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Biomedical subjects

D J Triggle

Publications and source records attributed to D J Triggle.

At least 163 records · Page 9Linked to original sources
PubMed1982

Benzilylcholine mustard and spare receptors in guinea pig ileum.

A comparison was made of muscarinic receptor occupancy by the irreversible antagonist benzilylcholine mustard (BCM) as determined from shifts in the dose-response curve to a muscarinic agonist and from 3H-QNB binding to homogenates of BCM-treated tissue. Major discrepancies were found. A low concentration of BCM (3x10-8M/15 min.) produced a parallel dose-response curve shift corresponding to 98-99% receptor occupancy by BCM, whereas 3H-QNB binding revealed only 48% receptor occupancy. Possible origins of this discrepancy are discussed. High concentrations of BCM (5x10-5M, 15 min.) fail to completely alkylate all 3H-QNB binding sites even though response is completely lost. Although significant (64%) recovery of response occurs after prolonged tissue washing (240 min.) this is not accompanied by an increase in 3H-QNB binding. The small fraction (approximately 5%) of sites inaccessible to BCM and with reduced affinity for 3H-QNB may represent a subpopulation of muscarinic receptors.

Animals↗
PubMed1982

gamma-Aminobutyric acid action in guinea-pig ileal myenteric plexus.

The responses of the guinea-pig ileum myenteric plexus-longitudinal muscle preparation to gamma-aminobutyric acid (GABA) and several analogs were examined in direct and electrically stimulated preparations. GABA, muscimol and 3-aminopropane sulfonic acid (3-APS), but not baclofen, produced a transient, concentration-dependent contraction followed by relaxation. These responses were antagonized by atropine, tetrodotoxin, bicuculline methiodide and picrotoxin. Responses to GABA and 3-APS exhibited a marked tachyphylaxis. GABA and baclofen, but not muscimol or 3-APS, exerted a relaxant effect on contractions induced by supramaximal field stimulation in the longitudinal muscle. These responses were insensitive to bicuculline, bicuculline methiodide and picrotoxin, and were unaffected by other pharmacological agents including adrenergic, cholinergic and histamine antagonists. The results suggest that GABA and its analogs act at a population of excitatory receptors mediating the release of acetylcholine from enteric neurons, and at a population of inhibitory receptors which inhibit the stimulated release of acetylcholine.

Amino Acids↗
PubMed1982

Inhibition by D 600 of norepinephrine- and clonidine-induced responses of the aortae from normotensive (WKY) and spontaneously hypertensive rats (SHR).

Comparison was made of the inhibition by D 600 of the norepinephrine (NE)- and clonidine-induced responses of aortic strips from normotensive (WKY) and spontaneously hypertensive rats (SHR). Clonidine-induced responses of aortae from both strains of rats were markedly more susceptible to inhibition by D 600 than those of NE. Omission of calcium from the physiological solution resulted in a greater reduction in response to clonidine. Aortae from SHR were less susceptible to inhibition by D 600 but showed no difference from WKY rats in their responses in nominally calcium-free physiological solutions. Our results clearly indicate a greater dependence on extracellular calcium by clonidine-induced responses of the aortae relative to those of NE.

Animals↗
PubMed1982

Crystal structures and pharmacological activity of calcium channel antagonists: 2,6-dimethyl-3,5-dicarbomethoxy-4-(unsubstituted, 2-methyl-, 4-methyl-, 3-nitro-, 4-nitro-, and 2,4-dinitrophenyl)-1,4-dihydropyridine.

The molecular structures of 2,6-dimethyl-3,5-dicarbomethoxy-4-phenyl-1,4-dihydropyridine and the 3-methyl-, 4-methyl-, 3-nitro-, 4-nitro-, and 2,4-dinitrophenyl derivatives were determined by X-ray diffraction methods. The dihydropyridine ring in each of the compounds exists in a boat-type conformation. However, the degree of ring puckering varies among the compounds. The observed ring distortions were found to be influenced to a great extent by the position of the substituent in the 4-phenyl ring and the conformation about the interring bond. The distortion at the apical nitrogen of the dihydropyridine ring was found to be linearly related to that at the apical tetrahedral carbon. A correlation was observed between the pharmacological activities of this class of calcium channel antagonists, determined by their ability to inhibit the Ca2+-dependent muscarinic mechanical responses of guinea pig ileal longitudinal smooth muscle, and the magnitude of the 1,4-dihydropyridine ring puckering; the more active compounds exhibited the smallest degree of ring distortion from planarity.

Calcium Channel Blockers↗
PubMed1982

Muscarinic receptors in guinea pig ileum. A study by agonist--3H-labelled antagonist competition.

A series of muscarinic agonists (n = 18) derived from dioxolane, furan, piperidine, and thiacyclohexane ring structures which have a degree of conformational restraint have been examined in guinea pig ileal smooth muscle. Binding to muscarinic receptors was determined by competition with 3H-labelled (-)-quinuclidinyl benzilate. Agonist binding was characterized by shallow displacement curves and Hill coefficients (nH) of less than 1. Binding (K1) was resolved into high (K1) and low (K2) affinity components. Correlations between drug-receptor binding and pharmacological activity were examined. A good correlation was found between K1 and K2 (pK1 = 1.33 X pK2 - 0.1), suggesting that the structural requirements for binding at low and high affinity sites are similar. Good correlations also exist between pK1 and pD2 (pK1 = 0.63 X pD2 + 1.27, furans and dioxolanes; pK1 = 0.71 X pD2 + 1.30, piperidines and thiacyclohexanes) confirming that a pharmacologically potent agonist has a high binding affinity. Although K1 represents only an "average" binding affinity its correlation with pD2 is better than those between pK1 or pK2 and pD2. The significance of these several correlations is discussed and some general limitations to the correlation of binding and response data at pharmacological receptors are noted.

Animals↗
PubMed1982

Calcium-channel antagonist binding to isolated vascular smooth muscle membranes.

The binding characteristics of the calcium-channel antagonist nitrendipine, an analog of nifedipine, have been measured in plasma membrane enriched microsomal fractions from the canine thoracic aorta, canine mesenteric artery, and rat mesenteric artery. The dissociation constants, KD, for the high-affinity binding sites were, respectively, 0.308, 0.254, and 0.101 nM and Bmax values for binding capacity were 20.3, 25.0, and 18.0 fmol/mg of microsomal protein. Studies with isolated tissues, in which the sensitivity of the high potassium mechanical response to nitrendipine was determined, indicate that the apparent KD for nitrendipine in the canine mesenteric artery, as reflected by the IC50 (mean inhibition constant) value, is 4.5-5.3 nM and for the rat mesenteric artery 2.5-6.6 nM.

Animals↗
PubMed1982

Inhibition by methoxyverapamil of the responses of smooth muscle from spontaneously hypertensive and normotensive rats.

Inhibition by methoxyverapamil (D 600) of the responses to norepinephrine (NE) and KCl of vascular (carotid and iliac arteries and aortae) strips and vasa deferentia from spontaneously hypertensive (SHR) and normotensive rats (WKY) were compared. The responses of aortic and carotid arterial strips from SHR to NE and KCl were inhibited to a lesser extent by low concentrations of D 600 (less than 10(-6) M). The isolated preparations of the iliac arteries and the vasa deferentia showed no differences in their susceptibility to inhibition by D 600. The responses to NE and KCl in calcium-free solutions of vascular strips from WKY were generally resistant to inhibition by D 600 (10(-6) M) in contrast to those from SHR which were markedly inhibited by D 600. Our results demonstrate that while the inhibitory action of D 600 on calcium movement may succeed in distinguishing vascular responses of SHR from those of WKY, the inhibitory pattern varies with different tissues and with experimental variations of calcium levels.

Animals↗
PubMed1981

Stereoselective and non-stereoselective effects of D 600 (methoxyverapamil) in smooth muscle preparations.

Mechanical responses in guinea-pig ileal longitudinal, rat vasa deferentia and rat portal vein smooth muscle strips elicited by receptor activation (muscarinic or alpha-adrenergic) or by K+ depolarization were blocked by D 600 (methoxyverapamil). Stereoselectivity was observed with the (-)-enantiomer being more potent than the (+)-enantiomer (the ratio varying from 6 to 180). The tonic (slow) component of response was more sensitive than the phasic (fast) component. D 600 competitively blocked binding of (-)-[3H]QNB and [3H]WB 4101 to muscarinic and alpha-adrenergic receptors respectively, but in marked contrast to the effects on mechanical responses antagonism of ligand binding was non-stereoselective. It is suggested that stereoselectivity of action of D 600 may be a useful criterion to distinguish between its several sites of action.

Animals↗
PubMed1981

Mechanisms of contraction induced by partially purified slow reacting substance from human polymorphonuclear leukocytes and leukotriene D in guinea pig ileal smooth muscle.

On the basis of the experiments described here, we suggest that the mechanism of action of SRS in guinea pig ileal longitudinal muscle is very similar to that used by other agonists in this preparation, namely interactions at a specific receptor to activate Ca++ channels leading to Ca++ influx and mechanical response. SRS responses differ in 1 important respect from those produced by other agonists. SRS and leukotriene D cause the generation of a slower contraction, which has a greater resistance to reversal by washing. The basis for this unique and prolonged duration of action is unknown but may represent an exceptionally tight, or even irreversible, association with a membrane component. Current studies on the structure of SRS may be helpful in this regard. Although not definitive, this report clearly indicates that a SRS "receptor" is, in fact, present on smooth muscle and that it utilizes a pool of calcium channels common to all smooth muscle agonists.

Animals↗
PubMed1980

Crystal structures of calcium channel antagonists: 2,6-dimethyl-3,5-dicarbomethoxy-4-[2-nitro-, 3-cyano-, 4-(dimethylamino)-, and 2,3,4,5,6-pentafluorophenyl]-1,4-dihydropyridine.

The crystal structures of 2,6-dimethyl-3,5-dicarbomethoxy-4-(2-nitrophenyl)-1,4-dihydropyridine (Nifedipine) and the 3-cyano-, 4-(dimethylamino)- and 2,3,4,5,6-pentafluorophenyl derivatives were determined. The 1,4-dihydropyridine ring in all four compounds has a boat-type conformation with varying degrees of puckering at the C4 position. Increasing distortion from planarity at this position shows a limited correlation with decreasing biological activity, determined as the ability to inhibit the Ca2+-dependent muscarinic-induced mechanical responses of guinea pig ileal longitudinal smooth muscle.

Animals↗
PubMed1980

Responses to noradrenaline of portal vein strips from normotensive and spontaneously hypertensive rats.

1 Responses to noradrenaline of isolated portal vein strips from 5-7 week and 15-17 week Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) have been examined. 2 15-17 week SHR tissue exhibited a greater sensitivity (lower ED50) to noradrenaline but only at reduced Ca2+EXT levels. 3 pA2 values for the alpha-adrenoreceptor antagonists WB 4101 and prazosin were significantly lower in 5-7 week SHR consistent with some change at the adrenoreceptor level. 4 Veins from SHR relaxed more rapidly in CA2+-free saline following removal of noradrenaline than did veins from WKY. 6 D600 is a competitive antagonist of the Ca2+EXT-dependent component of the noradrenaline response but K1 values were not significantly different in SHR and WKY.

Adrenergic alpha-Antagonists↗
PubMed1980

The responses of carotid vascular strips from spontaneously hypertensive and normotensive rats.

The responses to noradrenaline (NA) and KCl of carotid arterial strips from spontaneously hypertensive rats (SHR) and three strains of normotensive rats (NR) were compared using tissue obtained from young (5--7 weeks) or older (15--17 weeks) rats. The maximum responses and sensitivity of strips from SHR were less than those of NR in both age groups. Relaxation of maximum NA-induced responses was consistently faster, and relaxation of KCl-induced responses generally slower with strips from SHR. Carotid strips from young SHR showed a greater dependence on extracellular calcium in their responses to NA and a lesser dependence in their KCl-induced responses than tissues from NR. We conclude that the smooth muscle of carotid arteries from SHR differs intrinsically from that of NR and that the differences in vascular responses may be related to altered excitation-contraction processes in the SHR.

Animals↗
PubMed1980

The reactivity of iliac vascular strips from spontaneously hypertensive and normotensive rats.

Comparison of responses to norepinephrine (NE) and KCl of iliac arterial strips from spontaneously hypertensive rats (SHR) and three strains of normotensive rats (NR) were made in tissues obtained from 5- to 7- and 15- to 17-week-old animals. The systolic blood pressures of young rats were essentially similar while the 15- to 17-week-old SHR had markedly higher blood pressures than their normotensive counterparts. The contractility and sensitivity of strips to NE from SHR were less than those from NR in both age groups. Relaxation of NE-induced responses in normal physiological or calcium-free solutions was consistently more rapid with SHR tissues. In calcium-free solution, the fast component of responses to NE was smaller in young SHR; no difference in dependence on calcium was seen in tissues from older rats. Differences in KCl-induced responses were seen only in young animals, where reduced contractility and slower relaxation in normal physiological solutions were obtained with strips from SHR. We conclude that the iliac artery from SHR differs intrinsically from those of NR since the differences in responses were evident in young rats prior to the development of stable hypertensive state in the SHR.

Aging↗
PubMed1980

Pharmacology of agents that affect calcium. Agonists and antagonists.

Calcium utilization by smooth muscle is briefly reviewed. A variety of stimulant-evoked calcium mobilization processes exist including utilization of intracellular Ca2+ and translocation of Ca2+ through voltage-sensitive and insensitive channels. The extent of use of these several sources is both stimulant and tissue-dependent and it is probable that most smooth muscle excitation-contraction coupling processes employ more than a single Ca2+ source. A large number of agents have been described as "Ca2+-antagonists" and ideally there would exist antagonists specific for each mobilization process. This does not appear to be the case and the structural diversity of the many antagonists is consistent with multiple modes of action. Prominent among the Ca2+ antagonists are agents as verapamil, D600 and nifedipine which have as one component of their action inhibition of voltage sensitivie Ca2+ channels. However, the mechanisms by which these agents act are unknown and it is also clear that they have important effects at sites other than Ca2+ channels.

Action Potentials↗