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Biomedical subjects

J C Wanstall

Publications and source records attributed to J C Wanstall.

At least 55 records · Page 3Linked to original sources
PubMed1988

Inhibition of norepinephrine contractions by diltiazem on aorta and pulmonary artery from young and aged rats: influence of alpha-adrenoceptor reserve.

Inhibition of contractile responses to norepinephrine by either diltiazem (1 microM) or by reducing the extracellular calcium (from 2.5-0.25 mM) has been examined on isolated ring preparations of aorta and pulmonary artery from young (2 months old) and aged (19-21 months old) rats. On aorta, the reduction in the norepinephrine maximum contraction by diltiazem was significantly greater in aged rats (40% reduction) than in young rats (12% reduction). The results obtained by reducing the extracellular calcium were indistinguishable from those with diltiazem (reduction in norepinephrine maximum: aged, 55%; young, 19%). The potency (negative log EC50) of norepinephrine was less in aorta from aged than from young rats. This was not due to a lower affinity (pKA) of norepinephrine for the alpha adrenoceptors, but to a reduced alpha adrenoceptor reserve for norepinephrine. On pulmonary artery none of the above age-related changes was seen. It is concluded that, in aorta from aged rats, the inhibitory effect of diltiazem on norepinephrine-induced contractions is enhanced, and that this is due to the age-related reduction in alpha adrenoceptor reserve in this vessel.

Age Factors↗
PubMed1987

Influence of thyroid status on responses of rat isolated pulmonary artery, vas deferens and trachea to smooth muscle relaxant drugs.

1 Responses to relaxant drugs have been examined on isolated KCl-contracted smooth muscle preparations from rats in which thyroid status was changed by prior treatment with either thyroxine (T4) for 1 week (preparations of pulmonary artery, trachea and vas deferens) or methimazole for 10-12 weeks (pulmonary artery preparations). 2 On pulmonary artery preparations, T4 treatment caused a significant increase in the magnitude of the relaxant responses to noradrenaline and isoprenaline but not those to adrenaline. The potency of noradrenaline was increased 5.6 fold but that of isoprenaline and adrenaline was unchanged. This resulted in a change in the relative potencies from adrenaline greater than noradrenaline (controls) to noradrenaline = adrenaline (T4-treated). Methimazole treatment caused a significant reduction in the magnitude of the responses to noradrenaline and in its potency (2.8 fold). Isoprenaline and procaterol were unaffected. 3 On pulmonary artery preparations, T4 treatment did not affect the magnitude of the responses to forskolin, sodium nitrite or isobutylmethylxanthine (IBMX) or their potency. In vitro treatment with the monoamine oxidase (MAO) inhibitors, iproniazid or pargyline, did not potentiate responses to either noradrenaline or isoprenaline. Therefore, it was concluded that the T4-induced changes in the magnitude of the responses to noradrenaline and isoprenaline and in the potency of noradrenaline were unlikely to be due to reduced activity of cyclic nucleotide phosphodiesterase(s) or MAO. 4 On preparations of vas deferens and trachea, T4 treatment had no effect on the magnitude of the responses to noradrenaline, isoprenaline, adrenaline or procaterol. 5 We concluded that, on pulmonary artery T4 treatment of rats increased, while methimazole treatment reduced, the magnitude of the responses to, and/or the potency of, the beta-adrenoceptor agonists, noradrenaline and isoprenaline, by a mechanism which is specifically associated with the beta-adrenoceptors, and which is probably selective for the beta-subtype. T4 treatment caused no change in responses of vas deferens to beta-adrenoceptor agonists. On trachea the only change was a small increase in the potency of noradrenaline. The differences in the effects of T4 treatment on beta-adrenoceptormediated responses of rat pulmonary artery, vas deferens and trachea may be due to the differences in the beta-adrenoceptor populations of these three tissue types and/or differences in the effects of thyroid hormones on vascular compared with non-vascular smooth muscle.

Animals↗
PubMed1987

Choice and concentration of contractile agent influence responses of rat aorta to vascular relaxant drugs.

Concentration-response (relaxation) curves to diltiazem, forskolin, isobutylmethylxanthine (IBMX), procaterol, isoprenaline and sodium nitrite were obtained on isolated ring preparations of rat aorta contracted either submaximally or maximally with noradrenaline or KCl. Diltiazem was more potent on KCl-contracted than on noradrenaline-contracted preparations whether the preparations were submaximally or maximally contracted. The other relaxant drugs were at least 20-fold less potent against KCl than against noradrenaline, but only on maximally contracted preparations. On submaximally-contracted preparations there was no potency difference between preparations contracted with these two contractile agents. Increasing the KCl concentration had a marked influence on the location of the concentration-response (relaxation) curves to all the drugs except diltiazem. This influence was different for drugs that act via cyclic AMP and those that act via cyclic GMP. It is concluded that both the choice of contractile agent (noradrenaline or KCl) and the concentration (especially of KCl) influence relaxant responses of rat aorta to vasodilator drugs.

Animals↗
PubMed1987

Influence of beta-adrenoceptor-mediated relaxation on alpha-adrenoceptor-mediated contraction of rat pulmonary artery to adrenaline or noradrenaline.

Concentration-response (contraction) curves to either adrenaline or noradrenaline were obtained on isolated ring preparations of pulmonary artery from rats. In preparations from young rats the curve for adrenaline was bell-shaped, unless beta-adrenoceptors were blocked with propranolol (1 X 10(-6) M). The maximum contraction to adrenaline was less in the absence than in the presence of propranolol. In preparations from aged rats the adrenaline curve was no longer bell-shaped, even in the absence of propranolol. This reflected a decrease in the beta-adrenoceptor-mediated relaxant responses of preparations from aged rats, seen as a separation between the concentration-response (relaxation) curves to adrenaline on preparations (phenoxybenzamine-treated, KCl-contracted) from young and aged rats. In preparations from young rats the noradrenaline curve was not bell-shaped, but if the preparations were from young rats treated with thyroxine (T4), then a bell-shaped curve for noradrenaline was obtained, unless beta-adrenoceptors were blocked by propranolol. These data could be explained by an increase in beta-adrenoceptor-mediated relaxant responses of preparations from T4-treated rats, seen as a separation in the concentration-response (relaxation) curves to noradrenaline on preparations from control and T4-treated rats, respectively. Thus alpha-adrenoceptor-mediated contractile responses of rat pulmonary artery preparations, to adrenaline or noradrenaline, can be attenuated by activation of beta-adrenoceptors, mediating relaxation, and the extent of this attenuation changes under the influence of factors, such as ageing or T4-treatment, which modify beta-adrenoceptor-mediated relaxation in this blood vessel type.

Aging↗
PubMed1986

Thyroxine treatment of aged or young rats demonstrates that vascular responses mediated by beta-adrenoceptor subtypes can be differentially regulated.

Responses to vascular relaxant drugs were obtained on KCl (15 mM)-contracted isolated ring preparations of pulmonary artery and aorta from young (1-2 months old) and aged (greater than 16 months old) rats. These vessels contain both beta 1- and beta 2-adrenoceptors. Relaxant responses (i.e. relaxation expressed as a % of the KCl-induced contraction) to isoprenaline, procaterol (beta 2-selective partial agonist), fenoterol (beta 2-selective) and noradrenaline (beta 1-selective) but not those of forskolin, 3-isobutyl-1-methylxanthine, enprofylline or sodium nitrite, were smaller on preparations from aged rats than on those from young rats. Thyroxine (T4)-treatment (1 mg kg-1 s.c. thrice weekly for 3-5 weeks) of aged or young rats enhanced responses to isoprenaline and noradrenaline but reduced those to procaterol, when compared with preparations from age-matched saline-treated control rats. The agonist order of potency, determined in young rats, was isoprenaline greater than noradrenaline greater than adrenaline in preparations from T4-treated rats compared with isoprenaline greater than adrenaline greater than noradrenaline in saline-treated control rats. It is concluded (a) that the age-related decline in vascular responses to beta-adrenoceptor agonists involves beta-adrenoceptor mechanisms specifically and possibly beta 2-adrenoceptors more than beta 1-adrenoceptors; and (b) that T4-treatment of rats enhances beta 1-adrenoceptor-mediated and reduces, or does not change, beta 2-adrenoceptor-mediated responses of preparations of rat pulmonary artery and aorta. In preparations from control rats beta 2-adrenoceptors were functionally predominant but in preparations from T4-treated rats beta 1-adrenoceptors appeared to become functionally predominant.

Adrenergic beta-Agonists↗
PubMed1985

Responses to the beta 2-selective agonist procaterol of vascular and atrial preparations with different functional beta-adrenoceptor populations.

Relaxant responses to the beta-adrenoceptor agonist, procaterol, have been examined on preparations of guinea-pig pulmonary artery (beta 2-adrenoceptors only), rat and rabbit pulmonary artery and rat aorta (beta 2 greater than beta 1), and these responses have been compared with responses of dog left circumflex coronary artery (beta 1 only). Low concentrations of procaterol (3 nM to 100 nM) relaxed KC1-contracted preparations of rat aorta and pulmonary artery from rat, rabbit and guinea-pig whereas high concentrations (greater than 1 microM) were required to relax preparations of the dog left circumflex coronary artery. The dissociation constant (KP value) for procaterol on beta 1-adrenoceptors was 4.9 microM (determined on dog coronary artery) and on beta 2-adrenoceptors was 0.008 microM (rabbit pulmonary artery). Procaterol therefore had a beta 2:beta 1 selectivity value of 612. KP values obtained on guinea-pig atria for procaterol, on which the concentration-response curve was biphasic, confirmed that both beta 2- and beta 1-adrenoceptors mediate responses of this tissue. The KP values were 0.009 microM (data from the first phase of the control concentration-response curve) and 3.5 microM (data from the concentration-response curve in the presence of the beta 2-selective antagonist, ICI 118,551, 10 nM). Data obtained on rat atria indicated that chronotropic responses of preparations from some rats, but not others, involved a minor population of beta 2-adrenoceptors, but the beta 2-adrenoceptors, when present, were less important than in guinea-pig atria. 6 Procaterol appears to be a particularly useful drug for detecting a functional population of beta 2-adrenoceptors in tissues, whether they are the minor or the predominant receptor sub-type present.

Adrenergic beta-Agonists↗
PubMed1984

The classification of beta-adrenoceptors in isolated ring preparations of canine coronary arteries.

Relaxant responses to the beta-adrenoceptor agonists isoprenaline, fenoterol, noradrenaline or procaterol were obtained on isolated ring preparations of canine coronary arteries contracted with KCl (20 mM) or 5-hydroxytryptamine (3 microM). On left circumflex arterial preparations, Schild plots for the selective antagonists atenolol (beta 1-selective) or ICI 118,551 (beta 2-selective), when using noradrenaline or fenoterol as agonist, were superimposed. This suggested that only one subtype of beta-adrenoceptor was involved in the responses. The pA2 values on left circumflex artery preparations were: atenolol, noradrenaline as agonist 6.98, fenoterol as agonist 6.71; ICI 118, 551, noradrenaline as agonist 6.66, fenoterol as agonist 7.04. These data indicated that the beta-adrenoceptor subtype was beta 1. The relative potencies of isoprenaline: noradrenaline: fenoterol were left circumflex 100: 10.0: 2.3, left ventricular branch 100: 9.7: 2.0, septal branch 100: 10.9: 2.5. These data confirmed that beta 1-adrenoceptors were involved in the responses of all three arterial preparations. On preparations of left circumflex artery, left ventricular branch and septal branch, responses were obtained to high concentrations (1 to 100 microM) but not to low concentrations (0.001 to 0.1 microM) of procaterol. This observation confirmed the absence of beta 2-adrenoceptors in these arteries. Responses of left circumflex artery to isoprenaline were potentiated by the extraneuronal uptake inhibitor drugs, corticosterone and metanephrine. 7 It is concluded (a) that responses of canine left circumflex artery, left ventricular branch and septal branch are mediated by a homogeneous population of beta 1-adrenoceptors, and (b) that modulation of responses to isoprenaline by extraneuronal uptake is not confined to responses mediated by beta 2-adrenoceptors.

Adrenergic beta-Agonists↗
PubMed1984

Beta-1 and beta-2 adrenoceptor-mediated responses in preparations of pulmonary artery and aorta from young and aged rats.

Rat pulmonary artery contains both alpha adrenoceptors mediating contraction and beta-1 and beta-2 adrenoceptors mediating relaxation. Neither alpha nor beta adrenoceptor-mediated responses of this vessel to norepinephrine or epinephrine were potentiated by cocaine, despite evidence for the presence of some adrenergic nerves. Beta adrenoceptor-mediated relaxation of pulmonary artery, but not aorta, modulated alpha adrenoceptor-mediated contractions to epinephrine but not norepinephrine. Rat aorta also contains both beta-1 and beta-2 adrenoceptors mediating relaxation, in that Schild plots for atenolol (beta-1 selective antagonist) using a beta-1 selective agonist (norepinephrine) and a beta-2 selective agonist (fenoterol), respectively, were not superimposed. The Schild plot data for lCl 118,551 (beta-2 selective) indicated that the minor population (beta-1) was less important in aorta than in pulmonary artery. On preparations from 18-month-old rats, the maximum relaxation to isoproterenol (20.4%, aorta and 67.9%, pulmonary artery) was less than in preparations from young rats (79.8%, aorta and 96.9%, pulmonary artery), i.e., aging had reduced the beta adrenoceptor-mediated relaxation in both vessels, but particularly in aorta. Also, the negative log EC50 of fenoterol, but not of isoproterenol or norepinephrine, was less than in preparations from young rats. This could indicate that aging had affected beta-2 more than beta-1 adrenoceptor-mediated responses and may explain why aging depressed the maximum relaxation of aorta more than that of pulmonary artery.

Aging↗
PubMed1983

Relaxation of cat trachea by beta-adrenoceptor agonists can be mediated by both beta1- and beta2-adrenoceptors and potentiated by inhibitors of extraneuronal uptake.

1--Responses (relaxation) to the beta-adrenoceptor agonists, isoprenaline, fenoterol or noradrenaline, were obtained on cat tracheal preparations contracted with a submaximal concentration of carbachol (0.5 microM). 2--The relative potencies of isoprenaline: fenoterol: noradrenaline were 100:8.1:10.7. From this, it was concluded that responses were mediated predominantly by beta 1-adrenoceptors but that a minor population of beta 2-adrenoceptors might also be involved. 3--Schild plots for the selective antagonists atenolol (beta 1-selective) or ICI 118,551 (beta 2-selective) were in different locations, i.e. were separated, depending on whether the antagonist was antagonizing noradrenaline or fenoterol. This supported the conclusion that beta 2- as well as beta 1-adrenoceptors were involved in mediating the response. In this respect, cat trachea resembles cat atria (rate responses). 4--In the presence of atenolol the concentration-response curves to fenoterol became biphasic. This was interpreted as indicating that the beta 2-adrenoceptors were too few in number to elicit a maximum tissue response. 5--Responses to isoprenaline of cat trachea were potentiated by the extraneuronal uptake inhibitor drugs, corticosterone and metanephrine. This indicated that extraneuronal uptake could modulate beta-adrenoceptor-mediated responses (relaxation) of cat trachea. 6--Cat trachea resembles guinea-pig trachea in that (i) the beta-adrenoceptor population mediating relaxation is mixed (beta 1 + beta 2) and (ii) responses to isoprenaline are modulated by its extraneuronal uptake. However, cat trachea differs from guinea-pig trachea in that the predominant beta-adrenoceptor sub-type is beta 1 not beta 2.

Adrenergic beta-Agonists↗
PubMed1982

Pharmacological experiments demonstrate that toad (Bufo marinus) atrial beta-adrenoceptors are not identical with mammalian beta 2- or beta 1-adrenoceptors.

Chronotropic responses to sympathomimetic amines of isolated atrial preparations from toads (Bufo marinus) were mediated by beta-adrenoceptors since isoprenaline was more potent than adrenaline and noradrenaline, and propranolol was a potent antagonist (pA2, adrenaline as agonist = 9.33). The beta-adrenoceptors had some of the characteristics of mammalian beta 2-adrenoceptors in that (i) adrenaline was more potent than noradrenaline and (ii) the pA2 values of two selection beta-adrenoceptor antagonists, atenolol (pA2 = 5.84) and alpha-methylpropranolol (pA2 = 8.42), were close to the values reported on beta 2-adrenoceptors in mammalian tissues. However, the relative potencies of adrenaline, isoprenaline, noradrenaline, rimiterol, salbutamol and fenoterol (1 : 45.8 : 0.07 : 3.3 : 1.05 : 0.32) did not correspond to the relative potencies reported for these agonists on mammalian tissues which contain predominantly beta 2-adrenoceptors. Also the pA2 value for the beta 2-selective antagonist, ICI 118,551 (7.89, adrenaline as agonist) was lower than its reported pA2 on beta 2-adrenoceptors in mammalian tissues. There was no evidence that the response was mediated by both beta 1- and beta 2-adrenoceptors since Schild plots for ICI 118,551 using three agonists of differing selectivity (adrenaline, rimiterol and noradrenaline) were superimposed. It is concluded that, although toad atrial beta-adrenoceptors have several characteristics in common with beta 2-adrenoceptors in mammalian tissues, these amphibian beta-adrenoceptors are not identical with mammalian beta 2-adrenoceptors.

Adrenergic beta-Agonists↗
PubMed1981

Demonstration of both beta 1- and beta 2-adrenoceptors mediating relaxation of isolated ring preparations of rat pulmonary artery.

1 Cumulative concentration-response (relaxation) curves to three beta-adrenoceptor agonists, fenoterol (beta 2-selective), isoprenaline (non-selective) and noradrenaline (beta 1-selective) were obtained on isolated ring preparations of rat pulmonary artery contracted with 15 mM KCl. alpha-Adrenoceptors and neuronal and extraneuronal uptakes were blocked with phenoxybenzamine. The agonist concentration-response curves were reproducible. 2 Responses to each of the three agonists could be blocked by the beta-adrenoceptor antagonists atenolol (beta 1-selective) or ICI 118,551 (beta 2-selective) confirming the presence of beta-adrenoceptors. 3 The relative potencies of the agonists were isoprenaline : fenoterol : noradrenaline = 100 : 38 : 1.4. This indicated that the predominant beta-adrenoceptor type was beta 2. 4 Schild plots were obtained for atenolol and ICI 118,551 using the three different agonists. For each antagonist the location of the Schild plot varied depending on which agonist was used. This indicated that the beta-adrenoceptor population mediating relaxation responses to beta-adrenoceptor agonists was not homogeneous. 5 Atenolol was most potent when noradrenaline was the agonist and ICI 118,551 was most potent when fenoterol was the agonist. 6 It is concluded that isolated pulmonary artery ring preparations of the rat contain a mixed population of beta 1- and beta 2-adrenoceptors both mediating relaxation.

Adrenergic beta-Agonists↗
PubMed1981

A study designed to explore the hypothesis that beta-1 adrenoceptors are "innervated" receptors and beta-2 adrenoceptors are "hormonal" receptors.

It has been demonstrated that the chronotropic responses to sympathomimetic amines in rat atria were mediated only by beta-1 adrenoceptors. This was like guinea pig (beta-1) but unlike cat (beta-1 and beta-2). Extraneuronal uptake of isoproterenol into rat atrial myocardial cells was detected by fluorescence histochemistry but uptake was less than was seen in cat atria. Furthermore, it did not modulate responses of rat atrial preparations to isoproterenol. The lack of specific extraneuronal uptake in guinea-pig atrial myocardial cells was confirmed. Collation of data on the atria of these three species with data already available on guinea-pig trachea allowed the following conclusions. All four tissues contained a population of beta-1 adrenoceptors and were adrenergically innervated. Beta-2 adrenoceptors were present in cat atria and guinea-pig trachea and these tissues possessed a functionally effective extraneuronal metabolizing system for catecholamines. Beta-2 adrenoceptors were not detected in guinea-pig or rat atria and in these tissues extraneuronal uptake was either absent (guinea pig) or not functionally effective (rat). It is suggested that these data could support the hypotheses that 1) beta-1 adrenoceptors are "innervated" receptors mediating responses to neuronally released norepinephrine, whereas beta-2 adrenoceptors are "hormonal" receptors mediating responses to circulating epinephrine and 2) extraneuronal metabolizing systems are of particular importance in the dissipation of circulating catecholamines acting on beta-2 adrenoceptors.

Adrenergic beta-Agonists↗
PubMed1980

The use of guinea pig K+-depolarized tracheal chain preparations in beta-adrenoceptor studies.

Guinea pig tracheal chain preparations were K+-depolarized using Krebs solution in which all the Na+ was replaced by an equivalent amount of K+. This caused a sustained contraction of the preparations. Reproducible concentration-response (relaxation) curves to isoprenaline could be obtained provided that the preparations were repolarized by washing in normal Krebs solution between curves. pA2 values for propranolol (8.30) and butoxamine (5.89) were in good agreement with values obtained on other types of tracheal preparation. The maximum relaxation to salbutamol was less than that to isoprenaline and the maxima to both drugs were less than the maximum relaxation of the tissue (to papaverine). It is suggested that K+-depolarized tracheal preparations have no beta-adrenoceptor reserve and may, therefore, be useful in studies designed to compare the efficacies of beta-adrenoceptor agonists.

Animals↗
PubMed1980

A study of some propranolol analogues for selective beta-adrenoceptor antagonism using A2 values on isolated trachea and atria from guinea-pig.

1 PA2 values for beta-adrenoceptor antagonists were obtained on isolated preparations of guinea-pig trachea (intrinsic tone) and atria (rate), with isoprenaline, noradrenaline (beta 1-selective) and fenoterol (beta 2-selective) as agonists. Uptake mechanisms and alpha-adrenoceptors were inhibited. The antagonists studied were (+/-)-threo-alpha-methylpropranolol. (+/-)-1(4-benzimidazoloxy)-3-isopropylamino-2-propanol (4-BIP) and (+/-)-1-(5-benzimidazoloxy)-3-isopropylamino-2-propanol (5-BIP). 2 4-BIP was a potent beta-adrenoceptor antagonist but it was not selective for trachea (pA2 on trachea 7.88 and on atria 7.73, fenoterol as agonist). 5-BIP was less than one tenth as active as 4-BIP and was therefore not studied in detail. 3 alpha-Methylpropranolol was potent and it was also selective for trachea (pA2 on trachea 8.24 and on atria 7.56, fenoterol as agonist). This selectivity was not seen with isoprenaline as agonist. In tracheal preparations contracted by carbachol the slope of the Schild plot for alpha-methylpropranolol was less than 1.0 (isoprenaline as agonist). 4 alpha-Methylpropranolol, although not highly selective for beta 2-adrenoceptors, is considerably more potent than the alternative beta 2-selective antagonists available at present. Therefore, it may be useful in studies designed to classify beta-adrenoceptor subtypes in tissues.

Adrenergic beta-Antagonists↗