Autonomic and Autacoid Pharmacology最新文献

1 In vascular smooth muscle cells, relaxant actions of guanosine--3′,5′-cyclic monophosphate (cGMP) are well recognized, but there is increasing evidence that cGMP also plays regulatory roles in vascular endothelium. However, the autacoid and endocrine mechanisms controlling cGMP production in endothelium are not well understood. The objective of these studies was to examine the mechanisms of cGMP accumulation in human umbilical vein endothelial cells (HUVEC) in response to natriuretic peptides.

2 Expression in HUVEC of natriuretic peptide receptors, particulate guanylyl cyclases (GC)-A and GC-B, was confirmed by RT-PCR and Western blot analysis.

3 In the presence of the phosphodiesterase inhibitor IBMX 500 μm, 3 h incubation of HUVEC with B-type natriuretic peptide (BNP) (preferential GC-A agonist) or C-type natriuretic peptide (CNP) (preferential GC-B agonist) stimulated concentration-dependent increases in cGMP production. At 10 and 100 nm, we observed two to three-fold greater potency of CNP compared to BNP.

4 In the absence of IBMX, CNP-stimulated cGMP accumulation was significantly less than cGMP accumulation in response to sodium nitroprusside 1 mm. This greater sensitivity of GC-B-derived cGMP to phosphodiesterases suggests compartmentalization of two pools of cGMP from particulate and soluble guanylyl cyclases.

5 Although CNP 100 nm and 1 μm was observed to increase nitrite + nitrate (stable metabolites of NO) production in HUVEC two-fold above basal level, the soluble guanylyl cyclase inhibitor ODQ 10 μm did not significantly modify CNP-stimulated cGMP accumulation suggesting that endothelial actions of CNP may be NO-independent.

6 In conclusion, these studies indicate functional signaling by natriuretic peptides in endothelial cells, supporting possible roles of these mediators in regulating endothelial cell function.

1 It has been suggested that cholestasis accompanied with changes in autonomic balance and hyporesponsiveness in muscarinic and adrenergic receptors of some organs, e.g. cardiovascular system. Increased plasma levels of epinephrine and norepinephrine has been shown during cholestasis suggesting augmented activity of sympathetic nervous system. In this study we evaluate both α₁ and α₂ responsiveness in isolated rat vas deferens, as a tissue with rich adrenergic innervations.

2 Epididymal and prostatic halves of vas deferens responsiveness have been studied to phenylephrine and clonidine respectively in three groups of un-operated, sham-operated (sham), and bile duct-ligated (BDL) rats.

3 Our results indicate that in vas deferens of BDL animals, the concentration-response curve of both phenylephrine and clonidine shifted to rightward compared to control group, while the position of concentration-response curve of sham group did not change significantly (P > 0.05). EC₅₀ of phenylephrine and IC₅₀ of clonidine were increased showing a decreased responsiveness of tissue to phenylephrine (P < 0.05) and clonidine (P < 0.001) in BDL rats.

4 In this study, both subtype of α-adrenoceptors (α₁ and α₂) has been studied in cholestatic rat vas deference. Our results showed that cholestasis induce hyporesponsiveness to phenylephrine and clonidine. These results are consistent with previous reports, suggesting the hyporesponsiveness of α₁-adrenoceptors in pulmonary artery and papillary muscle and mesenteric beds. Our conclusion is that the cholestasis induces hyporesponsiveness to phenylephrine and clonidine in epididymal (α₁-adrenoceptors) and prostatic (α₂-adrenoceptors) halves of rat vas deferens respectively. Although the logical explanation to this hyporesponsiveness is the down regulation but it has been suggested that it is not because of down regulation.

1. This study investigated whether four anticholinergics which are not clinically used for relaxing the urinary bladder detrusor muscle inhibit the contraction of isolated caprine (goat) detrusor muscle: cyclopentolate (100 nm), homatropine (5 μm), ipratropium (500 nm) and valethamate (1 μm).

2. The effects of these anticholinergics were compared with tolterodine (3 μm), an anticholinergic clinically used for relaxing the detrusor muscle. The inhibitory effect of each of these five anticholinergics was studied on six strips of caprine detrusor muscle made to contract with 100 μm acetylcholine (ACh) by determining the percent inhibition of height of contraction and the area under the contractile curve (AUC).

3. It was found that all five anticholinergics inhibited the ACh-induced contraction of the caprine detrusor and that this inhibition was reversed by raising the concentration of ACh. Hence, these four anticholinergics, like tolterodine, may be useful in managing clinical conditions that require relaxation of the detrusor muscle.

1 Nicotine, which is tobacco alkaloid, still induces interests for researchers because of smokers addiction to nicotine. Nicotine having influence on the neuronal acetylcholine receptors (nAChRs) increases release of most certain neurotransmitters from the nerve endings. Also, nicotine, affecting the mitochondrial respiratory chains, contributes to the formation of reactive oxygen species.

2 In the present study, we investigated the effects of nicotine on smooth muscles of gastric fundus on the electrical field stimulation (EFS) that induces transition contraction via stimulation nAChRs. In addition, we aimed to investigate the interaction between release of acetylcholine, induced by nicotine, and the effects of reactive oxygen species.

3 Therefore, the effects of allopurinol (10⁻⁶–10⁻⁵ m), deferoxamine (10⁻⁴ m) and mannitol (10⁻⁴–5 × 10⁻³ m) were tested on the transient contraction induced by nicotine.

4 In conclusion, mannitol (5 × 10⁻³ m) significantly reduced contractile response to nicotine on EFS only in high concentration. Whereas in small concentrations mannitol (10⁻⁴ m) statistically did not cause any results. Deferoxamine and allopurinol also did not have any significant response.

1 Here I put forth the hypothesis that noradrenaline (NA), which is a signalling molecule in the brain and sympathetic nervous system (SNS), is an aetiological factor in a number of diseases.

2 In a previous paper (Fitzgerald, Int. J. Cancer, 124, 2009, 257), I examined evidence that elevated NA is a factor in various types of cancer. Here I extend the argument to several other diseases, including diabetes mellitus, open-angle glaucoma, osteoarthritis and rheumatoid arthritis and asthma.

3 The principal hypothesis is that, largely as a result of genetics, elevated noradrenergic tone in the SNS predisposes a large number of individuals to a broad range of diseases.

4 For each of the above five diseases, I briefly examine the following four lines of evidence to assess the hypothesis: i) whether pharmacological studies in rodents that manipulate NA levels or receptors affect these diseases; ii) whether pharmacological manipulation of NA in humans affects these diseases; iii) whether bipolar disorder, excessive body weight, and hypertension, which may all three involve elevated NA, tend to be comorbid with these diseases and iv) whether psychological stressors tend to cause or exacerbate these conditions, since psychological stress is associated with increased release of NA.

5 The four lines of evidence tend to support the hypothesis.

1 Possibly acting via μ-opioid receptors (MORs), morphine inhibits the formation of experimentally induced postoperative abdominal adhesions in rats. Mesothelial cells may participate in adhesion formation by secreting mediators that interfere negatively with fibrinolysis. Morphine may prevent adhesions by inhibiting the release of pro-adhesion mediators from mesothelial cells. This study aimed to investigate whether human mesothelial cells express ΜΟR-1; if so, such could constitute a site of action for morphine in adhesion prevention.

2 Cells from Met-5A, a human mesothelial cell line were seeded and prepared for immunocytochemistry and Western blotting.

3 Immunocytochemistry showed MOR-1 expression in mesothelial cells, predominantly in the nuclei. Western blotting showed two bands (c. 35 and 50 kDa) which correspond to those obtained with a control lysate from cells known to express MORs. In addition, we found MOR-1 expression with nuclear and cytoplasmatic localization in biopsies from human abdominal adhesions.

4 The current findings may suggest that morphine could interact directly with mesothelial cells via MOR-1 receptors, and thereby modulate adhesion formation, possibly by interfering with the release of pro-adhesion factors from these cells.

1 The molecular mechanism underlying stress-induced hyperglycemia has not been comprehensively clarified. Recently, we demonstrated in ischaemia-reperfusion (I-R) stress-subjected liver that inosine and adenosine are mainly responsible for the hyperglycemia observed.

2 We aimed to advance in the knowledge of the role of inosine plus adenosine as mediators of hepatic-induced hyperglycemia detected after I-R in lower limbs.

3 Acute ischaemia was conducted in anesthetized rats by occluding downstream abdominal aorta and cava vein; then, reperfusion was allowed. Blood samples from hepatic or abdominal cava veins were taken throughout the experiments to measure glucose, inosine and adenosine. Antagonists to adenosine (AdoR) and adrenergic receptors (AdrR) were administered during ischaemia to analyze their effect on hepatic glucose release.

4 Ischaemia up to 60 min produced minor increase of glucose and nucleosides blood values, but 5 min of ischaemia followed by 2- (or 10-) min reperfusion increased glucose 23%, and those of inosine or adenosine by 100%. After 60 min of ischaemia and 10 min of reperfusion, glycemia rose 2-fold and blood inosine and adenosine, 3.3- and 2.7-fold, respectively. A linear positive correlation, r², as high as 0.839 between glucose and either nucleoside blood values was calculated. The hyperglycemia response to I-R decreased by 0, 25, 33, 45 and 100% after selective inhibition of A_2B AdoR, A_2A AdoR, a_1B AdrR, A₁ AdoR, and A₃ AdoR, respectively.

5 Inosine-adenosine couple through activation of hepatic A₃ AdoR is the main signal for releasing glucose from liver glycogen and for promoting hyperglycemia following experimental injury of I-R from lower limbs.