Beta-adrenoceptor studies. III. On the beta-adrenoceptors in rat adipose tissue.
Explore the source record for details and available documents.
Adipose Tissue↗
Biomedical subjects
J Zaagsma
Publications and source records attributed to J Zaagsma.
Beta-adrenoceptor studies. 1. In vitro beta-adrenergic blocking, antiarrhythmic, and local anesthetic activities of a new series of aromatic bis(2-hydroxy-3-isopropylaminopropyl) ethers.
Explore the source record for details and available documents.
Adrenergic beta-Antagonists↗
Protection by verapamil and nifedipine against ischaemia-induced loss of [3H]-(+)-PN 200-110 binding sites in the rat heart.
We have studied the effects of 60 min global ischaemia and 30 min of subsequent reperfusion on the binding of [3H]-(+)-PN 200-110 and [3H]-(-)-devapamil (desmethoxyverapamil or D888) in rat heart membranes. The hearts were perfused in the Langendorff-mode and pretreated with 1 mumol/l verapamil, 30 nmol/l and 1 mumol/l nifedipine. After 60 min of global ischaemia in the absence of drugs, we found a reduction of [3H]-(+)-PN 200-110 binding sites, without changes in the equilibrium dissociation binding constant (Kd). After the subsequent reperfusion maximum specific binding (Bmax) was further reduced, whereas the Kd remained constant. [3H]-devapamil binding sites were influenced to a lower extend and showed only a decrease in Bmax at reperfusion. Pretreatment with 1 mumol/l verapamil completely prevented the changes which were observed for [3H]-(+)-PN 200-110. Pretreatment with a low, vasodilating concentration (30 nmol/l) of nifedipine displayed selective protection against the extra reduction in Bmax which was observed during reperfusion. It is concluded that calcium antagonists show protection against the ischaemia-induced loss of dihydropyridine binding sites in relation to their negative inotropic, energy-saving activity. Furthermore, nifedipine at low, vasodilating but not negative inotropic concentrations protects against further reperfusion-induced injury, which protection may be related to an improved flow during reperfusion.
Animals↗
Heterogeneous receptor binding of classical quaternary muscarinic antagonists. II. Modulation in bovine brain.
The heterogeneous binding behavior exhibited by classical quaternary muscarinic antagonists was further investigated in order to establish possible molecular and/or environmental differences between the high (Q1) and low (Q2) affinity binding sites. Using agents that are known to modulate (muscarinic) receptor binding (Na+ and Mg2+, 5'-guanylylimido diphosphate, dithiothreitol, N-ethylmaleimide), no evidence was obtained that the Q1 and Q2 binding site populations are molecularly different muscarinic receptor subtypes. Using membrane modulating agents (sodium dodecyl sulphate, digitonin, polyethylene glycol 6000, cholesteryl hemisuccinate), no evidence was obtained that the Q2 binding site population represents muscarinic receptors located in a different membrane environment less accessible to quaternary compounds. However, a qualitative correlation was found between lipid solubility and the appearance of Q1/Q2 binding heterogeneity for six quaternary muscarinic antagonists, suggesting that the low affinity binding sites may be (normal) muscarinic receptors located in a hydrophobic membrane domain.
Animals↗
Heterogeneous receptor binding of classical quaternary muscarinic antagonists. I. Bovine tissue distribution.
In competition experiments with the tertiary radioligand [3H]dexetimide, classical quaternary muscarinic antagonists like ipratropium bromide and N-methylscopolamine bromide distinguished two muscarinic binding sites in bovine brain (total brain minus cerebellum) membranes, in contrast to their tertiary analogues, atropine and scopolamine, which recognized only one binding site. This binding behavior was found to be almost identical in bovine striatal membranes, both in terms of binding affinities and proportions of high (Q1) and low (Q2) affinity binding sites. Both in total brain and in striatal membranes, the Q1/Q2 binding heterogeneity was independent of pirenzepine binding heterogeneity (M1/M2). In peripheral tissues, the binding properties of quaternary muscarinic antagonists varied. Whereas tertiary as well as quaternary compounds showed only high affinity binding towards muscarinic receptors in bovine atrial and left ventricular membranes, heterogeneous binding behavior was observed with quaternary but not with tertiary antagonists in bovine tracheal smooth muscle membranes. The tissue distribution found in the present study suggests that bovine tracheal smooth muscle contraction studies might shed light on the functional significance of the anomalous binding behavior of quaternary muscarinic antagonists.
Animals↗
pH-dependent effects of bepridil on Ca2+-extrusion across rat heart sarcolemma.
The inhibition by bepridil of ATP-dependent Ca2+-uptake and Na+/Ca2+-exchange was studied in isolated rat cardiac sarcolemmal vesicles over a pH range of 6.3 to 7.8. It was found that the protonated and deprotonated species of bepridil induced the same inhibition and no activation of these two transport systems. However, the intrinsic activities of both systems appeared to be strongly dependent on the pH.
Adenosine Triphosphate↗
Selectivity profile of some recent muscarinic antagonists in bovine and guinea-pig trachea and heart.
The functional affinities of some recently developed subtype-selective muscarinic antagonists towards bovine tracheal smooth muscle muscarinic M3 receptors were established and compared to binding affinities for bovine cardiac M2 and functional affinities for guinea-pig tracheal smooth muscle M3 receptors; functional affinities towards bovine or guinea-pig cardiac M2 receptors were determined when the M2/M3 selectivity in bovine tissues deviated from reported guinea-pig data. It was found that the M2-selective antagonist AQ-RA 741 showed similar high affinities in bovine and guinea-pig heart (8.27-8.41); the affinity in bovine trachea, however, was almost 10-fold higher than in guinea-pig trachea (7.51-6.63). The M3-selective antagonist DAC 5945 displayed functional affinities that were similarly high in bovine and guinea-pig trachea (8.16-8.24) and approximately a 100-fold lower in bovine and guinea-pig heart (6.15-6.36); with this compound, the binding affinity in bovine cardiac membranes (6.92) was clearly higher than the functional affinity, as has meanwhile also been reported for the guinea-pig. With the M3-selective muscarinic antagonists p-fluorohexahydrosiladifenidol and UH-AH 371, affinities towards bovine tracheal muscarinic M3 receptors were 0.3 log units higher than in guinea-pig trachea (7.36-7.09 and 8.43-8.13, respectively), and, in case of p-fluorohexahydrosiladifenidol, both were lower than previously reported for the guinea-pig ileum (typically 7.8). In some instances, especially AQ-RA 741 in bovine trachea and p-fluorohexahydrosiladifenidol in bovine and guinea-pig trachea, the M3 receptor affinities found here correlated better to the reported M1 than to the M3 receptor affinities. It is concluded that small, but occasionally clear species and tissue differences exist with regard to the affinities of muscarinic receptor antagonists for smooth muscle M3 receptors, and it is suggested that this may be due to small, but potentially important differences in their amino acid sequences.
Animals↗