Albrecht Ziegler

Affinity profiles of morphine, codeine, dihydrocodeine and their glucuronides at opioid receptor subtypes

The affinity of morphine, codeine, dihydrocodeine and their glucuronides for mu-, delta-, and kappa-opioid receptors was investigated. Binding was studied on guinea-pig brain homogenates with [3H]DAMGO, [3H]DPDPE, and [3H]U69593. The substitution of the free phenolic group of morphine caused a decrease in binding at opioid receptors without affecting the mu/delta-ratio nor that of mu/kappa. Glucuronidation of the 6-hydroxyl group of morphine, codeine or dihydrocodeine did not affect the affinity to mu-receptors, slightly increased the affinity for delta-receptors and reduced the affinity for kappa-receptors. The 6-glucuronides possess a decreased selectivity for mu-receptors over delta-receptors whereas that for mu- over kappa-receptors was increased. It is concluded that chemical variations at 3- and 6-position of morphine independently affect the affinity to opioid receptor subtypes.

Accumulation of drugs by resting or beating cardiac tissue

The rate and degree of accumulation of 12 neutral, anionic and cationic drugs were studied in resting and 2 Hz-stimulated isolated left auricles of the guinea pig. The uptake process was accelerated in muscles driven electrically. The time needed to reach equilibrium was related to the extent of accumulation which in turn corresponded with the lipophilicity of the drug. The frequency-induced changes in the kinetics of the accumulation disappeared under reduced mechanical activity of the muscle. It is suggested that the increased mechanical activity enhances drug disposition within the extracellular space, so that more drug is available for transmembrane penetration.

Endothelium‐dependent noradrenaline‐induced relaxation of rat isolated cerebral arteries: pharmacological characterization of receptor subtypes involved

1 The endothelium‐dependence of catecholamine‐induced relaxation of rat cerebral arteries was investigated in vitro. 2 In the basilar artery (BA), the maximal relaxant response was most pronounced with noradrenaline (NA), less with isoprenaline (Iso), and only very little with terbutaline. Methoxamine and the α2‐adrenoceptor selective agonists BHT 933 and clonidine, had no relaxant effect. 3 In BA, the relaxation by NA or Iso was markedly attenuated by Nω‐nitro‐l‐arginine (l‐NOARG) 10−4 m. Short term perfusion of the vessels by Triton X 100 (1:1000) suppressed the NA‐induced relaxation. 4 The relaxation induced by NA or Iso was markedly reduced in presence of l‐NOARG in the posterior, medial and anterior cerebral artery. 5 In BA, NA‐induced relaxation was non‐competitively inhibited by propranolol, atenolol, and the β1‐ and β2‐adrenoceptor selective antagonists, CGP 20712 A and ICI 118551. 6 The relaxant NA‐effect was not affected by prazosin but was non‐competitively blocked by phentolamine. 7 The Iso‐induced relaxation was competitively blocked by propranolol, whereas atenolol, CGP 20712 A and ICI 118551 caused a non‐competitive inhibition. 8 The experiments indicate that the catecholamine‐induced relaxation in rat isolated cerebral arteries depends upon the endothelium. They suggest that the NA‐induced relaxation of BA is mediated by different α‐ and β‐adrenoceptors and that the Iso‐induced relaxation is mediated by different β‐receptors. The findings would also be compatible with the idea of a receptor type which cannot be characterized by the pharmacological tools that we have used.

The vasorelaxant effect of pituitary adenylate cyclase activating polypeptide and vasoactive intestinal polypeptide in isolated rat basilar arteries is partially mediated by activation of nitrergic neurons

The structurally related neuropeptides pituitary adenylate cyclase activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) are recognised by two G protein-coupled receptors, termed VPAC(1)-R and VPAC(2)-R, with equal affinity. PACAP and VIP have previously been shown to relax cerebral arteries in an endothelium-independent manner. The aim of the present study was to test if intramural neurons are involved in the mediation of PACAP/VIP-induced vasodilatory responses. Therefore, the vascular tone of isolated rat basilar arteries was measured by means of a myograph. The vasorelaxing effect of PACAP was assessed in arteries precontracted by serotonin in the absence or presence of different test compounds known to selectively inhibit certain signaling proteins. The vasorelaxant effect of PACAP could be significantly reduced by the inhibitor of neuronal N-type calcium channels omega-conotoxin GVIA (omega-CgTx), as well as by 3-bromo-7-nitroindazole (3Br-7-Ni), an inhibitor of the neuronal nitric oxide-synthase (nNOS). The localization of N-type calcium channels and VPAC-Rs within the rat basilar artery was investigated by confocal laser scanning microscopy using omega-CgTx- and VIP-analogs labelled with fluorescent dyes. These findings suggest that activation of intramural neurons may represent an important effector mechanism for mediation of the vasorelaxant PACAP-response.

Kinetic events determining the effects of cardiac glycosides

Abstract Drugs pose kinetic problems on three different levels: (1) pharmacokinetics (dealing with drug disposition), (2) receptor kinetics, and (3) transformation kinetics (describing the transformation of the drug-receptor interaction into effects). The events occurring on these three levels have a highly complex interdependence. Receptor and transformation kinetics of naturally occurring cardiac glycosides and their semisynthetic congeners deserve more attention in view of their therapeutic importance.

Interactions between vasoconstrictors in isolated human cerebral arteries

SummaryThis study investigates whether different endogeneous vasoconstrictors exert synergistic effects in isolated human cerebral arteries, because potentiation of contractile effects may play a role in the pathogenesis of cerebral vasospasm.Isolated human pial arteries obtained from macroscopically intact tissue during brain tumour operations were mounted onto a wire myograph. Concentration-response curves of 5-hydroxytryptamine (5-HT) were constructed in the absence and presence of threshold concentrations of the thromboxane A2 (TXA)-analog U46619, and endothelin-1 (ET-1).Threshold concentrations of U46619 markedly enhanced the maximum contractile effect of 5-HT. The response to 5-HT Threshold concentrations of ET-1 increased the maximum response to 5-HT, and markedly shifted the dose-response curve to the left. Even after washout of ET-1, the dose-response curve of 5-HT remained shifted to the left. The increase of the contractile effect of 5-HT in the presence of U46619 did not correlate with the relaxant action of the endothelium-dependent vasodilator carbachol.Thus, synergism between contractile substances such as 5-HT, U46619, or ET-1 is seen in human cerebral arteries, and responses to 5-HT are potentiated even after washout of ET-1 and U46619. The potentiation does not depend on the endothelial function. We conclude that synergistic responses between endogeneous vasoconstrictors such as 5-HT, TXA and ET-1 may be involved in the pathogenesis of cerebral vasospasm after subarachnoid haemorrhage.

Plasma and Cerebrospinal Fluid Concentrations of Morphine and Morphine Glucuronides in Rabbits Receiving Single and Repeated Doses of Morphine

The pharmacokinetics of morphine in plasma and the distribution of morphine and its glucuronidated metabolites within the cerebrospinal fluid were investigated in rabbits.

Role of potassium channels in the relaxation induced by the nitric oxide (NO) donor DEA/NO in the isolated rat basilar artery

This study investigates whether potassium ion (K+) channels are involved in the nitric oxide (NO)-induced relaxation in segments of the isolated rat basilar artery, mounted onto a wire myograph. A high extracellular K+ concentration partly inhibited the relaxant effects of the NO donors DEA/NO and SIN-1 (3-morpholino-sydnonimine). Whereas single applications of the K+ channel inhibitors tetraethyl-ammonium (10(-3) M), glibenclamide (10(-6) M), 4-aminopyridine (10(-3) M), or BaCl(2) (5 x 10(-5) M) did not affect the responses to DEA/NO, a combination of these inhibitors reduced the effects of DEA/NO. These data suggest, that the relaxant effects of NO donors are partly mediated via activation of K+channels. Different K+ channel types seem to be involved that function in a redundant manner and compensate for each other.

A transient state concept of drug receptor interaction

Summary1.Experimental results obtained with muscarine-like drugs cannot be explained satisfactorily by existing drug receptor theories.2.The time courses and extents of the negative inotropic effects and that of the desensitization caused by cholinomimetic drugs were recorded in guinea-pig isolated, electrically driven atria. The uptake of 3H-carbachol by the tissue was measured under identical experimental conditions.3.A concept of drug receptor interaction is proposed based upon these experimental results. It differs from the existing theories by including both the disposal of the drug molecules in the biophase (drug transport) and the existence of an inactivated drug receptor complex. The active drug receptor complex is regarded as a transient state.4.The transient state concept makes it possible to use only one set of constants to describe uptake curves and effect curves over the entire dose range.

Effects of Potassium Channel Openers in Isolated Human Cerebral Arteries

The objective of this study was to compare the relaxant effects of the K+ channel openers pinacidil and lemakalim in isolated human pial arteries with the effects of the dihydropyridines nifedipine and nimodipine and the prostacyclin analog iloprost. Relaxation was measured in vessels contracted by 40 mmol/L K+. In contrast to the potent and consistent relaxant effects of nifedipine, nimodipine, and iloprost, the potency of pinacidil and lemakalim proved to be highly variable and inversely correlated with the onset velocity of the preceding contractions of K+ as well as with the endothelium-dependent relaxation of carbachol. Thus, in contrast to dihydropyridines and iloprost, pinacidil and lemakalim selectively elicited potent relaxations in those arteries that exhibited signs of altered vascular wall functions.