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Pharmacology of autacoids

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Indian Journal of Pharmacology 2000; 32: S3-S14
PHARMACOLOGY OF AUTACOIDS

PHARMACOLOGY OF AUTACOIDS

M. DIKSHIT

Pharmacology Division, Central Drug Research Institute, Lucknow-226 001.

1. Introduction Intracerebroventricular (icv) administration of serot-

Autacoids are the substances released from the cells onin antibodies (5-HTabs) in Balb/c mice leads to al-
in response to various types of stimulation to elicit nor- teration in the behaviour as well as in the levels of
mal physiological responses locally. An imbalance in 5-HT, dopamine (DA) and their metabolites in the sub-
their synthesis, release or in the transduction system stantia nigra (SN), nucleus raphe dorsalis (NRD) and
contributes significantly to pathological conditions such caudate putamen. 5-HTabs inhibited tail flick latency
as inflammation, allergy, hypersensitivity and ischae- but the tremor response to 5-methoxy N,N-dimethyl
mia - reperfusion. Nitric oxide (NO) was recognized by tryptamine was augmented. 5-HTabs also induced
Science1 magazine as the molecule of the year in 1992. increase in the 5-HT turnover in all the nuclei stud-
It has led to a spurt in the research on NO and oxygen ied; however, DA turnover was increased only in SN.
derived free radicals, which is very evident throughout This study helps in understanding the central neuro-
the world and also in India. Research work carried out transmitter control on behaviour. It might also help in
in India during the ‘report period’ on NO and reactive developing a 5-HT deficient model for studying clini-
oxygen species (ROS) has also been included in this cal disorders but it may not help in delineating the
article. This review includes the papers published in this underlying mechanism5.
area during 1994-1998 but does not cover abstracts or
conference proceedings. 5-HT uptake inhibitor, fluoxetine, is metabolised in
2. Studies on central nervous system the brain by the enzyme flavin monooxygenase, thus
this enzyme might be involved in local metabolism
Serotonin (5-HT) plays an important role in the regu- and modulation of the pharmacological effects of the
lation of various cognitive behavioural functions such psycho-active drugs6. It metabolises fluoxetine to its
as sleep, mood, learning, pain, depression and anxi- respective N-oxide and S-oxides7,8. Extirpation of the
ety by binding to its receptors on the cell membranes. adrenal glands per se did not alter the responses to
Alterations in the 5-HT synthesis, metabolism and in noxious stimuli but it increased the anti-nociceptive
the receptor characteristics leads to various patho- potency of imipramine in the rat9. The anticonvulsant
logical conditions. Chattopadhyay et al . 2, 3 have activity of the sepia shell might be due to the eleva-
worked on the solubility, absorbance and fluores- tion of the seizure threshold rather than the preven-
cence characteristics of the 5-HT1A receptor purified tion of the seizure spread. This action seems to be
from buffalo brain and its interaction with 5-HT. These mediated by the serotonergic transmission 10. Panax
studies might help further in understanding the inter- ginseng and diazepam both attenuated stress in-
action of 5-HT with its receptor. duced elevation in brain and hypothalamus 5-HT level
The mouse 5-HT1F receptor, which is predominantly and in the plasma corticosterone levels11. Pyrimidine
expressed in the cortex and hippocampus, is encoded thiols exhibit anticonvulsant activity, which seems to
by at least three transcripts as is also observed in be mediated by enhancing the GABA-ergic activity
the rat brain. The mouse 5-HT1F clone shows the and opening the chloride channels12. Twenty patients
coding region to be intron less and an intron splice of depression treated with imipramine as well as cent-
junction is seen in 5'-untranslated region that is con- propazine did not exhibit significant changes in the
served both in the rat and mouse4. blood pressure, heart rate, PR, QRS, Q-Tc intervals13.
S4 M. DIKSHIT

Oil extract of Celastrus paniculatus seeds improved recovery from reperfusion induced injury. It has been
the retention ability in rats. NE, dopamine, 5-HT and observed that glutathione is significantly decreased
their metabolites in brain and urine were significantly after the reperfusion for 1 hr following moderate or
decreased in the treated group suggesting a de- severe ischaemia for 30 min20. Tertiary butyl hydro-
crease in their turnover to improve the learning and peroxide caused increase in the lipid peroxidation and
memory14. The acetone soluble fraction of petroleum decrease in the reduced glutathione content in the
ether extract of Lawsonia inermis leaves exhibited striatum, which was prevented by alpha tocopherol
prominent nootropic activity and modified the 5-HT and nicotinamide21.
and NE mediated behaviour, suggesting towards
exploring its nootropic principle 15. Subordination in- Inhibition of endothelial nitric oxide synthase in the
duced decrease in the 5-HT and dopamine contents periphery is primarily known to be associated with
in the frontal cortex have been observed in the rats16. hypertension. However, involvement of NO/Arginine/
cGMP pathways in the central regulation of blood
Involvement of nitric oxide and oxygen derived free pressure is not very well understood. Studies on nor-
radicals has been suggested in the neurodegene- motensive cats showed the involvement of NO/Ar-
ration observed in the Parkinson’s disease and also ginine/cGMP pathways in the central regulation of
in the cerebral ischaemia. Studies carried out in In- blood pressure22. Topical application of sodium nitro-
dia have also investigated their role in the experimen- prusside (SNP) produced a significant hypotension
tal models of chemical and ischaemia induced le- and bradycardia, which was significantly blocked by
sions. A significant decrease in the phospholipids and methylene blue (MB), suggesting towards the possi-
membrane fluidity was observed, following 6-hydroxy- ble involvement of NO-cGMP mechanism in the cen-
dopamine (6-OHDA) induced bilateral lesions in the tral cardiovascular regulation23. An interrelationship
striatum. In addition, there was a significant increase between blood pressure level and brain nitric oxide
in intracellular calcium and malondialdehyde (MDA) synthase (NOS) activity in hypertensive rats has also
levels. However, glutathione content and the activity been indicated. NOS activity was significantly reduced
of superoxide dismutase (SOD) and glutathione per- in the medulla and hypothalamus of coarctation in-
oxidase (GSH-Px) was attenuated 72 hr after duced experimental model of hypertension in the rat.
6-OHDA injection into the striatum17. Studies on an- In the same study anti-hypertensive drugs, captopril,
other neurotoxic substance, methyl-4-phenyl-1,2,3,6- nifedipine, or centhaquin (a centrally acting antihyper-
tetrahydropyridine (MPTP) were performed in golden tensive compound developed at CDRI) normalised
hamsters. These animals were resistant to the toxic- blood pressure and the brain NOS activity 24.
ity observed following both acute and chronic admin- Cyclosporin A, a potent immunosuppressive agent,
istration of MPTP as indicated by lack of any altera- by interfering with calcium /calmodulin, inhibited the
tion from normal content of dopamine and its brain NOS activity both in vitro and in vivo in the rat25.
metabolites in the nucleus caudate putamen (NCP),
The permeability of the blood brain barrier (BBB) is
limbic system and SN. Balb/c and C57/BL mice ex-
altered in several metabolic derangements, infections,
hibited >50% and 70% depletion in DA following
poisoning and other pathological conditions. NO
MPTP administration respectively. The content of to-
mediated modulation of BBB permeability has been
tal monoamine oxidase (MAO) in golden hamster was
demonstrated by Shukla et al.26. Induction of NOS
one third to one sixth of any nuclei or mitochondria
activity after exposure to lipopolysaccharide contrib-
of both strains of mice. Differences in the distribution
utes to the increase in BBB permeability27. Thus the
and levels of MAO could be correlated with the MPTP
results obtained demonstrated the involvement of
neurotoxicity18. NO by reacting with superoxide radi-
NO/Arginine pathway and reactive oxygen species26-
cals (O - 2 ) generates more toxic and reactive 28
in the opening of the BBB.
peroxynitrite, reactive nitrogen species, which on
decompositions form more toxic and reactive hydroxyl Ginkgo biloba, a platelet activating factor (PAF) an-
radicals. This pathway has been found to mediate tagonist, potentiates the picrotoxin-induced convul-
neurodegeneration and neurotoxic action19. Rapid sions, which might be due to the involvement of
restoration of thiol homoeostasis in the brain during GABAergic system and chloride channel. While
reperfusion following cerebral ischaemia helps in the facilitation of the strychnine action suggests towards
 PHARMACOLOGY OF AUTACOIDS S5

the modulating action of Ginkgo biloba on glycine29. Central serotonergic system seems to play a critical
Ginkgo biloba treatment decreased the protective role in the immunomodulation40. Immue-21, a poly-
effect of sodium valproate and carbamazepine herbal product significantly potentiated humoral im-
against tonic convulsions in mice30. munity in rabbits41. Ascorbic acid stimulates the
3. Studies on peripheral system humoral immunity by increasing synthesis of IgG, IgA
and IgM and it also activates the macrophages42.
Calcium channel blockers (CCBs) significantly re- Benzodiazepine-GABA A and B receptors appear to
duced the 5-HT induced contractions and completely regulate the restrain stress induced modulation in
blocked histamine induced contractions in the rat release/activity of leucocyte migration inhibition fac-
aortic rings. Similarly histamine and 5-HT induced tor, a lymphokine released from the sensitized
contractions were also attenuated in aortic rings ob- lymphocytes43. In another study human aqueous pla-
tained from DOCA saline hypertensive rats in pres- cental extract was found to be immunostimulant for
ence of these blockers 31. In DOCA saline hyperten- humoral and cell mediated immunity in animals as
sive rats chronic treatment with prazosin reduced the well as in humans44.
pD2 value for norepinephrine (NE) and abolished the
phenylephrine (PE) response in isolated aortic strips. The response to 5-HT was inhibited while that of NE
However, chronic treatment with thyroxine and was potentiated in the anococcygeus muscle and vas
prazosin significantly augmented the pD2 value for deferens after 30-min incubation with fluoxetine. Treat-
NE but it was attenuated for PE in comparison to the ment of rats with fluoxetine for seven days suggests
thyroxine treated controls32. Furthermore chronic towards the depletion of catecholamines45. Contrac-
treatment with ethinyl oestradiol for 3 weeks did not tile activity of Alstonia boonei (used in West Africa to
alter the pD2 values of NE in the rat isolated aortic treat fever and malaria) extract observed in the iso-
strips, however, pD2 values of NE in the portal vein lated rat stomach strip and guinea pig ileum was
preparation was significantly increased33. antagonized by methysergide suggesting the role of
5-HT in the biological effect of the extract46.
Role of central serotonergic system in various
Nifedipine offered significant protection against the
pathologies has been reported. Changes in the se-
5-HT induced increase in the paw oedema and re-
rotonergic systems in the central nervous system
duced the volume of the fluid and weight of the granu-
have been reflected in the platelets as shown by many
lation tissue in the granuloma pouch but verapamil
investigators. A significant low basal platelet 5-HT
and diltiazem exhibited no protection47. Nifedipine,
and cerebrospinal fluid 5-hydroxy indole acetic acid
verapamil and diltiazem produced significant and
(5-HIAA) concentration in epileptic patients suggests
dose dependent anti-inflammatory effect in rat hind
the involvement of 5-HT in epilepsy34. Platelet 5-HT2
paw oedema produced by prostaglandin E1 (PGE1)
receptors have also been found to be associated with
and bradykinin48, which was better than aspirin.
severe social phobia35. Platelet 5-HT basal level up-
These inhibitors were ineffective against the hista-
take and efflux was not significantly different from
mine-induced increase in the paw volume47,48.
the 8 untreated depressive adolescents from age and
sex matched controls. However, fluoxetine, a 5-HT NO donor, 3-morpholinosydnonimine (SIN-1) induced
uptake inhibitor produced clinical recovery in all the a concentration dependent relaxation in the coronary
patients and reduced the 5-HT content and uptake artery rings precontracted with 30 mM K+. Pretreat-
as compared to the control and pre-treatment level36. ment of the rings with methylene blue, a guanylate
Increased sympathetic activity seems to be respon- cyclase inhibitor, shifted the SIN-1 induced response
sible for an increase in the platelet 5-HT, epinephrine curve towards right. Glibenclamide, a K+-channel
and norepinephrine content in the diabetic patients blocker blocked the pinacidil induced response but it
and also in the streptozotocin treated rats37. Increase had no effect on SIN-1 induced response49, suggest-
in the 5-HT levels seems to be associated with tox- ing that NO mediated relaxation is not mediated by
aemia of pregnancy38. In the patients of essential hy- K+-ATP channels. On the other hand pinacidil induced
pertension an increase in the platelet intracellular cal- vasorelaxation in 30 mM K+ preconstricted rings was
cium level seems to be due to a decrease in the Ca++ blocked by NOS inhibitor L-NAME, MB and by en-
ATPase activity39. dothelium denudement. However, levecromakalim
S6 M. DIKSHIT

(another K+-ATP channel opener) induced relaxation The oxidative burst of PMNLs is primarily meant for
was potentiated in the absence of basal NO. Papaver- the killing of ingested micro-organisms. However,
ine induced relaxation also remain unaltered by ba- research on these cells has shown that they also
sal NO. Thus basal NO deferentially modulates the play an important role in ischaemia reperfusion, in-
interaction of pinacidil and levecromakalim with the flammation and thrombosis. PMNLs release both
K+- (ATP) channels in goat coronary artery through NO and ROS. Investigation on the interaction of NO
a cGMP-dependent pathway50. NO mediated attenu- with superoxide radicals suggested towards the pos-
ation of the reactive oxygen species (ROS) depend- sibility of NO regulating the generation of ROS. NO
ent norepinephrine-induced contraction of the aortic donors like sodium nitroprusside (SNP) and diethyl-
rings has also been reported. The effect was not amine-nitric oxide (DEA-NO) as well as NO precur-
observed in the endothelium denuded preparations, sor, L-arginine inhibited formyl-methionine-leucyl-
suggesting that NO interact with ROS in the endothe- phenylalanine (FMLP, a chemotactic peptide), ara-
lium during contraction51. Similar attenuation in the chidonic acid (AA, NADPH-oxidase activator),
acetylcholine induced NO release and augmentation phorbol ester (PMA, protein kinase C activator) or
in the endogenous ROS generation plays an impor- opsonized zymosan (OZ, a phagocytic ligand) in-
tant role in the modulation of vasoreactivity in the duced luminol-dependent chemiluminescence (LCL),
renal hypertensive rats52. Thus both NO and ROS hydroxyl radical generation, oxygen consumption and
considerably influence vascular reactivity in the nor- NADPH-oxidase activity in the PMNLs. Both exog-
motensive as well as in hypertensive rats. Methyl- enous and endogenous NO inhibited the NADPH-
ene blue attenuated the acetylcholine (ACh) induced oxidase activity. Thus superoxide radical generation
relaxation in the endothelial intact monkey aortic was inhibited and NO also scavenged the free radi-
strips; therefore it appears that in these strips ACh cals released/generated from PMNLs60. NOS inhibi-
increases the intracellular cGMP levels. However, tors and their D-enantiomers attenuated the LCL re-
ACh induced contractions in the endothelial denuded sponse, which was not due to non-availability of NO.
rings were further augmented53. Therefore, effect of L-arginine analogues, and their
D-enantiomers was also investigated on NADPH-
Polymorphonuclear leukocyte (PMNL), the cohabit-
oxidase activity and oxygen consumption of the rat
ant of platelets in blood, release several factors that
PMNLs61. It was seen that NO mediated attenuation
alter platelet response. Following thrombosis circu-
of LCL response was due to the inhibition of NADPH-
lating PMNLs release more NO and less free radi-
oxidase activity and oxygen consumption. Neverthe-
cals54 and this could be a defence mechanism of the
less, NOS inhibitors and their antipodes inhibited LCL
body. A factor was found to be present in the PMNLs
response without inhibiting NADPH-oxidase activity
cell suspension, which inhibits ADP, arachidonic acid
and oxygen consumption. The results obtained thus
and calcium ionophore induced platelet aggrega-
warrant caution in using NOS inhibitors (arginine
tion55. Nonsteroidal anti-inflammatory drug, aspirin
analogues) to analyse the role of NO in PMNLs LCL
when taken along with nifedipine, a calcium channel
response, as they themselves seem to scavenge free
antagonist and anti-hypertensive drug exhibited a
radicals61.
synergistic inhibitory effect on collagen, ADP and
epinephrine induced platelet aggregation56. In an interesting study on the free radical generation
from PMNLs in control and in smokers (cigarette, bidi,
Free radical scavengers, PAF-antagonists 57 , hookah and mixed products), a significant increase
cyclo-oxygenase inhibitors and NO releasing com- in the superoxide radical generation was observed.
pound have been found to be effective in preventing Role of PMNLs and free radicals has been suggested
paralysis/death due to intravenous collagen and in the chronic obstructive pulmonary disease 62. NO
adrenaline injection in mice and rats. These findings production in the 26 patients of systemic lupus ery-
suggested that free radicals could be involved in the thematosus was increased in comparison to the con-
genesis of thrombosis. Therefore role of free radical trol, as evident by an increase in the serum nitrite
generating and scavenging enzymes in this patho- and citrulline levels63.
logical state had been investigated58,59. Involvement
of free radicals and neutrophils in thrombosis has Effect of Pasteurella multocida on hydrogen perox-
been suggested54. ide (H2O2) and NO generation from isolated PMNLs
 PHARMACOLOGY OF AUTACOIDS S7

was studied in control and in vaccinated buffaloes cine, vitamin E and C exhibit protective effect against
against haemorrhagic septicemia. Lipopolysaccha- CP induced emesis in dogs and rats72, 73. Certain anti-
ride (LPS) of P. multocida and live P. multocida both neoplastic drugs apart from their tumoricidal activity
potentiated the release of H2O2 and NO from the con- are also capable of acting as immunostimulants.
trol and the vaccinated animal cells in comparison to Supernatant collected from cells treated with cyto-
the non-activated cells. However, PMNLs isolated sine arabinoside (CA), vincristine sulfate (VS), cy-
from vaccinated animals exhibit a significant increase clophosphamide (CS), mitomycin C (MMC), hydroxyl
in H2O2 and NO release in comparison to control. urea (HU) or LPS enhanced production of TNFα α, IL-
Thus results obtained indicate an up regulation in 1, NO and lysozyme, thus indicating towards the mac-
oxidant defence system in presence of an rophage activating activity of these agents74.
antiphagocytic bacterium, in the PMNLs64. Septilin,
A traditional silver preparation used in the Indian sys-
an Ayurvedic formulation, showed significant protec-
tems of medicine exhibits moderate analgesic effects
tion in E. coli induced abdominal sepsis in normal
suggesting possibly the involvement of opioidergic
mice and Staphylococcus aureus induced sepsis in
mechanisms75. Activity of the glycolytic enzymes was
neutropenic mice. It also stimulated the phagocytic
significantly decreased while an increase in the
function of neutrophils and reticuloendothelial sys-
gluconeogenic enzymes was observed and
tem in mice. In normal rats, Septilin enhanced anti-
Serankottai Nei (a Siddha drug) prevented these
sheep RBC agglutination antibody titer by 6 folds and
changes in the arthritic rats76. The icv administration
showed significant protection against cyclophospha-
of Substance P, significantly accentuated formalde-
mide - induced humoral suppression 65. Involvement
hyde induced oedema volume along with proalgesic
of NO in the hypoglycemic activity of tolbutamide is
response thus, suggesting the pro-inflammatory
suggested66.
effect of substance P 77.
Calcium modulating agents such as EGTA, nifedipine, Indole, triazine, benzopyran derivatives and substi-
TMB-8 and calmodulin antagonist W7 inhibited the tuted quinazolines were evaluated for anti-inflamma-
Cisplastin (CP, a potent chemotherapeutic drug) in- tory activity in rats78-84. A crude extract from the roots
duced tumoricidal activity of peritoneal macrophages of Gmelina asiatica exhibited anti-inflammatory
by decreasing the release of tumor necrosis activity against carrageenan induced rat paw oedema
α (TNFα
factor-α α) and interleukin-1 (IL-1) in the super- and cotton pellet granuloma models in the rat. Anti-
natant67. CP and LPS pretreatment of murine perito- proliferative, anti-oxidant and lysosomal membrane
neal macrophages showed an enhanced production stabilisation activity of the drug85 possibly mediated
of NO and a tumoricidal activity against P815 mas- the inhibitory effect. 4',5,6-trihydroxy-3’, 7-dimethoxy
tocytoma cells. L-Nitro mono methyl arginine (L- flavone-from Vicoa Indica DC showed consistent anti-
NMMA) a specific NOS inhibitor, blocked this re- inflammatory and analgesic activity in various mod-
sponse68. Protein kinase C (PKC) inhibitor, H7 and els86. Methanolic and aqueous extract of Curculigo
chelerythrine chloride and tyrosine kinase inhibitor orchioides exhibited significant anti-inflammatory
genistein and levendustin A, inhibited the CP induced activity in comparison to ibuprofen and indometh-
IL-1 and TNFα α secretion and tumoricidal activity of acin87. Effect of triterpenes from Crataeva nurvala
macrophages69, thus suggesting the involvement of stem bark has been investigated on adjuvant induced
PKC and tyrosine kinase in activation of peritoneal arthritis in the rats88. The water-soluble extract of the
macrophages with CP. Expression and secretion of alcoholic extract of A. indica leaves exerted signifi-
Oncostatin M, a novel cytokine that regulates growth cant anti-inflammatory activity in cotton pellet
was increased following CP stimulation of granuloma assay in the rat89. Synthetic analogues of
macrophages. It might be responsible for the cyto- liposomes prepared from non-ionic surfactants known
toxic and cytostatic activity of CP70. CP in addition as niosomes have been used to prepare the trapped
κB content and its trans-
increases the intracellular NFκ diclofenac sodium. Formulations of diclofenac pre-
location, which involves serine/threonine phos- pared by 1:1 combination of Tween 85 and poloxamer
phatases, protein tyrosine phosphatases, genistein F-108 exhibited better and consistent anti-inflamma-
sensitive protein tyrosine kinase activities71. Antioxi- tory activity for more than 72 hr after administration
dants such as glutathione, N-2 mercapto propyl gly- of a single dose90.
S8 M. DIKSHIT

Combination of the non-steroidal anti-inflammatory 1H-pyrazolo [3,4-d]pyrimidine) inhibited the passive

drugs diclofenac, pitofenone and fenpiverinium might cutaneous anaphylaxis in rat and mice and mast cell
have antispasmodic activity as they inhibited the ACh degranulation of normal and passively sensitised rats
induced contractions in the rat colon91. Effect of ATP, induced by 48/80 or egg albumin, the effect was com-
adenosine or caffeine was investigated on Brewer’s parable to sodium cromoglycate104. Bleomycin, the
yeast induced peripheral inflammation and glycopeptide antibiotics used in the cancer therapy,
nociception after their icv administration. The results induced injury was protected by curcumin due to the
indicated that central purinergic system exerted anti- restoration of the antioxidant status in the rats105.
inflammatory effect92. Further study showed that cen- Superoxide dismutase alone or in combination with
trally administered PGF2αα exerts anti-inflammatory glutathione reduces the clastogenic action of
while PGE2 exerts pronociceptive effects on Brew- bleomycin106. Five analogues of Ala-Asp-Ser-Asp-
er’s yeast induced peripheral inflammation and pain93. Gly-Lys (ADSDK) with modification at position 1,2
Riboflavin supplementation showed increased activity and 6 have been tested for anti-allergic activity, one
of the glutathione redox cycle enzymes and glutath- of the peptides (compound 94/335) has shown anti-
ione content in the selinite induced cataractous rat allergic activity in various experimental models of
lenses94. Ocimum sanctum exhibits anti-cataract ac- allergy even by the oral route 107,108. Development of
tivity in different experimental models, which might mast cells from bone marrow precursor cells was
be due to the free radical scavenging95. performed in cultures using Concanavalin A stimu-
lated splenocyte supernatant109.
Involvement of both H1 and H2 receptors in the pro-
duction of histamine aerosol induced bronchospasm Prolonged treatment with oestrogen or progesterone
in the guinea pigs is observed 96. Sublingual nifed- led to a down regulation of histamine H1 and H2 re-
ipine exhibited clinical improvement in the moderately ceptors in the rat and guinea pig. The possible mecha-
symptomatic, non-smoking allergic bronchial asthma nism appears to be oestrogen and progesterone in-
patients97. Ethanolic extract of the leaves of Vitex duced elevation of the histamine levels in the blood110.
negundo Linn inhibited the immunologically induced
degranulation of the mast cells. It also inhibited the Diflunisal, a salicylic acid derivative produced sig-
oedema during active paw anaphylaxis in mice. It nificant changes in the neural tube development of
appears that this extract has the ability to alter cal- chick embryo. PGE1 and PGF2αα treatment potenti-
cium fluxes from the extracellular medium and in the ated the effect of diflunisal. It appears that diflunisal
membrane98. Furosemide significantly attenuated induced changes might be mediated at the cellular
compound 48/80 and egg albumin induced contrac- level111. L-NAME pretreatment led to a failure of im-
tions in the guinea pig tracheal rings by either caus- plantation when administered at 2.5 mg/kg per uter-
ing local release of PGE 2 or by affecting the media- ine horn on day 3 of pregnancy. L-NAME mediated
tor release from mast cells99. Fluticasone alone and effect was reversed by SNP pretreatment, suggest-
in various formulations effectively reduced histamine ing a role of NO in implantation112.
induced wheal and flare100. Ethanolic extract of Vitex Cauvery 100, an Ayurvedic formulation exhibited a
negundo Linn inhibited the 48/80 and antigen induced potent anti-ulcer effect against indomethacin induced
contractions in the guinea pig trachea. The results ulcers in the rat113. Effect of verapamil, nifedipine and
suggest that it interferes with histamine and arachi- diltiazem was evaluated on experimental models of
donic acid metabolite mediated responses101. 5-Me- ulcers in the rat114,115. Both verapamil and nifedipine
thyl benzoxazoline-2-one inhibited the contractile re- offered protection but diltiazem exacerbated the cy-
sponse to histamine, 5-HT, acetylcholine and barium steamine-induced ulcers115. Sulpiride, a D2 receptor
chloride in the guinea pig ileum but not to the same antagonist increased the total carbohydrate content
extent suggesting a non-specific antagonism of the and decreased the protein contents and exhibited
papaverine or sympathomimetic agents102. Coleonol, anti-ulcer activity116. An herbal drug formulation,
an adenylate cyclase activator, was shown to exert UL-409, displayed cytoprotective action against etha-
significant antipassive cutaneous anaphylaxis and nol induced ulcers in the rat. Alterations in the lipid
mast cell stabilising activity103. CDRI compound, 88/ peroxides and antioxidants status were reversed by
765 (4-amino-6-methyl thio-1-(2', 2'-diethoxyethyl) - UL-409117,118. Cholinergic involvement and a partial
 PHARMACOLOGY OF AUTACOIDS S9

role of NO in the gastrokinetic effects of exepanol in Studies on NO and free radicals have shown the
mice and guinea pig ileum have been demon- importance of these mediators in several physiologi-
strated119. It has been recently reported that ulcers cal and pathological conditions. Role of NO in cen-
in the rat are closely associated with augmented free tral regulation of blood pressure in both normoten-
radical generation120. Poly I: Poly C, an inhibitor of sive and hypertensive animals has been observed.
interferon inducer was found to inhibit the peptic ul- In the experimental models of Parkinson’s disease
cers in the rat 121 . Endoscopic evaluations of and in the cerebral ischaemia involvement of free
osteoarthritis patients for gastrointestinal problems radicals has been observed. In addition, BBB per-
after treatment with ketorolac and diclofenac sodium meability in the infectious conditions appears to be
suggested that short-term analgesic use of ketorolac increased by NO, while in the normal situation it does
is safer122. Ketorolac also provides progressively in- not seem to play an important role.
creasing and long lasting pain relief in comparison
to nefopam in immediate post-operative period fol- NO mediated vasorelaxation is not mediated by the
lowing upper abdominal surgery123. Ranitidine, famo- K+-ATP channels. However, vasorelaxant response of
tidine and omeprazole, potent anti-ulcer drugs, have K+-ATP channel opener, levecromakalim was potenti-
no significant effect on the hepatic functions and li- ated in the absence of basal NO. NE induced vaso-
pid profile when used for a period of 12 weeks in the constriction seems to be modulated by the endothe-
peptic disease patients 124. Central adenosine A1 via lial NO and ROS in the rat aortic rings. In addition
noradrenergic receptors and GABA-B receptors in- ACh induced NO release is attenuated while NE in-
dependently inhibit gastric acid secretion125. duced ROS generation was potentiated in the rings
obtained from hypertensive rats. Methylene blue, a
4. Conclusion guanylate cyclase inhibitor prevented the ACh in-
5-HT is involved in the pathophysiology of depres- duced relaxation in the monkey aortic strips but aug-
sion, anxiety, hypertension etc. All the physiological mented the ACh induced contraction in the denuded
and pathophysiological effects of 5-HT are due to its strips.
interaction with various distinct membrane receptors. Studies on PMNLs indicate that NOS inhibitor L-
Thus basic studies on the 5-HT interaction with the NAME scavenges free radicals. NO also seems to
receptor and behavioural changes following admin- modulate the free radical generation from PMNLs by
istration of monoclonal antibodies might help us in scavenging as well as by inhibiting the generation of
understanding the interaction at the receptor level free radicals. In addition, work on NO in relation to
and its involvement in the modulation of the behav- Leishmania has also been carried out in India125-127.
iour. In addition, studies on the metabolism of drugs
which modulate the concentration and availability of Cisplastin was found to induce the microbicidal ac-
5-HT in the brain is also quite useful as the variabil- tivity by inducing the release of various inflamma-
ity in the effect of drugs could be partly explained on tory mediators including NO. During the report pe-
this basis also. Studies on the herbal drugs have riod various natural and synthetic compounds were
shown that some of these drugs/active components found to exhibit, anti-inflammatory, anti-ulcer and anti-
exert their effect by modulating the 5-HT levels in the allergic activities.
brain or periphery. Interestingly changes in the cen-
tral serotonergic system have been reflected in the
platelets of the patients of social phobia and in epi- ACKNOWLEDGEMENTS
lepsy patients in comparison to the controls. In the
diabetic patients and in the toxemia associated with I wish to acknowledge the untiring help provided to
pregnancy, levels of 5-HT were elevated in the plate- me by the research fellows, Mr. M. K. Barthwal, Ms.
lets. 5-HT induced rat aortic ring contractions were Noopur Srivastava, Mr. Prashant Sharma, Ms.
blocked by the calcium channel antagonists and nifed- Chetna Dixit, Mr. M. P. Singh, Mrs. Sonia Sethi,
ipine was found to block the 5-HT induced increase Mr. S.A.V. Raghavan and Mr. Amitava Das in search-
in the paw volume thus suggesting that calcium is ing the contributions made by the Indian research
involved in the 5-HT induced responses. scientists.
S10 M. DIKSHIT

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34. Shukla R, Vrat S, Nag D, Verma M, Shanker K. Platelet 48. Aditya GN, Chattopadhyay S, Mandal S, Roy RK, Lahiri,
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36. Joshi G, Sitholey P, Gujrati VR, Saxena AK, Gurtu S et al. 50. Deka DK, Raviprakash V, Mishra SK. Basal NO release
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generation and nitric oxide release from rat polymorpho- 68. Sodhi A, Kumar R. Production of nitric oxide and its regu-
nuclear leukocytes following thrombosis. Thrombosis Res lation in murine peritoneal macrophages treated with
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55. Kumari R, Singh MP, Seth P, Dikshit M. Inhibition of plate-
let aggregation by a factor present in the rat peripheral 69. Kumar R, Sodhi A. Activation of murine macrophages with
neutrophil supernatant. Thrombosis Res 1998;91:75-82. cisplatin and lipopolysaccharide. Involvement of protein ki-
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Immunol Cell Biol 1997;75:492-6.
57. Seth P, Kumari R, Dikshit M, Srimal RC: Effect of PAF-
antagonists in models of thrombosis. Thromb Res 1994; 71. Sodhi A, Singh RAK. Mechanism of NF-κ κ B translocation
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58. Kumari R, Seth P, Dikshit M, Srimal RC. Alterations in the
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90. Raja Naresh RA, Pillai GK, Udupa N, Chandrashekhar G.
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 S14 M. DIKSHIT

108. Singh R, Gupta PP, Singh PP. Cultivation of mouse bone Sci 1997;73:684-91.
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