Agonist Procaterol Research Articles

Behavioural evidence for an interdependence between GABA A receptors and β2-adrenoceptors

The possibility of a functional interdependence between central GABA A receptors and β 2-adrenoceptors has been investigated using the ability of both types of agonist to potentiate the tic (head-twitch) response to 5-methoxy-N,N-dimethyltryptamine in the mouse. At a dose which selectively antagonised β 1- but not β 2-adrenoceptors, ICI 118,551 abolished the effects of single doses of muscimol, diazepam and pentobarbitone. Conversely, bicuculline abolished the potentiation caused by the β 2-adrenoceptor agonist procaterol. Thus there is preliminary evidence that these two receptor types do show mutual interdependence.

Beta 1- and beta 2-adrenoceptor binding and functional response in right and left atria of rat heart.

The properties of beta 1- and beta 2-adrenoceptors in right and left atria of rat heart, and their roles in mediating chronotropic and inotropic responses to beta-adrenoceptor agonists were examined. [125I](-)pindolol (125IPIN) bound saturably and specifically to a single class of high affinity sites in homogenates of both right and left atria. The k1's for association in right and left atria were 6.5 X 10(9) l/mol-min and 2.3 X 10(9) l/mol-min respectively, while the k-1's for dissociation were 0.20 min-1 and 0.17 min-1. The kinetically determined KD's were 75 pmol/l in right and 30 pmol/l in left atria and were similar to the equilibrium KD's determined from Scatchard analysis of saturation isotherms of specific 125IPIN binding. Inhibition of 125IPIN binding by beta-adrenoceptor antagonists was stereoselective and the order of potency was timolol greater than l-propranolol greater than d-propranolol greater than sotalol. Inhibition by beta 1- and beta 2-adrenoceptor subtype selective antagonists yielded flat displacement curves with low Hill coefficients. Nonlinear regression analysis of displacement by beta 1-selective (practolol, atenolol and metoprolol) and beta 2-selective (ICI 118,551) antagonists gave estimates of the proportion of beta 1- and beta 2-adrenoceptors present in rat atria. Right atria contained 67 +/- 4.2% beta 1- and 33 +/- 4.2% beta 2-adrenoceptors, while left atria contained 67 +/- 2.8% beta 1- and 33 +/- 2.8% beta 2-adrenoceptors. Increases in the rate of spontaneously beating right atria and the force of electrically driven left atria caused by beta-adrenoceptor agonists were also measured. pA2 values for non-subtype selective beta-adrenoceptor antagonists in inhibiting isoprenaline-induced increases in rate and force were highly correlated with KD values determined for specific 125IPIN binding. pA2 values for beta 1- and beta 2-selective antagonists in inhibiting isoprenaline-induced increases in rate and force correlated well with the pKD values of these drugs in binding to beta 1-adrenoceptors, but not with the pKD values in binding to beta 2-adrenoceptors. Dose-response curves for stimulation of both rate and force by the beta 2-selective agonists procaterol and zinterol were shifted to a much greater extent by selective blockade of beta 1-adrenoceptors with metoprolol than by selective blockade of beta 2-adrenoceptors with ICI 118,551, suggesting that these compounds caused their effects by activating beta 1-adrenoceptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Heart beta-receptors: on the functional role of heterogeneous binding sites.

ß-Receptor subtypes were studied in the myocardium of reserpine-pretreated kittens. Membrane particles were prepared from dispersed ventricular cells. Binding of 3H-(−)-propranolol to membranes revealed saturable characteristics of a single class of complex (KD 2.5 nmol/1). The agonist procaterol exhibited 2 binding components with KD's of 2.5 and 20000 nmol/1; ¼ of the sites has high-affinity characteristics. Procaterol stimulated the adenylyl cyclase (intrinsic activity 0.5 compared to (−)-isoprenaline); the effect was competitively antagonized by ß-blockers. Procaterol caused biphasic concentration-effect curves for the cyclase; a high-affinity component of the curve comprised 60-70% of the maximum enzyme stimulation by procaterol. Inotropic concentration-effect curves for procaterol were also biphasic on isolated papillary muscles and left atria; procaterol was a full inotropic agonist and the high-affinity component of the curve amounted to 30-40% of the maximal effect. The rate of spontaneously beating right atria was enhanced by procaterol with a 1000-fold higher potency than for inotropic effects; the chronotropic concentration-effect curve was monophasic. The positive chronotropic and inotropic effects of procaterol were competitively antagonized by ß-blockers. Both procaterol sites appear to mediate its positive inotropic effects. The high-affinity procaterol sites appear to encounter preferentially the adenylyl cyclase but the formed cAMP may be used less efficiently for inotropism than the cAMP formed from the low-affinity site. Procaterol may stimulate the beating rate of sinoatrial pacemakers predominantly through its high-affinity sites.

Cardiostimulatory effects of prenalterol, a beta-1 adrenoceptor partial agonist, in vivo and in vitro. Correlation between physiological effects and adenylate cyclase activity.

The cardiostimulatory effects of prenalterol, a beta-1-adrenoceptor partial agonist, were studied in vivo and in vitro and compared to those evoked by isoprenaline, a full agonist, and to those of other partial agonists. In the anaesthetized rat, prenalterol and terbutaline were found not to elevate the myocardial cyclic AMP content; this was in sharp contrast to isoprenaline. Both partial agonists did, however, produce significant effects on heart rate. In the anaesthetized cat, prenalterol exhibited chronotropic and inotropic intrinsic activities of 88 and 76% respectively in relation to isoprenaline. No statistically significant increase in myocardial cyclic AMP content could however be detected. Prenalterol did not stimulate adenylate cyclase significantly in the cat myocardial homogenate. This was also true of the beta-2-adrenoceptor selective partial agonist procaterol. In this preparation, isoprenaline, noradrenaline and adrenaline acted as full agonists. Furthermore, prenalterol produced a concentration-dependent inhibition of isoprenaline-activated adenylate cyclase. Our data indicate that maximal cardiac stimulation occurs at a low level of adenylate cyclase activation and low myocardial cyclic AMP concentration when provoked by a full beta-adrenoceptor agonist. The maximal physiological effects of a partial agonist such as prenalterol may consequently be achieved at a marginal activation of the adenylate cyclase. The present data may thus support the hypothesis of a large beta-adrenoceptor reserve for full agonists in the heart.

Pharmacological characteristics of beta-adrenoceptor binding sites in intact and sympathectomized rat spleen

[3H]-(--)-Dihydroalprenolol ([3H]-DHA) binds to rat spleen membranes with a dissociation equilibrium constant (KD) of about 0.7 nM and a maximal number of binding sites of 272 fmoles x mg protein-1. Approximately 90% of the sites labelled by 1 nM [3H]-DHA possess classical properties of beta-adrenoceptors. The labelled ligand is stereospecifically displaced by the isomers of propranolol and the order of potency of agonists is: isoprenaline greater than adrenaline greater than noradrenaline. Highly selective beta 1 antagonists such as practolol and atenolol displaced [3H]-DHA from spleen membranes in a biphasic manner indicating the co-existence of beta 1 and beta 2 sites (30--35% beta 1; 65--70% beta 2) in this tissue. Support for this classification was provided by the binding of the beta 2 agonist procaterol to spleen membranes. This drug possessed high affinity only for those sites that have low affinity for the beta 1 selective agents. Chemical sympathectomy induced by chronic 6-hydroxydopamine administration did not alter the number or the pharmacological properties of beta-adrenoceptor binding sites. The results suggest that both beta 1 and beta 2 adrenoceptors are probably postsynaptic in spleen.