Autonomic and Autacoid Pharmacology最新文献

1 The aim of this study was to clarify the effect of boric acid on contractions of rat isolated ileum.

2 Contractile responses expressed as E_max and pD₂ for acetylcholine (10⁻³–10⁻⁸ m, Ach), bethanechol (10⁻³–10⁻⁸ m) and potassium (10–80 × 10⁻³ m, KCl) were determined in the absence and presence of boric acid (10⁻³; 5 × 10⁻⁴; 10⁻⁴ m).

3 The contractile response to Ach in the presence of verapamil (10⁻⁶ or 10⁻⁸ m) or in calcium-free Tyrode’s solution was also determined in the absence and presence of boric acid.

4 Boric acid did not affect the contractile response to Ach, bethanechol or KCl. Single or cumulative treatment of boric acid did not affect ileum muscle contraction evoked by KCl. The atropine-resistant component of Ach-induced contraction and 4-diphenyl-acetoxy-N-methyl-piperidine methiodide-resistant component of bethanechol-induced contraction were not inhibited by boric acid (10⁻³ m). The contractile response to Ach was reduced in calcium-free Tyrode’s solution, and the contractile response was not affected by (10⁻⁸ m). The addition of boric acid (10⁻³ m) in combination with verapamil (10⁻⁸ m) did not significantly affect the contractile response to Ach.

5 In conclusion, boric acid does not affect contractions induced by Ach, bethanechol or potassium in rat isolated ileum.

1 The effect of angiotensin II (Ang II) on α_1A-, α_1B-, and a_1D-adrenoceptors (α₁-AR) expression was analyzed in aorta smooth muscle cells obtained from wild-type (WT) and knock out of α_1D-AR (α_1D-AR KO) mice.

2 The relative abundance of mRNA for the three α₁-ARs was determined in WT and α_1D-AR KO aortic smooth muscle cells. There were no significant differences between WT and α_1D-AR KO cells.

3 As early as 1 h Ang II increased α_1B-AR mRNA in WT cells ≈ 2 fold compared with control; in contrast, in α_1D-AR KO cells the α_1B-AR transcript was ≈ 50% of control.

4 Western blot assays showed that Ang II incremented protein content for α_1A-AR, 86% and 107% in WT and α_1D-AR KO cells, respectively.

5 Protein for α_1B- and α_1D-ARs did not change significantly with Ang II in both WT and a_1D-AR KO cells.

6 The effect of Ang II on α_1B-AR mRNA seems to be influenced by the absence of α_1D-AR in aortic smooth muscle cells, which might be important to understand the interactions among α₁-ARs.

1 The effect of pantoprazole on vecuronium-induced neuromuscular blockade in in vivo has not been clearly defined. In this study, we demonstrate that chronic administration, but not acute administration, of pantoprazole alters the pattern of vecuronium-induced neuromuscular blockade.

2 This study was designed to evaluate the effect of acute and chronic administration of pantoprazole on vecuronium-induced neuromuscular blockade using the rat in vivo sciatic nerve-stimulated gastrocnemius preparation.

3 Vecuronium was administered as a slow intravenous infusion (29.41 μg kg⁻¹ min⁻¹) until the gastrocnemius twitch response to sciatic nerve stimulation was completely abolished. The effect of acute (single dose, i.v.) and chronic administration (per oral for 21 days) of pantoprazole (3.64 mg kg⁻¹) on vecuronium-induced blockade was assessed by comparing ED₅₀ values, time required for 50% block, ED₉₅ values, block duration and percentage of recovery with respect to control.

4 Acute administration of pantoprazole had no significant effect on any parameter of vecuronium-induced neuromuscular blockade. Chronic administration of pantoprazole significantly reduced vecuronium ED₅₀ value, time for 50% block, ED₉₅ value and percentage recovery from blockade compared with the control group (P < 0.05). Reduction in the duration of vecuronium-induced blockade was not significantly affected by chronic treatment with pantoprazole compared with control.

5 On chronic administration, pantoprazole may produce earlier block, quick relaxation and reduces the recovery of vecuronium without affecting its duration of action.

1 Tetrodotoxin (TTX) is a useful pharmacological tool for distinguishing neural and myogenic responses of isolated visceral organs to drugs. Although TTX does not generally affect smooth muscle tonus, in this study, we have found that TTX causes contraction of the mouse colon. The aim of this study was to characterize this TTX-induced contraction in the mouse gastrointestinal tract.

2 Longitudinal and circular muscle strips from the stomach and small intestine were less sensitive to TTX. However, TTX contracted both smooth muscle strips from the proximal colon and distal colon.

3 Pretreatment with TTX, N^ω-nitro-l-arginine methyl ester (l-NAME), (1)H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) and apamin inhibited the TTX-induced contraction. l-NAME, ODQ or apamin itself caused contraction in the colon but not in the gastric and small intestinal strips. Region dependency of l-NAME, ODQ and apamin-induced contraction correlated with that of TTX-induced contraction.

4 l-Arginine but not d-arginine inhibited contractility of the colonic strips without affecting the contractility of muscle strips from other regions. Sodium nitroprusside caused strong relaxation of the colonic strips.

5 1,1-Dimethyl-4-phenylpiperazinium (DMPP) caused relaxation of proximal and distal colons, which was significantly decreased by l-NAME or apamin.

6 In conclusion, among mouse gastrointestinal preparations, TTX induces contraction of colonic strips preferentially through blockade of potent tonic inhibitory neural outflow, which involves nitrergic and apamin-sensitive pathways. Colon-specific responses to l-arginine, l-NAME, ODQ and apamin support the hypothesis that there is a continuous suppression of colonic motility by enteric inhibitory neurons.

1 Interaction between renin-angiotensin (RAS) and sympathetic nervous systems (SNS) was investigated by examining the effect of cumulative blockade of angiotensin II (Ang II) and adrenergic receptors in normal Sprague Dawley rats.

2 Rats were treated with losartan (10 mg/kg), carvedilol (5 mg/kg), or losartan plus carvedilol (10 + 5 mg/kg) orally for 7 days. On day 8, the animals were anaesthetized with pentobarbitone and prepared for systemic haemodynamic study. Dose–response relationships for the elevation of mean arterial pressure or change in heart rate (HR) in response to intravenous injections of noradrenaline (NA), phenylephrine (PE), methoxamine (ME) and Ang II were determined.

3 Losartan or the combination of losartan with carvedilol blunted vasopressor responses to ME and Ang II. Dose–response relationships for agonist action on HR were significantly inhibited by all treatments except for the combination of losartan and carvedilol on the decrease in HR induced by PE. Carvedilol decreased vasopressor responses to NA, PE and Ang II, and HR responses to NA, ME and Ang II. Combination treatment produced similar effects to losartan on the vasopressor and HR responses but had a greater effect on vasopressor responses to ME and Ang II, and on HR responses to NA and Ang II than carvedilol alone.

4 It is concluded that peripheral vasoconstriction induced by Ang II is partly mediated by adrenergic action and that the vasopressor responses to adrenergic agonists depend on an intact RAS. These observations suggest an interactive relationship between RAS and SNS in determining systemic haemodynamic responses in ‘normal’ rats.

1 Relaxant responses to isoprenaline (ISO) were studied in the pulmonary arteries of normotensive and hypertensive Dahl salt-sensitive rats. Rats were fed either a high-salt (4.0%) or low-salt (0.14%) diet for 5 weeks. Animals fed a high-salt diet (167/123 ± 2/2 mmHg) had a significantly higher blood pressure compared to those fed a low-salt diet (127/87 ± 2/2 mmHg).

2 Isoprenaline-elicited relaxations were not significantly different in tissues from hypertensive compared to normotensive animals. Responses to ISO were significantly attenuated in denuded tissues and substantially more so in hypertensive compared to normotensive animals. While relaxant responses to ISO were resistant to inhibition by N^ω-nitro-l-arginine methyl ester, indomethacin, glibenclamide or a combination of barium chloride and ouabain, they were inhibited by Rp-cAMP, anandamide and acidic buffer. The inhibitory impact of anandamide and acidic buffer was significantly greater in tissues from hypertensive vs. normotensive rats.

3 The resting membrane potential (E_m) of smooth muscle cells was −67.0 ± 0.7 mV (n = 43 cells) and −66.6 ± 0.8 mV (n = 55 cells) in pulmonary arteries from hypertensive and normotensive rats, respectively. Isoprenaline produced hyperpolarization of E_m which was significant in the blood vessels of hypertensive (−71.6 ± 0.8 mV; n = 29 cells) but not normotensive (−68.1 ± 0.7 mV; n = 49 cells) rats.

4 The endothelium plays a critical role in β-adrenoceptor-mediated relaxation but nitric oxide is not the mediator for the response. It is possible that the greater hyperpolarization caused by ISO in blood vessels from hypertensive compared to normotensive rats is mediated by activation of TASK-1 channels.

1 The role of the extraendothelial and constitutive isoforms of cyclo-oxygenase-2 (COX-2) in the contractile effect of angiotensin II (Ang II) was investigated using thoracic and abdominal aortic rings without endothelium from young Wistar rats.

2 Ang II elicited similar contractions in both aortic segments, and the effect was inhibited by pretreatment with NS398 (a selective COX-2 inhibitor) but not SC-560 [selective cyclo-oxygenase-1 (COX-1) inhibitor].

3 COX-2 mRNA was expressed under basal conditions in both aortic segments. Additionally, Ang II increased COX-2 mRNA expression in the abdominal but not the thoracic segment, while cycloheximide (a protein synthesis inhibitor) did not affect the contractile response to Ang II in either of the two segments; this suggests that the effect is not associated with de novo COX-2 synthesis.

4 In conclusion, the basal amount of COX-2 found in aortic smooth muscle cells is sufficient to explain the production of the prostanoids related to the contractile effect of Ang II. The production of these prostanoids, which are derived from constitutive COX-2, occurs independently of the endothelium vascular system.

1 Repeated maprotiline (a noradrenaline reuptake inhibitor) and fluoxetine (a serotonin reuptake inhibitor) treatment on gene expression of catecholamine biosynthetic enzymes were examined in adrenal medulla of unstressed control and chronic unpredictable mild stressed rats.

2 Maprotiline did not change gene expression of catecholamine biosynthetic enzymes in control and stressed rats.

3 Fluoxetine increased gene expression of tyrosine hydroxylase (TH) and dopamine-β-hydroxylase (DBH), but did not phenylethanolamine N-methyltransferase in both unstressed and chronic unpredictable mild stressed animals.

4 In conclusion, we have demonstrated that repeated administration of fluoxetine enhanced gene transcription of TH and DBH and subsequently stimulates noradrenaline synthesis in adrenal medulla of control and stressed rats.

1 Pregnancy courses with low response to angiotensin II and adrenergic agonists. In preeclampsia, both effects are reverted. It is known that angiotensin II regulates adrenergic system. It is not known, however, the interaction between both systems receptors.

2 Our aim was to study if AT₁R and α1D adrenoceptor heterodimerize in preeclampsia.

3 We used subrenal aorctic coarctation in pregnant rats. Aortic tissues were prepared for confocal imaging and coimmunoprecipitated for α1D and AT₁ receptors.

4 We found that AT₁R and α1D adrenoceptor heterodimerize in both, healthy and preeclamptic groups. In healthy pregnant rats, heterodimer is barely detected. In preeclamptic rats however, we found higher heterodimerization.

5 These results suggest that AT₁R and α1D -adrenoceptor may form heterodimers, and may play a role in preeclampsia.

1 Antidepressant therapy is considered as one of the factors leading to male infertility.

2 In this study, the effects of long-term treatment with fluoxetine or venlafaxine were investigated on electrical field stimulation (EFS, 1–64 Hz), noradrenaline (10⁻⁸ to 10⁻⁴ m), serotonin (10⁻⁸ to 10⁻⁴ m), adenosine 5′-triphosphate [ATP (10⁻⁸ to 10⁻⁴ m)] and 80 mm KCl-induced contractile responses in the epididymal and prostatic portions of rat isolated vas deferens strips.

3 Serotonin-induced contractile responses were significantly increased in the epididymal portion of the vas deferens obtained from the fluoxetine-treatment group, whereas in the prostatic portion there was no change. However, venlafaxine treatment had no effect on serotonin responses in the either portion of the vas deferens. Both fluoxetine and venlafaxine treatment significantly inhibited ATP-evoked contractions of the prostatic and epididymal portions of the rat vas deferens, but had no effect on EFS, noradrenaline- and KCl-evoked contractions of the vas deferentia in both portions.

4 In conclusion, these results suggest that chronic treatment with fluoxetine and venlafaxine affects vas deferens motility. Purinoceptors may, at least in part, responsible for the impaired motility in chronic treatment of venlafaxine and fluoxetine.