ABSTRACT
The autonomic nervous system contributes to prostate cancer proliferation and metastasis. However, the exact molecular mechanism remains unclear. In this study, muscarinic acetylcholine receptor M1 (CHRM1) expression was measured via immunohistochemical analysis in human prostate cancer tissue array slides. PC-3, LNCaP, and A549 cells were treated with pirenzepine or carbachol, and the cell migration and invasion abilities were evaluated. Western blotting and quantitative real-time PCR were performed to measure GLI family zinc finger 1 (GLI1), patched 1 (PTCH1), and sonic hedgehog (SHH) expression levels. High expression of CHRM1 was found in early-stage human prostate cancer tissues. In addition, the selective CHRM1 antagonist pirenzepine inhibited PC-3, LNCaP, and A549 cell migration and invasion, but the agonist carbachol promoted the migration and invasion of these three cell lines. Muscarinic signaling can be relayed by hedgehog signaling. These data show that CHRM1 is involved in the regulation of prostate cancer migration and invasion through the hedgehog signaling pathway.
Subject(s)
Humans , Male , Carbachol/pharmacology , Cell Movement/genetics , Cell Proliferation , Hedgehog Proteins/genetics , Muscarinic Agonists/pharmacology , Muscarinic Antagonists/pharmacology , Patched-1 Receptor/genetics , Pirenzepine/pharmacology , Prostatic Neoplasms/pathology , Receptor, Muscarinic M1/genetics , Zinc Finger Protein GLI1/geneticsABSTRACT
En este trabajo hemos la influencia de un ácido graso de cadena corta (acetato) sobre el número de células enterocromafines (EC) conteniendo serotonina (5HT) a dos diferentes pH (pH 6.9, estímulo absortivo y pH 2.9 estímulo secretor) infundido durante una hora en el colon. El número de células EC disminuye significativament con una solución infundida a pH 2.9, especialmente en el ciego. La acción de la pirencepina en prevenir esta reducción demuestra que el mecanismo se efectúa parcialmente a través de receptores colinérgicos. Por parte, se observa una disminución de la liberación de 5HT, a través de un mecanismo colinérgico, como lo indica la inhibición observada con la droga antimuscarínica
Subject(s)
Animals , Male , Rats , Fatty Acids, Volatile/pharmacology , Colon/cytology , Pirenzepine/pharmacology , Serotonin/metabolism , Acetates/pharmacology , Cecum/cytology , Cecum/drug effects , Cecum/metabolism , Enterochromaffin Cells , Enterochromaffin Cells , Colon/drug effects , Colon/metabolism , Hydrogen-Ion Concentration , Infusions, Intravenous , Intestinal Mucosa/cytology , Rats, Sprague-DawleyABSTRACT
Amiloride (AM) is a well known potassium sparing diuretic. The effects of AM at the cellular level include blockade of Na+/H+ exchange in several tissues and inhibition of passive sodium flux in epithelial cells. In this study we have explored the interactions of amiloride with muscarinic receptors, using isolated rat tracheal rings and compared its effects to those of the muscarinic receptor subtype-selective antagonist pirenzepine (PZ). The results obtained demonstrate the ability of AM (100 uM to 1mM) to inhibit the ACh induced rat tracheall contractions. The inhibition resulted in the reduction of the Emax values of ACh in this preparation, and the apparent Ki for AM was of 478 uM. This effect was also observed in a sodium-free choline medium, indicating that it is independent from sodium transport mechanisms sensitive to AM. In contrast to AM, PZ displayed a surmountable type of antagonism with a pA2 value of 6.52. The results demonstrate a differential antagonism by AM and PZ of the muscarinic receptors present in the smooth muscle of the rat trachea
Subject(s)
Rats , Animals , Male , Amiloride/pharmacology , Coated Pits, Cell-Membrane/enzymology , Pirenzepine/pharmacology , Receptors, Muscarinic , Trachea/drug effects , Allosteric Regulation , Carrier Proteins , Muscle Contraction , Dose-Response Relationship, Drug , Kinetics , Muscle, Smooth , Rats, Inbred Strains , Sodium/metabolismABSTRACT
Los receptores muscarínicos pre- y post sinápticos del vas deferens de la rata no son M1 ya que el antagonista muscarínico M1-selectivo pirenzepina (PZ) posee baja afinidad por ambos. Basándonos en este hecho las dos acciones de ACh, pre-0y post-sinápticas, en esta preparación parecen ser mediadas por receptores muscarínicos parecidos al subtipo M2. La siguiente serie de observaciones experimentales revelan que ambas respuestas son mediadas por receptores muscarínicos farmacológicamente distintos. El rango de orden de potencia desplegado por 3 antagonistas muscarínicos (Atropina, N-metil-escopolamina [NMS] y PZ) en cada uno de estos lugares son diferentes. Atropina y PZ son bloqueadores selectivos del receptor muscarínico presente en músculo liso. NMS es un antagonista selectivo del receptor pre-sináptico muscarínico que facilita la liberación de norepinefrina. Por último, PZ y NMS despliegan un antagonismo diferencial, siendo competitivos y no-competitivos pre- y post-sinápticamente, respectivamente. Los resultados sugieren que el receptor muscarínico post-sináptico presente en el músculo liso pertenece a los subtipos M2B (oM3). El receptor pre-sináptico pertenece a los subtipos M2A (o M2) o a una subclase de los receptores muscarínicos M2B (o M3)
Subject(s)
Rats , Male , Muscle, Smooth/innervation , Neuromuscular Junction/physiology , Receptors, Cholinergic/physiology , Receptors, Muscarinic/physiology , Synapses/physiology , Atropine/pharmacology , Binding, Competitive/drug effects , Membrane Potentials/drug effects , Pirenzepine/pharmacology , Scopolamine Derivatives/pharmacology , Terminology , Vas Deferens/innervationABSTRACT
1. The effect of pirenzepine, an antimuscarinic compound, on basal acid an pepsin secretion and on the kinetic characteristics (Vmax and ED50) of pentagastrin-stimulated gastric secretion was investigated in 11 duodenal ulcer male patients. 2. Each patient underwent two pentagastrin dose-response tests: one with placebo and the other with pirenzepine given as a 10-mg intravenous bolus followed by 2.5 mg/h continuous infusion. 3. Pirenzepine induced a marked reduction in basal acid secretion (4.4 vs 0.3 mEq/h) and pepsin secretion (76.3 vs 18.3 mPU/h). 4. The drug also caused a reduced response of parietal cells to pentagastrin, which resulted in an increase in ED50 (131 vs 299 ngKg-1h-1). The maximal acid secretory response (Vmax) was reduced (40.9 vs 32.3 mEq/h), but this effect was not demonstrable when the result was expressed as total output minus basal output. 5. Pentagastrin-induced pepsin secretion was not significantly affected by pirenzepine. 6. We conclude that the inhibitory action of pirenzepine on gastric acid secretion results from the effect of the drug on basal secretion and on parietal cell responsiveness to stimuli
Subject(s)
Adult , Middle Aged , Humans , Male , Pentagastrin , Pirenzepine/pharmacology , Duodenal Ulcer/physiopathology , Gastric Acid , Clinical Trials as Topic , Pepsin A/metabolismABSTRACT
La pirenzepina se ha utilizado ampliamente en el tratamiento de la úlcera gástrica y duodenal. En este trabajo hemos probado que esta droga puede prevenir la acción inflamatoria inducida en el colon con un estímulo intraluminal como el ácido acético. Estos datos sugieren una participación colinérgica en la respuesta inflamatoria del colon