ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1989.tb01583.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

SUMMARY1. Deviation supersensitivity and post‐junctional supersensitivity are important determinants in the control of the response of smooth muscle.2. Post‐junctional supersensitivity is a process whereby effector cells have augmented responsiveness as a consequence of an impaired physiological stimulus. Deviation supersensitivity which occurs as a result of inhibition of sites of loss or inactivation of the transmitter substance noradrenaline and its analogues also produces an enhanced response of smooth muscle cell preparations.3. The enzymes monoamine oxidase and catechol‐O‐methyl transferase are irreversible sites of loss of noradrenaline. Functional impairment of these enzymes results in deviation supersensitivity.4. The complexities involved in unravelling the contribution of noradrenaline metabolizing enzymes to deviation supersensitivity are highlighted with emphasis upon the pioneering work of Professor de la Lande in thi

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1989.tb01584.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

SUMMARY1. Depending upon the type of cell being studied, adaptive supersensitivity has been traced to molecular changes in receptors, the Na+/K+ pump or the G‐protein/adenylate cyclase system.2. Evidence is reviewed that indicates that adaptive supersensitivity in guinea‐pig atria is the result of changes in the G‐protein/adenylate cyclase s

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1989.tb01585.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

SUMMARY1. The effects of reserpine pretreatment on neurotransmission in the guinea‐pig vas deferens have been re‐examined with a view to study the role of noradrenaline (NA) in mediating postjunctional electrical responses and, in particular, excitatory junction potentials (EJP).2. Reserpine (5 mg/kg, i.p.) caused almost total depletion (below detection levels) of the NA content of the vas deferens. However, spontaneous and evoked excitatory junction potentials (SEJP, EJP) and currents (SEJC, EJC) could still be recorded in NA‐depleted tissues. The amplitude distribution of SEJC in control and reserpinized tissues was similar.3. Facilitation of EJP and EJC was markedly slowed in reserpinized tissues, EJP taking 50–60 pulses to facilitate fully. However the amplitudes of fully facilitated EJP were comparable to EJP recorded in control tissues.4. EJPs in reserpinized vasa deferentia were unaffected by the NA synthesis inhibitor, α‐methyl tyrosine, but were abolished in the presence of the stable ATP analogue α,β‐methylene ATP which desensitizes postjunctional P2‐purinoceptors.5. Local application of ATP, but not NA, mimicked the EJP. These results indicate that EJP are mediated by a non‐noradrenergic neurotransmi

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1989.tb01586.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

SUMMARY1. The α2‐adrenoceptor agonist TL99, in concentrations that had no other observable effect, enhanced constrictor responses to phenylephrine in perfused segments of the rat tail artery.2. Vasoconstrictor responses to phenylephrine were also enhanced by propranolol (0.3 μmol/L).3. Vasoconstrictor responses to phenylephrine in the presence of propranolol were further enhanced by TL99 (10 nmol/L).4. The enhancement of vasoconstrictor responses by α2‐adrenoceptor agonists is not due to the removal of a counteracting vasodilator component produced by activation of p‐adren

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1989.tb01587.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

SUMMARY1. Effects of uptake1and uptake2inhibition on the vasoconstrictor activity of noradrenaline (NA) in the perfused artery of the rabbit ear are reviewed in the light of data on NA metabolism and diffusion.2. The minor effect of uptake1inhibition on the response to intraluminal NA is related to location of the sympathetic nerves at the medial‐adventitial border, and low diffusivity together with loss of amine by uptake2in the media.3. The minor effect of uptake2inhibition on the vasoconstrictor activity of NA suggests that uptake2has little effect on steady‐state amine concentration in the media. This suggestion is supported by analyses of patterns of normetanephrine efflux from the artery.4. Attention is drawn to the ability of uptake inhibitors, and of constriction and distension, to influence entry of NA into the artery w

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1989.tb01588.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

SUMMARY1. Biological macromolecules are able to distinguish between enantiomeric substrates. A three‐point interaction between the drug enantiomers and the macromolecule (Easson‐Stedman hypothesis) can frequently account for this selectivity.2. Significant pharmacodynamic differences between enantiomers are more the rule than the exception.3. Pharmacokinetic differences between enantiomers are, in general, not as great as the pharmacodynamic differences. However, stereoselective protein binding, metabolism and renal clearance are still very important aspects of understanding drug disposition and the time course of drug action.4. There may be pharmacokinetic and pharmacodynamic enantiomer‐enantiomer interactions. Consequently, the activity and disposition of a racemic drug may not be the simple sum of the activities and disposition of the individual enantiomers.5. Enantiomers have been used as sensitive 3‐dimensional probes to establish structure‐activity relationships, to provide insights into genetic polymorphism of drug metabolism, and to provide insights into other aspects of drug disposition.6. A need for a 3‐dimensional understanding of pharmacodynamics and pharma‐cokinetics is implicit in the asymmetric nature of biological

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1989.tb01589.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

SUMMARY1. With the increasing appreciation that the enantiomers of a chiral drug can differ pharmacokinetically and/or pharmacodynamically, there is considerable interest in methods for the resolution and quantification of enantiomers.2. Enantiomers possess identical physical and chemical properties in a symmetrical environment and, therefore, their resolution requires the introduction of an asymmetric or chiral environment allowing diastereomeric interactions. This can be achieved using a number of chromatographic techniques, of which the most developed and widely used is high‐performance liquid chromatography (HPLC).3. Resolution and quantification of enantiomers can be performed using HPLC by either converting the enantiomers to covalent diastereomers prior to chromatography or introducing a chiral environment to the chromatographic system, thereby allowing temporary diastereomeric interactions.4. Antibodies are chiral molecules which can bind the enantiomers of a chiral drug in a differential manner. This is the basis of enantioselective immunoassay, which is a promising technique for the enantioselective analysis of drugs in biological fluids.5. Each of the methods available has its limitations, advantages and potential applications in the pharmaceutical industr

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1989.tb01590.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

SUMMARY1. Racemic drugs contain enantiomers which can differ substantially in pharmacological and dispositional properties. The development of chemical methods to separate and analyse drug enantiomers has led to a growing understanding of their biological properties and a regulatory dilemma as to whether only enantiomerically pure drugs should be marketed.2. Advantages of enantiomerically pure drugs include more selective pharmacological profiles leading to better therapeutic indices, less complex pharmacokinetics and interactions, and simpler interpretation of plasma concentration response relationships.3. As racemic drugs that are currently marketed and reaching marketing were developed when knowledge of drug enantiomers was less sophisticated, a flexible regulatory approach is required. At present, it is probably reasonable to require substantial information on the properties of enantiomers of racemic drugs but the balance is on the side of regulatory agencies needing to justify, provided adequate information is submitted, requirements for enantiomerically pure drugs.4. This balance will gradually change to a situation where enantiomerically pure drugs will be the standard, and a strong case will need to be put by sponsors wishing to market racemic drugs.

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1989.tb01591.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY

摘要:

SUMMARY1. In contrast to drug‐metabolizing cytochromes P‐450, the corresponding ster‐oidogenic enzymes appear to be highly specific with respect to substrates, reactions catalysed, and the sites in the substrate molecule that are attacked.2. Recent studies have shown that important exceptions to this generalization are encountered.3. The conversion of 11‐deoxycorticosterone to aldosterone requires three enzymatic reactions, the last of which (aldehyde synthetase), like the first two, requires a P‐450 mono‐oxygenation. The involvement of P‐450 in this third step (from alcohol to aldehyde) was demonstrated by photochemical action spectra and determination of stoichiometry. The three reactions were shown to be catalysed by a single enzyme as demonstrated by immunoprecipitation and the use of a homogenous enzyme.4. The conversion of pregnenolone and progesterone to the corresponding Δ16‐C19steroids, which are pheromones, is catalysed by a cytochrome P‐450 that also catalyses the conversion of progesterone to androstenedione (that is, C21side‐chain cleavage; hydroxylase/lyase). The synthesis of the Δ16compounds requires cytochrome b5.5. The conversion of testosterone and epitestosterone to androstenedione is catalysed by P‐450b. Studies of kinetic isotope effects using deuterium and18O2show that P‐450b catalyses this reaction with epitestosterone via the formation of a gem diol, whereas, with testosterone as substrate, one‐third of the product is formed via the same mechanism while the remainder results from the mechanism described a

ISSN:0305-1870    

DOI:10.1111/j.1440-1681.1989.tb01592.x

出版商:Blackwell Publishing Ltd    

年代:1989

数据来源: WILEY