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

1 BW A868C, a novel compound, behaved as a simple competitive antagonist in a human washed platelet aggregation assay. Anti-aggregatory concentration-effect curves to BW 245C were displaced in a parallel manner. The shifts accorded with a Schild plot slope of unity and a pKB of 9.26. 2 Inhibition of platelet aggregation by prostaglandin D2 (PGD2) was antagonized with a similar potency, as were the relaxation effects of BW 245C and PGD2 in the rabbit jugular vein. BW A868C can, therefore, be classified as a DP-receptor antagonist.3 Actions of BW A868C at other prostaglandin receptors (IP, EP,, EP2, TP and FP) were excluded at concentrations up to 1,000 times higher than the DP-receptor affinity. 4 Analyses of BW 245C-and PGD2-mediated effects were complicated by additional agonist receptor interactions which were revealed by BW A868C. In rabbit jugular vein a resistant phase of agonism was detectable, indicating that both agonists exerted effects through another receptor (possibly EP2). Also, PGD2, in addition to its anti-aggregatory effect on platelets, demonstrated a pro-aggregatory action in the presence of BW A868C. 5 The contractile effects of PGD2 in guinea-pig tracheal strips were resistant to 10 tM BW A868C indicating that they were not mediated through DP-receptors. 6 To our knowledge this is the first account of a well-classified competitive antagonist at the DP-receptor. Its potency and selectivity make it an important new tool in prostanoid receptor classification and identification.

Platelet aggregation, which plays an important role in acute myocardial infarction (AMI), is mediated by fibrinogen binding to the platelet membrane glycoprotein (GP)IIb-IIIa (CD41). This study measured the relative number of GPIIb-IIIa complexes on platelets from patients immediately following AMI (n = 14) compared with those from controls (n = 14). Flow cytometry was used to demonstrate that there were, on average, 20% more GPIIb-IIIa complexes on platelets after AMI compared with controls. Platelet size was also 7% greater in AMI and it is known that larger platelets are more reactive. Since platelet size and protein content are determined at thrombopoiesis the majority of these platelets must have been circulating prior to AMI. Larger platelets, with more GPIIb-IIIa may, therefore, be causally related to AMI.