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We previously reported that 6-shogaol, a phenolic compound from ginger has antiinflammatory properties in a Complete Freund's Adjuvant (CFA) model of mono-arthritic rats. In the present study, we investigated the effects of 6-shogaol on the production of inflammatory mediators from lipopolysaccharide (LPS) activated RAW 264.7 macrophages. These mediators (TNF-alpha, IL-1-beta and NO) and their output from macrophages are involved in various pathophysiological events of chronic inflammation and arthritis.Effects of 6-shogaol were investigated on the production of the mediators TNF-alpha, IL-1-beta and NO (measured as nitrate)from macrophages. Lipopolysaccharide activated RAW 264.7 macrophages were cultured in the presence and absence of 6-shogaol (2 microM, 10 microM and 20 microM) and ELISA was used to quantify the output of the mediators.6-shogoal (2 microM, 10 microM and 20 microM) significantly inhibited the production of nitric oxide (NO), IL-1beta and TNF-alpha from the LPS activated RAW264.7 macrophages.The results suggest that macrophages are targets for the anti-inflammatory effects of 6-shogaol. Also, the inhibitory effects against TNF-alpha, IL-1beta and NO production from LPS activated macrophages are cellular mechanisms by which 6-shogaol produced its anti-inflammatory effects. These mechanisms provide an explanation of the protection by 6-shogaol against development of joint inflammation and cartilage degradation in CFA induced mono-arthritis that we previously demonstrated (1). Based on these results with 6-shogaol, there is evidence that it exhibits exploitable anti-inflammatory properties.

A muscarinic alkaloid with a quaternary nitrogen was isolated from Trophis racemosa. Aqueous solutions (0.5%-2%) of the chloride salt of the alkaloid produced dose-dependent reductions of intra-ocular pressure ranging from 6.6 +/- 0.7 mmHg to 15.7 +/- 0.3 mmHg, (p0. 001, n = 5) in dogs. Atropine (0.1 mL of a 1% solution) and pirenzepine at a non selective antagonist dose (0.1 mL of 0.5% solution) for M(1) and M(3) receptors blocked the reduction of intra-ocular pressure, but alpha-adrenoceptor blockade with phenoxybenzamine (0.1 mL of a 1% solution) did not block the reduction of intra-ocular pressure. On the isolated guinea-pig ileum and trachea, the alkaloid produced contractions which were inhibited by atropine (6 x 10(-7) M or 0.4 microg/mL) and by pirenzepine at a non-selective antagonist dose (3.1 x 10(-6) M or 1.3 microg/mL) for M(1) and M(3) receptors. But neither selective blockade of M(2) receptors with gallamine (1.7 x 10(-6) M or 1.5 microg/mL) nor selective blockade of M(1) receptors with pirenzepine (7 x 10(-9) M or 3 ng/mL) inhibited the alkaloid-induced contractions. There was also no inhibition of the alkaloid-induced contractions in the presence of ganglionic nicotinic receptor blockade with pentolinium (5.6 x 10(-7) M or 0.3 microg/mL) and hexamethonium (1.7 x 10(-6) M or 0.6 microg/mL), but nicotine-induced contractions were inhibited by these ganglionic blockers. These results suggest that a muscarinic alkaloid from Trophis racemosa produced ocular hypotension via M(3) receptor stimulation in dogs.

Electrical field stimulation of guinea-pig tracheal muscle strips produced a frequency-dependent biphasic response consisting of an initial cholinergic contraction followed by relaxation. Both phases of the response were of neural origin. In the presence of methylene blue, a guanylate cyclase inhibitor, the resting tension and the contraction were increased, but the accompanying relaxation was inhibited. However, in the presence of sodium nitroprusside, a guanylate cyclase activator, the resting tension was reduced and the contraction was inhibited, but the relaxation was prolonged and increased. Similarly, in the presence of either 3-isobutyl-1-methylxanthine, which promotes cyclic guanosine monophosphate (cGMP) accumulation, or 8-bromo-cGMP, an analogue of cGMP, the resting tension was reduced and the contraction was inhibited but the relaxation was prolonged and increased. From these results, it is concluded that guanylate cyclase is involved in modulating the resting tension and the neurally-induced contraction of guinea-pig tracheal muscle.

Guinea-pig tracheal strips were used to investigate whether activation of guanylate cyclase in the trachea can reduce the contractile responses of the smooth muscle. Guanylate cyclase was activated by glyceryl trinitrate and a combination of sodium nitrite and ascorbic acid. These activators inhibited tracheal smooth muscle contractions produced by acetylcholine, histamine and electrical field stimulation. However, in the presence of methylene blue, a guanylate cyclase inhibitor, tracheal smooth muscle contractions were not inhibited by the activators. But, in the presence of propranolol, which blocked inhibition mediated by beta-adrenoceptor, both glyceryl trinitrate and the sodium nitrite/ascorbic acid combination were still capable of inhibiting tracheal smooth muscle contractions. Additionally, methylene blue inhibited tracheal smooth muscle relaxation that was electrically induced. These results suggest that the inhibitory action mediated by activated guanylate cyclase may be a mechanism for regulating tracheal smooth muscle contractile responses.

Ventasol syrup, a new locally produced salbutamol formulation, was compared with the standard salbutamol formulation, ventolin syrup, for determination of oral bioequivalence in stable asthmatic human subjects and in dogs. On separate occasions, each subject received a single 10 ml oral dose of each formulation containing 4 mg salbutamol. In the human subjects, statistically similar peak plasma concentrations of salbutamol were obtained (196 +/- 7 ng/ml for ventasol syrup and 185 +/- 6 ng/ml for ventolin syrup) 3 hours after oral administration of the formulations. From the ratio of the AUCo-infinity for the formulations (1.04), a relative oral bioavailability of 104%, indicating equivalent total salbutamol output, was also obtained in the human subjects. Similarly, in the dogs, the formulations produced statistically equivalent peak plasma concentrations of salbutamol (259 +/- 24ng/ml for ventasol syrup and 285 +/- 29ng/ml for ventolin syrup) 3 hours after oral administration. Also, from the ratio of the AUCo-infinity for the formulations (1.02), a relative oral bioavailability of 102%, indicating similar total salbutamol output, was obtained in the dogs. From these results, it is concluded that oral bioequivalence between ventasol syrup and ventolin syrup was demonstrated in human subjects and in dogs.

A diabetic state was induced with a single intraperitoneal dose (45 mg/kg) of streptozotocin in rats. Their fasting blood glucose concentrations oscillated between 12.7 +/- 1.9 mmol/l and 4.6 +/- 0.6 mmol/l during 35 days of monitoring. Their body weights were also reduced, while controls gained weight, although food consumption was not significantly different. Also, within the first 1/2-hour of the oral glucose tolerance test, blood glucose concentration increased in the diabetic and the control rats, but only in the control rats was there a simultaneous increase in serum IRI concentration (7.2 +/- 8 x 10(2) pmol/l to 27.0 +/- 5.2 x 10(2) pmol/l) which, like the blood glucose concentration, subsequently fell to fasting level in the control rats. In the diabetic rats, however, it was not until the following hour of the tolerance test that serum IRI concentration increased (3.4 +/- 0.3 x 10(2) pmol/l to 65.0 +/- 12.5 x 10(2) pmol/l) and blood glucose concentration began to fall. By the end of the test in the diabetic rats, blood glucose concentration fell but remained significantly higher than the control value. Additionally, no pancreatic tumours were identified in these diabetic rats. The results therefore suggest that an unstable diabetic state was produced by streptozotocin because the threshold for insulin secretion by glucose was increased, while the production of insulin by the pancreas was not significantly affected.

Cats, anaesthetized with alpha-chloralose, were used to investigate an interaction between the baroreceptor reflex and stimulation of the anterior hypothalamus (AH). In these cats, stimulation of the anterior hypothalamus gave autonomic responses that characterize the defense reaction. Stimulation of the anterior hypothalamus also interacted with the baroreceptor reflex without altering the effectiveness of the vasodepressor component of the reflex (induced by stimulation of the aortic nerves). However, in spinal cats the bradycardia component (induced by angiotensin at 0.097 nmol/kg pe min, i.v.) was inhibited by stimulation of the anterior hypothalamus and the inhibition was augmented by pretreatment with phentolamine (17.7 nmol) in the nucleus tractus solitarius (NTS). Pretreatment with phentolamine (17.7 nmol) in the nucleus tractus solitarius also reduced the sensitivity of the bradycardia component of the reflex and attenuated (3 and 6 nmol) the induced inhibition of the bradycardia induced by stimulation of the anterior hypothalamus. This attenuation induced by NE was abolished by pretreatment with phentolamine (17.7 nmol), but not by pretreatment with sotalol (16 nmol) or haloperidol (12 nmol) in the nucleus tractus solitarius. Additionally, NE was released from the nucleus tractus solitarius during activation of the baroreceptor and during stimulation of the anterior hypothalamus in cats with intact baroreceptor nerves, but not in baroreceptor-denervated cats. Moreover, the baroreceptor reflex attenuated the pressor response evoked by stimulation of the anterior hypothalamus, and also caused the release of NE from the anterior hypothalamus. At this site, injection of NE (3 and 6 nmol) attenuated the pressor response evoked by stimulation of the anterior hypothalamus and this attenuation was abolished by pretreatment with phentolamine (17.7 nmol), but not by pretreatment with sotalol (16 nmol) or haloperidol (12 nmol) in the anterior hypothalamus. It is concluded that NE participates at the nucleus tractus solitarius and the anterior hypothalamus as an attenuator in the interaction between the baroreflex and stimulation of nerve fibers in the anterior hypothalamus that mediate the defense reaction.