. (1995) Ann. Intern. Med. 122, 351-352 30 Ben-Sorek, E. S. W. and Wiesel, J. (1993) Intern. Med. 53, 2701-2702 31 Wesley, R. C., Jr and Turnquest, P. (1992) Am. Henrf 1. 123, 794-796 32 Harrington, G. R. and Froelich, E. G. (1993) Chesst103,1299-1301 33 Guideri, F. et al. (1995) Int. J. Cnrdiol. 48,67-73
I
I
Chymical name
1
PD81723: (2-ammo-4,5-drmethyl-3-threnyl)-[3-(trrfluromethyl)phenyl]methanone.
In the September issue.... The Trends Guide to the Internet (1997) Feeling left behind? Worried about time-wasting? through those all-important effectively.
This free guide will lead you
first steps towards using the Internet efficiently and
Written by an international
panel of experts, the guide will tell you
what to expect and where to find it. Articles include:
l
Key terms: the jargon explained
l
l
The origins of the Internet
Basic Internet facilities and how to connect l
l
USENET: setting up and joining newsgroups l
l
The World Wide Web
Creating your own home page
FTP: how to retrieve files from around the world l
What’s new in online journals l
Where to go next for help
Also including a poster listing useful sites to visit. For further information [email protected];
2 3 8
‘i-d’s -July
1997 (Vol. 18)
concerning bulk sales, contact Thelma Reid: e-mail,
Tel, +44 1223 311114; Fax, +44 1223 321410.
1