pyrimidinones and Ischemia

Topics: Aged; Analgesics; Arm; Aspirin; Carboxylic Acids; Clinical Trials as Topic; Codeine; Drug Synergism; Humans; Ischemia; Pain; Pyrimidinones

Topics: Antineoplastic Agents; Drug Therapy, Combination; Female; Fluorescein Angiography; Fundus Oculi; Humans; Imidazoles; Ischemia; MAP Kinase Kinase 1; Melanoma; Melanoma, Cutaneous Malignant; Middle Aged; Neoplasm Metastasis; Oximes; Proto-Oncogene Proteins B-raf; Pyridones; Pyrimidinones; Retinal Vasculitis; Retinal Vessels; Skin Neoplasms

To evaluate the distribution of a daily phosphodiesterase type 5 inhibitor dose (mirodenafil) in rat plasma and bladder and prostate tissue in a model of atherosclerosis-induced chronic pelvic ischemia.. Thirty-two 18-week-old male Sprague Dawley rats were divided into two groups. Group I (n = 16) comprised a chronic pelvic ischemia model treated with mirodenafil and group II (n = 16) comprised a sham-operated model also treated with mirodenafil. The mirodenafil concentrations in each organ were measured at specific time points after 14 days of daily mirodenafil administration. The drug distribution ratio of group I to group II of each organ was measured, and the bladder tissue-to-plasma and prostate tissue-to-plasma ratios were calculated.. The mean drug concentration in the bladder of the rats in group I did not differ significantly from that of group II after mirodenafil administration. In the prostate, the mean drug concentration of group I was significantly higher than that of group II at 1 and 4 hours after drug administration. The drug concentration was higher in the bladder tissue than in the prostate tissue and the bladder tissue-to-plasma ratio was significantly higher than the prostate tissue-to-plasma ratio.. Our results suggest that mirodenafil levels might be sufficient in the target tissue after daily treatment in an ischemia-induced aging model. Considering the difficulties of tissue distribution study in human subjects, the results of this investigation provided meaningful evidence of the application of daily doses of mirodenafil for treating lower urinary tract symptoms in an aging population.

Topics: Animals; Chronic Disease; Disease Models, Animal; Ischemia; Male; Pelvis; Phosphodiesterase 5 Inhibitors; Prostate; Pyrimidinones; Rats; Rats, Sprague-Dawley; Sulfonamides; Tissue Distribution; Urinary Bladder

The mechanism of water and sodium apparent diffusion coefficient (ADC) changes in rat skeletal muscle during global ischemia was examined by in vivo 1H and 23Na magnetic resonance spectroscopy (MRS). The ADCs of Na+ and water are expected to have similar characteristics because sodium is present as an aqua-cation in tissue. The shift reagent, TmDOTP5(-), was used to separate intra- and extracellular sodium (Na+i and Na+e, respectively) signals. Water, total tissue sodium (Na+t), Na+i, and Na+e ADCs were measured before and 1, 2, 3, and 4 hr after ischemia. Contrary to the general perception, Na+i and Na+e ADCs were identical before ischemia. Thus, ischemia-induced changes in Na+e ADC cannot be explained by a simple change in the size of relative intracellular or extracellular space. Na+t and Na+e ADCs decreased after 2-4 hr of ischemia, while water and Na+i ADC remained unchanged. The correlation between Na+t and Na+e ADCs was observed because of high Na+e concentration. Similarly, the correlation between water and Na+i ADCs was observed because cells occupy 80% of the tissue space in the skeletal muscle. Ischemia also caused an increase in the Na+i and an equal decrease in Na+e signal intensity due to cessation of Na+/K+-ATPase function.

Topics: Animals; Body Water; Diffusion; Extracellular Space; Intracellular Space; Ischemia; Magnetic Resonance Spectroscopy; Male; Muscle, Skeletal; Oxazoles; Phantoms, Imaging; Pyrimidinones; Rats; Rats, Inbred Strains; Sodium

Vascular inflammation and enhanced production of angiotensin II (ANG II) are involved in the pathogenesis of hypertension and diabetes, disease states that predispose the afflicted individuals to ischemic disorders. In light of these observations, we postulated that ANG II may play a role in promoting leukocyte rolling (LR) and adhesion (LA) in postcapillary venules after exposure of the small intestine to ischemia-reperfusion (I/R). Using an intravital microscopic approach in C57BL/6J mice, we showed that ANG II type I (AT(1)) or type II (AT(2)) receptor antagonism (with valsartan or PD-123319, respectively), inhibition of angiotensin-converting enzyme (ACE) with captopril, or calcitonin gene-related peptide (CGRP) receptor blockade (CGRP8-37) prevented postischemic LR but did not influence I/R-induced LA. However, both postischemic LR and LA were largely abolished by concomitant AT(1) and AT(2) receptor blockade or chymase inhibition (with Y-40079). Additionally, exogenously administered ANG II increased LR and LA, effects that were attenuated by pretreatment with a CGRP receptor antagonist or an NADPH oxidase inhibitor (apocynin). Our work suggests that ANG II, formed by the enzymatic activity of ACE and chymase, plays an important role in inducing postischemic LR and LA, effects that involve the engagement of both AT(1) and AT(2) receptors and may be mediated by CGRP and NADPH oxidase.

Topics: Acetophenones; Angiotensin II; Angiotensin II Type 1 Receptor Blockers; Angiotensin II Type 2 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Animals; Calcitonin Gene-Related Peptide; Captopril; Cell Adhesion; Chymases; Disease Models, Animal; Endothelial Cells; Imidazoles; Intestines; Ischemia; Leukocyte Rolling; Leukocytes; Male; Mice; Mice, Inbred C57BL; Microscopy, Video; NADPH Oxidases; Pyridines; Pyrimidinones; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Calcitonin Gene-Related Peptide; Reperfusion Injury; Tetrazoles; Valine; Valsartan; Venules

We report the case of a 57-year-old man who presented bilateral subacute and painless optic neuropathy after meningopolyradiculitis revealing a primary human immunodeficiency virus infection. Both antiretroviral and steroid treatments were ineffective. Clinical symptoms and evolutive pattern were consistent with a mechanism of microvascular ischaemia of the optic nerve head. Optic neuropathies related to HIV infection are rare compared to those resulting from opportunistic infections. There are several pathophysiological mechanisms involved.

Topics: AIDS Serodiagnosis; Anti-HIV Agents; Antiretroviral Therapy, Highly Active; Disease Progression; Drug Therapy, Combination; Evoked Potentials, Visual; Facial Nerve Diseases; HIV Infections; HIV Protease Inhibitors; HIV-1; Humans; Ischemia; Lamivudine; Lopinavir; Male; Meningitis, Viral; Methylprednisolone; Middle Aged; Optic Disk; Optic Nerve Diseases; Polyradiculopathy; Pyrimidinones; Reverse Transcriptase Inhibitors; Ritonavir; Visual Fields; Zidovudine

1. The antiarrhythmic and haemodynamic effects of three class III antiarrhythmic drugs, MS-551, sematilide and dofetilide, were examined in the coronary artery, ligation-reperfusion model of pentobarbitone-anaesthetized rats, a species deficient in functional cardiac IK. MS-551 is a non-selective potassium channel blocker, while both sematilide and dofetilide are selective delayed rectifier potassium (K) channel (IK) blockers. 2. Before coronary ligation, 3 and 10 mg kg-1 MS-551 decreased the heart rate by 6% (P < 0.01) and 12% (P < 0.01), and increased mean arterial pressure (MAP) by 14% (P < 0.05) and 33% (P < 0.01), respectively. Sematilide at 10 and 30 mg kg-1 also decreased the heart rate by 4% (P < 0.01) and 9% (P < 0.01), respectively, and the higher dose of 30 mg kg-1 decreased MAP by 29% (P < 0.01). Dofetilide, 1 mg kg-1, decreased the heart rate (P < 0.01), but had no significant effect on MAP. 3. The QT interval was increased by 10% (P < 0.01) and 31% (P < 0.01), when 3 and 10 mg kg-1 MS-551 were given. Sematilide and dofetilide had no effect on the QT interval. 4. Immediately after reperfusion, lethal ventricular fibrillation (VF) was induced in 80% of the saline group. MS-551 at 3 and 10 mg kg-1, reduced the incidence of lethal VF to 50% and 20% (P < 0.05). Neither dofetilide 1 mg kg-1 nor sematilide (10 and 30 mg kg-1) decreased the incidence of lethal VF (70%, 80% and 50%, respectively). None of the three drugs had any effect on the occurrence of reperfusion-induced VT or the total incidence of VF. However, 10 mg kg-1 MS-551 delayed the onset of reperfusion-induced VF (27 +/- 5 s compared with 12 +/- 2 s of the control group, P < 0.05). 5. In conclusion, in rats which are deficient in cardiac IK MS-551 prolonged the QT interval and reduced the incidence of sustained VF after reperfusion. Blockade of channels other than IK might participate in the defibrillatory effect of MS-551. Sematilide and dofetilide, which are selective IK blockers, did not increase the QT interval nor did they show antiarrhythmic effects Mechanisms other than K channel block may be involved in the different effects of the three drugs on blood pressure.

Topics: Animals; Anti-Arrhythmia Agents; Blood Pressure; Coronary Vessels; Heart Rate; Ischemia; Male; Phenethylamines; Procainamide; Pyrimidinones; Rats; Rats, Sprague-Dawley; Reperfusion; Sulfonamides

Topics: Arteriosclerosis Obliterans; Female; Humans; Ischemia; Leg; Male; Middle Aged; Pain; Pyrimidinones