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At least 397 records · Page 22Linked to original sources
PubMed1988

Characterization of cholinergic muscarinic receptors in the rabbit iris.

The sphincter smooth muscle of the iris is innervated by excitatory parasympathetic nerve fibers, and the activation of these fibers results in the breakdown of phosphatidylinositol 4,5-bisphosphate into its derived second messengers, myosin light chain phosphorylation and muscle contraction. The present study characterizes the muscarinic acetylcholine receptors (mAChRs) of the rabbit iris employing [3H]N-methylscopolamine ([3H]NMS) and L-[3H]quinuclidinyl benzilate ([3H]QNB) as probes. Binding studies indicated that [3H]NMS and [3H]QNB bound to homogeneous populations of mAChRs with apparent Bmax values of 0.67 and 1.09 pmol/mg protein respectively. Binding of radioligands was rapid, saturable, stereospecific, reversible, and inhibited by specific muscarinic agonists and antagonists in a competitive manner. [3H]NMS displayed a lower amount of nonspecific binding and a faster association and dissociation rate than [3H]QNB. The relative potencies for displacement of both radioligands, based on their Ki values, were (-)QNB greater than atropine greater than (+)QNB greater than pirenzepine greater than pilocarpine. Antagonist displacement of the radioligands appeared to obey the law of mass action, indicating interaction with a single binding site. However, displacement of the radioligands by the agonists carbamylcholine and methacholine indicated interaction with both high and low affinity binding sites. Comparison of the displacement of [3H]NMS and [3H]QNB by pirenzepine in microsomal fractions from rabbit iris, ileal muscle and cerebral cortex revealed the presence of a single subtype of mAChR in the iris which had an affinity for PZ that was slightly higher than that of ileal M2 receptors, but lower than that of brain M1 receptors. This suggests that the mAChRs in the iris may represent a subclass of receptors within the M2 subtype, or they may constitute an entirely different subtype of mAChRs.

Animals↗
PubMed1989

Modulation of oxidative stress in the gastrointestinal tract and effect on rat intestinal motility.

The amounts of different factors, which are involved in oxygen free radical production or in protection against oxygen radicals, were determined in different parts of the gastrointestinal tract (GI-tract). Glutathione and superoxide dismutase were present in lower amounts within the small intestine compared with the stomach and the large intestine. In the small intestine glutathione peroxidase and catalase both prevailed in the intestinal muscle compared to the mucosa, whereas in the large intestine both enzymes are equally distributed among the mucosa and muscle. Xanthine oxidase was mainly present in the small intestinal mucosa. Taken together, these results suggest that the large intestine is better provided with protective enzymic and non-enzymic factors against oxidative stress than the small intestine. The protective capacity of different intestinal preparations against lipid peroxidation in liver microsomes was assessed, and particularly the mucosal fractions from the small intestine showed a marked protection against lipid peroxidation, which is not easily explained with the presence of the enzymes measured in this study. Pretreatment of intestinal segments with hydrogen peroxide or cumene hydroperoxide resulted in a damaged contractile response of the longitudinal smooth muscle to methacholine in all parts of the GI-tract, expressed in a lower pD2 value and a decreased maximal response. Pretreatment with these peroxides also decreased contractions after depolarization with K+. The large intestine is more sensitive to hydrogen peroxide and cumene hydroperoxide than the small intestine, which parallels with the sensitivity to lipid peroxidation. The results obtained with hydrogen peroxide also correlate well with the catalase activity in the various segments of the intestine. In conclusion, oxidative stress in the GI-tract alters intestinal motility, especially in the large intestine. Probably this does not occur at the level of muscarinic receptors.

Animals↗
PubMed1990

Partial characterization of cyclic AMP-dependent protein kinases in guinea-pig lung employing the synthetic heptapeptide substrate, kemptide. In vitro sensitivity of the soluble enzyme to isoprenaline, forskolin, methacholine and leukotriene D4.

This paper describes the partial characterization of soluble cyclic AMP-dependent protein kinase (A-kinase) in guinea-pig lung using Kemptide, a synthetic serine-containing heptapeptide, and examines the sensitivity of this enzyme to drugs which are reported to increase and to decrease the intracellular concentration of cyclic AMP. Differential centrifugation of lung homogenates revealed that 78% of A-kinase was present in the 31,000 gmax x 15 min supernatant fraction. Both basal and cyclic AMP-stimulated phosphotransferase activity of this 'soluble' enzyme were abolished by the heat-stable inhibitor of A-kinase. Soluble A-kinase was Mg2(+)-dependent (apparent Km and and Kact 8.6 and 2.6 mM, respectively) and was stimulated nine-fold by saturating concentrations of both cyclic AMP (Kact: 131 nM) and cyclic GMP (Kact: 28.7 microM) at a protein (enzyme) concentration of 1.3 micrograms. Kinetic analysis of the effect of Kemptide and ATP revealed linear, Hanes plots with Michealis constants of ca. 12 and 13 microM, respectively. Chromatography of the soluble enzyme over DEAE-cellulose resolved three peaks of catalytic activity when fractions were assayed in the presence of cyclic AMP (10 microM): (i) free catalytic subunits (5%), (ii) Type I isoenzyme (5%) and (iii) Type II isoenzyme (90%). The A-kinase activity ratio was markedly increased in lung pre-treated with the smooth muscle relaxants isoprenaline and forskolin. This biochemical effect was both time- and concentration-dependent and was temporally associated with the ability of these drugs to reduce lung parenchymal tone. In contrast, the contractile agonists, methacholine (Mch) and leukotriene (LT) D4 exerted opposite effects on A-kinase activity. Thus, Mch significantly reduced cyclic AMP levels and lowered basal A-kinase activity whilst the converse was true for LTD4. For both drugs this biochemical effect accompanied contraction of the lung. Pre-treatment of lung tissue with flurbiprofen, an irreversible inhibitor of cyclo-oxygenase in vitro, abolished the ability of LTD4 to increase the A-kinase activity ratio suggesting that this biochemical response was mediated indirectly through the stimulated biosynthesis and release of a prostanoid(s) able to activate adenylyl cyclase; the increase in tension induced by LTD4, however, was not significantly affected by flurbiprofen pre-treatment. Collectively, these data support the concept that soluble A-kinase activity in guinea-pig lung can be regulated by changes in intracellular cyclic AMP and that activation and/or inhibition of this biochemical cascade may influence alterations in lung contractility.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine Triphosphate↗
PubMed1979

Pharmacological characterization of adrenal paraneurons: substance P and somatostatin as inhibitory modulators of the nicotinic response.

A pharmacological study was made of the effects of various muscarinic and nicotinic agonists and their antagonists on the release of [3H]noradrenaline ([3H]NA) from cultures of isolated bovine adrenal medullary cells. A study was also made of the effects of substance P and somatostatin on the release of [3H]NA evoked by nicotinic agonists. By 2 days in culture these adrenal 'paraneurons' had developed long varicose processes with growth cones and generally resembled noradrenergic neurons in culture. In the present study, adrenal paraneurons were incubated with [3H]NA which was taken up and stored in reserpine-sensitive sites. Exposure of the cultures to acetylcholine (ACh) resulted in release of [3H]NA into the external medium. High concentrations of K+ (56 mM) also evoked release of [3H]NA. The release of [3H]NA induced by ACh or K+ (56 mM) was Ca2+-dependent. Pharmacological studies with nicotinic (ACh, nicotine) and muscarinic (methacholine, pilocarpine) agonists and their antagonists (mecamylasmine, d-tubocurarine, hexamethonium; and atropine, scopolamine, respectively) showed that the adrenal paraneurons contained only nicotinic receptors. Substance P produced a dose-dependent inhibition of ACh (5 x 10(-5) M) stimulated [3H]NA release in the range of 10(-8) to 5 x 10(-5) M with an ID50 of 10(-6) M. A similar inhibition of NA release by substance P was obtained when nicotine (K X 10(-6) M) was used as the agonist, but not when K+ (50 MM) was used to depolarize the cells. Substance P (10-10) to 5 x 10(-5) M) by itself did not have a significant effect on the basal release rate of [3H]NA from these cells. Somatostatin at relatively high concentrations (10(-6)-10(-3) M; ID50 2 x 10(-5) M) inhibited the release induced by ACh, but not by K+ (56 mM). The present results provide the first direct evidence at a cellular level that substance P and somatostatin act as inhibitory modulators of the nicotinic ACh response, and support a role for these peptides as inhibitory neuromodulators at nicotinic receptor sites in the nervous system.

Acetylcholine↗
PubMed1987

A comparison of histamine and methacholine bronchial challenges using the DeVilbiss 646 nebulizer and the Rosenthal-French dosimeter.

We have compared bronchial challenge with both histamine and methacholine for the tidal breathing method and dosimeter method, using the DeVilbiss 646 nebulizer, in 18 patients with asthma. There was a significant difference between the PC20 FEV1 but not the PD20 FEV1 when either agonist was administered by the different techniques but not by the same method.

Adult↗
PubMed1988

The effect of nifedipine on bronchial reactivity to inhaled histamine and methacholine: a comparative study in normal and asthmatic subjects.

The effect of pretreatment with nifedipine 20 mg sublingually on the bronchoconstrictor response to inhaled histamine and methacholine in asthmatic and normal subjects has been studied. For each agonist the provocation concentration required to produce a 15% fall in FEV1 (PC15) and a 35% fall in specific conductance (PC35) was determined. In the group of asthmatic subjects the responses to histamine were significantly attenuated by histamine, PC15 increasing from 0.29 mg/ml to 0.68 mg/ml (P less than 0.001) and PC35 increasing from 0.25 mg/ml to 0.58 mg/ml (P less than 0.001). Responses to methacholine showed less modification by nifedipine. PC15 increased from 0.23 mg/ml to 0.32 mg/ml (P less than 0.05). Changes in PC35 were not significant. In the group of normal subjects no attenuation of the response to methacholine was produced by nifedipine but significant increases of PC15 (P less than 0.002) and PC35 (P less than 0.005) were produced by the agent. The results are consistent with nifedipine exerting an effect principally on mediators dependent on external calcium sources for stimulus-contraction coupling in the airways. The magnitude of change in the histamine response of the two groups was similar, suggesting calcium dependent mechanisms are not involved in asthmatic hyper-responsiveness.

Adult↗