ABSTRACT
PURPOSE: The inhibition of phosphodiesterase 5 produces an antinociception through the increase of cyclic guanosine monophosphate (cGMP), and increasing cGMP levels enhance the release of gamma-aminobutyric acid (GABA). Furthermore, this phosphodiesterase 5 plays a pivotal role in the regulation of the vasodilatation associated to cGMP. In this work, we examined the contribution of GABA receptors to the effect of sildenafil, a phosphodiesterase 5 inhibitor, in a neuropathic pain rat, and assessed the hemodynamic effect of sildenafil in normal rats. MATERIALS AND METHODS: Neuropathic pain was induced by ligation of L5/6 spinal nerves in Sprague-Dawley male rats. After observing the effect of intravenous sildenafil on neuropathic pain, GABAA receptor antagonist (bicuculline) and GABAB receptor antagonist (saclofen) were administered prior to delivery of sildenafil to determine the role of GABA receptors in the activity of sildenafil. For hemodynamic measurements, catheters were inserted into the tail artery. Mean arterial pressure (MAP) and heart rate (HR) were measured over 60 min following administration of sildenafil. RESULTS: Intravenous sildenafil dose-dependently increased the withdrawal threshold to the von Frey filament application in the ligated paw. Intravenous bicuculline and saclofen reversed the antinociception of sildenafil. Intravenous sildenafil increased the magnitude of MAP reduction at the maximal dosage, but it did not affect HR response. CONCLUSION: These results suggest that sildenafil is active in causing neuropathic pain. Both GABAA and GABAB receptors are involved in the antinociceptive effect of sildenafil. Additionally, intravenous sildenafil reduces MAP without affecting HR.
Subject(s)
Animals , Male , Rats , Baclofen/analogs & derivatives , Bicuculline/pharmacology , Blood Pressure/drug effects , Dose-Response Relationship, Drug , Heart Rate/drug effects , Hemodynamics/drug effects , Neuralgia/drug therapy , Pain Threshold/drug effects , Phosphodiesterase Inhibitors/therapeutic use , Piperazines/therapeutic use , Purines/therapeutic use , Rats, Sprague-Dawley , Receptors, GABA-A/antagonists & inhibitors , Receptors, GABA-B/antagonists & inhibitors , Sulfones/therapeutic useABSTRACT
Gamma-amino butyric acid [GABA], an amino acid, present in some inhibitory neurons of the central nervous system, is also found in relatively high levels in the islets of Langerhans. Results of different studies concerning the effect of GABA on insulin secretion are controversial. The aim of this study was to determine the role of GABA and GABAB receptors on glucose-stimulated insulin secretion in isolated islets of rats. The collagenase digestion technique was used to isolate the islets from pancreata of 45 male Wistar rats [200-250g]. Insulin secretion was assessed in eight islets in each cup exposed to different concentrations of glucose [8.3 and 16.7 mM] in the presence or absence of GABA [25, 50, 100 micro M], baclofen [10, 20, 50 micro M] [GABAB agonist] and saclofen [50,100 micro M] [GABAB antagonist]. Insulin concentration was measured by the ELISA method. Insulin release was reported as mean +/- SEM micro U/isIet/50 min and p values of <0.05 were considered significant. GABA inhibited glucose [8.3 and 16.7 mM]-induced insulin secretion in isolated islets [P<0.05]. Different concentrations of baclofen had no significant effect on glucose-induced insulin secretion; however glucose [16.7 mM] stimulated insulin secretion in the presence of 100 micro M saclofen [91 +/- 8.8 micro U/islet/60 min] was significantly [p<0.05] higher compared to insulin secretion stimulated by 16.7 mM glucose alone [67.7 +/- 2.58 micro U/islet/60 min]. These findings indicate that GABA has an inhibitory effect on glucose-induced insulin secretion; and therefore it may play a regulatory role in insulin secretion. This effect needs to be taken in to account in the pathophysiology of diabetes
Subject(s)
Male , Animals, Laboratory , Islets of Langerhans/physiology , Diabetes Mellitus/physiopathology , Insulin/metabolism , Rats, Wistar , Baclofen/analogs & derivativesABSTRACT
Since GABA and its related enzymes had been determined in beta-cells of pancreas islets, effects of GABA on pancreatic exocrine secretion were investigated in the isolated perfused rat pancreas. GABA, given intra-arterially at concentrations of 3, 10, 30 and 100 microM, did not exert any influence on spontaneous or secretin (12 pM)-induced pancreatic exocrine secretion. However, GABA further elevated cholecystokinin (10 pM)-, gastrin-releasing peptide (100 pM)- or electrical field stimulation-induced pancreatic secretions of fluid and amylase, dose-dependently. The GABA-enhanced CCK-induced pancreatic secretions were completely blocked by bicuculline (10 microM), a GABAA receptor antagonist but not affected by saclofen (10 microM), a GABA(B) receptor antagonist. The enhancing effects of GABA (30 microM) on CCK-induced pancreatic secretions were not changed by tetrodotoxin (1 microM) but partially reduced by cyclo-(7-aminoheptanonyl-Phe-D-Trp-Lys-Thr[BZL]) (10 microM), a somatostatin antagonist. In conclusion, GABA enhances pancreatic exocrine secretion induced by secretagogues, which stimulate enzyme secretion predominantly, via GABA(A) receptors in the rat pancreas. The enhancing effect of GABA is partially mediated by inhibition of islet somatostatin release. GABA does not modify the activity of intrapancreatic neurons.