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Biomedical subjects

D J Triggle

Publications and source records attributed to D J Triggle.

At least 181 records · Page 10Linked to original sources
PubMed1979

Calcium antagonists and contractile responses in rat vas deferens and guinea pig ileal smooth muscle.

The effect of depletion of extracellular Ca2+ (Ca2+ext) on the loss of responsiveness of the guinea pig ileal longitudinal muscle (g.p.i.l.m.) and the rat vas deferens (r.v.d.) to K+ and cis-2-methyl-4-dimethylaminomethyl-1,3-dioxolane methiodide (CD), and K+ and noradrenaline (NA), has been examined and compared with the effects of a variety of local anesthetics and calcium antagonists. The results indicate that qualitative similarities are apparent with respect to the dependence of agonist-induced activity on Ca2+ext in both the g.p.i.l.m. and r.v.d. Distinct differences, however, in the Ca2+ translocation processes in these two tissues, in response to the different agonists, can be shown by the use of a variety of 'calcium antagonists' thus indicating that such translocation processes are both tissue and agonist selective. It is thus noted that, contrary to the Ca2+ depletion studies, D 600 and the usually more potent BAY-1040 showed no discrimination of action or potency in their ability to inhibit components of the NA response in the r.v.d. In contrast, D 600 and the more potent BAY-1040 selectively inhibited the tonic component of the K+ response. Treatment with SKF 525A and parethoxycaine (PC) in the g.p.i.l.m. and SKF 525A in the r.v.d. resulted in a nonselective inhibition of responses of the tissues to all stimulants. However, in the r.v.d. PC potentiated NA action, and its methobromide (MeBr) derivative potentiated both NA and K+ action and also, like PC, partially shifted to the left the dose-response curve to Ca2+ in NA-depolarizing Ca-free Tyrode's. The quaternary MeBr and the tertiary 2-chloroethyl (2Cl) derivatives of SKF 525A and PC were selectively more effective against CD- than K+ supported contractile activity in the g.p.i.l.m. and the 2Cl derivatives were more effective against NA than K+ responses in the r.v.d. The 2Cl derivative of PC also was more effective in antagonizing the Ca2+ dose-response curve in high-CD or high-NA than in high-K+ Ca2+-free Tyrode's.

Animals↗
PubMed1978

Molecular properties of the adrenergic alpha-receptor. I--Structural requirements for specific covalent occupancy by N,N'-bis--(5-aminopentyl)cystamine derivatives.

The synthesis and alpha-adrenoreceptor blocking activity of several substituted analogs of the prototype alpha-blocker N,N'-bis-(5-aminopentyl)cystamine (APC) are described. The three optical forms of the analog carrying methyl groups on the carbons alpha- to the sulfurs were synthesized and shown to be equipotent and somewhat less active than APC. The omega, omega'-bis-guanidino analog of APC was less active. Significant improvement in potency was observed only with APC analogs carrying benzyl and substituted benzyl groups on the terminal nitrogens. Linking the terminal nitrogens of APC with a p.xyledenyl group so as to give the 26-membered analog caused a sharp drop in activity. The significance of these results as regards the alpha-receptor topography is discussed.

Adrenergic alpha-Antagonists↗
PubMed1977

The action of diazoxide analogs on aortic reactivity in normotensive and spontaneously hypertensive rats.

Diazoxide and four related 1,2,4-benzothiadiazines reduced the maximum responses to noradrenaline (NA) and KCl in aortic rings from normotensive and spontaneously hypertensive rats (SHR). These agents were more active against NA than against KCl responses, and more effective against either NA or KCl responses in aortae from hypertensive animals. Further studies with V (3-cyclopentenyl-6,7-dichloro-1,2,4-benzothiadiazine-1,1-dioxide), the most active member of the series, showed it to be significantly more effective against NA responses; when calcium was added to calcium-free solutions containing eith NA or KCl, V was more effective in inhibiting either response in SHR aortae and was about 100 times more effective in inhibiting the calcium-NA responses. These data are consistent with previous findings that vascular smooth muscle from normotensive and SHR differs in sensitivity to diazoxide. However, the site(s) at which this difference is exhibited remains to be elucidated.

Animals↗
PubMed1976

Calcium and the muscarinic receptor.

Pharmacological receptors may be viewed as composed of two linked functions, a recognition site through which the specificity and selectivity of ligand action is expressed and an amplification or catalytic site which translates the ligand-recognition site interaction into response. The successful elucidation of receptor mechanisms requires analysis of both sites. The muscarinic cholinergic receptors of guinea-pig ileal longitudinal smooth muscle will be discussed from this two function stand point and the source and utilization of Ca2+ in excitation-contraction coupling discussed.

Acetylcholine↗
PubMed1976

An analysis of the action of cations of the lanthanide series on the mechanical responses of guinea-pig ileal longitudinal muscle.

1. The inhibitory effects of lanthanide cations (Ln3+) on mechanical responses and 45Ca uptake in guinea-pig ileal longitudinal smooth muscle were studied. 2. Ln3+ strongly inhibited the phasic and tonic component of the response to the muscarinic agonist cis-2-methyl-4-dimethylaminomethyl-1,3-dioxolane methiodide (CD) the two components being affected to the same extent. Inhibition was also obtained for the responses evoked by high K+ but here the effect was mainly on the phasic response, the tonic component was merely delayed. 3. Other members of the Ln3+ series, with the exception of cerium, were found to be more effective than lanthanum in their ability to inhibit the CD response. Thulium, Tm3+, the thirteenth member of the series was the most effective cation. 4. Analysis of 170Tm uptake revealed at least two components. The concentration-dependence of one component, saturating at 2-5 x 10(-6) Tm, corresponded closely to that of the inhibitory effect of Tm3+ on contraction. 5. 170Tm uptake as a function of time showed a secondary rise after 30 min of exposure to the lanthanide. 6. Although 2-5 x 10(-6) M-Tm3+ produced 90% inhibition of the CD and the high K+ induced responses significant reduction of 45Ca uptake by the muscle was only detected when much higher Tm3+ concentrations (greater than or equal 10(-3) M-Tm3+) were used. 7. It is concluded that Ln3+ combine with membrane sites specifically involved in Ca2+ translocation during excitation-contraction coupling.

Animals↗
PubMed1976

The effects of lanthanum and thulium on the mechanical responses of rat vas deferens.

1. The contractile responses of rat vas deferens to noradrenaline and K+ are composed of phasic and tonic components both of which are dependent upon the concentration of extracellular Ca2+. 2. Lanthanum, La3+, and thulium ions, Tm3+, inhibited the noradrenaline and K+ induced responses, complete inhibition being obtained at approximately 10(-3) M-Ln3+. 3. La3+ and Tm3+ were equally effective in inhibiting noradrenaline and K+ responses. The phasic and tonic components of the noradrenaline response were equally sensitive to lanthanide cations, Ln3+, but the phasic component of the K+ response was more sensitive than the tonic component. 4. 170Tm binding did not show any saturable component over the concentration range in which inhibition of the pharmacological response was obtained. 5. It is suggested that the actions of Ln3+ in the rat vas deferens are mediated through some kind of membrane stabilization rather than via a specific Ca2+ binding site concerned with excitation-contraction coupling, the mechanism previously postulated for the Ln3+ action in guinea-pig ileal longitudinal muscle.

Animals↗
PubMed1975

The action of the ionophores, X-537A and A-23187, on smooth muscle.

The cation ionophore X-537A in the concentration range of 10(-6) to 3 X 10(-5) M produced contractions in the rat and guinea-pig vas deferens. No contractile effect was produced in either of the vasa deferentia preparations by the ionophore A-23187 in the concentration range of 10(-7) to 5 X 10(-5) M. In contrast, X-537A had no contractile effect on the guinea-pig ileal longitudinal smooth muscle while A-23187 produced a dose and [Ca2+] dependent contraction. The contractile effect of X-537A in the vasa deferentia preparations is abolished by phenoxybenzamine or prior reserpine treatment and is therefore attributed to the release of norepinephrine. The effect of A-23187 in the intestinal smooth muslce is attributed to a direct Ca2+ transporting action since its contractile effect is unaffected by histamine, acetylcholine, or 5-hydroxytryptamine antagonists.

Animals↗
PubMed1975

Intestinal smooth muscle contraction and the effects of cadmium and A23187.

Pretreatment of the guinea-pig ileal longitudinal muscle preparation with cadmium (Cd++) in the concentration range 5 to 1000 muM resulted in an inhibition of the phasic and tonic contractions induced by both high potassium and the muscarinic agonist, cis-2-methyl-4-dimethylaminomethyl-1,3-dioxolane methiodide. The K+ contracture was significantly more sensitive to the inhibitory action of Cd++ in the concentration range 5 to 100 muM, but not at concentrations of Cd++ above 100 muM. Low concentrations of Cd++, 0.1 to 0.01 muM, were found to increase by an atropine-sensitive mechanism, the spontaneous activity of approximately 50% of the preparations tested. It was also shown that the ionophore A23187 produced a concentration-dependent contraction in the guinea-pig ileal longitudinal muscle that was dependent upon the presence of extracellular calcium. When 1.8 mM Cd++ was added to a tissue that had been incubated in Ca++-free media for 60 minutes and pretreated with 5 muM A23187 for 15 minutes, a slow contractile response was recorded. Similar, but significantly smaller, contractions were also recorded when 1.8 mM Ca++, Mn++, Sr++, Pb++ and Ba++, but not when Co++, Ni++, Hg++, UO2++, and Tm++ and Th++++ were administered. It was concluded that the contractile action of these cations was dependent on ionic radius, hydration energy, valency and, perhaps, coordination number, and was due to the intracellular entry of the cation where it resulted in the release of bound Ca++ and/or directly activated the smooth muscle troponin system.

Animals↗