In human right atria obtained from 21 patients during open-heart surgery, beta-adrenoceptor density [assessed by iodine-125-labeled (-)-cyanopindolol binding] and responsiveness (positive inotropic responses to isoprenaline) were linearly related to the beta-adrenoceptor density in the corresponding circulating lymphocytes. This direct relation of human myocardial and lymphocyte beta-adrenoceptor alterations, therefore, makes it possible to monitor drug- or disease-induced beta-adrenoceptor changes in tissues not easily accessible in humans.

On the isolated electrically driven muscle strip of human right atrial appendages the beta-adrenoceptor subtypes mediating the positive inotropic effects of isoprenaline, dobutamine and procaterol were characterized using the beta 1-selective antagonist bisoprolol and the beta 2-selective antagonist ICI 118,551. The three agonists induced concentration-dependent increases in force of contraction with an order of potency: procaterol (pD2-value: 8.03) greater than isoprenaline (pD2-value: 7.73) greater than dobutamine (pD2-value: 5.44). In saturating concentrations all three agonists produced the same maximum of developed tension. ICI 118,551 (10(-9)--10(-7) mol/l) and bisoprolol (10(-9)--10(-7) mol/l) were nearly equipotent in antagonizing the positive inotropic effects of isoprenaline and dobutamine. However, the slopes of the Schild-plots for both antagonists against both agonists were significantly less than 1.0 indicating interaction with beta 1- and beta 2-adrenoceptors. On the other hand, ICI 118,551 (10(-10)--10(-8) mol/l) was approximately 100 times more potent than bisoprolol (10(-8)--10(-6) mol/l) in antagonizing the positive inotropic effect of the highly selective beta 2-agonist procaterol. In addition, the slopes of the Schild-plots for antagonism of ICI 118,551 and bisoprolol against procaterol were not significantly different from unity indicating interaction with a homogeneous class of beta-adrenoceptors. The pA2-value for ICI 118,551 was 9.49, for bisoprolol it amounted to 6.99.(ABSTRACT TRUNCATED AT 250 WORDS)

The time course of the effects of isoprenaline (3 X 10(-7) mol/l) on contractile force and on the cyclic AMP level was studied in the electrically driven isolated muscle strip of the human right atrium. Isoprenaline produced a rise in cyclic AMP content (maximum increase after 60 s) preceding the increase in contractile force. The effects of isoprenaline on contractile force and on the intracellular level of cyclic AMP were enhanced in the presence of the phosphodiesterase inhibitor papaverine (10(-5) mol/l). On the other hand, the beta-adrenoceptor antagonist propranolol (10(-7) mol/l) suppressed isoprenaline-induced cyclic AMP increases, but reduced the increase in force of contraction by only 35%. In addition, both the beta 1-selective antagonist bisoprolol (3 X 10(-9)-3 X 10(-8) mol/l) and the beta 2-selective antagonist ICI 118,551 (3 X 10(-9)-3 X 10(-8) mol/l) inhibited the isoprenaline-induced cyclic AMP increase concentration-dependently; ICI 118,551 produced more pronounced inhibition than bisoprolol. It is concluded that cyclic AMP is involved in the positive inotropic action of isoprenaline evoked by beta 1- and beta 2-adrenoceptor stimulation in isolated human right atrium; however, an additional cyclic AMP independent mechanism cannot be ruled out.

Background: The interaction between leukocytes and various parenchymal cells is the first step of inflammation. Therefore, the adhesion of eosinophils to lung fibroblasts is thought to be a crucial step in the inflammatory process of asthma. Procaterol, a β₂-selective full agonist, is currently prescribed for patients with asthma. In addition to its potent bronchodilatory action, the agonist has been reported to have anti-inflammatory actions. In this study, to examine whether procaterol can potentiate the anti-inflammatory action of glucocorticoids, the effect of procaterol on eosinophil adhesion to normal human lung fibroblasts (NHLF) was assessed in the presence and absence of budesonide, one of the most potent glucocorticoids. Methods: Following pretreatment of NHLF with tumor necrosis factor-α (TNF-α) in the presence of various concentrations of procaterol and/or budesonide, the eotaxin-stimulated eosinophil adhesion was determined using the peroxidase activity of eosinophils. To investigate the mechanism of the inhibitory action of procaterol, TNF-α-induced expression of adhesion molecules, ICAM-1 and VCAM-1, in NHLF was also evaluated. Results: Pretreatment with procaterol inhibited the adhesion of eosinophils to NHLF in a concentration-dependent manner, and shifted the concentration-response curve of budesonide to the left. Both procaterol and budesonide resulted in concentration-dependent inhibition of expression of ICAM-1 and VCAM-1 in NHLF, and an additive inhibitory effect was found when the agents were combined. Conclusions: Given the results of this study which indicated that procaterol exerted an additive action on the anti-inflammatory effect of budesonide, procaterol and glucocorticoids may provide better control for asthma when used together than when used separately.

Key Words: OPC-13340-€alcium antagonist-Hypertension-EDRF-Cerebral blood flow.OPC-13340 is a new dihydropyridine calcium antagonist that is now under clinical trials as a long-acting antihypertensive and an antianginal agent. OPC-13340 was found to have the most potent and the longest hypotensive action among six compounds (OPC-13340, nifedipine, nitrendipine, nisoldipine, nicardipine, and diltiazem) tested in various hypertensive rat and dog models. Its hypotensive action is more specific for hypertensive than for normotensive animals. In normotensive conscious rats, OPC-13340 increased cerebral blood flow more than nicardipine or nimodipine. Also, in the aged spontaneously hypertensive rat (SHR) model, OPC-13340 did not decrease cerebral blood flow during severe hypotension. OPC-13340 has a unique action on endothelium-dependent relaxation in isolated rat aorta, namely it prolongs the duration of endothelium-dependent relaxation, while other calcium antagonists tested did not have such an effect at a clinically relevant concentration range. The following review summarizes preclinical and clinical experience with this compound to date. CHEMISTRY