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Biomedical subjects

E M Williams

Publications and source records attributed to E M Williams.

At least 91 records · Page 5Linked to original sources
PubMed1973

The effects on cardiac muscle and nerve of a fluorinated decahydroquinoline derivative, L7810, rapidly absorbed after oral administration.

1. L7810 (4-carbamoyloxy-1-(4-(4-fluorophenyl)-4-oxobutyl) decahydroquinoline, has a local anaesthetic action on frog nerve 1.75 times that of procaine.2. L7810 protected anaesthetized guinea-pigs against ouabain-induced ventricular fibrillation and increased the lethal dose of ouabain.3. L7810 reduced the rate of rise of intracellularly recorded action potentials in rabbit isolated atria; the resting potential was not affected, but the duration of the action potential was prolonged.4. Unlike most drugs with local anaesthetic properties L7810 did not depress contractions in isolated atria but increased them.5. L7810 reduced the spontaneous frequency, maximum follow frequency and conduction velocity of rabbit isolated atria.6. L7810 had no blocking action on the chronotropic or positive inotropic actions of isoprenaline on isolated atrial muscle.7. In anaesthetized dogs L7810 caused a small dose-related bradycardia, and a large dose-related decrease in peripheral vascular resistance. There was no blockade of the effects of isoprenaline on heart rate or peripheral blood flow.

Action Potentials↗
PubMed1973

Further studies regarding the structure activity relationships of beta-adrenoceptor antagonists.

1. The ortho (M66,527) and para (M66,368) analogues of 1-t-butylamino-3-(methoxyphenoxy)-2-propanol and para substituted tertiary butylphenoxy-1-N-isopropylamine-3 propanol-2 oxalate acid (L8429) were tested in dogs for their beta-adrenoceptor blocking activity.2. M66,527, which contains a methoxy group in the ortho position of the benzene ring, was found to be comparable to propranolol in blocking cardiac and peripheral vascular responses to isoprenaline. Like propranolol, M66,527 was more potent on peripheral receptors.3. Transference of the methoxy group to the para position (M66,368) reduced the overall potency; however, this compound was found to be relatively cardioselective in that it was 2 to 3.6 times more active in blocking cardiac responses to isoprenaline.4. The cardioselective properties of the short chain para methoxy substituent were less than those reported for compounds with longer para substitutions (i.e. practolol, para oxprenolol and para alprenolol).5. L8429, with a tertiary butyl group in the para position, was a weak beta-adrenoceptor antagonist without cardioselective properties. A longer, less bulky n-butyl group may provide for a more potent and selective antagonist.6. The results support the view that the size and site of the substituent on the benzene ring may be of importance in determining the cardioselective potency of beta-adrenoceptor antagonists.

Adrenergic beta-Antagonists↗
PubMed1971

Effects on cardiac muscle of the -adrenoceptor blocking drugs INPEA and LB46 in relation to their local anaesthetic action on nerve.

1. As a local anaesthetic on frog nerve, LB46 had 0.4 times the activity of procaine and 2 times that of INPEA.2. In reducing the maximum rate of depolarization (MRD) of intracellularly recorded cardiac action potentials, LB46 was 20 times more potent than INPEA.3. As an antagonist of the chronotropic effect on atrial muscle and of the inotropic effects on ventricular muscle of isoprenaline the pA(2) values for LB46 were 9.05+/-0.15 and 9.30+/-0.06 respectively, and for INPEA 6.00+/-0.16 and 6.10+/-0.12.4. LB46 was 8 times more active than racemic propranolol in blocking the effects of isoprenaline on isolated cardiac muscle, and since its direct action on the cardiac membrane was only 0.1 times that of propranolol, there was a net gain of 80 times in the specificity of LB46 for class 2 (antisympathetic) over class 1 (depression of MRD) antidysrhythmic actions.5. INPEA was 2.5 times less active as a beta-adrenoceptor blocking drug on cardiac muscle than (+)-propranolol, and 1,300 times less active than LB46.6. INPEA, but not LB46, prolonged the duration of both atrial and ventricular intracellular action potentials.

Action Potentials↗
PubMed1970

Local anaesthetic and anti-arrhythmic actions of alprenolol relative to its effect on intracellular potentials and other properties of isolated cardiac muscle.

1. Alprenolol, a beta-adrenoceptor blocking drug reported to have the same potency as propranolol in vitro and in vivo, was found to be four times more active than procaine as a local anaesthetic on frog sciatic nerve.2. At doses of 0.125 mg/kg and above alprenolol protected anaesthetized guinea-pigs against ouabain-induced ventricular fibrillation.3. In isolated rabbit atria, resting potentials were unchanged, and the duration of the action potential was not prolonged, by concentrations of alprenolol up to 10.5 x 10(-6)M. The maximum rate of depolarization (MRD), however, was reduced by 30% at a concentration of 0.525 x 10(-6)M. This was 214 times less than the concentration which reduced the frog action potential height by 25%.4. The concentration of alprenolol required to produce more than 15% decrease in contraction or maximum driven frequency was 3.5 x 10(-6)M.5. As a test of the direct action of alprenolol on isolated cardiac muscle, MRD was also a more sensitive test than the measurement of electrical threshold or conduction velocity.

Action Potentials↗
PubMed1970

The effect of altered thyroid state on atrial intracellular potentials.

1. A group of rabbits was made hypothyroid by thyroidectomy, and another group was injected daily with L-thyroxine. After an appropriate interval respective alterations in thyroid state were confirmed by measurement of heart weight and of plasma iodine, and the animals' atria were isolated for recording.2. Measurements were made of atrial contractions, conduction velocity, spontaneous heart rate and maximum driven frequency, and action potentials were recorded with intracellular micro-electrodes.3. The resting potential and action potential heights were not affected by differences of thyroid state.4. Atrial arrhythmias are common in hyperthyroidism, rare in myxoedema. The possibility that hypothyroidism might reduce the rate of rise of the action potential, as do anti-arrhythmic drugs, and hyperthyroidism increase it, was investigated. Although the rate of rise was slower in hypothyroid atria at some driving frequencies, this could not alone account for an anti-arrhythmic effect, because at frequencies near the spontaneous heart rate the rate of rise of the action potential was not reduced.5. The duration of the repolarization phase of the action potential was greatly prolonged in atria from thyroidectomized rabbits, and was shortened in hyperthyroid atria. These changes could account for a reduced probability of arrhythmias in hypothyroidism, and the converse in hyperthyroidism.

Action Potentials↗
PubMed1969

A comparison of the anti-arrhythmic actions of I.C.I. 50172 and (--)-propranolol and their effects on intracellular cardiac action potentials and other features of cardiac function.

1. I.C.I. 50172 had marked quinidine-like effects on intracellular cardiac action potentials at concentrations above 20 mg/l. (6.61 x 10(-5)M). The rate of rise and overshoot of the action potential, conduction velocity and contractions were decreased. (-)-Propranolol had similar effects at less than 1/30 this concentration.2. I.C.I. 50172 had 1/100 the activity of (-)-propranolol as a local anaesthetic. Since this is also the ratio of their in vitro beta-receptor blocking activities, I.C.I. 50172 provides no net increase in specificity of beta-receptor blockade.3. In contrast, the in vivo activity of I.C.I. 50172 in protecting anaesthetized guinea-pigs against ouabain-induced ventricular fibrillation was 40% that of (-)-propranolol.4. Structure-activity relations of beta-receptor blocking drugs are discussed.

Acetanilides↗