- Email: [email protected]
Pharmacological assessment of cerebral and coronary vasospasm
85
TIPS - F e b r u a r y 1 9 8 5
strated a m a g n e s i u m - d e p e n d e n t kinase activity associated with h i g h l y p u r i f i e d g l u c o c o r t i c o i d rec e p t o r 23. If steroid r e c e p t o r c o m p o n e n t s do h a v e p r o t e i n k i n a s e activities, f i n d i n g a n d i d e n t i f y i n g physiological substrates should greatly aid o u r u n d e r s t a n d i n g of steroid r e c e p t o r function. N o w that s t e r o i d r e c e p t o r p h o s p h o r y l a t i o n has b e e n d e m o n s t r a t ed, o t h e r f u n c t i o n s w h e r e p h o s p h o r y l a t i o n m i g h t p l a y a role s h o u l d be i n v e s t i g a t e d . It has often b e e n s u g g e s t e d that r e c e p t o r d e p h o s p h o r y l a t i o n m i g h t occur d u r i n g r e c e p t o r t r a n s f o r m a t i o n to the n u c l e a r - b i n d i n g form, b u t this p o s s i b i l i t y has still n o t b e e n clearly tested. W h e t h e r or n o t d e p h o s p h o r y l a t i o n p r o v e s to b e an integral part of the t r a n s f o r m a t i o n process, i n v e s t i g a t i n g the effects of d i f f e r e n t r e c e p t o r p h o s p h o r y l a t i o n states on the s p e e d a n d extent of r e c e p t o r t r a n s f o r m a t i o n c o u l d well p r o v e fruitful. R e c e p t o r p h o s p h o r y l a t i o n could also affect the b i n d i n g of steroid r e c e p t o r s at the n u c l e a r sites, w h e r e t h e y act to p r o m o t e or i n h i b i t g e n e t r a n s c r i p tion. F u r t h e r i n v e s t i g a t i o n s of steroid r e c e p t o r p h o s p h o r y l a t i o n s h o u l d e x p a n d o u r k n o w l e d g e of
the
function
and
regulation
of
t h e s e i n t e r e s t i n g molecules.
References
1 King, W. J. and Greene G.L. (1984) Nature (London) 307, 745--747 2 Welshous, W. B., Lieberman, M. E. and Gorski, J. (1984) Nature (London) 307,
747-749 3 Payvar, F., DeFranco, D., Firestone,
Catelli, M.G., Garcia, T., Gasc, I.M., Groyer, A., Joab, I., Moncharmont, B., Radanyi, C., Renoir, J. M., Tuohimaa, P. and Mester, J. (1983) in Nobel Symposium No. 57; Steroid Hormone Receptors: Structure and Function (Gustafsson, J. A.
4 Munck, A. and Brinck-Johnsen, T. (1968) J. Biol. Chem. 243, 5556-5565 5 Sando, J.J., LaForest, A.C. and Pratt, W. B. (1979) J. Biol. Chem. 254, 4772-4778 6 Nielsen, C. J., Sando, J. J. and Pratt, W. B. (1977) Proc. Natl Acad. Sci., USA 74,
7 8
9 10
1398-1402 Nishigori, H. and Toft, D. (1980) Biochemistry 19, 77~3 Weigel, N. L., Tash, J. S., Means, A. R., Schrader, W.T. and O'Malley, B.W. (1981) Biochem. Biophys. Res. Commun. 102, 513-519 Goueli, S. A., Holtzman, J. L. and Ahmed, K. (1984) Biochem. Biophys. Res. Commun. 123, 778-784 Dougherty, J. J. in Molecular Mechanism of Steroid Hormone Action (Moudgil, V. K., ed.), Walter de Gryter and Co.,
17 18 19 20 21 22
Berlin, in press
11 Migliaccio, A., Lastoria, S., Moncharmont, B., Rotondi, A. and Auricchio, F. (1982) Biochem. Biophys. Res. Commun. 109, 1002-1010 12 Migliaccio, A., Rotondi, A. and Auricchio, F. (1984) Proc. Natl. Acad.
Noboru Toda
The effects of vasoactive endogenous substances, and autonomic nerve activation differ in cerebral or coronary vessels. N o b o r u T o d a s u m m a r i z e s the p h a r m a c o l o g y of these agents in m a m m a l s , including h u m a n s , and considers the influence o f pathological conditions on response to vasodilator interventions.
Noboru Toda is Professor and Chairman in the Department of Pharmacology, Shiga University of Medical Sciences, Seta, Ohtsu 520-21, Japan.
16 Baulieu, E.-E., Binart, N., Buchou, T.,
G. L., Edgar, B., Wrange, O., Okret, S., Gustafsson, J.-A. and Yamamoto, K. R. (1983) Cell 35, 381-392
Pharmacological assessment of cerebral and coronary vasospasm
C e r e b r a l and c o r o n a r y artery vasospasms may play a much m o r e i m p o r t a n t role in the p a t h o g e n e s i s of i s c h e m i c b r a i n and heart d i s e a s e s t h a n has p r e v i o u s l y been considered. Vasospasm characterized angiographically by
Sci., USA 81, 5921-5925 13 Ghosh-Dastidar, P., Coty, W. A., Griest, R.E., Woo, D.D.L. and Fox, C.F. (1984) Proc. Natl Acad. Sci,, USA 81, 1&54-1658 14 Dougherty, l- J., Puri, R. K. and Toft, D.O. (1982) J. Biol. Chem. 257, 14226-14230 15 Dougherty, J. J., Purl, R. K. and Toft, D. O. (1984) J. Biol. Chem. 259, 8004-8009
a reversible, sub-total or total narr o w i n g of m a j o r b r a n c h e s of the arteries, results in cerebral Or m y o c a r d i a l i s c h e m i a a n d is m a n i fested b y a v a r i e t y of n e u r o l o g i c a l and cardiovascular symptoms. Such circulatory disturbances d e r i v e m a i n l y f r o m functional abn o r m a l i t i e s of localized, large arteries, i n c l u d i n g i n c r e a s e d contractility a n d d e c r e a s e d relaxation p o t e n t i a l of the vessel. C o r o n a r y
23
and Eriksson, H., eds), pp. 45-72, Elsevier Science Publishers, Amsterdam Birnbaumer, M., Schrader, W. T. and O'Malley, B. W. (1983) J. Biol. Chem. 258, 1637-1644 Housley, P. R. and Pratt, W. B. (1983) J. Biol. Chem. 258, 4630-4635 Grandics, P., Miller, A., Schmidt, T.I. and Litwack, G. (1984) Biochem. Biophys. Res. Commun. 120, 59-65 MacDonald, R. G., Okulicz, W. C. and Leavitt, W. W. (1982) Biochem. Biophys. Res. Commun. 104, 570-576 Fleming, H., Blumenthal, R. and Gurpide, E. (1983) Proc. Natl Acad. Sci., USA 80, 2486--2490 Garcia, T., Tuohimaa, P., Mester, l., Buchou, T., Renoir, J-M. and Baulieu, EE. (1983) Biochem. Biophys. Res. Commun. 113, 960-966 Kurl, R. N. and Jacob, S. T. (1984) Biochem. Biophys. Res. Commun. 119 700-705
artery v a s o s p a s m is associated w i t h artery s m o o t h m u s c l e contractions, since the s p a s m is effectively o v e r c o m e b y nitroglycerin, p r e v e n t e d b y Ca 2+ antagonists, and p r o v o k e d b y c o r o n a r y vasoconstrictors, such as e r g o n o v i n e , m e t h a c h o l i n e , h i s t a m i n e , etc. O n the o t h e r h a n d , cerebral artery v a s o s p a s m p r o v o k e d several days after s u b a r a c h n o i d h e m o r r h a g e appears to be c a u s e d b y b l o o d c o n s t i t u e n t s or s u b s t a n c e s prod u c e d d u r i n g t h e course of h e m o lysis of a b l o o d clot. Effective therapeutic and/or prophylactic agents for treating posth e m o r r h a g e v a s o s p a s m are not clinically available. D e f i n i t i v e evid e n c e for the p a r t i c i p a t i o n of e i t h e r v a s c u l a r s m o o t h m u s c l e or o t h e r tissues of the b l o o d vessel in the i n t e n s e , p e r s i s t e n t n a r r o w i n g of cerebral arteries has not b e e n documented. Intense, p r o l o n g e d m u s c l e contractions can be i n d u c e d b y sust a i n e d actions of e n d o g e n o u s v a s o c o n s t r i c t o r s and also b y i m p a i r m e n t of v a s c u l a r dilator functions.
1985, Elsevier Science Publishers B.V., Amsterdam
0168- 6147/85/$02.00
86 Endogenous vasoconstrictors Cerebral artery Norepinephrine contracts cerebral arteries isolated from humans, monkeys, dogs, cats, rabbits, cows and goats in a concentration-dependent manner. The magnitude of contractions induced by the amine, relative to reference contractions such as those produced by high concentrations of K +, varies considerably with cerebral arteries from a variety of mammals. The contraction of human and monkey cerebral arteries is evidently greater than that of the dog arteries 1. However, even in these primate cerebral arteries, the amineinduced contractions are appreciably less than those in the mesenteric, gastroepiploic, renal and femoral arteries. Electrical stimulation of sympathetic nerves causes only a slight or no contraction in isolated and in-situ cerebral arteries in experimental animals, including Japanese monkeys 2. Epinephrine also contracts cerebral arteries; however, the magnitude is less than that of the peripheral arteries. 5-HT produces a marked contraction in proximal portions of cerebral arteries obtained from different animal species. The cerebroarterial contractions mediated by serotonergic receptors are greater than those in peripheral arteries. Thromboxane (Tx) A2 and its stable analog, carbocyclic TxA2 (cTxA2), in small concentrations produce marked contractions of human, monkey, dog and bovine cerebral arteries. Maximum contractions induced by cTxA2 are identical to those induced by prostaglandin (PG) F2c~; however, based on the EDs0 values, cTxA2 is approximately 150 times more potent than PGF2a3. TxA2 may not participate in maintaining intense cerebroarterial contractions, because of an extremely short biological half-life; however, this compound is undoubtedly an important cerebrovascular constrictor which would trigger cerebral artery vasospasm. Supematants of hemolysed erythrocyte or whole blood selectively contract cerebral arteries. According to analyses using acetylsalicylic acid and indometacin (PG synthesis inhibitors), polyphloretin phosphate (a PG antagonist) etc., the contractions appear to be mediated mainly by
TIPS - February 1985 substances which release vasoconstrictor PGs from the arterial wall, by oxyhemoglobin acting directly on arterial smooth muscle and by 5-HT (when whole blood is used) 4,5. Substances derived from hemolysis of a blood clot following subarachnoid hemorrhage could be involved in the genesis of delayed cerebral vasospasms. Coronary artery Different responsiveness to norepinephrine has also been observed in coronary arteries isolated from different species. Moderate or marked contractions are induced by norepinephrine in humans. In contrast, only relaxations are induced in the dog arteries 6. In monkey coronary arteries, contractions are seen in response to low concentrations and relaxations with high concentrations of norepinephrine 7. When adrenergic nerves are stimulated electrically or chemically by nicotine and tyramine, monkey coronary arteries contract, whereas dog and sheep arteries relax. Contractions of human and monkey arteries induced by norepinephrine or adrenergic nerve stimulation are suppressed or reversed to relaxations by c~-adrenoceptor blockade. Epinephrine produces a greater contraction than norepinephrine in human and monkey coronary arteries. Increased efferent discharges of sympathetic nerves innervating the coronary vasculature and adrenal medulla may thus be related to vasoconstriction of the proximal coronary arteries.
Acetylchoiine contracts isolated human coronary arteries, but produces an endothelium-dependent relaxation in monkey and dog coronary arteries 6. These induced responses are sensitive to low concentrations of atropine, thereby suggesting involvement of muscarinic receptors. In fact, injections (i.v.) of methacholine provoke coronary vasospasm in patients with variant angina, again suggesting activation of
muscarinic receptors. Histamine also produces human coronary artery contractions, which are mediated by histaminergic H1 receptors 6. In contrast, monkey and dog coronary arteries relax in response to histamine. 5HT contracts proximal portions of human, monkey and dog coronary arteries, cTxA2 and PGF2~ contract coronary arteries of different species; cTxA2 is approximately 300 times more potent than PGF2a in human arteries. Thrombin exerts contractions in dog coronary arteries which are potentiated by removal of the endothelium 8, whereas human coronary arteries do not respond to the proteinase.
Endogenous vasodilator interventions and their inhibition Transmural electrical stimulation or nicotine applied to human, monkey and dog cerebral arteries produces a relaxation in a frequency- or concentration-related manner. The response to the electrical stimulation is abolished by tetrodotoxin 9, and the nicotineinduced relaxation is abolished by hexamethonium or cocaine 1°. Therefore, the relaxation appears to be induced by stimulation of intramural nerve terminals, which liberate vasodilator substance(s). The involvement of ~-adrenergic, muscarinic, histaminergic, adenosine-related, PG-related, and electrogenic Na + pump mechanisms in the relaxation has been excluded 2,1°. In dogs with experimentally-induced cerebral vasospasm several days after subarachnoid hemorrhage, the nicotineinduced relaxation is suppressed or abolished, whereas the relaxation induced by adenosine is unaffected. Relaxations induced by a minute amount of K+ are evidently greater in cerebral than in the other arteries 11. These relaxations are clearly seen in the presence of 5.4 mM [K+]0 (external concentrations of K +) in cerebral arteries from various mammals, including humans; thus, the physiological role in dilating cerebral vessels has been postulated 11. The relaxation is suppressed or abolished by ouabain, low temperature, elevated [K+]0 and reduced [Na+]0, suggesting that the addition of K + activates the electrogenic Na + pump and,
T I P S - F e b r u a r y 1985
87
as a result, hyperpolarizes smooth muscle cell membranes. O u a b a i n in low concentrations selectively contracts h u m a n , m o n k e y and dog cerebral arteries, possibly due to i n h i b i t i o n of m e m b r a n e ATPase or Na + p u m p , b u t not secondarily to a release of n o r e p i n e p h r i n e from adrenergic nerves seen in peripheral arteries 12. Prolonged i m p a i r m e n t s of circulation in vascular smooth muscle could be i n d u c e d by a s u r r o u n d i n g blood clot derived from subarachnoid hemorrhage, circulatory disturbances of vasa vasorum etc.; u n d e r these conditions, the activity of m e m b r a n e ATPbase in the muscle cells and the production of ATP as a substrate would be reduced. This may result in sustained contractions of cerebral artery smooth muscle, such as is seen i n response to ouabain. The activity of Ca2+-activated Mg 2+ATPase (which is responsible for p u m p i n g Ca 2+ into intracellularly-stored sites) may also be suppressed, thus increasing the concentration of active Ca 2+ in the vicinity of the contractile proteins. PGI2, a potent e n d o g e n o u s vasodilator in h u m a n cerebral and coronary arteries, is liberated from the arterial wall by chemical and physical stimulations responsible for vasoconstriction. There is accumulating evidence that the e n d o t h e l i u m is a major site for PGI2 production 13. The endotheli u m also releases other vasodilator
Non-biased drug information H a n d b o o k of clinical pharmacology (second edition) edited by F. Bochner, T. K a m p m a n n a n d J. Brown & Company, 352 pages) I S B N 0 31
G. Carruthers, Steiner, Little, 1983. (xiii + 610064 1
This c h u b b y paperback follows the format of the 1978 edition. Its four authors are from Australia, Canada, Denmark and England, and reflect an international contribution. The suggestion that 'medical students, physicians, interns and nurses will welcome this
substances, w h e n stimulated by acetylcholine14, histamine, ADP, ATP, t h r o m b i n , etc.; the vasodilatation may be associated with lipoxygenase products and other substances yet to be identified. Therefore, functional and histological i m p a i r m e n t s of the endothelium result in a lack of buffering actions of vasodilators against vasoconstrictor interventions and, as a result, increase the ability of smooth muscle to respond with contractions. []
[]
[]
to a striking imbalance of vasoconstrictor and vasodilator regulations (Fig. 1) b y local (neural and chemical influences, atherosclerosis, endothelial lesion and dysfunction, anoxia, platelet aggregation, blood coagulation, etc) as well as systemic pathogenic factors (neural and hormonal anomalities, hypercholesterolemia, plasma Mg2+-deficiency15, alkalosis 16, etc).
References
Effects of vasoactive endogenous substances and autonomic nerve activation differ in cerebral, coronary and other vasculatures, and species differences in responses of cerebral and coronary artery are evident. It should therefore be emphasized that data obtained from experimental animals cannot always be extrapolated to healthy and diseased humans. From findings in the h u m a n arteries, it appears that the coronary artery tone is regulated b y vasoconstrictor interventions to a greater extent than is the cerebroarterial tone, whereas the latter is controlled by vasodilator interventions to a greater extent (Fig. 1). The nature and the mechanism u n d e r l y i n g cerebral and coronary artery vasospasms are thus probably quite different. The artery vasospasm is attributed possibly
1 Toda, N. (1983) J. Pharmac. Exp. Ther. 226, 861~68 2 Toda, N. (1982) Am. J. Physiol. 243, H145-H153 3 Toda, N. (1982)Circ. Res. 51,675-682 4 Toda, N., Shimizu, K. and Ohta, T. (1980)J. Neurosurg. 53. 312-322 50kamoto, S., Handa, H. and Toda, N. (1984) Stroke 15, 60~4 6 Toda, N. (1983) Am. [. Physiol. 245, H937-H941 7 Toda, N. (1981)Circ. Res. 49, 1228-1236 8 Ku, D. D. (1982)Science 218, 576-578 9 Lee, T. J.-F., Su, C. and Bevan J.A. (1975) Experientia 31, 1424-1426 10 Toda, N. (1975) J. Pharmac. Exp. Ther. 193, 376-384 11 Toda,N. (1974)Am. J. Physiol. 227, 12061211 12 Toda, N. (1980) Am. J. Physiol. 239, H199-H205 13 Toda, N. (1984) Br. J. Pharmacol. 81, 301-307 14 Furchgott, R. F. and Zawadzki, J.V. (1980) Nature (London) 288, 373--376 15 Tuflapaty,P. D. M. V. and Altura,B. M. (1980) Science 208, 198-200 16 Yasue, H., Omote, S., Takizawa, A., Nagao, M., Nosaka, K. and Nakajima, H. (1981)Am. Heart J. 102,206-210
time-saving source of essential information' is certainly appropriate. This h a n d b o o k is d i s t i n g u i s h e d however from a simple reference book b y the first eleven chapters that occupy a quarter of the book. A n introductory chapter by Professor Daniel Azarnoff, 'Do we achieve rational drug therapy?' is challenging and in effect defines one objective of the book, the provision of n o n - b i a s e d drug information. The following chapters deal with drugs and renal disease, drugs and liver disease, medication d u r i n g pregnancy, d u r i n g lactation, medication in children, in the elderly. Finally, chapter 11
offers a definition and explanation of pharmacokinetic terms. These chapters are very clearly and succinctly written and provide an exceptionally fine exposition, not readily available elsewhere. The bulk of the book, chapter 12, consists of the drug profiles of some h u n d r e d commonly used drugs, based entirely on Approved or Adopted Names arranged alphabetically. However, it is highly desirable to use the index. There are two reasons for this: the nomenclature is American (salbutamol - see albuterol), also several drugs are often listed together with a common therapeutic class (ibuprofen - see propionic acid derivatives; maprotiline - see newer antidepressants). This system of grouping of like drugs is advantageous and largely compensates for the inconvenience
TIPS - F e b r u a r y 1 9 8 5
strated a m a g n e s i u m - d e p e n d e n t kinase activity associated with h i g h l y p u r i f i e d g l u c o c o r t i c o i d rec e p t o r 23. If steroid r e c e p t o r c o m p o n e n t s do h a v e p r o t e i n k i n a s e activities, f i n d i n g a n d i d e n t i f y i n g physiological substrates should greatly aid o u r u n d e r s t a n d i n g of steroid r e c e p t o r function. N o w that s t e r o i d r e c e p t o r p h o s p h o r y l a t i o n has b e e n d e m o n s t r a t ed, o t h e r f u n c t i o n s w h e r e p h o s p h o r y l a t i o n m i g h t p l a y a role s h o u l d be i n v e s t i g a t e d . It has often b e e n s u g g e s t e d that r e c e p t o r d e p h o s p h o r y l a t i o n m i g h t occur d u r i n g r e c e p t o r t r a n s f o r m a t i o n to the n u c l e a r - b i n d i n g form, b u t this p o s s i b i l i t y has still n o t b e e n clearly tested. W h e t h e r or n o t d e p h o s p h o r y l a t i o n p r o v e s to b e an integral part of the t r a n s f o r m a t i o n process, i n v e s t i g a t i n g the effects of d i f f e r e n t r e c e p t o r p h o s p h o r y l a t i o n states on the s p e e d a n d extent of r e c e p t o r t r a n s f o r m a t i o n c o u l d well p r o v e fruitful. R e c e p t o r p h o s p h o r y l a t i o n could also affect the b i n d i n g of steroid r e c e p t o r s at the n u c l e a r sites, w h e r e t h e y act to p r o m o t e or i n h i b i t g e n e t r a n s c r i p tion. F u r t h e r i n v e s t i g a t i o n s of steroid r e c e p t o r p h o s p h o r y l a t i o n s h o u l d e x p a n d o u r k n o w l e d g e of
the
function
and
regulation
of
t h e s e i n t e r e s t i n g molecules.
References
1 King, W. J. and Greene G.L. (1984) Nature (London) 307, 745--747 2 Welshous, W. B., Lieberman, M. E. and Gorski, J. (1984) Nature (London) 307,
747-749 3 Payvar, F., DeFranco, D., Firestone,
Catelli, M.G., Garcia, T., Gasc, I.M., Groyer, A., Joab, I., Moncharmont, B., Radanyi, C., Renoir, J. M., Tuohimaa, P. and Mester, J. (1983) in Nobel Symposium No. 57; Steroid Hormone Receptors: Structure and Function (Gustafsson, J. A.
4 Munck, A. and Brinck-Johnsen, T. (1968) J. Biol. Chem. 243, 5556-5565 5 Sando, J.J., LaForest, A.C. and Pratt, W. B. (1979) J. Biol. Chem. 254, 4772-4778 6 Nielsen, C. J., Sando, J. J. and Pratt, W. B. (1977) Proc. Natl Acad. Sci., USA 74,
7 8
9 10
1398-1402 Nishigori, H. and Toft, D. (1980) Biochemistry 19, 77~3 Weigel, N. L., Tash, J. S., Means, A. R., Schrader, W.T. and O'Malley, B.W. (1981) Biochem. Biophys. Res. Commun. 102, 513-519 Goueli, S. A., Holtzman, J. L. and Ahmed, K. (1984) Biochem. Biophys. Res. Commun. 123, 778-784 Dougherty, J. J. in Molecular Mechanism of Steroid Hormone Action (Moudgil, V. K., ed.), Walter de Gryter and Co.,
17 18 19 20 21 22
Berlin, in press
11 Migliaccio, A., Lastoria, S., Moncharmont, B., Rotondi, A. and Auricchio, F. (1982) Biochem. Biophys. Res. Commun. 109, 1002-1010 12 Migliaccio, A., Rotondi, A. and Auricchio, F. (1984) Proc. Natl. Acad.
Noboru Toda
The effects of vasoactive endogenous substances, and autonomic nerve activation differ in cerebral or coronary vessels. N o b o r u T o d a s u m m a r i z e s the p h a r m a c o l o g y of these agents in m a m m a l s , including h u m a n s , and considers the influence o f pathological conditions on response to vasodilator interventions.
Noboru Toda is Professor and Chairman in the Department of Pharmacology, Shiga University of Medical Sciences, Seta, Ohtsu 520-21, Japan.
16 Baulieu, E.-E., Binart, N., Buchou, T.,
G. L., Edgar, B., Wrange, O., Okret, S., Gustafsson, J.-A. and Yamamoto, K. R. (1983) Cell 35, 381-392
Pharmacological assessment of cerebral and coronary vasospasm
C e r e b r a l and c o r o n a r y artery vasospasms may play a much m o r e i m p o r t a n t role in the p a t h o g e n e s i s of i s c h e m i c b r a i n and heart d i s e a s e s t h a n has p r e v i o u s l y been considered. Vasospasm characterized angiographically by
Sci., USA 81, 5921-5925 13 Ghosh-Dastidar, P., Coty, W. A., Griest, R.E., Woo, D.D.L. and Fox, C.F. (1984) Proc. Natl Acad. Sci,, USA 81, 1&54-1658 14 Dougherty, l- J., Puri, R. K. and Toft, D.O. (1982) J. Biol. Chem. 257, 14226-14230 15 Dougherty, J. J., Purl, R. K. and Toft, D. O. (1984) J. Biol. Chem. 259, 8004-8009
a reversible, sub-total or total narr o w i n g of m a j o r b r a n c h e s of the arteries, results in cerebral Or m y o c a r d i a l i s c h e m i a a n d is m a n i fested b y a v a r i e t y of n e u r o l o g i c a l and cardiovascular symptoms. Such circulatory disturbances d e r i v e m a i n l y f r o m functional abn o r m a l i t i e s of localized, large arteries, i n c l u d i n g i n c r e a s e d contractility a n d d e c r e a s e d relaxation p o t e n t i a l of the vessel. C o r o n a r y
23
and Eriksson, H., eds), pp. 45-72, Elsevier Science Publishers, Amsterdam Birnbaumer, M., Schrader, W. T. and O'Malley, B. W. (1983) J. Biol. Chem. 258, 1637-1644 Housley, P. R. and Pratt, W. B. (1983) J. Biol. Chem. 258, 4630-4635 Grandics, P., Miller, A., Schmidt, T.I. and Litwack, G. (1984) Biochem. Biophys. Res. Commun. 120, 59-65 MacDonald, R. G., Okulicz, W. C. and Leavitt, W. W. (1982) Biochem. Biophys. Res. Commun. 104, 570-576 Fleming, H., Blumenthal, R. and Gurpide, E. (1983) Proc. Natl Acad. Sci., USA 80, 2486--2490 Garcia, T., Tuohimaa, P., Mester, l., Buchou, T., Renoir, J-M. and Baulieu, EE. (1983) Biochem. Biophys. Res. Commun. 113, 960-966 Kurl, R. N. and Jacob, S. T. (1984) Biochem. Biophys. Res. Commun. 119 700-705
artery v a s o s p a s m is associated w i t h artery s m o o t h m u s c l e contractions, since the s p a s m is effectively o v e r c o m e b y nitroglycerin, p r e v e n t e d b y Ca 2+ antagonists, and p r o v o k e d b y c o r o n a r y vasoconstrictors, such as e r g o n o v i n e , m e t h a c h o l i n e , h i s t a m i n e , etc. O n the o t h e r h a n d , cerebral artery v a s o s p a s m p r o v o k e d several days after s u b a r a c h n o i d h e m o r r h a g e appears to be c a u s e d b y b l o o d c o n s t i t u e n t s or s u b s t a n c e s prod u c e d d u r i n g t h e course of h e m o lysis of a b l o o d clot. Effective therapeutic and/or prophylactic agents for treating posth e m o r r h a g e v a s o s p a s m are not clinically available. D e f i n i t i v e evid e n c e for the p a r t i c i p a t i o n of e i t h e r v a s c u l a r s m o o t h m u s c l e or o t h e r tissues of the b l o o d vessel in the i n t e n s e , p e r s i s t e n t n a r r o w i n g of cerebral arteries has not b e e n documented. Intense, p r o l o n g e d m u s c l e contractions can be i n d u c e d b y sust a i n e d actions of e n d o g e n o u s v a s o c o n s t r i c t o r s and also b y i m p a i r m e n t of v a s c u l a r dilator functions.
1985, Elsevier Science Publishers B.V., Amsterdam
0168- 6147/85/$02.00
86 Endogenous vasoconstrictors Cerebral artery Norepinephrine contracts cerebral arteries isolated from humans, monkeys, dogs, cats, rabbits, cows and goats in a concentration-dependent manner. The magnitude of contractions induced by the amine, relative to reference contractions such as those produced by high concentrations of K +, varies considerably with cerebral arteries from a variety of mammals. The contraction of human and monkey cerebral arteries is evidently greater than that of the dog arteries 1. However, even in these primate cerebral arteries, the amineinduced contractions are appreciably less than those in the mesenteric, gastroepiploic, renal and femoral arteries. Electrical stimulation of sympathetic nerves causes only a slight or no contraction in isolated and in-situ cerebral arteries in experimental animals, including Japanese monkeys 2. Epinephrine also contracts cerebral arteries; however, the magnitude is less than that of the peripheral arteries. 5-HT produces a marked contraction in proximal portions of cerebral arteries obtained from different animal species. The cerebroarterial contractions mediated by serotonergic receptors are greater than those in peripheral arteries. Thromboxane (Tx) A2 and its stable analog, carbocyclic TxA2 (cTxA2), in small concentrations produce marked contractions of human, monkey, dog and bovine cerebral arteries. Maximum contractions induced by cTxA2 are identical to those induced by prostaglandin (PG) F2c~; however, based on the EDs0 values, cTxA2 is approximately 150 times more potent than PGF2a3. TxA2 may not participate in maintaining intense cerebroarterial contractions, because of an extremely short biological half-life; however, this compound is undoubtedly an important cerebrovascular constrictor which would trigger cerebral artery vasospasm. Supematants of hemolysed erythrocyte or whole blood selectively contract cerebral arteries. According to analyses using acetylsalicylic acid and indometacin (PG synthesis inhibitors), polyphloretin phosphate (a PG antagonist) etc., the contractions appear to be mediated mainly by
TIPS - February 1985 substances which release vasoconstrictor PGs from the arterial wall, by oxyhemoglobin acting directly on arterial smooth muscle and by 5-HT (when whole blood is used) 4,5. Substances derived from hemolysis of a blood clot following subarachnoid hemorrhage could be involved in the genesis of delayed cerebral vasospasms. Coronary artery Different responsiveness to norepinephrine has also been observed in coronary arteries isolated from different species. Moderate or marked contractions are induced by norepinephrine in humans. In contrast, only relaxations are induced in the dog arteries 6. In monkey coronary arteries, contractions are seen in response to low concentrations and relaxations with high concentrations of norepinephrine 7. When adrenergic nerves are stimulated electrically or chemically by nicotine and tyramine, monkey coronary arteries contract, whereas dog and sheep arteries relax. Contractions of human and monkey arteries induced by norepinephrine or adrenergic nerve stimulation are suppressed or reversed to relaxations by c~-adrenoceptor blockade. Epinephrine produces a greater contraction than norepinephrine in human and monkey coronary arteries. Increased efferent discharges of sympathetic nerves innervating the coronary vasculature and adrenal medulla may thus be related to vasoconstriction of the proximal coronary arteries.
Acetylchoiine contracts isolated human coronary arteries, but produces an endothelium-dependent relaxation in monkey and dog coronary arteries 6. These induced responses are sensitive to low concentrations of atropine, thereby suggesting involvement of muscarinic receptors. In fact, injections (i.v.) of methacholine provoke coronary vasospasm in patients with variant angina, again suggesting activation of
muscarinic receptors. Histamine also produces human coronary artery contractions, which are mediated by histaminergic H1 receptors 6. In contrast, monkey and dog coronary arteries relax in response to histamine. 5HT contracts proximal portions of human, monkey and dog coronary arteries, cTxA2 and PGF2~ contract coronary arteries of different species; cTxA2 is approximately 300 times more potent than PGF2a in human arteries. Thrombin exerts contractions in dog coronary arteries which are potentiated by removal of the endothelium 8, whereas human coronary arteries do not respond to the proteinase.
Endogenous vasodilator interventions and their inhibition Transmural electrical stimulation or nicotine applied to human, monkey and dog cerebral arteries produces a relaxation in a frequency- or concentration-related manner. The response to the electrical stimulation is abolished by tetrodotoxin 9, and the nicotineinduced relaxation is abolished by hexamethonium or cocaine 1°. Therefore, the relaxation appears to be induced by stimulation of intramural nerve terminals, which liberate vasodilator substance(s). The involvement of ~-adrenergic, muscarinic, histaminergic, adenosine-related, PG-related, and electrogenic Na + pump mechanisms in the relaxation has been excluded 2,1°. In dogs with experimentally-induced cerebral vasospasm several days after subarachnoid hemorrhage, the nicotineinduced relaxation is suppressed or abolished, whereas the relaxation induced by adenosine is unaffected. Relaxations induced by a minute amount of K+ are evidently greater in cerebral than in the other arteries 11. These relaxations are clearly seen in the presence of 5.4 mM [K+]0 (external concentrations of K +) in cerebral arteries from various mammals, including humans; thus, the physiological role in dilating cerebral vessels has been postulated 11. The relaxation is suppressed or abolished by ouabain, low temperature, elevated [K+]0 and reduced [Na+]0, suggesting that the addition of K + activates the electrogenic Na + pump and,
T I P S - F e b r u a r y 1985
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as a result, hyperpolarizes smooth muscle cell membranes. O u a b a i n in low concentrations selectively contracts h u m a n , m o n k e y and dog cerebral arteries, possibly due to i n h i b i t i o n of m e m b r a n e ATPase or Na + p u m p , b u t not secondarily to a release of n o r e p i n e p h r i n e from adrenergic nerves seen in peripheral arteries 12. Prolonged i m p a i r m e n t s of circulation in vascular smooth muscle could be i n d u c e d by a s u r r o u n d i n g blood clot derived from subarachnoid hemorrhage, circulatory disturbances of vasa vasorum etc.; u n d e r these conditions, the activity of m e m b r a n e ATPbase in the muscle cells and the production of ATP as a substrate would be reduced. This may result in sustained contractions of cerebral artery smooth muscle, such as is seen i n response to ouabain. The activity of Ca2+-activated Mg 2+ATPase (which is responsible for p u m p i n g Ca 2+ into intracellularly-stored sites) may also be suppressed, thus increasing the concentration of active Ca 2+ in the vicinity of the contractile proteins. PGI2, a potent e n d o g e n o u s vasodilator in h u m a n cerebral and coronary arteries, is liberated from the arterial wall by chemical and physical stimulations responsible for vasoconstriction. There is accumulating evidence that the e n d o t h e l i u m is a major site for PGI2 production 13. The endotheli u m also releases other vasodilator
Non-biased drug information H a n d b o o k of clinical pharmacology (second edition) edited by F. Bochner, T. K a m p m a n n a n d J. Brown & Company, 352 pages) I S B N 0 31
G. Carruthers, Steiner, Little, 1983. (xiii + 610064 1
This c h u b b y paperback follows the format of the 1978 edition. Its four authors are from Australia, Canada, Denmark and England, and reflect an international contribution. The suggestion that 'medical students, physicians, interns and nurses will welcome this
substances, w h e n stimulated by acetylcholine14, histamine, ADP, ATP, t h r o m b i n , etc.; the vasodilatation may be associated with lipoxygenase products and other substances yet to be identified. Therefore, functional and histological i m p a i r m e n t s of the endothelium result in a lack of buffering actions of vasodilators against vasoconstrictor interventions and, as a result, increase the ability of smooth muscle to respond with contractions. []
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to a striking imbalance of vasoconstrictor and vasodilator regulations (Fig. 1) b y local (neural and chemical influences, atherosclerosis, endothelial lesion and dysfunction, anoxia, platelet aggregation, blood coagulation, etc) as well as systemic pathogenic factors (neural and hormonal anomalities, hypercholesterolemia, plasma Mg2+-deficiency15, alkalosis 16, etc).
References
Effects of vasoactive endogenous substances and autonomic nerve activation differ in cerebral, coronary and other vasculatures, and species differences in responses of cerebral and coronary artery are evident. It should therefore be emphasized that data obtained from experimental animals cannot always be extrapolated to healthy and diseased humans. From findings in the h u m a n arteries, it appears that the coronary artery tone is regulated b y vasoconstrictor interventions to a greater extent than is the cerebroarterial tone, whereas the latter is controlled by vasodilator interventions to a greater extent (Fig. 1). The nature and the mechanism u n d e r l y i n g cerebral and coronary artery vasospasms are thus probably quite different. The artery vasospasm is attributed possibly
1 Toda, N. (1983) J. Pharmac. Exp. Ther. 226, 861~68 2 Toda, N. (1982) Am. J. Physiol. 243, H145-H153 3 Toda, N. (1982)Circ. Res. 51,675-682 4 Toda, N., Shimizu, K. and Ohta, T. (1980)J. Neurosurg. 53. 312-322 50kamoto, S., Handa, H. and Toda, N. (1984) Stroke 15, 60~4 6 Toda, N. (1983) Am. [. Physiol. 245, H937-H941 7 Toda, N. (1981)Circ. Res. 49, 1228-1236 8 Ku, D. D. (1982)Science 218, 576-578 9 Lee, T. J.-F., Su, C. and Bevan J.A. (1975) Experientia 31, 1424-1426 10 Toda, N. (1975) J. Pharmac. Exp. Ther. 193, 376-384 11 Toda,N. (1974)Am. J. Physiol. 227, 12061211 12 Toda, N. (1980) Am. J. Physiol. 239, H199-H205 13 Toda, N. (1984) Br. J. Pharmacol. 81, 301-307 14 Furchgott, R. F. and Zawadzki, J.V. (1980) Nature (London) 288, 373--376 15 Tuflapaty,P. D. M. V. and Altura,B. M. (1980) Science 208, 198-200 16 Yasue, H., Omote, S., Takizawa, A., Nagao, M., Nosaka, K. and Nakajima, H. (1981)Am. Heart J. 102,206-210
time-saving source of essential information' is certainly appropriate. This h a n d b o o k is d i s t i n g u i s h e d however from a simple reference book b y the first eleven chapters that occupy a quarter of the book. A n introductory chapter by Professor Daniel Azarnoff, 'Do we achieve rational drug therapy?' is challenging and in effect defines one objective of the book, the provision of n o n - b i a s e d drug information. The following chapters deal with drugs and renal disease, drugs and liver disease, medication d u r i n g pregnancy, d u r i n g lactation, medication in children, in the elderly. Finally, chapter 11
offers a definition and explanation of pharmacokinetic terms. These chapters are very clearly and succinctly written and provide an exceptionally fine exposition, not readily available elsewhere. The bulk of the book, chapter 12, consists of the drug profiles of some h u n d r e d commonly used drugs, based entirely on Approved or Adopted Names arranged alphabetically. However, it is highly desirable to use the index. There are two reasons for this: the nomenclature is American (salbutamol - see albuterol), also several drugs are often listed together with a common therapeutic class (ibuprofen - see propionic acid derivatives; maprotiline - see newer antidepressants). This system of grouping of like drugs is advantageous and largely compensates for the inconvenience