TIPS - September 19889 [Voi. $1

TABLE II. The -lag IC, values of various ~/~~~rn alkalofds for inhibi8on of rsclio- lab&d dopamine binding in tissue home- genates from corpora stfista of rats

Compound -Log molar Afflnily if&,, (k SE) rStl0

Dopamine (14) 7.75 f 6.05 1 Obamogine (3) 7.16 f 0.66 1~4 Reticuline (4) 6.66 f 0.17 1:16 Golumbamine (3) 5.50 + 0.52 1: 176 Thalistyline (3) 5.41 f 0.46 1:216 Palmatine (3) 6.33 + 0.16 1:26S

Data taken from Ref. 13.

tion. JVeverfheless, it was only 25% as effective as (+)-tubo- curarineZo. Thalistyline appears to interact with the nicotinic receptor at the neuromuscular junction in a reversible way. In contrast, the dimeric alkaloid obamegine, did not show any neuromuscularblock- ing activity.

Antibacterial activity Many Tkalictrum alkaloids were

tested for antibacterial activity against S~uph~lococc~s aureus, E. coli, Sa~mffnel~a ga~l~na~~m, He&- siella pneum~n~ae, M~~oba~~~*~rn smegmatis and Candida &&cans, using streptomycin as a reference drug. The minimum inhibitory concentrations of hemandezine, thalicthuberine, thalistyline, and thalrugossmine either for Myco-

bacie~um sme~af~s or Ca~dida albicans were between 2.X0 ug nil-l (Refs 6, 7) and had 2% the activity of streptomycin. Many other Thalictrum alkaloids required higher concentrations to inhibit the microbes.

q q q

Synthetic analogs of tetra- hydroisoquinolines are potent smooth muscle relaxantsr4 and in certain conditions the natural sub- stance or compounds resembling Tha~~c~~rn alkaloids have been detected in neonatal rat tissue as well as plantPF

more commonly in However the wide

diversity of action of the Thalic- trum alkaloids means that their potential use is limited by the need for further research.

POPAT N. PATIL AND JACK L. BEAL

The Ohio State &kw&y, College of Pkar- mncy, Lloyd PA, Parks ffizll‘ SO@ w. zztil Avenue, Co~u~b~, OH 43210, USA.

References 1 Dutschewska, H. B. and Kuzmanov,

B. A. (198211. Nat. Prod. 45.295-310 2 Shtf; P. i. and Doskotch;R. W. (1970)

Lloydia 33,403-452 3 Shamma, M. and Monjot, J. L. (1978)

329

The lsoqoi~o~~ne ~kaloids f&eorck (1972-1977), Fimmm Press

4 Patil, P. N., Mack, R., Tye, A. and Beal, I- L. W651 I. Pkarm. Sci. 5Q,l387-1388

S Hahn, R. A., Nebo.1, J. W., Tye, A. and Beat, J. L. (1966) f. Pkarm. Sci. 55, 466.. 469

6 Wu, W-N., Beal, J. L., Mitscher, L. A. Safman, K. N. and Patti, P. (1976) Lfoydia 39, 204-212

7 Liao, W-T., Bee! J. L: Wu, W-N. and Doskotch, R. ‘N. (1978) Lloydia 4l,B7- 270

8 Hahn, R. A., Kelly, M. G., Shamma, M. and Be& J. J.. (1972) Arch. ht. Pkmma- codyrt. Ther. 198,39%396

9 Pate!. D. G., Tye, A., Pat& P. N., B&c- man, A. M. and Beal, J. L. (1970) Lfoydiu 33,36-Q

10 Banning, J. W., Satman. K and Pat.& P. N. (1982) J. Nat. Prod. 45, X8-177

11 Arunlakshana, 0. and Schtld, HO. (1959) Br. J. Pkannacoi. 14,4&58

12 KeBey, P. H., Miller, R J. and Neumeyer, J. L. (1976) Eur. I. Pkarmacol. 35,85-92

13 Banning, J. W., Uretaky, N. J., Pat& P. N. and Beaf, J. L. (1980) Life Sci. 26, 2083-2091

14 Sheppard, H. and Burghardt, C. R. (1978) Biockem. Pkarmacof. 27, 1113- 1116

15 Nelson, S. Hz and Steinsland, 0. S. (1985) Eur. 1. i’kurmucof. 108,209-2X!

16 Mu#opa~yay, A,Navran,S. S., Amin, H. M., Abdet-A&, S. A., Char& J., Sober, D. J.. Milfer, D. D. and Fefler, D. R. (1985) J. Pkarmacui. Exp. Tker. 232, l-9

17 Nesterick, C. A. and Rahwan, R. G. (1979) J. Ckromatog. 144.205-216

18 Holtz, P. (1966) Pknrmacol. Rev. 18, pati 1) 85-m

Does captopril elevate mood? The first mention of a mood elevating effect of captopril was made in 1984. The report’ des- cribed three patients with medical indications for captopril and with depression. Improvement in mood appeared to be related to captopril administration, since elevations and depressions in mood observed in each patient correlated with changes in the dose of captopril.

More recently, the antidepress- ant effect of captopril was reported in a 52-year-old patient with hypertension and a DSM-III diagnosis of major depression*. During the second week of cap- topril treatment (150 mg d-l], the patient’s depressed mood improved significantly; his ability to concentrate returned; and his lethargy, psychomotor retarda- tion, and anhedonia decreased considerably. The patient was subsequently discharged and remained free of symptoms six

months later. Mood elevation in this case also seemed to parallel the ant~~e~~ive response to captopril.

These anecdotal reports are partly supported by the results of a multicenter randomized double- blind clinical trial among 626 men with mild to moderate hyperten- sion to determine the effects of captopril, methyldopa: or propra- nolo1 treatment on the quality of life3. Assessment of the quality of life was based on five measures: (1) sense of well-being and satis- faction -with life; (2) physical state; (3) emotional state; (4) intellectual functioning; and (5j ability to perform in social roles and the degree of satisfaction derived from those roles. The influence of treatment was measured by differ- ences between scores obtained by questionnaire at the end of the one month placebo period and at the end of the six months active treatment period. Most of the

results wl:re expected. For in- stance, the physical symptoms distress index and the sexual symptoms distress index show significant change for the worse with methyldopa and proprsrt&i. Also, on the Reitan Trail-Making Test, which measures visual motor speed and integration, al.l subjects improved with practice as evidenced by the increase in scores between the beginning and the end of the treatment phase. Some of the results of the study were unexpected, however, be- cause of the direction or the size of the change. For instance, the life satisfaction index (which eval- uates 14 areas of life including marriage, finances, standard of living, housing, and degree of social participation) was signifi- cantly changed for the worse oniy

with methyldopa and propranolol. The most surprising results were those obtained with a work per- formance and satisfaction SC&Z covering areas such as the ability to keep pace with the job, on-the- job fatigue, problems of concen-

330

tration and job satisfaction. Here, the captopril group showed a significant improvement com- pared to a significant deteriora- tion with methyldopa and no change with propranoloi~ On the well-being adjustment scale, which measures areas such as anxiety, depression, general health, positive well-being, self control and vitality, only the cap- topril group showed an improve- ment.

It is difficult to discard those findings on the basis that the apparent improvement on the quality of life simply reflected a general dissatisfaction with pre- vious treatments. Indeed, such a contrast would be expected to be readily apparent at the end of the one month placebo period which preceded the six month drug treatment period. Furthermore, the patients were not chosen for this study on the basis of their dissatisfaction with the previous tmatment or because of side- efIects associated with previous treatment. It is also difficult to discard those findings as chance events because of their multipli- city and concordance. Finally, this study, designed as it was to capture as many aspects of the ‘quality of life’ as possible, identi- fied a subtle but positive psychopharmacological effect of propranolol, one of the two com- parison drugs. The social partici- pation index showed a significant improvement only with proprano- 1oI. This is concordant with the expected properties of this com- pound in various social manifes- tations of anxiety and therefore lends credence to the finding of a mood elevating effect of captopril. On the other hand, most clinicians would agree that patients often do not realize the CNS side-effects of their antihypertensive medication until quite a while after they have been withdrawn from them. Thus the study of Croog ef al.3 is consistent with the possibility that angiotensin II converting enzyme (ACE) inhibitors might elevate mood.

Several mechanisms have been proposed to account for the CNS effects of captoprll: a direct i.-siiLuitor~_ effect on the metabol- ism of enkephalins, endorphins or other peptides’@; an indirect, angiotensin II effect on noradre- nergic regulation74; an indirect, angiotensin II effect on the

h~othalamic pituitary adrenal axis by stimulation of adrenocorti- cotrophic hormone (ACTH) and vasopressin releaselo*l’; and fin- ally an indirect angiotensin II effect on the median eminence and paraventricular nuclei with a secondary influence on the release of other neuropeptides like corticotropin-releasingfactor,witb behavioral effects resulting from glucocorticoid action’. To this list of hypothetical mechanisms we would like to add one more. It is known that plasma angio- tensin II exerts central effects on water regulation and blood pressure by acting on circumven- tricular organs like the neuro- h~ophysis and median eminence of the hypothalamus, which are located outside the blood-brain barrier (BBB). Peripherally admin- istered captopril and associated changes in plasma angiotensin II could modulate behavior and affect mood through an action on these circumventricular organs as well. The role of the circumventri- cular organs and other ACE-rich brain regions might be more important than generally recog- nized; the distribution of peptida- ses in brain is such that the regions which are not protected by the BBB endothelium appear to be dramatically enriched in ACE1*. This, in turn, suggests that there are two types of BBB: the specialized endothelium of the BBB and peptidase-rich regions not covered by such an endothe- lium. The peptidase-rich regions might be subject to biochemical

TE!i - September 1987 CVol. 83

tuning by peptidase ~hibitors such as captopril and ‘gate’ the passage of peripheral neuropep- tides into those regions of the brain from where they would diffuse or be transported to other brain structures.

PIERRE E. ETIENNE

AND GEORGE S. ZUBENSKO*

Research Depurtmenf, Ph~uceufica~ Divi- sion, Ci&u-Geigy, Summit, h!j 07901, USA, and Western Psychiatric Institute and Clinic, Department of Psychiatry, University of Piftsbu~k, Pittsburgh, PA 15213, USA,

References 1 Zubenko, G. S. and Nixon, R. A. (1984)

Am. I. Psyckiatr. 141,110-111 2 Deicken, R. F. (1986) Biol. Psyckiatr. 21,

1425-1428 3 Crook, S. H., Levine, S., Byron, B.,

BulFitt, C. J., Jenkins, C. D., Klerman, G. L., Wiliiamson,G. H. andTesta,M. A. (1986) N. Et@. j. Med. 314,1657-X64

4 Stine, S. M., Yang, H-Y. T. and Costa, E. (1980) Bruin Res. 188,295--299

5 Schwartz, J. C., de la Baume, S., Yi, C. C., Chaillet, I?., Marcais-Collazo, H. and Costentin, J. (1982) Prog. Neuro-Psycko- pka~acal. &al. Psyckiatr. 6,66%67l

6 Gillrnan, M. A. and Sandyk, R. (1985) Am. 1. Psyckiatr. 142,270

7 Roth, R. H. (1972) Proc. Am. SW. Exp. Biol. 31,1358-1364

8 Mendelsohn, F. A., Q&ion, R. and Saavedra, J. M. (1984) Proc. Nat1 Acad. Sci. USA 81,1575-1579

9 Strittmatter, S. M., Lo, M. M., Javitch, J. A. and Snyder, S. H. (1984) Proc. Natl Acad. Sci. USA 81, X599-1603

10 Maran, J. W. and Yates, E. F. (1977) Am. I. Pkysiol. 233, E273-E285

11 Ramsay, D. J., Keif, K. C., Sharp, M. C. and Shinsako, J. (1978) Am. 1. Physiol. ^. 1,* __* .Y&, IWO-K/l

12 Snyder. S. H. (1986) in Second Co~o9u~um in Eiologicai Sciences (Vol. 463) (BurrelI, C. D. and Strand, F. L., eds), pp. 21-30, New York Academy of Sciences

A~e~~$ine and dqpamine function in the CNS A large body of evidence now exists to support a role for the purine riboside, adenosine, in mammalian CNS function**2. However, unlike the more classi- cal neurotransmitters, it appears that receptor density, rather than adenosine availability per se, reflects the actions of this neuro- modulator since relatively high concentrations of the purine occur in most mammalian tissues. This fact has tended to contribute to a skepticism as to the physiologIca relevance of adenosinel. However, the purine has potent effects {10m9- lo4 M) on various biochemical

and elect~physiological processes in brain tissue acting via two types of receptor, A1 and Az, either indirectly via inhibition of the release of transmitters such as acetylcholjne, GABA, glutamate, doparnine, noradrenaline and 5- HT or directly via actions at both pre- and postsynaptic loci2. Con- sistent with these actions, the xanthine adenosine antagonists, caffeine and theophylline, have been shown to increase cell firing and transmitter release*.

Despite the apparent plethora of effects on transmitter release, there is considerable evidence