The glucagon-receptor antagonist MK-3577 reduces glucagon-stimulated plasma glucose and insulin concentrations in metabolically healthy overweight cats.

The role of glucagon disturbances in diabetes mellitus is increasingly recognized and, hence, glucagon antagonism might aid in treatment of hyperglycemia and other metabolic disturbances. The aim of this study was to assess the pharmacokinetics of the glucagon receptor antagonist MK-3577 and its effect on plasma glucose, insulin, and glucagon concentrations in healthy cats. In a cross-over placebo-controlled study, 5 purpose-bred cats were treated with either Placebo, MK-3577 (1 mg/kg), or MK-3577 (3 mg/kg). Glucose, insulin and glucagon concentrations were measured at 0, 15, 225, 240 min post-treatment administration. Glucagon (20 mcg/kg, IM) was administered at 240 min and glucose and insulin were measured at 255, 265, 275, 285 and 300 min. Plasma MK-3577 concentrations peaked at 4.2 and 3.2 hours after 1 and 3 mg/kg dosing with a half-life of 14.8h and 15.5h respectively. Baseline glucose, insulin and glucagon concentrations did not differ significantly between treatment groups. At a dose of 3 mg/kg, MK-3577 blunted the glucagon-stimulated rise of glucose (p=0.0089) and insulin (p=0.02). Similar trends were observed with MK-3577 at the 1 mg/kg dose but the effect was smaller, and not significant. In conclusion, the GRA MK-3577 has a pharmacokinetic profile suitable for diminishing the glucagon-induced rise of glucose and insulin in healthy cats.

Effects of aging, gender, and hypogonadism on mandibular bone density.

AIM: The aim of the present study was to evaluate how aging, sex, and hypogonadism influence mandibular bone density with and without the benefits of hormone treatment. METHODS: Three-month old Wistar rats were randomly assigned to three experimental groups, with eights animals per group: controls, castrated (orchiectomized [ORX], ovariectomized [OVX]) and castrated with hormonal treatment (ORX + testosterone, OVX + estradiol benzoate). Females were previously evaluated by vaginal cytology. The corporal mass was verified weekly, and after three experimental periods (90, 120, and 150 days), the animals were killed. Blood was collected, and bones underwent densitometric and biomechanical analyses. RESULTS: After castration, the male rats demonstrated low gain in body weight compared to females (P < .05). Male and female castrated animals presented serum concentrations of sex steroid hormones lower than the control group (P < .05). Bone mineral density and biomechanical properties of the L4 vertebrae and femur were reduced earlier in females than in males (P < .05). However, mandibles were affected only in the male rats at the most chronic experimental period. CONCLUSION: Hypogonadism promotes alterations in the mandible over chronic periods, especially in males, and these alterations could be minimized by hormone treatment.

Bronchoconstrictor reactivity to NKA in allergic dogs: a comparison to histamine and methacholine.

Airway hyperresponsiveness to neurokinin A (NKA) occurs in inflammatory airway diseases like asthma. In this study, bronchoconstrictor reactivity to NKA was measured in beagle dogs neonatally sensitized to and challenged with ragweed. Comparisons were made to histamine and methacholine. Lung resistance (R(L)) and dynamic lung compliance (C(Dyn)) were measured in anesthetized, spontaneously breathing dogs before and after aerosol challenge with NKA, histamine or methacholine. The concentration of these agents increasing R(L)by 25% above baseline (PC(25)) was calculated before and 24 h after aerosolized ragweed challenge. Before ragweed, the bronchoconstrictor reactivity to NKA was four-fold higher in ragweed-sensitized dogs (PC(25)=0.036+/-0.006%) compared to non-sensitized controls (PC(25)=0.177+/-0.030%, P<0.05). On the other hand, there was no difference in the bronchoconstrictor reactivity to histamine or methacholine between these two groups. Twenty-four hours after ragweed challenge to sensitized dogs, NKA reactivity was unchanged from pre-ragweed values but histamine and methacholine reactivity was increased by 2-3-fold. These results demonstrate airway hyperresponsiveness to NKA, histamine and methacholine in allergic beagle dogs although hyperresponsiveness to NKA exists in these allergic dogs before an antigen challenge. This animal model may prove to be useful to evaluate the role of tachykinins in hyperractive airway diseases.

A simple non-invasive method to measure the cough reflex in dogs.

INTRODUCTION: This study describes a method to measure the cough reflex in dogs that is simple to perform, requires no surgical intervention and can be used to profile efficacy and side-effect liabilities of antitussive drugs. METHODS: Experiments were performed in propofol-anesthetized dogs in which cardiopulmonary functions were non-invasively monitored before and after the induction of cough produced by spraying 0.75 ml of distilled water into the trachea. RESULTS: The magnitude of the cough response, measured by the frequency and amplitude was not different for individual dogs performed with repeated trials on different days. Treatment with the opioid antitussive drug, torbutrol (0.055-0.0055 mg/kg, s.c.) inhibited the cough frequency but not the amplitude induced by the water challenge. Furthermore, side effects of torbutrol were identified as mild respiratory depression and an anesthetic-sparing effect with propofol. DISCUSSION: This method offers many distinct advantages to evaluate efficacy of antitussive drugs including the fact that no surgery is required, it takes only 15-20 min to complete an experiment, and it can be used to simultaneously profile antitussive and side effect liabilities of drugs developed for the treatment of cough.

Cardiopulmonary effects of the alpha2-adrenoceptor agonists medetomidine and ST-91 in anesthetized sheep.

To test the hypothesis that pulmonary alterations are more important than hemodynamic changes in alpha2-agonist-induced hypoxemia in ruminants, the cardiopulmonary effects of incremental doses of (4-[1-(2,3-dimethylphenyl)ethyl]-1H-imadazole) hydrochloride (medetomidine; 0.5, 1.0, 2.0, and 4 micrograms/kg) and 2-(2, 6-diethylphenylamino)-2-imidazol (ST-91; 1.5, 3.0, 6.0, and 12 micrograms/kg) were compared in five halothane-anesthetized, ventilated sheep using a placebo-controlled randomized crossover design. Pulmonary resistance (RL), dynamic compliance, and tidal volume changes in transpulmonary pressure (DeltaPpl) were determined by pneumotachography, whereas cardiac index (CI), mean pulmonary artery pressure (Ppa), and pulmonary artery wedge pressure (Ppaw) were determined using thermodilution and a Swan-Ganz catheter. The most important finding was the fall in partial pressure of oxygen in arterial blood (PaO2) after administration of medetomidine at a dose (0.5 micrograms/kg) 20 times less than the sedative dose. The PaO2 levels decreased to 214 mm Hg as compared with 510 mm Hg in the placebo-treated group. This decrease in PaO2 was associated with a decrease in dynamic compliance and an increase in RL, DeltaPpl, and the intrapulmonary shunt fraction without changes in heart rate, CI, mean arterial pressure, pulmonary vascular resistance, Ppa, or Ppaw. On the other hand, ST-91 only produced significant changes in PaO2 at the highest dose. After this dose of ST-91, the decrease in PaO2 was accompanied by a 50% decrease in CI and an increase in mean arterial pressure, Ppa, Ppaw, and the intrapulmonary shunt fraction without significant alterations of RL and DeltaPpl. The study suggests that the mechanism(s) by which medetomidine and ST-91 produce lower PaO2 are different and that drug-induced alterations in the pulmonary system are mainly responsible for the oxygen-lowering effect of medetomidine.

Histopathologic alterations induced in the lungs of sheep by use of alpha2-adrenergic receptor agonists.

OBJECTIVE: To study effects of central- and peripheral-acting alpha2-adrenergic receptor agonists on lung parenchyma, platelets, and pulmonary intravascular macrophages (PIM) of sheep. ANIMALS: 12 healthy mature female sheep. PROCEDURE: Group-1 (control, n = 2) sheep received 5 ml of physiologic saline solution IV and were euthanatized 3 minutes later. Sheep of group 2 (n = 8) received xylazine (150 microg/kg of body weight, IV), then 2 sheep each were euthanatized 3, 10, or 60 minutes, or 12 hours later. Sheep (n = 2) of group 3 were given ST-91 (30 microg/kg, IV), then were euthanatized 3 minutes later. Immediately after euthanasia, the lungs were fixed intratracheally and tissue was obtained for light and electron microscopy after 1 hour. RESULTS: Pulmonary parenchymal damage or morphologic alterations in PIM and platelets were not evident in control sheep. Three minutes after xylazine administration, morphologic changes in PIM were appreciable. After 10 minutes, extensive damage to the capillary endothelium and alveolar type-I cells, intra-alveolar hemorrhage, and interstitial and alveolar edema were evident. Most PIM had complete internalization of the surface coat. Similar changes were seen 60 minutes after xylazine administration; however, by 12 hours, morphologic features of PIM and lung parenchyma were almost completely restored. Evidence of PIM activation, obvious damage to capillary endothelium, and extensive pulmonary edema also were evident 3 minutes after ST-91 administration. CONCLUSIONS: XYLAZINE induces severe pulmonary parenchymal damage when administered at clinical sedative doses in sheep; morphologic changes in PIM within 3 minutes after administration of these drugs are substantial; and platelet aggregation is not apparent.

The comparative hypoxaemic effect of four alpha 2 adrenoceptor agonists (xylazine, romifidine, detomidine and medetomidine) in sheep.

In the present study, the hypoxaemic potential of four alpha 2 agonists possessing different selectivity for alpha 2 adrenoceptors and of a saline placebo was studied in five clinically healthy sheep using a randomized Latin square design and equipotent sedative doses. Baseline values for heart rate (HR), mean arterial pressure (MAP), arterial oxygen (PaO2)f and carbon dioxide (PaCO2) tensions, respiration rate and maximum change in pleural pressure (delta Ppl) were obtained, followed by the intravenous administration of either: xylazine (150 micrograms/kg); romifidine (50 micrograms/kg); detomidine (30 micrograms/kg); medetomidine (10 micrograms/kg) or placebo. Subsequent recordings were made up to 60 min after drug administration. No significant (P < or = 0.05) alterations in any variable occurred with placebo. All the alpha 2 agonists significantly (P < or = 0.05) decreased PaO2 levels without a significant (P < or = 0.05) change in PaCO2. The lowest PaO2 values were 29-42 mm Hg (3.9-5.5 kPa) with no significant difference between drugs. Respiratory rate and delta Ppl increased significantly within 2 min of drug administration; the duration of this effect varied with the alpha 2 agonist, lasting longest with romifidine. As compared to the saline treated group, a significant increase in MAP was observed up to 10 min after administration of romifidine and detomidine, however, a significant decrease was seen at 10 and 45 min after xylazine and medetomidine, respectively. The alpha 2 agonists studied induced a similar change in PaO2 at peak effect, despite their reported variable selectivity for alpha 2 vs. alpha 1 adrenoceptors.

Cardiopulmonary effects of clonidine, diazepam and the peripheral alpha 2 adrenoceptor agonist ST-91 in conscious sheep.

The cardiopulmonary effects of the intravenous administration of clonidine (15 micrograms/kg), ST-91 (30 micrograms/kg) and diazepam (0.4 mg/kg) were compared in five healthy sheep using a randomized cross-over design, to determine whether the hypoxaemic effects of alpha 2 adrenoceptor agonists are due to sedation, or to peripheral alpha 2 adrenoceptor stimulation. All three drugs significantly lowered arterial oxygen tension (PaO2) levels within 2 min of their administration; however, clonidine and ST-91 produced long lasting and severe hypoxaemia with mean PaO2 levels of approximately equal to 40 mm Hg and 50 mm Hg (5.3 kPa and 6.6 kPa), respectively. The fall in PaO2 was considerably less with diazepam (63 mm Hg or 8.4 kPa at 2 min) and by 15 min the values did not differ from placebo treated animals. None of the drugs increased arterial carbon dioxide tension (PaCO2) levels when compared to saline treatment and the acid base variables did not show any significant change. A significant increase was recorded in the packed cell volume of the ST-91 treated group throughout the study. Within 2 min of their administration, all drugs caused a significant increase in mean arterial pressure (MAP) as compared to the placebo treated group. The MAP remained significantly increased for 5 and 60 min after clonidine and ST-91 treatment, respectively. The study shows that ST-91 and clonidine produce a greater degree of hypoxaemia than occurs with diazepam sedation, and that the hypoxaemic effect of alpha 2 adrenoceptor agonists in sheep are mainly mediated by peripheral alpha 2 adrenoceptors.