Biomedical subjects

E W Gill

Publications and source records attributed to E W Gill.

At least 19 recordsLinked to original sources

PubMed1992

Actions and mechanisms of action of novel analogues of sotalol on guinea-pig and rabbit ventricular cells.

1. The actions and mechanisms of action of novel analogues of sotalol which prolong cardiac action potentials were investigated in guinea-pig and rabbit isolated ventricular cells. 2. In guinea-pig and rabbit cells the compounds significantly prolonged action potential duration at 20% and 90% repolarization levels without affecting resting membrane potential. In guinea-pig but not rabbit cells there was an increase in action potential amplitude and in rabbit cells there was no change in the shape or position of the 'notch' in the action potential. 3. Possible mechanisms of action were studied in more detail in the case of compound II (1-(4-methanesulphonamidophenoxy)-3-(N-methyl 3,4 dichlorophenylethylamino)-2-propanol). Prolongation of action potential duration continued to occur in the presence of nisoldipine, and calcium currents recorded under voltage-clamp conditions were not reduced by compound II (1 microM). Action potential prolongation by compound II was also unaffected in the presence of 10 microM tetrodotoxin. 4. Compound II (1 microM) did not influence IK1 assessed from the current during ramp changes in membrane potential (20 mV s-1) over the range -90 to -10 mV. 5. Compound II (1 microM) blocked time-dependent delayed rectifier potassium current (IK) activated by step depolarizations and recorded as an outward tail following repolarization. When a submaximal concentration (50 nM) was applied there was no change in the apparent reversal potential of IK.6. Submaximal concentrations of compound II were without effect on activation of IK with time at a membrane potential of + 40 mV, and no changes were detected in the time constants of the two components of IK decay over the range of potentials - 60 to 0 mV. Compound 11 (50 nM) appeared to cause a small shift in the activation of IK with membrane potential (an apparent shift of approximately 10mV in the depolarizing direction at the mid-point of the curve).7. Log dose-response curves for action potential prolongation and for blockade of IK by compound II were similar. The IC50 for compound II was approximately 30 nM.8. It is concluded that this novel series of compounds prolongs action potential duration, and that in the case of compound II the evidence supports a potent selective effect on the time-dependent potassium current IK, an effect which can account for this prolongation.

Action Potentials↗

PubMed1991

The synthesis and potassium channel blocking activity of some (4-methanesulfonamidophenoxy)propanolamines as potential class III antiarrhythmic agents.

The synthesis of 22 (4-methanesulfonamidophenoxy)propanolamines and their testing on isolated guinea pig cardiac myocytes, on isolated preparations from guinea pig atria, and on rat blood pressure are described. Secondary amines in the series (11a-f) showed residual beta-blocking activity, whereas incorporation of N-methyl phenylalkyl and 4-phenyl alicyclic amine groups abolished beta-blocking activity but led to enhanced ability to block the channel conducting the delayed rectified potassium current, and hence produced an increase in the cardiac action potential duration (APD). Incorporation of hydrophobic Cl and CF3 groups further enhanced potassium channel blocking activity. Compounds 81 and 8m produced a significant increase in APD at nanomolar concentrations, with no effect on cardiac muscle conduction velocity, and hence merit further investigation as Class III antiarrhythmic agents. Methylation of the methanesulfonamido group abolished channel-blocking activity; 4-carboxy and 3-methanesulfonamido analogues retained activity but at a reduced level.

Animals↗

PubMed1988

Metabolites of procainamide and practolol inhibit complement components C3 and C4.

Drug-induced systemic lupus erythematosus arises from toxic side-effects of administration of hydralazine, isoniazid, procainamide and practolol. Hydralazine and isoniazid are nucleophilic drugs and inhibit the covalent binding reaction of complement components, C3 and C4, an effect likely to lead to deposition of immune complexes (a feature of systemic lupus erythematosus). Procainamide and practolol do not themselves inhibit C3 and C4. A range of metabolites and putative metabolites of procainamide and practolol were synthesized, and tested for their ability to inhibit the covalent binding reactions of C3 and C4. The highly nucleophilic hydroxylamine metabolite of procainamide was strongly inhibitory in both tests, as was a putative hydroxylamine metabolite of practolol. These studies indicate a potential role for the hydroxylamine metabolites in mediating the toxic side-effects of procainamide and practolol, and emphasize the need for adequate measurements of hydroxylamine metabolites in human tissue.

Acecainide↗

PubMed1984

Drugs that induce systemic lupus erythematosus inhibit complement component C4.

The syndrome resembling systemic lupus erythematosus (SLE) associated with long-term treatment with hydralazine and isoniazid seems to be due to the drugs themselves rather than their metabolites. This syndrome is associated with deposition of immune complexes; and in the complement system inhibition of C4 is likely to increase deposition of immune complexes. In vitro, hydralazine and isoniazid inhibited 50% of the binding of C4 at 840 mumol/l and 1.05 mmol/l, respectively--ie, within the concentration ranges that have been used in therapy. Acetylated metabolites were not inhibitory at the maximum concentrations tested; and iproniazid, which does not cause SLE, gave 50% inhibition only at a concentration far exceeding that used in therapy.

Acetylation↗

PubMed1976