Postjunctional effect of pinacidil on contractility of isolated bovine trachealis.

Potassium channel openers hyperpolarize the smooth muscle cell membrane and relax airway smooth muscle. In this study, pre- and postjunctional effects of pinacidil ((+/-) N-cyano-N'-(4-pyridil)-N"-(1,2,2-trimethylpropyl)-guanidine monohydrated), an adenosine triphosphate (ATP)-sensitive K(+)-channel opener, were determined in isolated bovine trachealis. The effects of pinacidil on the frequency-response to electrical field stimulation (EFS), 0.1-32 Hz, and on the concentration response to acetylcholine (ACh), 10(9)-10(-4) M, were compared in muscle strips from six animals. In addition, the effect of pinacidil on the inhibitory nonadrenergic noncholinergic (iNANC) system was evaluated in histamine-contracted muscle strips from another eight animals. Pinacidil (10(-6) or 10(-5) M) shifted both the EFS frequency-response and the ACh concentration-response curves significantly (p < 0.01) to the right. Glibenclamide (10(-7)-10(-5) M) antagonized these responses in a concentration-dependent manner. The inhibitory effects of pinacidil on contractions of the same magnitude induced by EFS or exogenous ACh were not significantly different (p = 0.11), suggesting that pinacidil had only a postjunctional effect. Pinacidil had no effect on iNANC-mediated muscle relaxation. We conclude that pinacidil attenuates the contraction of isolated bovine tracheal smooth muscle by postjunctional mechanisms.

Opioid agonists modulate release of neurotransmitters in bovine trachealis muscle.

BACKGROUND: Stimulation of opioid receptors in the airways can modulate cholinergic neurotransmission and thereby reduce bronchoconstriction. This protecting effect of opioids against bronchoconstriction may be of clinical interest. Inhalation of opioids as a method of analgesia is likely to result in an opioid concentration at airway receptors sufficient to protect against bronchoconstriction; the concentration may be insufficient when opioids are administered by conventional techniques. In addition, new selective opioids may be developed that could more selectively protect the airways against bronchoconstriction. METHODS: The effect of three selective opioid agonists on the contractile response to electric field stimulation (EFS) was studied in isolated muscle strips from four regions of the bovine trachea (upper, or laryngeal; upper middle; lower middle; lower, or carinal). RESULTS: The selective kappa agonist trans-3,4-dichloro-N-methyl-N-(2-1-pyrrolidinyl) cyclohexyl benzene acetamide (U-50488 H) and the selective mu-opioid agonist D-Ala2-N-MePhe4-Gly-ol5-enkephalin (DAMGO) reduced significantly (P < 0.001 and P < 0.001, respectively) the contractile response to EFS. The attenuation of the contractile response by U-50488 H was concentration-dependent (P < 0.0001) and tended to be larger at low stimulating frequencies (P = 0.055). The attenuation of the contractile response by DAMGO was frequency-dependent (P < 0.01). The selective delta-opioid agonist D-penicillamine2-D-penicillamine5-enkephalin had no significant effect on the contractile response to EFS (P = 0.71). There were no significant differences among the four regions of the trachea in their responses to the selective opioid agonists U-50488 H (P = 0.50) and DAMGO (P = 0.44). Neither U-50488 H nor DAMGO altered the contractile response to acetylcholine P > 0.11, P > 0.21, respectively), suggesting that the opioid agonists have a prejunctional effect. The attenuation of the contractile response to EFS by U-50488 H was partially but significantly antagonized by 10(-5) M naloxone (P < 0.01) and by 10(-5) and 10(-6) M of the selective kappa-opioid antagonist 2,2'-[1,1'-biphenyl] 4,4'-diyl- bis [2-hydroxy-4,4-dimethyl-morpholinium] (P < 0.05). Naloxone (10(-5) M) abolished the inhibitory effect of DAMGO, suggesting that opioid receptors are involved in the attenuation of the contractile response to EFS afforded by DAMGO and U-50488 H. CONCLUSIONS: We conclude that prejunctional kappa- and mu-opioid receptors attenuate the contractile response of isolated bovine trachealis muscle to EFS by inhibiting cholinergic neurotransmission. This effect is uniform throughout the trachealis muscle. delta-Opioid receptors are apparently not present in the bovine trachealis muscle. Caution must be used in extrapolating these results to the intact human. In this study little or no inhibitory effect of the opioids was observed at concentrations expected at airway receptor sites when administered by conventional techniques. However, the effect may be large enough to protect against bronchoconstriction when nebulized opioids are administered by inhalation.

Single daily dose of cefodizime in patients with community-acquired pneumonia: an open-label, controlled, randomized study. The Italian Multicentre Community-Acquired Pneumonia Group.

The objective of this study was to compare the clinical and bacteriologic efficacy and safety of cefodizime 1 g intramuscularly (IM) once daily (group A) versus cefodizime 1 g IM twice daily (group B) and versus ceftriaxone 1 g IM once daily (group C) in patients with community-acquired pneumonia. A total of 298 patients, affected by bronchopneumonia or pneumonia with known or suspected bacterial cause, new focal signs on examination of chest, and radiographic evidence of a recent infiltrate, were randomized in three comparable groups. The infection was rated as mild, moderate, or severe. A total of 283 patients were assessable for efficacy: 95 in group A, 94 in group B, and 94 in group C. Mean (+/- SD) duration of treatment was 5.96 +/- 1.39 days in group A, 6.24 +/- 1.57 days in group B, and 6.66 +/- 1.95 days in group C. Symptoms such as purulent sputum, cough, and dyspnea improved significantly after treatment in all groups; temperature normalized by about day 3. Clinical efficacy was rated good in 94.74% of patients in group A, in 92.55% in group B, and in 87.23% in group C. Positive bacteriologic cultures were obtained before treatment from 144 patients: bacteriologic responses were rated good in 98.11%, 98.08%, and 92.80% in groups A, B, and C, respectively. No significant differences were found between the three treatment groups for any measures of clinical efficacy. No serious adverse event occurred in any of the groups. We conclude that cefodizime 1 g IM once daily is an effective dosing regimen in the treatment of patients with community-acquired pneumonia.

Effects of volume history and time dependence of flow-volume curves on assessment of bronchial response to inhaled methacholine in normals.

The behavior of maximum expiratory flow-volume curves and partial expiratory flow-volume curves with and without volume history of total lung capacity was studied in 11 healthy subjects before and after methacholine inhalation challenge. Flow-volume curves were superimposed at absolute lung volumes by measuring thoracic gas volumes at which inspiratory maneuvers began. The results show that maximum inspiratory effort reduced significantly residual volume, either before or after challenge, while flow rates at 40% of control total lung capacity achieved with partial expiratory flow-volume curves with history of total lung capacity were significantly greater than those without history of maximal inflation. These findings are explained by the stress relaxation as an effect of volume history ot total lung capacity and by the appearance of time dependence as an index of inhomogeneity of lung emptying. After methacholine the effects of volume history on maximum flows and residual volume were increased. In conclusion, the results of this study emphasize the probability of errors when only maximum expiratory flow-volume curve are used in assessment of bronchial responses.