General pharmacology最新文献

1. Endothelin-1 (ET-1) caused a concentration-dependent increase in the formation of inositol phosphates (IPs) in isolated rabbit detrusor and urethral smooth muscle preparations prelabelled with myo-[3H]inositol. 2. The increase in accumulation of IPs was slow in onset in both detrusor and urethra, with no significant accumulation demonstrable during the first 30 min. The increase in IPs accumulation found after exposure of detrusor tissue to ET-1 (10(-7) M) for 2 hr (250 +/- 38%, n = 7) was not significantly different from that found in the urethra (279 +/- 40%, n = 6), when expressed as per cent of corresponding control values. 3. Pretreatment with nifedipine (10(-6) M) did not reduce IPs formation. In contrast, no increase in IPs formation was demonstrated in Ca(2+)-free medium. 4. ET-1 (10(-11)-10(-7) M) produced concentration-dependent, slowly developing contractions in both detrusor and urethral preparations. Pretreatment with H-7 (3 x 10(-5) M) for 30 min before ET-1 application resulted in a non-parallel shift of the ET-1 concentration-response curve with significant reductions in maximal responses in both tissues. 5. ET-1-induced contractions in urethral preparations were markedly inhibited by Ni2+ (3 x 10(-4) M), whereas the effect of Ni2+ in the detrusor was less pronounced. 6. The results suggest that ET-1 stimulates phosphoinositide hydrolysis in the rabbit detrusor and urethra. Both IPs formation and contractile activation evoked by ET-1 are dependent on extracellular Ca2+.(ABSTRACT TRUNCATED AT 250 WORDS)

1. Following in vitro treatment with 12 microM 6-hydroxy-dopamine, 2 microM B-oestradiol, 0.1 microM propranolol and 10 microM cocaine vasa deferentia isolated from young rats (21-23 days old) showed supersensitivity to norepinephrine (NE) compared to those from adult (3 months old) rats. 2. The pA2 values for prazosin were higher in young (9.6 +/- 0.1) than in adult (8.3 +/- 0.1) rat vas deferens, with the slopes of the Schild plots not different from 1.0 (0.78 +/- 0.26 and 1.14 +/- 0.14, respectively). 3. The treatment of young rats with a single dose of testosterone abolished the supersensitivity to NE and the higher affinity for prazosin. 4. We conclude that there is a reduction of neuronal NE uptake and a decrease in the sensitivity to NE in the vas deferens as the rat matures sexually. 5. Testosterone induces a decrease in the sensitivity to NE, probably via an action on the alpha 1-adrenoceptor population and the sympathetic nerve discharge in this organ.

1. Intravenous morphine decreases cortisol and increases prolactin concentrations in male sheep whereas naloxone has the opposite effect. 2. In this investigation, the effects of intracerebroventricular injections of naloxone, morphine (mu agonist), dynorphin (kappa agonist) and DADLE (delta/mu agonist) on cortisol and prolactin release were investigated. 3. None of the drugs affected cortisol secretion. 4. Naloxone transiently decreased prolactin levels (P < 0.05). 5. All the opioids tended to enhance prolactin secretion and the highest dose (300 micrograms) of DADLE produced a significant (P < 0.007) sustained increase. 6. These results are consistent with the view that exogenous and endogenous opioids affect the pituitary to influence cortisol release in sheep but act also at the hypothalamic level to influence prolactin secretion.

1. The recovery of rat parotid beta-adrenergic receptors (beta-AR) and adenylate cyclase (AC) from heat (33 degrees C)-induced desensitization was studied. 2. Down-regulated cell surface beta-AR and AC activity in response to isoprenaline (IPR) returned to the control level 120 hr after the termination of heat exposure. 3. However, beta-AR in parotid crude membranes increased over the control level for 48-120 hr. 4. Coupling between beta-AR and G protein(s) was attenuated at 120 hr. 5. These data suggest that beta-AR on the cell surface, but not those internalized, can transduce biological responses.

1. Decreased beta-adrenergic responses have been reported in both gastro-intestinal tract and atrium of experimentally-induced diabetic rats. The present study was undertaken to investigate in vitro effects of insulin on decreased beta-adrenergic responses of the duodenum and atrium from streptozotocin-diabetic rats. 2. Insulin incubation (16.67 micrograms/ml) in bathing medium for 5 hr enhanced the decreased beta-adrenergic responses in the diabetic rat duodenum, but not those in the diabetic atrium. Incubation of bovine insulin with anti-bovine insulin antibody in the test-tube inhibited the improving effect of insulin on the decreased beta-adrenergic responses of diabetic rat duodenum. 3. In vitro treatment with the same dose of bovine insulin in bathing medium caused a decrease in the beta-adrenergic responses of the atria from both non-diabetic and diabetic rats. Anti-bovine insulin antibody also abolished the inhibitory effect of insulin on the rat atria. 4. These results strongly suggest that the experimental diabetes affects beta-adrenergic responsiveness of the rat gastro-intestinal tract through a different mechanism from that of the rat myocardium.

1. The effects of glyburide were studied on the myocardial contractile force and heart rate in the atria isolated from non-diabetic and non-insulin-dependent diabetic rats (diabetic). 2. In order to examine the myocardial changes in the alloxan model of non-insulin-dependent diabetes, atrial functions of 11-week old diabetic rats were evaluated by comparing with the atria from their age-matched controls. 3. Diabetic atria were found to possess an increased contractile force and reduced inotropic responses to isoprenaline as a consequence of non-insulin-dependent diabetes induced by neonatal alloxan injection. 4. However, no significant change was observed in the heart rate of diabetic atria in response to isoprenaline when compared with controls. 5. Since apparent affinity constant (pD2 value) calculated for the inotropic response of diabetic atria to isoprenaline was also reduced, it might be suggested that non-insulin-dependent-diabetes causes a decrease in the beta-adrenoceptor affinity of the rat atria. 6. Glyburide treatment (5 mg/kg/day per os) for 3 weeks was able to improve the reduced responsiveness of rat atria due to non-insulin-dependent diabetes as well. The results obtained in this study indicated that glyburide possesses an improving effect on the decreased beta-adrenergic responses of rat atria with non-insulin-dependent diabetes mellitus.

1. The antinociceptive action of calcium channel blockers administered intracerebroventricularly to mice using the acetic acid writhing test was studied. 2. The drugs produced dose-dependent inhibition of the number of writhes induced by the intraperitoneal administration of 10 ml/kg of 0.6% acetic acid. 3. The CaCBs may be ranked from most to least potent as follows: verapamil > nimodipine > diltiazem > flunarizine > nifedipine > cinnarizine. 4. Since naloxone pretreatment was not able to inhibit the antinociception produced by CaCBs an opioid mechanism of action is excluded. 5. It is suggested that CaCBs can induce analgesia through a decrease in cellular Ca2+ availability, increasing the nociceptive threshold.

1. Aminophylline (cumulative concentrations of 0.036-3.60 mmol/l) produced a concentration-dependent increase in both tension developed (Td) and the maximum rate of rise of tension (dT/dt max) of the isolated hemidiaphragm of the rat both during direct single-pulse and subtetanic stimulation. 2. The repeated series of additions of aminophylline into the bathing medium (the second and the third series) produced even further, more pronounced potentiation of both Td and dT/dt max during subtetanic stimulation only, the potentiation being the strongest after the third series of additions of the drug ("antifatigue effect"). The antifatigue effect of aminophylline was much more pronounced than the antifatigue effect of the equimolar concentrations of caffeine. 3. The presence of intact beta 1-adrenergic receptors seems to be essential for the antifatigue action of aminophylline under our experimental conditions. 4. The antifatigue effect of aminophylline was not affected by reserpine or 6-OHDA pretreatment of rats. 5. In a Ca(2+)-free medium the stimulatory effect of aminophylline on Td and dT/dt max was abolished or depressed (single-pulse and subtetanic stimulation, respectively). After returning the muscle into the medium containing Ca2+, the effect of aminophylline was significantly potentiated during both types of the stimulation. 6. The antifatigue action of aminophylline was preserved even in the presence of nicardipine or its solvent in the bathing medium. 7. In the presence of heparin (which produced a significant depression of both Td and dT/dt max by itself during direct subtetanic stimulation) the stimulatory effects of aminophylline on Td and dT/dt max (the second and third series of additions) were significantly potentiated in comparison with the effects of the first series of additions of aminophylline (with no heparin in the bathing medium). 8. The dose-response curves for the effects of aminophylline in the presence of Ni2+ on Td and dT/dt max during direct single-pulse stimulation were significantly shifted to the right. Ni2+ by itself produced significant and dose-related depression of both Td and dT/dt max during single-pulse and subtetanic stimulation, the subtetanic stimulation being much more sensitive. The antifatigue effect of aminophylline during subtetanic stimulation was preserved in the presence of Ni2+. 9. Our results indicate the important role of the extracellular calcium and the involvement of intact beta 1-adrenergic receptors in the antifatigue action of aminophylline. Also, the potentiating effect of heparin on the antifatigue action of aminophylline is presumably due to the influx of extracellular calcium through L-type Ca2+ channels during subtetanic stimulation. Our results indicate the possibility of the presence of T-type calcium channels (which can be blocked by Ni2+) in the isolated hemidiaphragm of the rat, but they do not seem to be involved in the antifatigue action of aminophylline.

1. Carbachol produced a relaxation of dilator muscle at a concentration lower than 1 microM and a contraction at a concentration higher than 1 microM. 2. We studied the effects of the M1-selective antagonist, pirenzepine, the M2-selective antagonist, himbacine, the M3-selective antagonist, 4-diphenyl-acetoxy-N-methylpiperidine methiodide (4-DAMP) and the non-selective antagonist, atropine, on carbachol-induced relaxation and contraction of the rat iris dilator smooth muscle. All the antagonists competitively inhibited both the responses to carbachol. 3. In relaxation and contraction, the low affinity of pirenzepine and himbacine suggest that the rat iris dilator smooth muscle receptors are not of the M1 and M2 subtypes. In contrast, 4-DAMP potently inhibited the carbachol-induced relaxation and contraction with affinities similar to those reported for the M3 subtype. 4. Carbachol-induced relaxation and contraction of the rat iris dilator appears to be mediated through a homogeneous population of M3 subtype.

1. The responsiveness of isolated aortic rings from 1, 4 and 12 week streptozotocin-induced diabetic rats to noradrenaline (NA) and 5-hydroxytryptamine (5-HT) were compared with those of non-diabetic controls under standard organ bath procedure. 2. There were significant increases in the maximum contractile responses to both agents after 1 and 4 weeks but not after 12 weeks of diabetes mellitus. 3. The variable responses show that duration-dependent functional changes occur in the course of streptozotocin diabetes in rats.