Effects of phosphodiestrase type 5 inhibitors in epinephrine-induced arrhythmia in rats: Involvement of lactate dehydrogenase and creatine kinase downregulation and adiponectin expression.

Cardiac arrhythmia is a common cause of mortality, and its progression may be due to abnormal sympathetic nerve activity and catecholamine release. Besides, lactate dehydrogenase (LDH) and creatine kinase (CK) downregulation and adiponectin expression play important roles in promoting coronary artery disease. The study aimed to examine the possible cardioprotective effect of members of phosphodiesterase type 5 (PDE-5) inhibitors in epinephrine-induced arrhythmia in rats. Arrhythmia was induced by cumulative boluses of epinephrine (4, 8, 16, 32, 64, and 128 mg/kg) given at 10-min intervals. Rats were randomly allocated into five groups. Group I: Normal control group received only saline. Group II: Rats injected with epinephrine and served as arrhythmia group. Groups III, IV, and V: Rats received daily oral sildenafil (0.5 mg/kg), vardenafil (3 mg/kg), and tadalafil (10 mg/kg), respectively, for 30 days prior to epinephrine injections. Injection of epinephrine to rats decreased heart rate and QTc interval but increased RR interval and duration of arrhythmia. Epinephrine group had lower serum reduced glutathione (GSH) and adiponectin levels and higher serum malondialdehyde (MDA), nitric oxide (NO), heart LDH, and CK contents. Histopathological investigations of epinephrine group provoked necrotic changes with strong positive immunoreactivity for caspases-3. While pretreatment of rats with PDE-5 inhibitors improved GSH and adiponectin contents, ameliorated serum MDA and NO levels and heart LDH and CK contents and corrected epinephrine-induced histopathological changes. PDE-5 inhibitors may delay epinephrine-induced arrhythmia through expression of adiponectin and downregulation of heart LDH and CK.

Temporary sacral nerve stimulation alters rectal sensory function: a physiological study.

BACKGROUND: The indications for sacral nerve stimulation are increasing, but the mechanism remains poorly understood. OBJECTIVE: This study aimed to examine the effect of sacral nerve stimulation on rectal compliance and rectal sensory function. DESIGN: This was a prospective study. SETTINGS: This study took place at a university teaching hospital. PATIENTS: Twenty-three consecutive consenting patients (22 female; median age, 49 y) undergoing temporary sacral nerve stimulation for fecal incontinence were prospectively studied. Clinical response was assessed by the use of bowel diaries and Wexner scores. MAIN OUTCOME MEASURES: Anal manometry, rectal compliance, volume and pressure thresholds to rectal distension (barostat), and rectal Doppler mucosal blood flow were measured before and at the end of stimulation. RESULTS: Sixteen patients (70%) had a favorable clinical response. Median anal squeeze pressures increased with stimulation from 40 (range, 6-156) cmH2O to 64 (range, 16-243) cmH2O. Median rectal compliance did not significantly change with stimulation (prestimulation: 11.5 (range, 7.9-21.8) mL/mmHg, poststimulation: 12.4 (range, 6.2-22) mL/mmHg, P = .941). Rectal wall pressures associated with urge (baseline: 15.4 (range, 11-26.7) mmHg, poststimulation: 19 (range, 11.1-42.7) mmHg, P = .054) and maximal tolerated thresholds (baseline: 21.6 (8.5-31.9) mmHg, poststimulation: 27.1 (14.3-43.3) mmHg, P = .023) significantly increased after stimulation. Rectal Doppler mucosal blood flow did not significantly change with stimulation (baseline: 125.8 (69.9-346.8), poststimulation: 112.4 (50.2-404.1), P = .735). Changes in anal resting pressure and rectal wall pressures with stimulation were evident only in responders; however, changes in anal squeeze pressures were evident in both responders and nonresponders. LIMITATIONS: The study reports results following short-term stimulation in a small but homogenous group of patients. A larger long-term study will follow. CONCLUSION: Temporary sacral nerve stimulation does not change rectal compliance, but is associated with significant changes to the pressure thresholds of rectal distension. This, together with the observation that outcome is not related to sphincter integrity, supports the hypothesis of an afferent-mediated mechanism of action.

A laser doppler study of the effect of 2-alkylthio-4-ethyl-4-methyl-4,5 dihydro-1H-imidazolin-5-one oxime (oxime) on the ischaemic rat lower limb.

The potential vasodilator effect of the novel compound 2-alkylthio-4-ethyl-4-methyl-4,5 dihydro-1H-imidazolin-5-one oxime (oxime) was investigated in a model of lower limb ischaemia induced in rats by unilateral ligation of the right femoral artery using Laser Doppler Flowmetry. The effect of oxime was compared with that of isoprenaline or L-arginine. Test drugs were injected systemically into the femoral vein or applied locally on the planter surface of the rat hind paw. Serum level of nitrite (NO(2) (-)) and nitrate (NO(3) (-)) were measured by ELISA. Immediately after operative induction of right lower limb ischaemia, blood flow ratio (Right/Left limb ratio: BFR) decreased to 0.33-0.39 in different groups. The intravenous (i.v.) administration of oxime increased BFR in a dose-dependent manner. Compared with pre-drug BFR, oxime administered at doses of 0.064, 0.128 or 0.256 mg/kg increased BFR to 178.8, 328.9 and 705.9 %, respectively. Meanwhile, L-arginine given i.v. at 100 mg/kg increased BFR to 560 %. Isoprenaline given i.v. at 1 microg/kg increased BFR to 274.3 %, while isoprenaline combined with oxime (0.064 mg/kg) increased BFR to 402.7 %. Similarly, after topical application of oxime, BFR increased to 113.5, 261.1 and 433.3 %, respectively. L-arginine given at 1000 mg/kg increased BFR to 389.7 %. Isoprenaline given at 10 microg/kg increased BFR to 231.6 %, while isoprenaline administered in combination with oxime (0.064 mg/kg) increased BFR to 308.3 %. The concentration of NO in serum was significantly increased after systemic or topical administration of either 0.128 and 0.256 mg/kg oxime or 100 and 1,000 mg/kg L-arginine, respectively. It is concluded that systemic or topical oxime results in marked enhancement of blood flow in the rat ischaemic lower limb. This effect of oxime is likely to be mediated through the release of NO.