piperidines and metrenperone

This study evaluated the effects of metrenperone on healing of unilateral, collagenase-induced lesions in the Superficial Digital Flexor Tendons (SDFT) of rabbits.. After controlled injury of the left SDFT, nine rabbits received daily treatment with metrenperone for 28 days. Another nine were untreated controls; in both groups the contra-lateral tendons served as uninjured controls. Histological and ultrastructural changes, mechanical properties, dry weight, collagen content, and amount of DNA in healing and control tendons were assessed 28 days after injury.. Restoration of structural hierarchy was more organized in treated than in untreated tendons while cellularity was greater in the latter. At the ultrastructural level, collagen in treated lesions was predominantly in the form of small-diameter, new fibrils, with few large, old fibrils; in untreated lesions there was a high proportion of large, old fibrils but relatively few small, new ones. The amount of DNA in untreated injuries was much greater than in normal tendons, while in treated lesions it was not significantly different from that of uninjured controls. There were no significant differences in total collagen, stiffness and ultimate strength of injured, treated, and untreated tendons 28 days after injury. Both were significantly weaker than their corresponding contralaterals.. The findings suggest that metrenperone had positive effects on collagen turnover, remodelling, and organization during acute inflammation and fibroplasia. Provided that the new fibrils subsequently matured in a normal manner, mechanical characteristics of the organized scar should be better than those of an untreated lesion.

Topics: Animals; Biomechanical Phenomena; Collagen; Collagenases; DNA; Female; Piperidines; Rabbits; Serotonin 5-HT2 Receptor Antagonists; Tendon Injuries; Tendons; Tensile Strength; Wound Healing

The cardiovascular response to 5-hydroxytryptamine (5-HT) challenge has been previously described in cattle. Abrupt bradycardia, followed by tachycardia, triphasic systemic blood pressure response, and pulmonary hypertension were the major changes elicited by 5-HT. The purpose of the present study was to determine whether the cardiovascular response to 5-HT in calves was attributable to 5-HT2 receptors. A specific 5-HT2 antagonist (metrenperone, 0.05 mg/kg) was administered intramuscular to six unsedated Friesian calves 30 min before the animals were given a 5-min intravenous 5-HT infusion. Mean systemic arterial (SAP), mean pulmonary arterial (PAP), pulmonary capillary wedge (PW) pressures were obtained by means of fluid-filled catheters, and cardiac output (CO) was measured by the thermodilution technique. Heart rate, stroke volume, systemic (SVR) and pulmonary (PVR) vascular resistances were calculated. Administration of 5-HT after metrenperone induced a short-lasting period of severe bradycardia followed by tachycardia and increased CO. The systemic blood pressure response was exclusively hypotensive and associated with a decrease in SVR. Conversely, PAP, PW, and PVR were not modified by 5-HT administration. The results establish that 5-HT induced systemic as well as pulmonary hypertension is mediated through the activation of type-2 serotonergic or alpha-adrenergic receptors, or both. In contrast, neither apnoea, bradycardia and hypotension, nor the positive chronotropic effect induced by 5-HT in cattle are mediated through such receptors.

Topics: Animals; Body Temperature; Bradycardia; Cardiovascular System; Cattle; Hypotension; Kinetics; Muscle, Skeletal; Piperidines; Receptors, Serotonin; Serotonin; Serotonin Antagonists; Sleep Stages

To evaluate a 5-hydroxytryptamine type-2 receptor antagonist, metrenperone (MET), in alleviating respiratory distress associated with experimentally induced Pasteurella haemolytica pneumonia in feedlot calves.. Double-blind controlled clinical trial.. 30 healthy 6- to 8-month-old Hereford-type calves (250 to 450 kg).. Initial measurements were made of rectal temperature (RT), arterial blood gas (ABG) tensions, and pulmonary mechanics. Calves were then infected with P haemolytica in logarithmic phase of growth by intratracheal inoculation. 18 hours later, determination of RT and ABG tensions, and pulmonary function testing were repeated and calves were selected for inclusion in the study on the basis of having 2 of the following: respiratory rate > 50 breaths/min, RT > 40 C, or PaO2 > 20 mm of Hg below the baseline value. MET (0.1 mg/kg of body weight, IM) or an equivalent vehicle dose was then administered. RT, ABG, and pulmonary mechanics measurements were repeated at 0.5, 1, 2, 3, 4, 6, 12, and 24 hours after treatment. Calves were then euthanatized, and gross necropsy scoring and histologic examination were performed on the lungs.. Infection with P haemolytica caused significant increases in RT and respiratory rate, and reduction in PaO2, PaCO2, and tidal volume 18 hours after inoculation. MET-treated calves and significantly reduced rectal temperature between 1 and 12 hours, compared with vehicle-treated calves. In addition, MET-treated calves had reduced respiratory rate with concomitantly increased tidal volume between 0.5 and 2 hours after treatment, compared with vehicle-treated calves. Necropsy revealed acute lobar bronchopneumonia in all 30 calves, but there was no difference in necropsy score between treatment groups.. MET may have an antipyretic effect on calves with pneumonia caused by P haemolytica. Its influence on pulmonary mechanics was minimal however, and it did not induce lung lesions in the short term.

Topics: Animals; Appetite; Body Temperature; Carbon Dioxide; Cattle; Lung; Mannheimia haemolytica; Oxygen; Partial Pressure; Pasteurella Infections; Piperidines; Receptors, Serotonin; Respiration; Respiratory Function Tests; Serotonin Antagonists; Tidal Volume; Time Factors

This study was designed to investigate whether 3-methylindole (3-Mi), a tryptamine analogue, could cause pulmonary injury in calves other than by cytotoxicity. Injection of 3-Mi resulted in a marked increase of respiratory rate, decrease of tidal volume and increase in minute ventilation. Pulmonary mechanics values were also profoundly affected, lung dynamic compliance being reduced to approximately one-third of its baseline value and total pulmonary resistance being increased two-fold. Arterial oxygen partial pressure was dramatically reduced. Successive challenges with 3-Mi after physiological saline pretreatment resulted in quantitatively identical alterations of pulmonary function values. Conversely, all these ventilatory, mechanical and gas exchange changes were abolished by pretreatment with serotonergic antagonists. It was concluded that intravenous administration of 3-Mi to healthy calves induced immediate and reversible bronchoconstriction which affected both central and peripheral airways. Because the effect was abolished by pretreatment with antiserotonin drugs, it is suggested that 3-Mi acts either directly by stimulating serotonergic receptors or indirectly through the release of serotonin from platelets. Current concepts of the physiopathological cascade underlying the toxicity of 3-Mi should, therefore, be re-evaluated in the light of this pharmacological mechanism.

Topics: Analysis of Variance; Animals; Carbon Dioxide; Cattle; Lung; Male; Oxygen; Piperidines; Pulmonary Ventilation; Serotonin Antagonists; Skatole; Time Factors

The effects of saline (control, group C) and metrenperone (treated, group M) on systemic and pulmonary hemodynamics were determined in conscious 7- to 15-day-old calves after they were intratracheally inoculated with Pasteurella haemolytica. Metrenperone, a specific serotonin (5-hydroxytryptamine) receptor antagonist, was injected intramuscularly (100 micrograms.kg-1) 2 h after the calves were inoculated. Central venous, pulmonary arterial and capillary wedge, and systemic arterial pressures were measured, using fluid-filled catheters. Cardiac output was measured by the thermodilution technique. Heart rate, stroke volume, and pulmonary and systemic vascular resistances were calculated. The parameters were measured hourly from the 1st to the 10th h after inoculation. In group C, cardiovascular response to P. haemolytica inoculation was marked and typically consisted of two systemic hypotensive phases and two pulmonary hypertensive phases. The first phase occurred by the 2nd h post inoculation and was induced by a transient bradycardia and a systemic vasodilation, leading to profound hypotension and reduced venous return. Cardiac performance then transiently recovered, but systemic hypotension persisted. The second hypotensive hypodynamic phase occurred by the 7th h after inoculation, and was associated with a decline in stroke volume, an increase in heart rate, and pulmonary hypertension and vasoconstriction. In group M, the early response to P. haemolytica exposure was similar to that in controls, indicating that, as in sheep, 5-hydroxytryptamine does not contribute to the early hypodynamic response to endotoxemia. In contrast, metrenperone completely abolished late increases in pulmonary arterial pressure and pulmonary vascular resistance, suggesting that 5-hydroxytryptamine contributes to the late pulmonary vasoconstriction. Metrenperone treatment also allowed better restoration of heart rate, and hence, cardiac output was maintained. In conclusion, 5-hydroxytryptamine might have a role in mediating pasteurellic endotoxin induced changes in pulmonary hemodynamics through its type-2 receptors.

Topics: Analysis of Variance; Animals; Carbon Dioxide; Cattle; Heart Rate; Hemodynamics; Lung; Male; Mannheimia haemolytica; Pasteurella Infections; Piperidines; Pneumonia; Serotonin Antagonists; Vascular Resistance

During this investigation, which involved 58 Belgian White and Blue double-muscled calves affected by a naturally occurring Acute Respiratory Distress Syndrome, the clinical efficiency of a 5-HT2 receptor blockade with metrenperone (group A) was compared to the efficiency of a non-steroidal (flunixine meglumine--group B) and a steroidal (prednisolone sodium succinate--group C) antiinflammatory drug. Each animal of this trial was treated with ceftiofur sodium as antimicrobial agent. A clinical score and a breathing score were calculated at each step of the investigation period, i.e. before (T0) and 1 hour (T1), 12 hours (H), 24 H, 48H and 168 H (T3) after the first treatment, the interval 12H-48H being considered as period T2. Three clinical parameters were also taken into account separately: rectal and peripheral temperatures and heart rate. A significant improvement of the clinical score was registered at T2 in group A and at T3 in groups A and B, while this score did not significantly change in group C. In group A, the breathing score was significantly improved at T2 and T3, but not in groups B and C. Peripheral and rectal temperatures recorded at T1 were, in group A, significantly increased and decreased respectively, but not significantly changed in groups B and C. The proportions requiring change of treatment during the investigation period were significantly (P = 0.022) different in the three groups, being 5.6, 21.4 and 50.0% in groups A, B and C respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cattle; Cattle Diseases; Piperidines; Respiratory Insufficiency; Serotonin Antagonists; Syndrome

Ninety-four Belgian White and Blue double-muscled calves were involved in this study which aimed to compare the efficacy of a serotonin-S2 receptor blockade at two different stages of an acute respiratory distress syndrome (ARDS), i.e. at the occurrence of first clinical signs or when another anti-inflammatory compound was clinically shown to be ineffective. Metrenperone, a 5-hydroxytryptamine (5-HT2) blocker, was injected (intramuscularly, 5 times, at 12 hourly intervals, dose rate: 0.1 mg/kg) to (1) 58 calves referred to our laboratory after a treatment (group I) which lasted from 3 to 5 days and which did not improve the clinical status of the animals and (2) 36 calves investigated as soon as first clinical signs occurred (group II). Following the severity of the ARDS, the animals from group I needed to be classified into 2 groups: group IA (moderate ARDS - n = 45) and group IB (severe ARDS - n = 13). For animals in group I, the antibacterial compound previously used was maintained and administered during 4 more days whilst the previous anti-inflammatory drug was suppressed and replaced by metrenperone administered as mentioned above. In group II, each animal was treated with ceftiofur sodium as an antibacterial agent. A clinical score and a breathing score were calculated at each step of the investigation period, i.e. before (T0) and 1 hour (T1) after the first treatment, during the interval 12H-48H (T2) which followed this treatment and 168 H (T3) after this treatment. Four clinical parameters were also taken into account separately: rectal and cutaneous temperatures, respiratory and heart rates.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Cattle; Cattle Diseases; Cephalosporins; Drug Therapy, Combination; Piperidines; Respiration; Respiratory Distress Syndrome; Serotonin Antagonists

The effects of a 5-hydroxytryptamine (5-HT) challenge infusion on pulmonary function values were studied in healthy calves, pretreated with varying doses of metrenperone, a selective type 2 serotonergic (5-HT2) antagonist. In the first part of the experiment, the 5-HT challenge was performed 30 minutes after administration of metrenperone at a dose of 0.025 mg kg-1 (group 1, n = 8), 0.050 mg kg-1 (group 2, n = 8) and 0.100 mg kg-1 (group 3, n = 7). In the second part, the 5-HT challenge was performed 12 hours after administration of metrenperone at a dose of 0.050 mg kg-1 (group 4, n = 5) and 0.100 mg kg-1 (group 5, n = 5). None of the three doses of metrenperone influenced the 5-HT-induced ventilatory changes. For the challenge performed 30 minutes after blockade, all three doses inhibited the bronchoconstrictive process triggered by the 5-HT challenge. There was no dose-related inhibition. On the other hand, when the challenge was performed 12 hours after metrenperone, there was a dose-related inhibition with only the higher dose (0.100 mg kg-1) showing a significant efficacy in inhibiting 5-HT-induced bronchoconstriction. It is concluded that, if 5-HT is involved in the pathophysiological processes of respiratory diseases in cattle, a 5-HT2 blockade with metrenperone at a dose rate of 0.100 mg kg-1 and with a dosage interval of 12 hours should improve pulmonary function.

Topics: Animals; Cattle; Dose-Response Relationship, Drug; Lung Diseases; Male; Piperidines; Respiration; Respiratory Function Tests; Serotonin; Serotonin Antagonists; Tidal Volume

Eighteen of 91 seven- to nine-month-old Belgian white and blue double-muscled male fattening cattle developed typical signs of shipping fever. They were all injected intramuscularly once a day for three days with 5 mg/kg of enrofloxacin, and in addition nine selected at random were injected intramuscularly five times at 12 hour intervals with 0.1 mg/kg of metrenperone, a 5-hydroxytryptamine blocker, the other nine receiving a placebo. During the outbreak of shipping fever metrenperone showed effective antipyretic properties, and all the calves treated with it made a complete recovery. Moreover, during the 360 day fattening period following the outbreak, the cattle treated with metrenperone gained on average 45.4 kg more weight than the control cattle.

Topics: Animals; Anti-Infective Agents; Cattle; Disease Outbreaks; Drug Therapy, Combination; Enrofloxacin; Fluoroquinolones; Injections, Intramuscular; Male; Pasteurellosis, Pneumonic; Piperidines; Quinolones; Respiration; Respiratory Function Tests; Weight Gain

The purpose of this study was to investigate the mechanism by which 5-hydroxytryptamine (5-HT) modifies respiratory function, specifically, hyperventilation, diffuse bronchoconstriction, and pulmonary arterial hypertension in cattle. We determined whether the IV response to 5-HT in calves was attributable to stimulation of 5-HT2 receptors. Six healthy unsedated young bull calves of the Friesian (n = 4) and of the Belgian White and Blue (n = 2) breeds were used. A specific 5-HT2 antagonist (metrenperone, 0.05 mg/kg of body weight) was administered IM 30 minutes before the cattle were given a 5-minute IV 5-HT infusion. Pulmonary function values were registered before, during, and after the 5-HT challenge infusion. Minute volume increased significantly, because of an increase in respiratory rate. Conversely, lung dynamic compliance, total pulmonary resistance, and pulmonary arterial pressure were not changed. We concluded that in cattle, 5-HT-induced ventilatory response is not mediated through activation of 5-HT2 receptors. However, the 5-HT2 receptors are involved in 5-HT-induced broncho- and pulmonary vasoconstriction.

Topics: Animals; Blood Gas Analysis; Cattle; Injections, Intravenous; Lung; Male; Piperidines; Receptors, Serotonin; Serotonin; Serotonin Antagonists

In anesthetized piglets the influence of an LD100 of Escherichia coli endotoxin (0.5 mg/kg IV, bolus injection) on several hemodynamic parameters and on survival time was studied. Endotoxin provoked a pronounced decrease in arterial pressure and cardiac output and an increase in portal venous and pulmonary arterial pressure and heart rate. Total peripheral and mesenteric vascular resistances displayed an initial increase followed by a sustained decrease, whereas pulmonary vascular resistance revealed a pronounced biphasic increase. All pigs died within 210 min following endotoxin administration. Pretreatment with the 5-HT2-antagonists R 41468 and R 50970 and with the prostanoid-synthesis inhibitor flurbiprofen induced a significant attenuation of the increase in pulmonary vascular resistance and beneficial effects on survival. Best survival results were obtained with prednisolone sodium succinate, although these results can only partly be ascribed to beneficial hemodynamic effects. The experiments with the opiate antagonists, however, point to detrimental effects.

Topics: Adrenal Cortex Hormones; Anesthesia; Animals; Bacterial Toxins; Blood Pressure; Cardiac Output; Enterotoxins; Escherichia coli Proteins; Flurbiprofen; Heart Rate; Hemodynamics; Ketanserin; Narcotic Antagonists; Piperidines; Prednisone; Pulmonary Circulation; Serotonin Antagonists; Shock, Septic; Swine; Time Factors; Vascular Resistance