Effects of chloroquine on smooth muscle contracted with noradrenaline or high-potassium solutions in the rat thoracic aorta.

The effects of chloroquine on the smooth muscle of isolated rat aortic segments were investigated in preparations contracted with either noradrenaline or high-potassium. At rest, chloroquine (up to 10(-4) M) produced no mechanical response, while noradrenaline (10(-6) M) produced a sustained contraction. In the presence of 10(-4) M chloroquine, however, the amplitude of contractions produced by noradrenaline was attenuated by about 70%, with no alteration of the resting tension. In preparations contracted either with noradrenaline or with high-K solutions, chloroquine produced a concentration-dependent relaxation. The tension decreased below resting level as a result of the co-application of these stimulants. The relaxing actions of chloroquine were not altered by methylene blue (an inhibitor of guanylate cyclase), suggesting that the cyclic GMP-related mechanism was not involved. The ratio of the amplitude of chloroquine-induced relaxation was similar in contractions produced by different concentrations of potassium ions, suggesting that chloroquine did not cause relaxation as a result of membrane hyperpolarization. These results suggest that the inhibition of aortic smooth muscle contraction caused by chloroquine is different to that produced by endothelium-derived vasodilating factors. It is possible that the inhibition of aortic smooth muscle contraction by chloroquine involves modulation of the contractile systems and of their regulatory proteins.

Studies on the anti-inflammatory and related pharmacological properties of the aqueous extract of Bridelia ferruginea stem bark.

The anti-inflammatory profile of the aqueous extract of Bridelia ferruginea stem bark was investigated using both in vivo and in vitro models. The extract exhibited strong topical anti-inflammatory effect shown as inhibition of croton oil-induced ear oedema in mice, and reduced hind-paw swelling and growth retardation in the adjuvant-induced arthritis model in rats, following oral administration at 10, 20, 40 or 80 mg/kg. The extract (10-80 mg/kg, p.o.) caused an inhibition of increase in vascular permeability in both cyclophosphamide-induced haemorrhagic cystitis and acetic acid-induced vascular permeability in rats and mice, respectively. B. ferruginea produced stabilization of erythrocytes exposed to heat and stress-induced lysis. Antipyretic and analgesic properties of the extract were also observed.

Studies on the anti-inflammatory, antipyretic and analgesic properties of Alstonia boonei stem bark.

The methanol extract of the stem bark of Alstonia boonei was investigated for anti-inflammatory property. The analgesic and antipyretic properties of the extract was also evaluated. The extract caused a significant (P<0.05) inhibition of the carrageenan-induced paw oedema, cotton pellet granuloma, and exhibited an anti-arthritic activity in rats. Vascular permeability induced by acetic acid in the peritoneum of mice was also inhibited. The extract also produced marked analgesic activity by reduction of writhings induced by acetic acid, as well as the early and late phases of paw licking in mice. A significant (P<0.05) reduction in hyperpyrexia in mice was also produced by the extract. This study has established anti-inflammatory, analgesic and antipyretic activities of the stem bark of A. boonei.

Traditional African medicine: theory and pharmacology explored.

Traditional African medicine (TAM) is a shorthand reference to indigenous forms of healing that are practiced all over Africa. Although TAM is based on the accumulated experience of ancient Africans, its mode of transmission by word-of-mouth has hindered emergence of a generally accepted theory and hence of the systematic development of TAM as a self-regulating profession. A major therapeutic objective in the treatment of illness in TAM is diffusion of emotional stress. This article summarizes the argument for such a therapy, and suggests that TAM is a distinct system of health care and not a rudimentary form of modern Western medicine.

Demonstration of prostaglandin activity in lungs of the rainbow lizard (Agama agama) by bioassay.

Extracts and perfusate effluents of lungs of the rainbow lizard (Agama agama) were assayed for prostaglandin-like activity. Results of differential bioassay and thin-layer chromatography suggested that the prostanoid was predominantly PGE2-like. The mean PGE2-like content of 10 lizard lung extracts was 2.9 micrograms g-1 wet weight compared with 146 ng g-1 in rat lungs. Mechanical pressure applied to the lung during perfusion through the pulmonary vasculature provoked the release of large quantities of PGE2-like material. This release was blocked by fatty acid cyclooxygenase inhibitors. Compared with guinea-pig and rat lungs, lizard lungs exhibited a markedly low capacity for inactivating PGE2. In view of an apparently high prostaglandin-forming and a low inactivating capacity, we speculate that under certain circumstances, lizard lungs may release vasoactive substances into the circulation.

Responses of the isolated rectum of the rainbow lizard (Agama agama) to sympathomimetics.

The relaxant effects of isoprenaline, noradrenaline, and adrenaline on the isolated rectum of the rainbow lizard (Agama agama) were studied. Responses were measured as a reduction of carbachol-induced contractions for each sympathomimetic agent. Isoprenaline, adrenaline, noradrenaline produced a dose-dependent relaxation of this preparation and the order of potency was as given. The pD2 value of 8.15 +/- 1.88 obtained for isoprenaline was significantly different (p less than 0.05) from those for adrenaline (5.80 +/- 0.90) and noradrenaline (5.25 +/- 1.18). H35/25, propranolol, and practolol competitively antagonized the relaxant effects of isoprenaline on the isolated lizard rectum. The pA2 values for these beta-adrenoceptor antagonists did not differ significantly (at p less than 0.05). alpha-Adrenoceptor antagonists, phentolamine and phenoxybenzamine, failed to alter the relaxant responses of these sympathometics to any appreciable extent. These results are interpreted to suggest that the relaxant effect produced by these sympathomimetics are mediated predominantly by beta-adrenoceptors that are not significantly differentiated into subtypes. alpha-Adrenoceptors in this preparation contribute minimally to the observed inhibitory response following sympathomimetic stimulation.

Platelet reactions after interaction with cultured Plasmodium falciparum infected erythrocytes.

An in vitro model for studying the interaction between normal human platelets and Plasmodium falciparum infected erythrocytes in culture is described. After the interaction, changes in platelet function such as enhanced aggregation response to exogenous ADP and increased secretion of dense granule contents were reproduced. Some of these responses represented manifestations of platelet hypersensitivity described earlier in acute malaria infections in man and mice. Preliminary investigations of the mechanisms involved in such reactions revealed that ADP and thromboxane A2 mechanisms contributed about 79% and 18.5% of the enhanced aggregation response to exogenous stimuli in the system.

Platelet reactions in acute Plasmodium berghei infection in Swiss albino mice.

Swiss albino mice were infected by the intraperitoneal route with P. berghei berghei malaria parasite, and platelets, white cell counts and some coagulation parameters were monitored in order to find out whether changes reported in man also occurred in the mice. Parasitaemia developed form the 2nd post-infection day and reached significant levels by the 4th-6th day. Reduced circulating platelets which reached severe thrombocytopenic levels were observed. parallel with the increasing degree of parasitaemia. Anaemia which progressed to severe degree was also observed as was a slight leucocytosis attributed to the presence of normal mouse erythrocytes in the peritoneal space. All untreated animals died by the 6th day of infection. Intramuscular chloroquine sulphate (20 micrograms/g body wt.) given for 7 days completely cured the malaria, and white cell and platelet counts were restored to preinfection levels in each animal about 2 weeks after treatment had ceased. Platelet hypersensitivity to exogenous ADP was observed within 48 hours of infection and persisted with the parasitaemia. Prothrombin time (PT) and activated partial thromboplastin time (APTT) were prolonged while clottable fibrinogen concentration was reduced.

Cyclo-oxygenase inhibitors antagonize indirectly evoked contractions of the guinea-pig isolated ileum by inhibiting acetylcholine release.

The effects of indomethacin, sodium meclofenamate and ketoprofen on the contractile responses of the guinea-pig isolated ileum to directly and indirectly evoked stimuli were investigated. The effects of the cyclo-oxygenase inhibitors on acetylcholine (ACh) release from plexus containing longitudinal muscle strips were also studied. The cyclo-oxygenase inhibitors reduced contractile responses to transmural stimulation (TMS) and nicotine at concentrations which had no effect on ACh-induced contractions. In whole ileum preparations (WIP) indomethacin and ketoprofen (40 micrograms ml-1) reduced TMS responses by 17 +/- 1.8% and 12 +/- 1.8% (n = 6), respectively (30 min incubation). In longitudinal muscle strips (LMS) in which Auerbach's plexus is exposed, indomethacin and ketoprofen (1 microgram ml-1) reduced TMS responses by 28 +/- 2.3% and 34 +/- 2.7% (n = 6), respectively (10 min incubation). Thus the cyclo-oxygenase inhibitors were up to 80 times more effective in LMS than in WIP. The drugs were similarly more effective in blocking nicotine contractions in LMS than in WIP. The cyclo-oxygenase inhibitors reduced basal and stimulated ACh release from LMS. For example, indomethacin (1 microgram ml-1) reduced stimulated ACh release by 35% after 10 min incubation. The percentage inhibition increased to 79% after 40 min incubation (n = 6). Prostaglandin E2 (PGE2) (0.1-2.5 ng ml-1) restored the contractile responses and ACh release depressed by the cyclo-oxygenase inhibitors but not the contractile responses depressed by atropine. PGF2 alpha had no effect on mechanical responses or ACh release depressed by the cyclo-oxygenase inhibitors. 6 It is concluded that the cyclo-oxygenase inhibitors studied reduced responses to transmural stimulation and nicotine by inhibiting ACh release. The site of action is the postganglionic parasympathetic nerve. 7 It is suggested that the reason why previous investigators needed to use high doses of cyclooxygenase inhibitor in the ileum is because the action of the inhibitor is limited by diffusion barriers. There was no evidence to support the view that there is more than one pool of cyclo-oxygenase in guinea-pig gut.

Restoration of vasoconstrictor responses to noradrenaline by prostaglandin E2 after alpha-adrenoceptor blockade in rat isolated mesenteric artery.

1 The effects of prostaglandin E2 (PGE2) on responses to noradrenaline (NA) after alpha-adrenoceptor blockade were studied in the isolated mesenteric artery of the rat. 2 Phentolamine (32 nM) tolazoline (41 microM) and yohimbine (1.28 microM) blocked NA-induced vasoconstriction competitively with dose-ratios of 13.9 +/- 1,22.01 +/- 1 and 26.6 +/- 0.9 respectively. 3 PGE2 (28 nM) restored responses to NA during alpha-adrenoceptor blockade and reduced NA dose-ratios to 2.8 +/- 0.1 (phentolamine), 5.9 +/- 0.4 (tolazoline) and 1.7 +/- 0.1 (yohimbine). 4 At low concentrations (0.29 nM), phenoxybenzamine blockade of NA-induced vasoconstriction was also antagonized by PGE2. 5 PGE2 did not reduce the pA2 of the competitive antagonists; therefore the antagonism of alpha-adrenoceptor block by PGE2 was not due to a reduction in the affinity of the antagonist for the receptor. 6 The calcium ionophore, A23187, also antagonized competitive alpha-adrenoceptor blockade but was less potent than PGE2. 7 Evidence is provided to suggest that although both PGE2 and A23187 can potentiate the action of NA in this preparation, the two compounds probably reverse alpha-adrenoceptor blockade by different mechanisms. 8 Inhibition of NA-induced vasoconstriction caused by the calcium antagonists cinnarizine, verapamil and high concentrations of phenoxybenzamine (greater than 2 nM) were not affected by PGE2. 9 It is proposed that PGE2 restores responses to NA after alpha-adrenoceptor blockade by increasing intracellular Ca2+ ion concentration or by activating alpha-adrenoceptor-associated Ca2+ channels.

Mechanism of noradrenaline potentiation by prostaglandin E2 in rat mesenteric artery.

1 Effects of prostaglandins E2 and F2 alpha (PGE2 and PGF2 alpha) on vasoconstrictor responses to noradrenaline (NA) and methoxamine in isolated mesenteric arteries of the rat were investigated. 2 PGE2 and to a lesser extent PGF2 alpha potentiated vasoconstrictor responses to NA and methoxamine. 3 Prior treatment with reserpine increased, and bretylium reduced, the extent of potentiation significantly. 4 NA vasoconstriction persisted for 1 h after Ca2+ was removed from the perfusing Krebs solution. Prostaglandin-induced potentiation was absent in Ca2+-free Krebs, but increased proportionately with increase in external Ca2+ concentration. 5 Vasoconstriction induced by high potassium, was not potentiated by PGE2. 6 It is concluded the PGE2 potentiates NA vasoconstriction by facilitating Ca2+ influx.

The response of the isolated ductus arteriosus to transmural stimulation and drugs.

1 Responses of isolated ductus arteriosus preparations from near term guinea-pigs and lambs to transmural electrical stimulation and drugs were studied in a low oxygen medium (Po(2) 19 to 28 mmHg).2 Acetylcholine and noradrenaline contracted both vessels in a dose-dependent manner, their threshold being between 10(-8) and 10(-7) M. Transmural stimulation (pulse width 0.2 to 0.6 ms, typically 20 Hz) also contracted the vessels.3 Atropine and phentolamine or dibenzyline selectively blocked responses to acetylcholine and noradrenaline, respectively.4 In the guinea-pig ductus, part of the response to transmural stimulation was due to activation of intrinsic adrenergic nerves since the responses were reduced by alpha-adrenoceptor antagonists, bretylium or prior reserpine treatment, but not by atropine. The response of the lamp ductus to transmural stimulation varied greatly in magnitude and was inconsistently affected by alpha-adrenoceptor blocking drugs.5 There was no evidence that transmural stimulation activated cholinergic nerves in either species.6 After inactivation of alpha-adrenoceptors with dibenzyline, noradrenaline caused a beta-adrenoceptor-mediated relaxation. Both this effect and isoprenaline-mediated relaxation were blocked by propranolol. beta-Adrenoceptor activity was more prominent in the ductus of the guinea-pig than of the lamb.7 Raising the Po(2) from 19-28 to 92-98 mmHg increased the response of the guinea-pig ductus to transmural stimulation suggesting that, in this species, physiological elevation of oxygen tension at birth may increase transmitter release from intrinsic adrenergic nerves. Whether this mechanism would contribute to ductus closure remains an open question.8 We postulate that beta-adrenoceptor-mediated relaxation has a role in maintaining ductus patency in the guinea-pig foetus.

Effects of animal maturity on smooth muscle and blood pressure responses to prostaglandins E2 and F2alpha.

The effects of prostaglandins E2 (PGE2) and F2alpha (PGF2-alpha) on muscle strips from mature and immature rats and guinea-pigs and on rat blood pressure were investigated in the presence of atropine. The colon and stomach strips from immature rats were equally responsive to PGE 2 and PGF2alpha where mature colons were significantly more sensitive to PGF2ALPHA AND MATURE STOMACH STRIPS SIGNIFICANTLY MORE SENSITIVE TO PGE2. On the ileum from immature guinea-pigs the maximum responses to PGE2 and PGF2alpha were 16 and 8% of the histamine maximum respectively. The corresponding figures on the mature ileum were 86 and 75%. Whereas PGE2 was only twice as active as PGF2alpha on immature ilea, it was ten times more active than PGF2alpha on mature muscles. On blood pressure PGF2alpha and PGE2 were both hypotensive in immature rats whereas PGE2 was hypotensive and PGF2alpha hypertensive in mature rats. The results suggest that as the animal gets older, receptors for prostaglandins became increasingly differentiated.