- Email: [email protected]
Pharmacological aspects of coronary arterial spasm
TIPS
234 that its value, for each specific value x, of measurement of effect, of which there are the independent variable, will be different. several, must be made at the time of peak The dependeut variable Y, corresponding concentration. 4 . Values of the dissociation ¢oqstants tax, is thus a r a n d o m variable, in the theory of regression analysis it is assumed that cor- for both agonist and antagonist compounds responding to cach.~, there is a 'true' value have been obtained from studies of their /1, = o + /~r, that is approximated by Y,. displace ment of radiolabeled substances of Hence. Y~ = / ~ + e,, where e~ is an error ran- high specific activity from a common high dom variable. These e, are a~sumed to be affinity binding site. The constants independent of x,. have mean zero and obtained are usually expressed as IIC~], unknown :,=riance an. Only when these the concentration which displaces the conditions p.evail can we apply the usual laheled compound by 50%, and are statistical (regression) techniques for get- obtained from a regression analysis. The ling mean values of K with correct standard equation for compe!itivc inhibition proerrors and confidence limits. It ~ e m e d vides the relation K~ = t I C . ] / ( 1 + [,4 I/IG). appropriale to mention this topic here [,41 and KA are the concentration and dissim:e the precision of the estimated dissoci- sociation constant of the labeled comation constants is important to their proper pound, respectively, and Kt i~ the dis,sociau ~ in drawing conclusions about recep- l ion constant sought. tors. The theory, underlying the use of 5. Dissociation constants obtained from regression techniques' is not only the con- binding procedures, along with those cern of statistical and mathematical special- obtained from both in vitro and in viva isls, for it was atso emphasized by pharmacological procedures, represent a Gaddum r. It .~ems noteworthy again three-pronged apwoaeh to the quantital~:re h : c a u ~ of the many studies, among tive characterization of receptors that is biochemists and among in viva and in vitro sure to be useful to our further understandpharmacologists, directed toward the ing of the mode of action of drugs and to common objective of characterizing ret~ep- our understanding of both normal and tars quantilatively. abnormal physiological states. Summary 1. The drug-receptor dissociation constunt for agonist compounds K4, is generally not equal to the A~o or EDso obtained from the dose-response relation. The computation of this constant requires more elaborate experimental procedures. 2. The KR (or - l o g KB) for a competitive antagonist is computed fn)m the equieffective agonist concentration ratio X = [A'i/[A ] corresponding to a concentration [B] Of the antagonist. When interpreted according to the simple theory of competitive antagonism, X - 1 = [BI/Ka, and the corresponding Schild-Plot intercept (the pAs) gives a direct reading of -Iog,o K,. Confidence limits for the intercept are determined from an analysis of the constrained ( - I slope) Schild plot and not from the conventional formulas4. An alternate approach to the determination of KR and its confidence limit is by direct subsiltation into the equation X - 1 = | B ]/KR. 3. Values of Ks (or I G ) bt viva have the unit of administered dose and route and mus~ be convened to tissue concentration for comparison of these with values obtained in isolated tissue. Also, the dosing schedule is based on the assumption that peak t~gsue concentration is proportional m administered dose; thus pharmacokinetics ol both agonist and antagonist in the species must be known and a schedule of I1|,~
- ¢~|4TiI(I/INI~RI
- (N)O0/$il2
]|l
-
Seplemher 1981
3 Bar, R. S. and Roth. J. (1977)An.h. Intern. Mud.
137.474-481 4 Ihtd~y, R. C. and Falhmda, R. J. Z l'hcor. B.d. (in prus~) 5 Clark, A..I. ( Iq?,3) i he .ttade of At'litm of Dnegs on Cells, Williamsand Wilkins.BaRialore 6 Furchgou,R. F.(1978) Fed. Pn~-. 37. 115-12u 7 Gaddum,J. H.(lq53)Pharmacol. Rer. 5.87-134 80Isen. R, W.. Reisine,T. D, and Yan|:|mura,H. I. (1°480)Life ~'i. [ Minireview)27, 801-808 9 Schild.H O.(1949)Br.J. PharmacoL 4, 277-280 IO Takcmori. A. E. (1974) in Nan'mi| Antagonist.~' (Braude. M. C,. tlarris,L, S..May. E. I...Smith, J. P. and Villarcal.J. E.,cds),Advanc¢~ in Biochcmical Ps}chopharm:|cology. Vol. 8. ilp.335-.344. Ralph Prcss.N e w York II Takcmori, A. E,, Hyashi. G. and 8atils.S. E. ( I q72) Ear. J, Pharmacol. 241,85-92
12 Tallarida. R. J., Cowan, A. and Adler, M. W. ( ItJ79)Lift' ScL (Minireview) 25,637-654 13 Tallarida, R. J. and Jacob, I.. S. 0979) The Dose Response Relation in Phamtacology. SpringerVcrlag. New York, Heidelbergand Berlin 14 Tallarida.R. J. and Murray. R. B. ( 1981) Maattal of Pharmaodogic Cah'alations ~','ith Computer Programs, Springer-Verlag, New York. Heidel-
berg and Berlin 15 Yamamura, II. I.. Enna. S. J. and Kuhar. M. J. (1978) Nearotransmittcr Receptor Binding. p. 71. Raven Press.New York
Ronald ]. Tallarida began his profes.~im|al careerin rite Department of .~lathematic~ at Drexel University. Philadelphia. where he reeeired the Lindback award for dL~tingaixhed teaching hi 1964. Subvequcntly he received a Special Felloa.ship from the National htv6. Reading list uae of Gene~l Medical Sciences in order to pursue 1 Ari6ng,E. J.. Simonis,A, M, and Van Rossum.J. graduate training in pharmacology. Upon completion M. (1964) in Molecular Pharmacology ( Ari6ns.E. of his Ph.D. he jobwd the filcully oJ'the School of J.. ca.), Vol. 1, pp. 119-269, Academic Press. ,~ledicine at Temple Unirersity m Philadelphia when" New York he is non. Promisor of Pharmacology. tiL~ special 2 Arunlakshana.O. and Schild. H. O. (1959) Br. J. interests include pharmacokinelics and receptor Pharmacol. 14.48-58 mechanLt-m.~.
Pharmacological aspects of coronary arterial spasm Matao Sakanashi Department o/Pharmacology. Kumamo;o University Medical School, 2.2.1 Hon]o. Kumamoto 860, Japan.
Since Prinzmetal et al. (1959) reported a variant form of angina pectoris, coronary arterial spasm has been an interesting subject for cardiologists. Recently an opinion has developed that 7(k-80% of all cases of angina peetoris are related to coronary arterial spasm, Though many investigators have made efforts In clarify the mechanism involved in coronary arterial spasm, it is not established even now. Pharmacologic.ally, coronary arterial spasm corresponds In coronary arterial contraction. Most pharmacological studies on coronary arle-
rial spasm have been performed on normal or healthy material and not on pathological or diseased tissue, and the experimental results have often shown discrepancies between in viva and in vitro studies. Thus, available experimental procedures are not always suitable to estimate the pathogenesis of coronary arterial spasm and treatments for it. it is with these limitations in mind thai the following discussion on va~aetive substancgs which seem to generate coronary arterial spasm should be considered. Most of the data described are
T I P S - S e p t e m b e r 1981
based on my own experiences with the iralaled coronary artery of the dog.
23g A a
AdRmrak ~ ' ~ Coronary arteries are known to have a distribution of both adrenergi¢ alpha and beta receptors in their smooth muscles; II1¢ former are dominant in relatively large vessels and the latter in relatively small vessels ~. Though adrenergic hera receptors are divided into beta, and beta= types, there has been no decisive evidence about which of them the coronary arterial beta receptors are. Generally, activation of adrenergic alpha reo:ptors c a u e s contraction of coronary arteries, while that of beta receptors causes relaxation. Experimentally, norcpinephrine and epinephrine at low doses produce relaxation of isolated coronary arteries through beta adrenoceptor activation, and high doses cause contraction through alpha adrenoceptor activation. Therefore. by alpha adrenoceptor blockade the contractile response of coronary arteries to norepinephrine and epinephrine is easily reversed to the relaxant one. and by beta adrenoceptor blockade the relaxant ncsponse is inhibited and occasionally reversed to give the contractile one. Phenylcphrine also produces contraction of coronary arteries and this is not reversed to relaxation, but is inhibited by alpha adrenoceptor blockade, since phenylcphfine is a pure alpha adrcnoceptor stimulant. Clinically. it has been suggested that adrenergic alpha receptor blocking agents may have beneficial effects on angina pectorts due to coronary arterial spasm, while beta adrenoceptor blocking agents may have undesirable effects on this condition. However, the depression of coronary arterial spasm by adrcncrgic alpha receptor blocking agents is not ;,Iways stable in practice. Moreover, some clinical reports have shown that beta adrenoceptor blocking agents do not necessarily cau~ a worsening of angina pectoris but may relieve at tacks. Recently, I have shown that propranolol, at high doses, relaxes ist,latcd coronar~ arterial strips of the dog under pota:siumcontracture, probabl) through a c;,Icium antagonistic action. So it seems likely that some beta adrenoccptor antagonists may have beneficial effects on angina pcctoris with or without coronary arterial spasm.
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¢
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"
B a
I
d
F~R. I. Typical re+pon+e~ +,fl~;lared dog cor+m+r+ arlerud +rrlpt r+,rrg+,met+: w .+t ¢.u:t,#. I1 a~+'Pud.ums.'r.u,m o~dlhvdrr~rg+~;umme I¢, %t fu)('r~+~melnm' /O %1. thl IO "~. ¢+I 1¢~ ~t; f,D I ~ *u ~ uht,~,~t~,,a, ,+~, ~ 2 ¢ t, ,+ th, rerlical bar an
mcthacholine and pilocarpine can induce coronary arterial spasms. On the other hand. a mu~arinic antagonist, atropine, is reported to be efficacious in relief of anginal attacks in ,~mc cases. In isolated coronary arteries of the dog. acctylcholinc produces h/phasic responses with relaxation followed by contraction. Relaxant responses of the arteries to acetylcholinc are mediated through a muscarinic actkm. since the responses are depressed by atropine alone, while contractile rcH~mses arc mediated through an activation of both muscarinic and adrcncrgic alpha receptors. since the responses were significantly depressed when atropine was administered together with phcntolaminc. Perhaps. acetylcholinc directly constricts the arteries through a muscarinic action and simultaneously causes norepinephrine release from sympathetic nerve cnding~ b~ acting on prcsynaptic nicotinic receptors. resulting in the contraction of ct,ronary arteries s. Thus, atropine is partialb effective in depression of coronary arterial spasms, but there base been some cases reported in which anginal attacks were relieved by atropine alone. This is probably due to a weak alpha adrenergic receptor blocking action of atropine in addition to its muscarinic antagonisms. In in viro studies using anesthetized dogs, both the sympathetic and parasympathetic nervous systems can be simultaneously activated by carotid chemoreceptor excitation induced by an intra-artcrial infusion of NaCN or
hypo~ic b l l ~ d "Fh¢~ can thu~ produce a decrease in coronar~ bh~,d flo~ ~hich t~ not depressed h.~ phcntolamine alone but by i)henlolamlne together ~ith alr(,pin¢. ~hich
suggests
t h e c~,i,qcnuL-
St
;I
par;J-
s.~mpathctic ~a,~'on~lrich,r mccham~m+ Ergol~ Of all the spasmogenic agents. ergomelrine i,, the drug ~hich provokes the most stable spasms of corona~ ancric,, m patients ~ith the ~ariant form of angina pectoris, and hence it is utilized throughout the ~orld a~ a diagnostic a,.!,cnl tot the variant fl)rm. RecentlL I reported the possible mechanisms in~olved in the action of ergomctrine on coronar~ a~eries, it produces contractions of i~)lated corona~ arteries of the dog. which are significantl~ depres~-d h~ mcth.~,.crgide lamiserotonergic agent) or dih.~dr(~:rgotamine [anti-,,crotoncrgic and aIpi,a adrcnoccpIor blocking agent) [ Fig. I ) ~:.gomctrine ma~ act on coronao arteri¢~ maml.~ through an acti~ alien of sero~onergic receptors s. J udging from the smfilarit~ of their chemical structure, it is likeb that other ergt,: alkaloids will sho~ a constrictor effect on corona~ arteries through an identical mechanism. The tact that ergometrin¢ is Ilk." most cff,:cti~.: agent in producing corona + arterial ,.pasta,, StlggC.,ts that it',, pharmacological prt~wrtie, m~r, proxide clues about the gcneqs of the ~ariant h,rm of angina pcctoris. Hot~eter. gith ill t i t s studies on intact anunal~, it i~, dlfficuh It+
mh;blIIon Of' blOs¥ nll~es Js 0f
de~ tease in c o r o n a ~
D inlrsmural prostaCychn
UlOod flOW and o¢ coronary aReflal Contraction
inactivation of Chelinergi¢ drugs ( indometacin in in vivo studies, intracoronary injec- -aspirin % ~ inhibition o f I~osynthesis o f ..-~,preve ntion o f pl,a~ele! tion of acetyleholine increases coronary t h l o m b o x s n e Az aggnt~gahon blood flow. However, it has been proved clinically by coronary angiographic Fig, 2. PresNmahh'schenm o f m.tion e l anu.ml~ummatory u~'nl~ +m c+w+marv circulau,,l~, ttJgh ,h ~ e~ . t mdo~a'm. methods that muscarinic agonists such as tin or aspirin mu)" emphasize the'l~ltlrwav mdiculed by the ~did hm'
TIPS -. S q ~ w m h e r i 981
236 pro~,oke coronary arterial spasm by injection of ergometrinc. Proslaglandins Prostaglandins (P(is'~ including PGEh PGE~ or PGh., produce contraction of isolated coronary arteries and increase coronary blood flow in whole hearts ~. The discrepancy between these observations has not yet been fully explained. One possibility is th,- ~ifference of materi:fls utilized: b~ vitro, Ohm:.,arge coronary arteries are generally used. Another possibility is the ability of PGs to stimulate furtiier synthesis of PGs themselves'~. in whole hearts primary PGs may activate biosynthesis of endogenous PGs more markedly than in coronary arterial smooth muscles. In 1he U.K.. it h~)s hecn reported that aspirin is useful for the prevention of myocardial re-infarction through its anticoagulant action. On the other hand, in the U.S.A.. aspirin is thought to be an undesirable therapeutic agent for the prevention of a second attack of myocardial infarction. Di~repancy between these results may be related to the dose administered: 300 mg per day in the U.K. and 1.0 g per day in the U.S.A. When a high dose of aspirin is administered, the biosynthesis of prostacyclin, which prevents platelet aggregation and relaxes vascular smooth muscle, may be dominantly inhibited. In fact, it is reported that aspirin at a high dose (4.0 g day-') aggravates a variant angina v. In our experimental studies on dogs, indomctacin which has similar antiinflammatoD' effects to aspirin produces a decrease in coronary blood flow anJ contraction of isolated coronary arteries". This study also shows that some stimulants of PG biosynthesis inhibit indometacininduced contractions of the arteries. Thus, drugs which inhibit the biosynthesis of intramural PGs through an inactivation of cyclo-oxygcnase have the ability to provoke coronary arterial spasms, although they have anti-coagulant action, too (Fig. 2). Detailed cxphmations of cardiovascular actions of prostacyclin and thromboxane A~ can be found in Ref. 9. Future directions of research One of the problems in the present experimental studies on coronary arterial spasms is that most of the studies are performed on normal or healthy tissues. When vasoactive agents are administered in humans, coronary arterial spasms are not provoked in all individuals but only in those predisposed to this response. Recently. it has been reported that cholesterol sensitizes isolated coronary t |'l~tl,'l/%,,vth-||,dl;md Ilh.ncd~,d Prr~ l l J ~ * h 1 4 7 i I ~ l ! l H H g l - 1141~1~1;$(12"~ll
I~i~l
arteries to external calcium ions, anti hence it is proposed that acquisition of ntemhrane cholesterol ntay alter the contractile prt)perties of co[(nlary arterial s l n o o t h muscle t°. It is imfmrtant to establish or explore the spasmogenic conditions which produce a tendency towards coronary arterial spasm. For this purpose we must further investigate which drugs produce the most stable coronary arterial spasm, which drugs enhance the spasms induced by spasmogenic agents and whiclt drugs are most efficacious in relief of coronary arterial spasm.
7 Mi~.a.K., Kanlhara. It, arid Kaw;li, C. (1979) lamcet, ii, 131';2 8 SiLk;maxhi, M. Araki. II. and Yonenmra. K, (19811)J. (~rrdio va,w. I'har,#ucol. 2. 657-.665 q~ Mollelp,l;i. %. and Vilne. J, R. (Iq~714)Pharmacol. Rer. 3(1, 2~J3-331 I I) Yokoyam.L, M and Henry. P. D. ( 19791Cin'. Re.~. 45,479-..4146
Reading list I Morishita, It. (1979) Arch. Int. Pharmacodyn. Ther. 23o. 195-207 2 Sakana,;hL M., Ilirata, A. and Takenaka, F. (1981)Jpn../h.artJ. 22.211-217 3 Sakanashi, M. Furukawa, T.and Horio, Y. (1979) Jt i. tleartJ. 20,75-82 4 Tomomatsu. E., Nishi. K., Araki. H., Takenaka, F, and Yoshikawa, Y. (1977) Proc. lSlh Ira. Congr. Neuroveg. Rex. (Tokyo), pp. 303-3(15 5 Sakana.~hi, M..'rod Yonemura, K, 1198a) Ear. J. Pharmacol. (~4. 157-160 6 De Deekere, E. A. M. (1979) Eur. J. Pharmactd. 58,211-213
Dr Motto Sakanmhi ret'ei~vd hi~ degree and dtwtorate from the glu,amoto Ufliver.;itv Medical &'hind. Since 1968 he ha.~ been carrying out research in the Depart. ment o f Pharmacology at the Kunmmoto U,ivt, ruty ~fedical School, Kmnmnoto. on cardmrascular pharmacology esfwcially on (~)ronary arterial xolooth mu:~ch..~, Hi~ present poxithm £~ In~trut'tor o f Pharmac.dogy.
Immunoregulation by sympathetic nervous system H. O. Besedovsky*, M. Da Prada*, Adriana del Rey* and E. Sorkin* Schweizerische~ Fbr~chungsitt~titut, Medizmi,whe Ahteihmg, CH-72 70 Davo~. ,~witzerland *and F. Hoffimmn-l.u Roche & Cie.AG. Pharnuweutical l)ivisiotl. CH-4002 Ba.~el, Switzerhmd t.
In mammals, the immune system consists of the multiple regulatory mechanisms of B- and T lymphocytes comprising in involved in the immune response. Followman about 10 'g cells each, and accessory ing antigenic challenge, at least four cells such as macrophages. While B- autoregulatory mechanisms have been lymphocytes are mainly committed to pro- proposed for the control of the immune duce antibodies, different subsets of T system: (1) helper and suppressor T cells lympht)cyles possess, am~mg others, help- and their products, (2) antibody feedback er, suppressor or killer functions, These system(s), (3) idiotypic-anti-idiotypic nettwo populations of cells are subdivided into work of interacting antibodies, (4) genes clones with differing specificities. Both cell specifying regulatory factors fi)r response. types express a huge repertoire of cell- To date, the experimental findings surface receptors which allows recognition obtained indicate that the immune system of several millions of antigens. The could have a degree of autonomy similar to immune system behaves as a complex rec- that of other systems of the body. It is ognition machine, organized in a geneti- therefore not surprising that the immtlne cally determined network of interacting system can operate hi vitro outside its cells which exchange a variety of specific physiological and anatomical environment. and non-specific signals. Hormones and neurotransmitters, howAs a consequence o f the increasing ever, are normally present in the environknowledge of the cellular and humoral ment of immunological cells and influence elements of the immune system, major their performance. Moreover, dynamic efforts are directed now to the elucidation interactions between the immune ~,ystem
234 that its value, for each specific value x, of measurement of effect, of which there are the independent variable, will be different. several, must be made at the time of peak The dependeut variable Y, corresponding concentration. 4 . Values of the dissociation ¢oqstants tax, is thus a r a n d o m variable, in the theory of regression analysis it is assumed that cor- for both agonist and antagonist compounds responding to cach.~, there is a 'true' value have been obtained from studies of their /1, = o + /~r, that is approximated by Y,. displace ment of radiolabeled substances of Hence. Y~ = / ~ + e,, where e~ is an error ran- high specific activity from a common high dom variable. These e, are a~sumed to be affinity binding site. The constants independent of x,. have mean zero and obtained are usually expressed as IIC~], unknown :,=riance an. Only when these the concentration which displaces the conditions p.evail can we apply the usual laheled compound by 50%, and are statistical (regression) techniques for get- obtained from a regression analysis. The ling mean values of K with correct standard equation for compe!itivc inhibition proerrors and confidence limits. It ~ e m e d vides the relation K~ = t I C . ] / ( 1 + [,4 I/IG). appropriale to mention this topic here [,41 and KA are the concentration and dissim:e the precision of the estimated dissoci- sociation constant of the labeled comation constants is important to their proper pound, respectively, and Kt i~ the dis,sociau ~ in drawing conclusions about recep- l ion constant sought. tors. The theory, underlying the use of 5. Dissociation constants obtained from regression techniques' is not only the con- binding procedures, along with those cern of statistical and mathematical special- obtained from both in vitro and in viva isls, for it was atso emphasized by pharmacological procedures, represent a Gaddum r. It .~ems noteworthy again three-pronged apwoaeh to the quantital~:re h : c a u ~ of the many studies, among tive characterization of receptors that is biochemists and among in viva and in vitro sure to be useful to our further understandpharmacologists, directed toward the ing of the mode of action of drugs and to common objective of characterizing ret~ep- our understanding of both normal and tars quantilatively. abnormal physiological states. Summary 1. The drug-receptor dissociation constunt for agonist compounds K4, is generally not equal to the A~o or EDso obtained from the dose-response relation. The computation of this constant requires more elaborate experimental procedures. 2. The KR (or - l o g KB) for a competitive antagonist is computed fn)m the equieffective agonist concentration ratio X = [A'i/[A ] corresponding to a concentration [B] Of the antagonist. When interpreted according to the simple theory of competitive antagonism, X - 1 = [BI/Ka, and the corresponding Schild-Plot intercept (the pAs) gives a direct reading of -Iog,o K,. Confidence limits for the intercept are determined from an analysis of the constrained ( - I slope) Schild plot and not from the conventional formulas4. An alternate approach to the determination of KR and its confidence limit is by direct subsiltation into the equation X - 1 = | B ]/KR. 3. Values of Ks (or I G ) bt viva have the unit of administered dose and route and mus~ be convened to tissue concentration for comparison of these with values obtained in isolated tissue. Also, the dosing schedule is based on the assumption that peak t~gsue concentration is proportional m administered dose; thus pharmacokinetics ol both agonist and antagonist in the species must be known and a schedule of I1|,~
- ¢~|4TiI(I/INI~RI
- (N)O0/$il2
]|l
-
Seplemher 1981
3 Bar, R. S. and Roth. J. (1977)An.h. Intern. Mud.
137.474-481 4 Ihtd~y, R. C. and Falhmda, R. J. Z l'hcor. B.d. (in prus~) 5 Clark, A..I. ( Iq?,3) i he .ttade of At'litm of Dnegs on Cells, Williamsand Wilkins.BaRialore 6 Furchgou,R. F.(1978) Fed. Pn~-. 37. 115-12u 7 Gaddum,J. H.(lq53)Pharmacol. Rer. 5.87-134 80Isen. R, W.. Reisine,T. D, and Yan|:|mura,H. I. (1°480)Life ~'i. [ Minireview)27, 801-808 9 Schild.H O.(1949)Br.J. PharmacoL 4, 277-280 IO Takcmori. A. E. (1974) in Nan'mi| Antagonist.~' (Braude. M. C,. tlarris,L, S..May. E. I...Smith, J. P. and Villarcal.J. E.,cds),Advanc¢~ in Biochcmical Ps}chopharm:|cology. Vol. 8. ilp.335-.344. Ralph Prcss.N e w York II Takcmori, A. E,, Hyashi. G. and 8atils.S. E. ( I q72) Ear. J, Pharmacol. 241,85-92
12 Tallarida. R. J., Cowan, A. and Adler, M. W. ( ItJ79)Lift' ScL (Minireview) 25,637-654 13 Tallarida, R. J. and Jacob, I.. S. 0979) The Dose Response Relation in Phamtacology. SpringerVcrlag. New York, Heidelbergand Berlin 14 Tallarida.R. J. and Murray. R. B. ( 1981) Maattal of Pharmaodogic Cah'alations ~','ith Computer Programs, Springer-Verlag, New York. Heidel-
berg and Berlin 15 Yamamura, II. I.. Enna. S. J. and Kuhar. M. J. (1978) Nearotransmittcr Receptor Binding. p. 71. Raven Press.New York
Ronald ]. Tallarida began his profes.~im|al careerin rite Department of .~lathematic~ at Drexel University. Philadelphia. where he reeeired the Lindback award for dL~tingaixhed teaching hi 1964. Subvequcntly he received a Special Felloa.ship from the National htv6. Reading list uae of Gene~l Medical Sciences in order to pursue 1 Ari6ng,E. J.. Simonis,A, M, and Van Rossum.J. graduate training in pharmacology. Upon completion M. (1964) in Molecular Pharmacology ( Ari6ns.E. of his Ph.D. he jobwd the filcully oJ'the School of J.. ca.), Vol. 1, pp. 119-269, Academic Press. ,~ledicine at Temple Unirersity m Philadelphia when" New York he is non. Promisor of Pharmacology. tiL~ special 2 Arunlakshana.O. and Schild. H. O. (1959) Br. J. interests include pharmacokinelics and receptor Pharmacol. 14.48-58 mechanLt-m.~.
Pharmacological aspects of coronary arterial spasm Matao Sakanashi Department o/Pharmacology. Kumamo;o University Medical School, 2.2.1 Hon]o. Kumamoto 860, Japan.
Since Prinzmetal et al. (1959) reported a variant form of angina pectoris, coronary arterial spasm has been an interesting subject for cardiologists. Recently an opinion has developed that 7(k-80% of all cases of angina peetoris are related to coronary arterial spasm, Though many investigators have made efforts In clarify the mechanism involved in coronary arterial spasm, it is not established even now. Pharmacologic.ally, coronary arterial spasm corresponds In coronary arterial contraction. Most pharmacological studies on coronary arle-
rial spasm have been performed on normal or healthy material and not on pathological or diseased tissue, and the experimental results have often shown discrepancies between in viva and in vitro studies. Thus, available experimental procedures are not always suitable to estimate the pathogenesis of coronary arterial spasm and treatments for it. it is with these limitations in mind thai the following discussion on va~aetive substancgs which seem to generate coronary arterial spasm should be considered. Most of the data described are
T I P S - S e p t e m b e r 1981
based on my own experiences with the iralaled coronary artery of the dog.
23g A a
AdRmrak ~ ' ~ Coronary arteries are known to have a distribution of both adrenergi¢ alpha and beta receptors in their smooth muscles; II1¢ former are dominant in relatively large vessels and the latter in relatively small vessels ~. Though adrenergic hera receptors are divided into beta, and beta= types, there has been no decisive evidence about which of them the coronary arterial beta receptors are. Generally, activation of adrenergic alpha reo:ptors c a u e s contraction of coronary arteries, while that of beta receptors causes relaxation. Experimentally, norcpinephrine and epinephrine at low doses produce relaxation of isolated coronary arteries through beta adrenoceptor activation, and high doses cause contraction through alpha adrenoceptor activation. Therefore. by alpha adrenoceptor blockade the contractile response of coronary arteries to norepinephrine and epinephrine is easily reversed to the relaxant one. and by beta adrenoceptor blockade the relaxant ncsponse is inhibited and occasionally reversed to give the contractile one. Phenylcphrine also produces contraction of coronary arteries and this is not reversed to relaxation, but is inhibited by alpha adrenoceptor blockade, since phenylcphfine is a pure alpha adrcnoceptor stimulant. Clinically. it has been suggested that adrenergic alpha receptor blocking agents may have beneficial effects on angina pectorts due to coronary arterial spasm, while beta adrenoceptor blocking agents may have undesirable effects on this condition. However, the depression of coronary arterial spasm by adrcncrgic alpha receptor blocking agents is not ;,Iways stable in practice. Moreover, some clinical reports have shown that beta adrenoceptor blocking agents do not necessarily cau~ a worsening of angina pectoris but may relieve at tacks. Recently, I have shown that propranolol, at high doses, relaxes ist,latcd coronar~ arterial strips of the dog under pota:siumcontracture, probabl) through a c;,Icium antagonistic action. So it seems likely that some beta adrenoccptor antagonists may have beneficial effects on angina pcctoris with or without coronary arterial spasm.
b
c
b
¢
...... .,.
"
B a
I
d
F~R. I. Typical re+pon+e~ +,fl~;lared dog cor+m+r+ arlerud +rrlpt r+,rrg+,met+: w .+t ¢.u:t,#. I1 a~+'Pud.ums.'r.u,m o~dlhvdrr~rg+~;umme I¢, %t fu)('r~+~melnm' /O %1. thl IO "~. ¢+I 1¢~ ~t; f,D I ~ *u ~ uht,~,~t~,,a, ,+~, ~ 2 ¢ t, ,+ th, rerlical bar an
mcthacholine and pilocarpine can induce coronary arterial spasms. On the other hand. a mu~arinic antagonist, atropine, is reported to be efficacious in relief of anginal attacks in ,~mc cases. In isolated coronary arteries of the dog. acctylcholinc produces h/phasic responses with relaxation followed by contraction. Relaxant responses of the arteries to acetylcholinc are mediated through a muscarinic actkm. since the responses are depressed by atropine alone, while contractile rcH~mses arc mediated through an activation of both muscarinic and adrcncrgic alpha receptors. since the responses were significantly depressed when atropine was administered together with phcntolaminc. Perhaps. acetylcholinc directly constricts the arteries through a muscarinic action and simultaneously causes norepinephrine release from sympathetic nerve cnding~ b~ acting on prcsynaptic nicotinic receptors. resulting in the contraction of ct,ronary arteries s. Thus, atropine is partialb effective in depression of coronary arterial spasms, but there base been some cases reported in which anginal attacks were relieved by atropine alone. This is probably due to a weak alpha adrenergic receptor blocking action of atropine in addition to its muscarinic antagonisms. In in viro studies using anesthetized dogs, both the sympathetic and parasympathetic nervous systems can be simultaneously activated by carotid chemoreceptor excitation induced by an intra-artcrial infusion of NaCN or
hypo~ic b l l ~ d "Fh¢~ can thu~ produce a decrease in coronar~ bh~,d flo~ ~hich t~ not depressed h.~ phcntolamine alone but by i)henlolamlne together ~ith alr(,pin¢. ~hich
suggests
t h e c~,i,qcnuL-
St
;I
par;J-
s.~mpathctic ~a,~'on~lrich,r mccham~m+ Ergol~ Of all the spasmogenic agents. ergomelrine i,, the drug ~hich provokes the most stable spasms of corona~ ancric,, m patients ~ith the ~ariant form of angina pectoris, and hence it is utilized throughout the ~orld a~ a diagnostic a,.!,cnl tot the variant fl)rm. RecentlL I reported the possible mechanisms in~olved in the action of ergomctrine on coronar~ a~eries, it produces contractions of i~)lated corona~ arteries of the dog. which are significantl~ depres~-d h~ mcth.~,.crgide lamiserotonergic agent) or dih.~dr(~:rgotamine [anti-,,crotoncrgic and aIpi,a adrcnoccpIor blocking agent) [ Fig. I ) ~:.gomctrine ma~ act on coronao arteri¢~ maml.~ through an acti~ alien of sero~onergic receptors s. J udging from the smfilarit~ of their chemical structure, it is likeb that other ergt,: alkaloids will sho~ a constrictor effect on corona~ arteries through an identical mechanism. The tact that ergometrin¢ is Ilk." most cff,:cti~.: agent in producing corona + arterial ,.pasta,, StlggC.,ts that it',, pharmacological prt~wrtie, m~r, proxide clues about the gcneqs of the ~ariant h,rm of angina pcctoris. Hot~eter. gith ill t i t s studies on intact anunal~, it i~, dlfficuh It+
mh;blIIon Of' blOs¥ nll~es Js 0f
de~ tease in c o r o n a ~
D inlrsmural prostaCychn
UlOod flOW and o¢ coronary aReflal Contraction
inactivation of Chelinergi¢ drugs ( indometacin in in vivo studies, intracoronary injec- -aspirin % ~ inhibition o f I~osynthesis o f ..-~,preve ntion o f pl,a~ele! tion of acetyleholine increases coronary t h l o m b o x s n e Az aggnt~gahon blood flow. However, it has been proved clinically by coronary angiographic Fig, 2. PresNmahh'schenm o f m.tion e l anu.ml~ummatory u~'nl~ +m c+w+marv circulau,,l~, ttJgh ,h ~ e~ . t mdo~a'm. methods that muscarinic agonists such as tin or aspirin mu)" emphasize the'l~ltlrwav mdiculed by the ~did hm'
TIPS -. S q ~ w m h e r i 981
236 pro~,oke coronary arterial spasm by injection of ergometrinc. Proslaglandins Prostaglandins (P(is'~ including PGEh PGE~ or PGh., produce contraction of isolated coronary arteries and increase coronary blood flow in whole hearts ~. The discrepancy between these observations has not yet been fully explained. One possibility is th,- ~ifference of materi:fls utilized: b~ vitro, Ohm:.,arge coronary arteries are generally used. Another possibility is the ability of PGs to stimulate furtiier synthesis of PGs themselves'~. in whole hearts primary PGs may activate biosynthesis of endogenous PGs more markedly than in coronary arterial smooth muscles. In 1he U.K.. it h~)s hecn reported that aspirin is useful for the prevention of myocardial re-infarction through its anticoagulant action. On the other hand, in the U.S.A.. aspirin is thought to be an undesirable therapeutic agent for the prevention of a second attack of myocardial infarction. Di~repancy between these results may be related to the dose administered: 300 mg per day in the U.K. and 1.0 g per day in the U.S.A. When a high dose of aspirin is administered, the biosynthesis of prostacyclin, which prevents platelet aggregation and relaxes vascular smooth muscle, may be dominantly inhibited. In fact, it is reported that aspirin at a high dose (4.0 g day-') aggravates a variant angina v. In our experimental studies on dogs, indomctacin which has similar antiinflammatoD' effects to aspirin produces a decrease in coronary blood flow anJ contraction of isolated coronary arteries". This study also shows that some stimulants of PG biosynthesis inhibit indometacininduced contractions of the arteries. Thus, drugs which inhibit the biosynthesis of intramural PGs through an inactivation of cyclo-oxygcnase have the ability to provoke coronary arterial spasms, although they have anti-coagulant action, too (Fig. 2). Detailed cxphmations of cardiovascular actions of prostacyclin and thromboxane A~ can be found in Ref. 9. Future directions of research One of the problems in the present experimental studies on coronary arterial spasms is that most of the studies are performed on normal or healthy tissues. When vasoactive agents are administered in humans, coronary arterial spasms are not provoked in all individuals but only in those predisposed to this response. Recently. it has been reported that cholesterol sensitizes isolated coronary t |'l~tl,'l/%,,vth-||,dl;md Ilh.ncd~,d Prr~ l l J ~ * h 1 4 7 i I ~ l ! l H H g l - 1141~1~1;$(12"~ll
I~i~l
arteries to external calcium ions, anti hence it is proposed that acquisition of ntemhrane cholesterol ntay alter the contractile prt)perties of co[(nlary arterial s l n o o t h muscle t°. It is imfmrtant to establish or explore the spasmogenic conditions which produce a tendency towards coronary arterial spasm. For this purpose we must further investigate which drugs produce the most stable coronary arterial spasm, which drugs enhance the spasms induced by spasmogenic agents and whiclt drugs are most efficacious in relief of coronary arterial spasm.
7 Mi~.a.K., Kanlhara. It, arid Kaw;li, C. (1979) lamcet, ii, 131';2 8 SiLk;maxhi, M. Araki. II. and Yonenmra. K, (19811)J. (~rrdio va,w. I'har,#ucol. 2. 657-.665 q~ Mollelp,l;i. %. and Vilne. J, R. (Iq~714)Pharmacol. Rer. 3(1, 2~J3-331 I I) Yokoyam.L, M and Henry. P. D. ( 19791Cin'. Re.~. 45,479-..4146
Reading list I Morishita, It. (1979) Arch. Int. Pharmacodyn. Ther. 23o. 195-207 2 Sakana,;hL M., Ilirata, A. and Takenaka, F. (1981)Jpn../h.artJ. 22.211-217 3 Sakanashi, M. Furukawa, T.and Horio, Y. (1979) Jt i. tleartJ. 20,75-82 4 Tomomatsu. E., Nishi. K., Araki. H., Takenaka, F, and Yoshikawa, Y. (1977) Proc. lSlh Ira. Congr. Neuroveg. Rex. (Tokyo), pp. 303-3(15 5 Sakana.~hi, M..'rod Yonemura, K, 1198a) Ear. J. Pharmacol. (~4. 157-160 6 De Deekere, E. A. M. (1979) Eur. J. Pharmactd. 58,211-213
Dr Motto Sakanmhi ret'ei~vd hi~ degree and dtwtorate from the glu,amoto Ufliver.;itv Medical &'hind. Since 1968 he ha.~ been carrying out research in the Depart. ment o f Pharmacology at the Kunmmoto U,ivt, ruty ~fedical School, Kmnmnoto. on cardmrascular pharmacology esfwcially on (~)ronary arterial xolooth mu:~ch..~, Hi~ present poxithm £~ In~trut'tor o f Pharmac.dogy.
Immunoregulation by sympathetic nervous system H. O. Besedovsky*, M. Da Prada*, Adriana del Rey* and E. Sorkin* Schweizerische~ Fbr~chungsitt~titut, Medizmi,whe Ahteihmg, CH-72 70 Davo~. ,~witzerland *and F. Hoffimmn-l.u Roche & Cie.AG. Pharnuweutical l)ivisiotl. CH-4002 Ba.~el, Switzerhmd t.
In mammals, the immune system consists of the multiple regulatory mechanisms of B- and T lymphocytes comprising in involved in the immune response. Followman about 10 'g cells each, and accessory ing antigenic challenge, at least four cells such as macrophages. While B- autoregulatory mechanisms have been lymphocytes are mainly committed to pro- proposed for the control of the immune duce antibodies, different subsets of T system: (1) helper and suppressor T cells lympht)cyles possess, am~mg others, help- and their products, (2) antibody feedback er, suppressor or killer functions, These system(s), (3) idiotypic-anti-idiotypic nettwo populations of cells are subdivided into work of interacting antibodies, (4) genes clones with differing specificities. Both cell specifying regulatory factors fi)r response. types express a huge repertoire of cell- To date, the experimental findings surface receptors which allows recognition obtained indicate that the immune system of several millions of antigens. The could have a degree of autonomy similar to immune system behaves as a complex rec- that of other systems of the body. It is ognition machine, organized in a geneti- therefore not surprising that the immtlne cally determined network of interacting system can operate hi vitro outside its cells which exchange a variety of specific physiological and anatomical environment. and non-specific signals. Hormones and neurotransmitters, howAs a consequence o f the increasing ever, are normally present in the environknowledge of the cellular and humoral ment of immunological cells and influence elements of the immune system, major their performance. Moreover, dynamic efforts are directed now to the elucidation interactions between the immune ~,ystem