Bronchoconstrictor and respiratory effects of neurokinin A in dogs

Neurokinin A (NKA) is the primary bronchoconstrictor tachykinin in the lungs of several species, including humans and has been implicated as an important mediator of inflammatory lung disorders, such as asthma. In this study, we investigated the effect of NKA on airway mechanics (lung resistance, dynamic lung compliance) and respiration (tidal volume, respiratory rate) in anesthetized, spontaneously breathing, male beagle dogs. The dogs were challenged with aerosolized NKA that was delivered from a jet nebulizer to the airways through an endotracheal tube. The challenge consisted of five separate inflations of 600 ml of air/inflation over a 1-min period. Challenge with aerosolized NKA (0.1-1%) produced a dose-dependent increase in lung resistance and a decrease in dynamic lung compliance. The bronchoconstriction induced by 1% NKA peaked at 0.5 min after challenge and had a duration of approximately 5 min. Challenge with 1% NKA also reduced tidal volume and increased respiratory rate. Pretreatment of dogs with the NK-2 receptor antagonist, SR 48968 dose-dependently (1-10 mg/kg, p.o.) blocked the bronchoconstriction and respiratory responses to NKA challenge. Pretreatment with the NK1-receptor antagonist, CP 99994 (1 mg/kg, i. v.) had no effect on the increase in lung resistance and the decrease in dynamic lung compliance due to NKA challenge, but blunted the respiratory response to NKA. Pretreatment of dogs with inhaled ipratropium bromide (0.01%) slightly, but significantly reduced the increase in lung resistance due to NKA challenge but had no effect on the decrease of dynamic lung compliance or on the respiratory responses to NKA. As expected, the bronchoconstrictor response to inhaled methacholine was completely blocked by inhaled ipratropium bromide (0.01%). In conclusion, we have identified an NK2-receptor mediated bronchoconstrictor effect of NKA in dogs. Cholinergic reflexes play a small, but significant role in this response. Furthermore, both NK1 and NK2-receptors appear to be involved with the development of the rapid, shallow breathing response to NKA challenge. These results demonstrate an effect of tachykinins on airway mechanics and ventilatory reflexes in dogs.     

Main results of the losartan versus amlodipine (LOA) study on drug tolerability and psychological general well-being. LOA Study Group

OBJECTIVE: To compare two losartan regimens (with and without hydrochlorothiazide) and amlodipine in treating mild-to-moderate hypertension regarding their blood-pressure-lowering effect, drug tolerability and quality of life. DESIGN: A 12-week, randomized, double-blind, parallel-group, multi-centre study. After 4 weeks of placebo, patients with a diastolic blood pressure (DBP) in the range 95-115 mmHg were allocated randomly to be administered 50 mg losartan (increased to 100 mg if the DBP was 90 mmHg or more after 6 weeks), 50 mg losartan (plus 12.5 mg hydrochlorothiazide under the above conditions), or 5 mg amlodipine (increased to 10 mg under the above condition). The tolerability of the treatment and the quality of life were evaluated by spontaneous reporting, active questioning and the Psychological General Well-Being (PGWB) index. STUDY POPULATION: In total 898 hypertensives, mainly referred from primary health care (mean age 57.8 years) of whom 52% were men. RESULTS: Administration of 50 mg losartan (plus 12.5 hydrochlorothiazide if necessary) and of 5 mg amlodipine (or 10 mg if necessary) lowered the blood pressure as well as or better than did 50 mg losartan (or 100 mg if necessary). The incidence of 'any discomfort' and 'swollen ankles' increased with amlodipine but not with losartan treatment. The opposite was found for 'dizziness upon standing'. The incidence of drug-related adverse events and the number of patients withdrawn from therapy were higher with amlodipine than they were with losartan treatment. The PGWB index at week 12 indicated that improvements from baseline had occurred in some domains for the losartan groups whereas it remained unchanged for the amlodipine group. CONCLUSION: Both losartan and amlodipine were effective in lowering the blood pressure and were tolerated well. Administration of 50 mg losartan (plus 12.5 mg hydrochlorothiazide if necessary) and of 5 mg amlodipine (or 10 mg if necessary) lowered the blood pressure equally well or better than did 50 mg losartan (or 100 mg if necessary). Drug-related adverse effects and withdrawal from the study were more common for the amlodipine group. The clinical significance of the improvements in the PGWB index with losartan needs to be studied further.     

Regulation of growth hormone-releasing hormone and somatostatin from perifused, bovine hypothalamic slices. I. Alpha 2-adrenergic receptor regulation

An in vitro perifusion system was developed for bovine hypothalamic tissue to examine the role of alpha 2-adrenergic receptors in the regulation of growth hormone-releasing hormone (GHRH) and somatostatin (SRIF) release. Up to three sagittal slices (600 microns) of hypothalamus, immediately parallel to the midline, were cut in an oxygenated balanced salt solution at 4 degrees C, placed in 5 cc syringes, and perifused at 37 degrees C with oxygenated minimum essential medium-alpha at a flow rate of 0.15 ml/min. Three experiments were conducted, and medium effluent was collected every 20 min before (two samples), during (one or three samples), and after (six samples) treatment. Areas under GHRH and SRIF response curves (AUC), adjusted by covariance for pretreatment values, were calculated from samples collected during the treatment/post-treatment period. Location from which slices were cut, relative to the sagittal midline, had no effect on basal release of GHRH and SRIF, but variation in basal release of GHRH and SRIF differed among animals. Medium containing 60 mM KCI increased AUC for GHRH 39% and 161% for SRIF when compared with perifusion of medium alone, thereby verifying that tissue remained viable for at least 14 hr. Activation of alpha 2-adrenergic receptor with 10(-6) and 10(-4) M clonidine increased AUC for GHRH from 54.8 (control) to 79.1 and 108.7 +/- 2.5 ng.ml-1 min for 10(-6) M and 10(-4) M clonidine, respectively. Guanabenz, another alpha 2-adrenergic receptor agonist, at 10(-8), 10(-6), and 10(-4) M also increased GHRH release from 45.5 (control) to 52.8, 66.2, and 86.7 +/- 1.6 ng.ml-1 min, respectively. Clonidine and guanabenz did not affect release of SRIF. An alpha 2-adrenergic receptor antagonist, idazoxan, blocked clonidine-induced release of GHRH without affecting release of SRIF. We concluded that alpha 2-adrenergic receptor stimulation of in vivo growth hormone secretion in cattle is mediated via an increase in release of GHRH and not a change in release of SRIF.     

Interleukin-8 concentration predicts the neutrophil count in middle ear effusion

Interleukin-8 (IL-8), a potent neutrophilic chemoattractant and inflammatory cytokine, is present in middle ear effusions (MEEs) of children with otitis media and is thought to be responsible for the accumulation of neutrophils in MEEs. We hypothesized that IL-8 concentration predicts the total number and proportion of neutrophils in MEEs. IL-8 concentration and total and differential cell counts were measured in MEEs of children undergoing tympanostomy tube placement for otitis media. IL-8 was present in 80 (98%) of 82 effusions. The mean +/- SEM value for IL-8 was 7342 +/- 847 pg/mL. The mean +/- SEM count and percentage of neutrophils were 1.34 x 10(6) +/- 3.44 x 10(5) and 70.6 +/- 3.1%, respectively. IL-8 concentrations correlated positively with the total number (r = +0.30; P = 0.02) and percentage of neutrophils (r = +0.32; P = 0.01) in the effusion. Additionally, purulent effusions had greater IL-8 concentrations (P = 0.003) and greater neutrophil count (P = 0.03) than mucoid or serous effusions. We conclude that IL-8 is consistently present in MEEs of children and IL-8 concentration predicts the total number and proportion of neutrophils. Furthermore, IL-8 concentration and the total number of neutrophils correlate positively with the type of effusion. These results support the hypothesis that IL-8 recruits neutrophils to the middle ear in MEEs.     

Autonomic control of skeletal muscle vasodilation during exercise

Despite extensive investigation, the control of blood flow during dynamic exercise is not fully understood. The purpose of this study was to determine whether beta-adrenergic or muscarinic receptors are involved in the vasodilation in exercising skeletal muscle. Six mongrel dogs were instrumented with ultrasonic flow probes on both external iliac arteries and with a catheter in a branch of one femoral artery. The dogs exercised on a treadmill at 6 miles/h while drugs were injected intra-arterially into one hindlimb. Isoproterenol (0.2 microg) or acetylcholine (1 microg) elicited increases in iliac blood flow of 89.8 +/- 14.4 and 95.6 +/- 17.4%, respectively, without affecting systemic blood pressure or blood flow in the contralateral iliac artery. Intra-arterial propranolol (1 mg) or atropine (500 microg) had no effect on iliac blood flow, although they abolished the isoproterenol and acetylcholine-induced increases in iliac blood flow. These data indicate that exogenous activation of beta-adrenergic or muscarinic receptors in the hindlimb vasculature increases blood flow to dynamically exercising muscle. More importantly, because neither propranolol nor atropine affected iliac blood flow, we conclude that beta-adrenergic and muscarinic receptors are not involved in the control of blood flow to skeletal muscle during moderate steady-state dynamic exercise in dogs.     

Higher-order chromatin structure-dependent repair of DNA double-strand breaks: modeling the elution of DNA from nucleoids

A 36-year-old male with unspecific symptoms and normal physical examination had right cardiac enlargement on chest X-ray. Two-dimensional echocardiographic and thoracic computed tomography demonstrated an intracardiac mass. The tumor was surgically resected and the pathological diagnosis was mixed-type epicardial hemangioma. We discuss this case and review the literature.