The clinical effects of treatment with ␤-adrenoceptor (␤-AR) agonists and antagonists in heart failure vary with duration of therapy, as do the effects of ␤-AR agonists in asthma. Therefore, we hypothesized that chronic effects of ''␤-blockers'' in asthma may differ from those observed acutely. We tested this hypothesis in an antigen (ovalbumin)-driven murine model of asthma. Airway resistance responses (R aw) to the muscarinic agonist methacholine were measured by using the forced oscillation technique. In comparison with nontreated asthmatic mice, we observed that: (i) The ␤-AR antagonists nadolol or carvedilol, given as a single i.v. injection (acute treatment) 15 min before methacholine, increased methacholine-elicited peak R aw values by 33.7% and 67.7% (P < 0.05), respectively; when either drug was administered for 28 days (chronic treatment), the peak R aw values were decreased by 43% (P < 0.05) and 22.9% (P < 0.05), respectively. (ii) Chronic treatment with nadolol or carvedilol significantly increased ␤-AR densities in lung membranes by 719% and 828%, respectively. (iii) Alprenolol, a ␤-blocker with partial agonist properties at ␤-ARs, behaved as a ␤-AR agonist, and acutely reduced peak Raw value by 75.7% (P < 0.05); chronically, it did not alter Raw. (iv) Salbutamol, a ␤-AR partial agonist, acutely decreased peak R aw by 41.1%; chronically, it did not alter Raw. (v) None of the ␤-blockers produced significant changes in eosinophil number recovered in bronchoalveolar lavage. These results suggest that ␤-AR agonists and ␤-blockers with inverse agonist properties may exert reciprocating effects on cellular signaling dependent on duration of administration.␤-blockers ͉ sympathomimetics ͉ airway resistance ͉ inverse agonist

Background-The functional significance of cross-regulation between the renin-angiotensin system (RAS) and tumor necrosis factor (TNF) has been established in nonmyocyte cell types; however, the degree and functional significance of the interaction between RAS and TNF has not been characterized in the heart. Methods and Results-We examined the expression of components of the RAS in a line of transgenic mice (MHCsTNF) with cardiac restricted overexpression of TNF. When examined at 4, 8, and 12 weeks of age, the MHCsTNF mice had increased activation of myocardial RAS, as shown by an increase in ACE mRNA level and ACE activity and increased angiotensin II peptide levels. Furthermore, myocardial angiotensin receptor mRNA and protein levels were reduced in the MHCsTNF mice, consistent with homologous desensitization of the receptors. However, expression of renin and angiotensinogen was not increased in MHCsTNF mice compared with littermate controls. To determine the functional significance of RAS activation in the MHCsTNF mice, we treated the mice with an angiotensin type I receptor antagonist, losartan (30 mg/kg), or diluent from 4 to 8 weeks of age. Analysis of cardiac structure with MRI showed that treatment with losartan normalized left ventricular mass and wall thickness. Furthermore, treatment with losartan reduced myocardial collagen content and reduced the incidence of myocyte apoptosis. Conclusions-Taken together, these results show that there are functionally significant interactions between RAS and TNF in the heart and that these interactions play an important role in the development and progression of left ventricular remodeling. (Circulation. 2003;108:598-604.)

. Frequency dependence of respiratory system mechanics during induced constriction in a murine model of asthma. J Appl Physiol 94: 245-252, 2003; 10.1152/japplphysiol.00593.2002.-Airway dysfunction in asthma is characterized by hyperresponsiveness, heterogeneously narrowed airways, and closure of airways. To test the hypothesis that airway constriction in ovalbumin (OVA)-sensitized OVA-intranasally challenged (OVA/OVA) mice produces mechanical responses that are similar to those reported in asthmatic subjects, respiratory system resistance (Rrs) and elastance (Edyn,rs) spectra were obtained in OVA/OVA and control mice during intravenous methacholine (MCh) infusions. In control mice, MCh at 1,700 g ⅐ kg Ϫ1 ⅐ min Ϫ1 produced 1) a 495 and 928% increase of Rrs at 0.5 Hz and 19.75 Hz, respectively, 2) a 33% rise in Edyn,rs at 0.5 Hz, and 3) a mild frequency (f)-dependent increase of Edyn,rs. The same MCh dose in OVA/OVA mice produced 1) elevations of Rrs at 0.5 Hz and 19.75 Hz of 1,792 and 774%, respectively, 2) a 390% rise in Edyn,rs at 0.5 Hz, and 3) marked f-dependent increases of Edyn,rs. During constriction, the f dependence of mechanics in control mice was consistent with homogeneous airway narrowing; however, in OVA/OVA mice, f dependence was characteristic of heterogeneously narrowed airways, closure of airways, and airway shunting. These mechanisms amplify the pulmonary mechanical responses to constrictor stimuli at physiological breathing rates and have important roles in the pathophysiology of human asthma. airway closure; resistance; elastance; airway hyperresponsiveness AIRWAY NARROWING IS A MAJOR abnormality in the mechanism of diseases affecting pediatric and adult patients. Reductions in airway diameters can be predominately homogeneous or heterogeneous in nature; i.e., decreases in airway diameters can display a minimal or a large variability throughout the airway tree, respectively (5, 14). These categories of airway constriction bring about distinct patterns of frequency-dependent variations of lung mechanics. For example, homogeneously narrowed airways produce increases in lung resistance (RL) at physiological breathing rates that are commensurate to those of RL at high frequencies (5, 14). In contrast, heterogeneous airway narrowing is associated with increases of RL at physiological breathing rates that exceed those of RL at high frequencies (5, 14). Furthermore, a large variability in the reduction of airway caliber is more likely to produce closure of airways, which enhances the magnitude of dynamic lung elastance (Edyn,L) and may impair gas exchange.Pulmonary resistance and Edyn,L spectra obtained in subjects with severe asthma during periods of clinical stability and in subjects with mild or moderately severe asthma during agonist-induced constriction are consistent with a pattern of severe and heterogeneous airway constriction and closure of airways (11,12,15). These manifestations of airway dysfunction are of paramount clinical importance because marked elevations of RL and Edyn,L at phys...