1,4-Dihydropyridine activators and antagonists: structural and functional distinctions

1,4-Dihydropyridine activators and antagonists: structural and functional distinctions

TiPS - December 1989 [Vol. IOJ Gundlach, A. L. (1986) Trends Pharmacol. Sci. 7, 448-451 10 Steinfels, G. F., Tam, S. W. and Cook, L. (1986) Life Sci...

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TiPS - December

1989 [Vol. IOJ

Gundlach, A. L. (1986) Trends Pharmacol. Sci. 7, 448-451 10 Steinfels, G. F., Tam, S. W. and Cook, L. (1986) Life Sci. 39, 2611-2415 11 Steinfeels,G. F., Alberici, G. P., Tam, S. W. and Cook, L. (1978) Neuropsychopharmacology 1, 321-327 12 Holtzman, S. G. (1989) 1. Pharmacol. Exp. Ther. 248,1054-1062 13 Balster, R. L. (1989) J. Pknrmacol. Exp. 7%er. 249, 74Y-756 14 Sanders, M. S., Keana, J, F. W. and Weber, E. (1988) Trends Neurosci. 11, 37-40 15 Snyder, S. S. and Largent, B. L. (1989) J. Nezropsychiatry 1, 7-15 16 Cowan, A., Geller, E. B. and Adler, M. W. (1980) NIDA Res. Monogr. Ser. 27, 198-204 17 Tortella, F. C., Davey, R., Pellicano, M. and Bowery, N. G. NIDA Res. Monogr. Ser. (in press) 18 Laxer, K. D., Robertson, R. M. J. and Dow, R. S. (1980) in Antiepileptic Drugs: Mechanism of Action (Glaser, G. H., Penry, J. K. and Woodbury, D. M., eds), pp. 415-427, Raven Press 19 Tortella, F. C. and Musacchio, J. M. (1986) Brain Res. 383, 314-318 20 Tortella, F. C., Witkin, J. M. and Musacchio, J. M. (1988) Eur. \. Pharma-

507 col. 155, 69-75 21 Wang, B. Y., Coulter, D. A., Choi, D. W. and Prince, D. A. (1988) Neurosci. Lett. 85, 261-266 22 Apland, J. P., Sparenborg, S. and Braitman, D. J. (1988) Sot. Neurosci. Abstr. 14,238 23 Aram, J. A. et al. (1989) J. Pharmacol. Exp. Ther. 248.320-328 24 Ferkany, J. W., Borosky, S. A., Clissold, D. B. and Pontecorvo, M. J. (1988) Eur. J. Pkannocol. 151.151-154 25 Feeser, H. R., Kadis, J. L. and Prince, D. A. (1988) Neurosci. Lett. 86,340-345 26 Chapman, A. G. and Meldrum, B. (1989) Eur. I. Pharmacol. 166,201-211 27 Leander. I. D.. Rathbun. R. C. and Zimme&n, d. M. (198s) Brain Res. 454.368-372 28 Swinyard, E. A. and Woodhead, J. H. (1982) m Antiepileptic Drugs (Woodbury, D. M., Pemy, J. K. and Pippenger, C. E., eds), pp. 111-126 29 Choi, D. W. et al. (1987) Brain Res. 403,333-336 30 George, C. P., Goldberg, M. P., Choi, D. W. and Steinberg, G. K. (1988) Brain Res. 440,375-379 31 Steinberg, G. K., Saleh, J. and Kunis, D. (1988) Neurosci. Lett. 89, 193-197 32 Prince, D. A. and Feeser, H. R. (1988)

1,4=Dihydropyridine activators and antagonists: structural and functional distinctions David J. Triggle and David Rampe The dihydropyridine series of drugs contains both potent antagonists and The structural differences between potent activators of Ca2+ channels. antagonists and activators are small and, indeed, activators can behave as antagonists at high levels of membrane depolarization. -Here, David Triggle and David Rampe descn’be recent insights into the factors - including structure of the drug and activation state of the channel - that influence the behavior of these drugs, and discuss mode!s that have been proposed to describe their mechaniim of action. cardiovascular important drugs the Ca2+ channel antagonists have been the focus of major attention over the past decade. Their properties and the properties of the subclass of voltagedependent Ca2+ channels with which they interact have been (see, for extensivel!r reviewed example, Refs 1 and 2). The prototypical drugs verapamil, nifedirepresent pine and diltiazem discrete classes of compound. The 1,4-dihydropyridines (1,4-DHPs), AS

D. 1. Trigglc is Professor and Dern of The School of Pharmacy, State University of New York, Buffalo. NY 14260, and D. Rampe is Senior Research Pharmacologist at The Merrell-Dow Research Institute. Cincivnufi, OH 45215, USA.

represented by nifedipine, make up the most potent and largest series of compounds available experimentally and clinically (Fig. 1); the series embraces both potent antagonist and potent activator species3,4 (Fig. 2). There are only small structural differences between activator and antagonist 1,4-DHPs, but activator activity is generally associated with the s-enantiomers and antagonist activity with the Renantiomers (Refs 4 and 5, and see Ref. 3). However, the activities of 1,4-DHPs are both qualitatively and quantitatively dependent upon membrane potential. Activities of antagonists increase significantly with decreasing membrane potential (depolarization),

Neurosci. Lett. 55, 291-296 33 Monyer, H. and Choi, D. W. (1988) Brain Res. 446, 144-148 34 Tortella, F. C. et al. (1989) Brain Res. 482, 179-183 35 Church, J., Lodge, D. and Berry, S. C. (1985) Eur. /. Pknrmncol. 111, 185-190 36 Tortella, F. C., Ferkany, J. W. and Pontecorvo, M. J. (1988) Life Sci. 42, 250%2514 37 Wang, E. H. F., Knight, A. R. and Woodruff, G. N. (1988) J. Neurochem. 50, 274-281 38 Musacchio, J. M. and Klein, M. (1988) Cell. Mol. Neurobiol.8, 149-156 39 Carpenter, C. L., Marks, S. S., Watson, D. L. and Greenberg, D. A. (1988) Brain Res. 439,372-375 40 Fletcher, E. J., Drew, C., Lodge, D. and O’Shaughnessy, C. T. (1989) Neuropharmacology 28.661666 I+)-3-PPP:(+)-3-(3_hydroxyphenyl)-N-(lpropyl)piperidine SKF-10047: N-allyl-N-normetazocine MK-8llI:(+)-5-methyl-l0,11-dihydro-5ffdiberuo[a,dJcyclohepten-5,10-imine maleate PCP: phencyclidine AP5zamino 5-phosphonopentanoate TCP: N-[l-(2+hienyl)cyclohexyl]piperidine

whereas activators change to antagonists with increasing depolarization (see Ref. 3 for review). These properties, together with some competition data from pharmacological and radioligand studies, have generated models for 1,4-DHP binding that are more complex than simple interaction at a single site&l’. The issue of the number of binding sites is, however, but one of the questions fundamental to the elucidation of the structural and mechanistic distinctions between 1,4-DHP activators and These questions antagonists. include: @ Is Ca2+ channel activation a property of all 1,4-DHPs? o What is the influence of channel state on the relative expression antagonist and activator of properties? o What are the structural requirements in 1,4-DHPs for activation and antagonism? o Do activator and antagonist 1,4DHPs occupy the same or different binding sites? o Are dual activator and antagonist properties unique to the 1,4DHPs? Ca2+ channel activation as a

general property of WDHPs me Ca*’ channel activating

of 1,4-DHPs were properties that noted in early reports nifedipine produced, at very low

0 1989, Elsevisr Science Publishers Ltd. IUK)

0165 - 6147/89/MZW

TiPS -December

nifedipine

nitrendipine

MeOOC Me

1989 CVol. 101

binding affinities seen in cardiac preparations (see Refs 1 and 3). Several observations indicate that 1,CDHP activators exhibit voltageless significantljj dependent behavior than their antagonist counterparts. Although membrane potential affects the qualitative expression of ligand activity (activation or antagonism at polarized and depolarized membrane potentials, respectively), this occurs with small changes in measured affinities. The abilities of s-202-791 and SBax K-8644 to increase myocardial Ca + current are either independent of or only modestly deped;e2$ upon membrane poten-

Support for the existence of voltage-independent actions of the 1,4-DHP activators is provided by radioligand binding studies performed in polarized and depolarized myocytes9,21*“. Both competition experiments with sPN 200-l 10 Bay K-8644 and s-202-791 and direct binding studies with s-[~HBay K-8644 reveal affinity changes of two- to fivefold between polarized (5 mM KCl) and depolarized (50 mM KCl) preparations (Table I). However, the affinity changes seen for both activator and antagfelodipine onist species measured by radioligand binding are less than those Fi. 1. Sftucfuralbrmulae of 1,GDHP antagonists. measured electrophysiologically _-I (Table I), presumably because higher and more stable resting concentrations (10-11-10-9 g ml-‘), mining the activator/antagonist membrane potentials are achievpositive inotropic e’fects and effects of 1,4-DHPs. able in the electrophysiological tension increases in papillary preparations. muscle preparations”*‘2. ConfirThese observations suggest a mation of these studies7 was model for 1,4-DHP interactions in State dependence of 1,4-DHP accompanied by several reports which potent activators exhibit interactions that, under certain conditions, little discrimination between Contrary to early indications, 1,4-DHPs such as nitrendipine the 1,4-DHP Ca2+ channel antagopen and inactivated states, and and ~-202-791 showed the actiantagonists exhibit preferential onists do exhibit significant voltvator effects characteristic of other age dependence of interaction. binding to the inactivated state of 1,4-DHPs, notably the long chanThe electrophysiological investithe channel. Thus activators will nel openings (see, for example, gations of Sanguinctti and Kass16 exhibit either activator or antagRefs 6,10 and 13-15). These cbserand BeanI in cardiac preparations onist activity according to the vations indicate that Ca2+ channel revealed that the affinities of fractional channel state: activator activation may be a general several agents are substantially potency will be enhanced by propmty of 1,4-DHPs, although enhanced under depolarizing conmodest levels of membrane deit probably Gcninates in some ditions: there was an approxipolarization. Antagonists may structures. mately thousandfold enhanceexhibit activator properties but The activator effects of domiment of affinity for the inactivated only through interactions at polarnantly antagonistic species are state, corresponding to a I& value ized states of the channel. Precharacteristically seen at the of -W9 M, compared with Iv M sumably, 1,4-DHPs with a preferbeginning of experiments and for the resting state. The lOO-lOOO- ential affinity for closed channel generally un$er poiarized cell fold differences in affinity seen in states should also exist. Such comconditions. Ca2+ channel state is these and similar studies between pounds will alter the frequency of influenced by membrane potenthe resting and inactivated states channel opening and may have tial (and possibly by other factors) parallels the differences between activator or antagonist properties and is a major factor in deterpharmacological and radioligand depending upon the rate con-

TiPS - December

1989 /Vol. 201

stants to and from that state under drug-free and drug-bound conditions (see, for example, Ref. 10). At the tissue level such an agent may be selective for cardiac or neuronal tissue over vascular smooth muscle since the former tissues probably favor a resting channel population. Additionally, this simple model suggests that, in contrast to the situation with the antagonists, there should be little discrepancy between the binding and pharmacological affinities in cardiac preparations for 1,4-DHP activators. For a limited series of compounds this has proved to be the case23. It is also anticipated that there will be a continuum of molecules and that the differential affinity between the open and inactivated states will serve as one factor controlling the expression of activator and antagonist properties. According to this model, Bay K-8644 and 202-791 are ‘partial activators’; a ‘full’ activator in the 1,4-DHP series would be highly selective for the open channel state. This model does not exclude the possibility that factors other than or additional to membrane potential may also contrcl the activator/ antagonist properties of 1,4-DHPs. The G proteins are an obvious candidate. They are of increasingly recognized significance to the regulation of ion channels, including voltage-dependent Ca*+ channels of the L class24, with which they interact directly. The

s-(-)-Bay K-8644

R-(+)-Bay K-8644

Fig. 2. Structural fcvmuae of 1,4-DHP activator/antagonist pairs.

stable analog of GTP, GTPyS, reduces Ca*+ current in rat dorsal root ganglion neurones, and the residual current is potentiated by both Bay K-8644 (racemic form) and nifedipine. The stimulant effects of nifedipine and Bay K-8644 in the presence of GTPyS are reduced under depolarizing conditions and both Jntrol and GTPyS-mediated currents are abolished by prior treatment with

pertussis toxin’4*25. These data suggest that both activated G proteins and hyperpolarization promote a channel state at which 1,4-DHPs can initiate activation. Interactions of GTP and its analogs with high affinity 1,4-DHP binding had been reported previouslf6. Most recently, and quite consistent with the results of Scott and Dolphin25, Gpp(NH)p has been shown to potentiate the

TABLE I. Voltage-dependent interactions of 1,CDHP antagonists and activators in cardiac cells

a-(+)-[3H]PN200-110

s-(-)j3H]Bay

K-8644

R-(+)-Bay K-6644

membranes

polarized

depolarized

0.73 0.35

0.060 0.060

52

56

2.9

3.0

3.49

4.4 1.4

85

1.3

S-(-)-Bay K-B644

s-(+)-202-791

R-(-!-202-791

Ca*+ current (EC& or IC,, H x IO-‘)

Ftadioligand binding (If* M x lo-~)

1,CDllP

100 8.6

0.055 0.012

polarized

Ref.

depolartzed

400

4.5

29

C

9” 21b 18 22 18

21b

5.0 13

8000

26

CR

CR

80

C

37

96 180

C

18 21a 20

1.0

ga 21b 16

2.3 0.16

0.23 200

21b 16

Data for [3H]Bay K-8644 and !%]PN 200-l IO are from direct binding studies. The other data are from competition studies with either 13HlPN299110 or PHlnitrendipine. “Depolarizing medium contained 137 mM K+., “depolarizing medium contained 50 mw K+; =not measured but strong voltage dependencenot indicated.

TiPS - December 1989 fVo1. 201

510 ability of Bay K-8644 but not nitrendipine to compete with J3H]PN 200-110 binding in neuronal membranes. This effect was blocked by pertussis toxinz7. As noted by Scott and Dolphin, the involvement of GTP in the modulation of 1,4-DHP responses could underlie the variable results described in the literature for the

existence and magnitudes of acti-

vator responses to 1,4-DEE.

Structurai requirements for activation and antagonism by 1,4-DHPs Regardless of whether activator

and antagonist l,&DHPs interact at the same site expressed in different states or at separate sites that may be expressed or accessed according to channel state, it is anticipated that there will be different underlying r?ructure+ activity relationships. Data are available for antagonist series, but are extremely scarce for activators (see Ref. 3 for review). Limited comparisons suggest that the effects of Pphenyl substituents on both binding and pharmacological activities are greatly reduced in the activator series”. The presence of the C-5 NOz or lactone groups generates the most potent activators. The limited range of compounds for which data are available demonstrate stereoselectivity, with the s-enantiomer displaying much greater potency than the n-enantiomer at the activator state or site; s- and u-enantiomers are approximately equipotent at the antagonist state or site. These observations suggest that the C-5 substituent of 1,4-DHPs is important to the initiation of activator properties through a vectorial interaction, perhaps at the voltage-sensor component of the channel (Ref. 28 and D. A. Langs, P. D. Strong and D. J. Triggle, unpublished). However, activator properties are also observed in non-chirall,4-DHPs including the potent antagonists with ester functions at C-3 and C-5. It is thus

clear that activator/antagonist activity in the IPDHPs is also critically dependent upon channel

state as influenced by membrane potential. Do activators and antagonists interact at different sites? The majority of investigations

have identified a single IP-DFP site that appears to be functionally associated with the CaZf channel. In both radio&and binding and functional pharmacological experiments, almost without excep1,4-DHP activators and tion, antagonists behave as competitive species (see Refs l-3 for review). However, efforts to distinguish simple competitive from allosteric antagonism have generally not been made. Furthermore, radioligand studies almost always use membrane fragments: here, it may be assumed that competition with only the depolarized charmeL state is available and &et endogenous G protein interactions may have been lost. A simiiar limitation applies to comparisons of lP-DHP activator and antagonist binding site densities, and the use of racemic ligands where both enantiomers may bind adds further complexity to these comparisons2y. However, binding densities of s[3H]Bay K-8644 and R-J~H]PN 200110 under polarized and depolarized states in cardiac myocytes are identicalzz. Other 1,PDHP binding sites have also been identified which are generally of lower affinity and higher capacity; their functional relationship to the 1,4-DHPsensitive channel is unclear1-3. In many instances these binding sites are related not to channel function, but to adenosine transporters, mitochond~al benzodiazepine sites and other ion transporters*. The use of highly purified plasma membrane preparations may limit or exclude such low affinity binding=. In a few instances, however, multiple binding sites have been correlated with channel function. In guinea-pig cardiac myocytes, nitrendipine stimulated Ca2+ currents when the holding potential was less than -90 mV and the dose-response curve was ccnsistent with the existence of two independent binding sites with affinities of lo-6 M and lp M. At depolarized potentials, however, only inhibition of Ca*+ current, described by a single high affinity binding constant, was observed. Similarly, actions of Bay K-8644 could be fit by mono- and biphasic curves according to membrane potentiali3. Interpretation of these and related studies is complicated

because of the racemic compounds employed. This limitation does not apply to the observed potentiation of ( +)-[3H]PN 200-

110 binding to polarized, but not depolarized, myocytes by s-( +)202-791, and the potentiation of Ca*+ current induced by s-(+)202-791 by the simultaneous presence of the R-enantiomer. An interpretation of these findings is

that there are separate, but allosterically linked activator and antagonist si%es, the relative affinities of which are modulated by membrane potential’. However, other studies in similar systems have not revealed such interpretations.

q

q

cl

The majority of studies are consistent with the existence of a single 1,4-DHP site that mediates both activator and antagonist actions. Frequently, but not always, the experimentally reported multiple sites have not been correlated with function.

However, the most recent model of I,&DHP gating of Ca2+ channels does involve interaction at two discrete sites, differential occupancy of which is necessary to mediate transitions between closed states and thence to the open state lo. It is quite clear that voltage-dependent transitions between high and low affinity binding states do exist and can be measured by electrophysiological and radioligand binding techniques. However, these studies do not readily dis~~ish between an interconvertible state and distinct sites differentially revealed by voltage change. It is critically important that all future studies with 1,4-DHPs (and other Ca2+ channel ligands) be conducted with enantiomers of established purity. Any description of 1,4-DHP activator and/or antagonist interactions must acknowledge that the property of activation or antagonism within a single molecu!e is also found with other structural classes of Ca2+ channel drugs, including verapamil, gallopamil (D600) and diltiazem and possibly others (Ref. 14, and see Ref. 30 for review}. There is a general similarity between the dual actions of 1,4-DHPs and those mediated by the other structural classes: the

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stimulation is short-lived, dependent on low drug concentrations and on negative holding potentials, and of non-uniform occurrence. Such observations suggest that the dual response orginates in a process or processes common to channel gating and drug binding rather than to the unique properties of each ligand class. Given the homology between Na+ and Ca*+ channels it is therefore appropriate to note that the property of activation/antagonism is also associated with actions of 1,4DHPs at the Na+ channe131. Dual activator and antagonist properties may be a general property of drugs active at Ca*+ channels and are derived from the fundamental gating properties of this and related ion channels.

References 1 Janis, R. A., Silver, P. and Trig@, D. J.

(1987) Ado. Drug Res. 16, 301-591 2 Glossmann, H. and Striessnig, J. (1988) Vitam. Harm. 44,155-328 3 Langs, D. A., Janis, R. A. and Triggle,

D. J. (1989) Med. Kes. Rev. 5). 123-180 4 Bechem, M., Hebisch, 5. and Schramm, M. (1988) Trends Pharmacol. Sci. 9,257-261 5 Hof, R. I’., Riiegg, U. T., Hof, A. and Vogel, A. (1985) J. Cardiovasc. Phannacol. 7, 689-693 6 Hess, P., Lansman, J. B. and Tsien, R. W. (1984) Nature 311,538-545 7 Thomas, G., Gross, R. and Schramm, M. (1984) J. Cardiovasc. Pharmacol. 6, 1170-1176 8 Dube, G. I’., Baik, Y. H. and Schwartz, A. (1985) J. Card&ax. Pharmacol. 7, 377-389 9 Kokubun, S., Pmd’hom, B., Becker, C., Porzig, H. and Reuter, H. (1986) Mol. Pharmacol. 30, 571-584 10 Lacerda, A. E. and Brown, A. M. (1989) J. Gen. Dhysiol.93, 1243-1273 11 Straver, B. E. (1974) Int. J. CJin. PharmaCOL9, 101-107 12 Himori, N. (1976) Jpn. 1. Pharmacol. 28, 427-435 13 Brown, A. M., Kunze, D. L. and Yatani, A. (1986) I. Physic!. 379,495-.514 14 Scott, R. H. and Dolphin, A. C. (1987) Nature 330,760-762 15 Hering, S., Beech, D. J. and Bolton, T. 8. (1987) Biomed. Biochim. Acfa 46. s657&661 16 Sanguinetti, M. C. and Kass, R. S. (1984) Circ. Res. 55. 336-348 17 Bean, B. P. (1984) Proc. Nat2 Acad. Sci. USA 81,6388-6392 18 Hamilton, S. L., Yatani, A., Brush, K., Schwartz, A. and Brown, A. M. (1987) Mol. Phanaacol. 31.221-231

19 Kass, R. S. (1987) Circ. Res. 61 (Suppl. I), l-5 20 Kamp. T. J.. Sanguinetti, M. C. and Miller, R. J. (1989) Circ. Res. 64,33%351 21 Wei, X-Y., Rutledge,A. and Ttiggle, D. J. (198% Mol. Phartracol. 35, 541-552 22 Ferrante, J.; Luchowski, E., Rutledge, A. and Triggle, D. J. (1989) Bi&em. Biophys. Res. Commun.158,149-154 23 K. .n, Y-W. et al. (1989) NaunynSchmiedeberg’s Arch. Phormocol. 339, 19-30 24 Brown, A. M. and Bimbaumer, L. (1988) Am. I. Physiol. 254, H401-H410 25 Scott, R. and Dolphin, A. C. (1988) Neurosci. Lett. 89, 17C-175 26 Janis, R. A., Bellemann, P., Sarmiento, J. G. and Triggle, D. J. (1985) in Bayer Symposium IX: Cardiovascular Effects of Dihydropyridine-Type Calcium Antagonists and Agonists (Fleckenstein, A., van Breemen, C., Gross, R. and Hoffmeister, F., eds), pp. 140-155, Springer-Verlag 27 Bergamaschi, S., Govoni, S., Cominetti, I’., Parenti, M. and Trabucchi, M. (1988) Biochem. Biophys. Res. Commun. 156, 1279-1286 28 Holtje, H-D. and Marrer, S. (1987) J. Cornput. Aided Mol. Design1, 23-30 29 Rampe, D., Poder, T., Zhao, Z-Y. and Schilling, W. P. (1989) /. Cardiovasc. Phanacol. 13,547-556 30 McDonald, T., Peizer, D. and Trautwein, W. (1989) 1. PhysioZ.(London) 414,569-586 31 Yatani, A., Kunze, D. L. and Brown, A. M. (1988) Am. 1. Physhl. 2%. H140-H147

and particularly thromboxane leukotienes, probably have a critic?! ro!e in airway disease. The eicosanoids, their airway pharmacology, and effects of inhibitors of cyclooxygenase and 5-lipoxygenase, as well as glucocorticosteroids, are reviewed in detail in Chapters 3 and 4. Chapter 9 reviews several pharmacological approaches to treat asthma, including inhibitors of arachidonate metabolism. Chapter 13 provides interesting discussion of an aspirin-induced asthma, as well as beneficial effects of aspirin. Another ubiquitous lipid mediator, PAF, and airway effects of its antagonists are covered in Chapter 8. Chapter 1 reviews autonomic and reflex neuronal control of airway calibre, from the nose to the terminal bronchioles. This topic is extended, in Chapter 7, to the myriad neuropeptides implicated in airway disease, and recent interest in the so-called ‘axon reflex’ and its contribution to neurogenic inflammation. Widdi-

combe, however, stresses that axon reflexes, whereby stimulation of afferent nerve endings leads not only to CNS reflexes, but also to local, antidromic release of have mediators, inflammatory been examined only in animals. Their significance in asthma, if any, is unknown and development of peptide antagonists is critical to understanding in this field. On the subject of inflammation, Chapter 6 discusses airway hyperreactivity and late phase asthmatic reactions. Although the underlying mechanisms are not understood at present, they probably inflammatory chronic involve changes in asthmatics’ airways. Also provided is a discussion of the few animal models of airway hyper ctivity and late onset respol ,c’s. Chapter 2 is a concise overview of molecular mechanisms underlying airway smooth muscle contraction and relaxation. Homeostatic control of intracellular cation obvious with concentrations, emphasis on calcium, is discussed. Much of our knowledge of biochemical regulation of airway contractile proteins, including the function of protein kinase C, is in

Books Asthma and tonic Asthma: Basic Mechanisms Therapeutic Perspectives

and

edited by]. R. Vane, G. A. i-iiggs, S. A. Marsico and G. Nistic6, Pythagora Press, 1989. E40.00 (xiv + 252 pages) ISBN 88 85852 02 7 Of two pleasant aspects of reviewing books for EPS, the first is that the reviewer has several weeks to do so. I kept this volume beside my favourite armchair, and have enjoyed perusing it of an evening, accompanied occasionally by a gin and tonic. Given the modest size (and price) of this monograph, the editors succeed in describing a wide range of topics. Eight chapters cover mechanisms and abnormalities of airway control, and five describe traditional, as well as new approaches to treating asthma. There are several chapters on arachidonic acid metabolites, perhaps indiLating a slight partiality on the part of the editors. Conversely, eicosanoids, and