Biomedical subjects
D C Benton
Publications and source records attributed to D C Benton.
The effects of cetiedil and its congeners on levcromakalim-stimulated 86Rb efflux from smooth and skeletal muscle.
The effects of cetiedil on levcromakalim-stimulated 86Rb efflux from rat aorta, rat anococcygeus and frog sartorius muscle have been investigated. In experiments on rat aorta, cetiedil inhibited the tracer efflux stimulated by 10 microM levcromakalim with an IC50 of 1.3 +/- 0.4 microM. In the rat anococcygeus and frog sartorius 10 microM cetiedil caused 67 +/- 11% and 84 +/- 4% inhibition of the responses to 10 microM and 50 microM levcromakalim respectively. The effect of two analogues of cetiedil, UCL 1285 (cetiedil methiodide) and UCL 1495 (triphenyl acetic acid-2-N[5-ethyl-2-methylpiperidinoethyl] ester) were also tested on rat aorta. UCL 1285 caused inhibition of the response to 10 microM levcromakalim with an IC50 of approximately 6 microM. In contrast, UCL 1495 (10 microM) had no significant effect. It is concluded that cetiedil is an effective blocker of the action of levcromakalim in smooth and skeletal muscle but does not distinguish between tissues. The relative activities of cetiedil, UCL 1285 and UCL 1495 are discussed in relation to their activity at other cetiedil-sensitive K+ channels.
Discrimination between subtypes of apamin-sensitive Ca(2+)-activated K+ channels by gallamine and a novel bis-quaternary quinolinium cyclophane, UCL 1530.
1. Gallamine, dequalinium and a novel bis-quaternary cyclophane, UCL 1530 (8,19-diaza-3(1,4),5(1,4)-dibenzena-1 (1,4),7(1,4)-diquinolina-cyclononadecanephanedium) were tested for their ability to block actions mediated by the small conductance, apamin-sensitive Ca(2+)-activated K+ (SKCa) channels in rat cultured sympathetic neurones and guinea-pig isolated hepatocytes. 2. SKCa channel block was assessed in sympathetic neurones by the reduction in the slow afterhyperpolarization (AHP) that follows an action potential, and in hepatocytes by the inhibition of the SKCa mediated net loss of K+ that results from the application of angiotensin II. 3. The order of potency for inhibition of the AHP in sympathetic neurones was UCL 1530 > dequalinium > gallamine, with IC50 values of 0.08 +/- 0.02, 0.60 +/- 0.05 and 68.0 +/- 8.4 microM respectively, giving an equi-effective molar ratio between gallamine and UCL 1530 of 850. 4. The same three compounds inhibited angiotensin II-evoked K+ loss from guinea-pig hepatocytes in the order dequalinium > UCL 1530 > gallamine, with an equi-effective molar ratio for gallamine to UCL 1530 of 5.8, 150 fold less than in sympathetic neurones. 5. Dequalinium and UCL 1530 were as effective on guinea-pig as on rat sympathetic neurones. 6. UCL 1530 at 1 microM had no effect on the voltage-activated Ca2+ current in rat sympathetic neurones, but inhibited the hyperpolarization produced by direct elevation of cytosolic Ca2+. 7. Direct activation of SKCa channels by raising cytosolic Ca2+ in hepatocytes evoked an outward current which was reduced by the three blockers, with dequalinium being the most potent. 8. These results provide evidence that the SKCa channels present in guinea-pig hepatocytes and rat cultured sympathetic neurones are different, and that this is not attributable to species variation. UCL 1530 and gallamine should be useful tools for the investigation of subtypes of apamin-sensitive K+ channels.
The synthesis and some pharmacological actions of the enantiomers of the K(+)-channel blocker cetiedil.
Cetiedil ((+/-)-2-cyclohexyl-2-(3-thienyl)ethanoic acid 2-(hexahydro-1 H-azepin-1-yl) ethyl ester) possesses anti-sickling and analgesic, antispasmodic, local anaesthetic and vasodilator activities. A total synthesis and circular dichroism spectra of the enantiomers of cetiedil is described, together with a comparison of their effectiveness as blockers of the Ca(2+)-activated K+ permeability of rabbit erythrocytes; the contractile response of intestinal smooth muscle to acetylcholine; the Ca(2+)-dependent contraction of depolarized intestinal muscle; and the cell volume-sensitive K+ permeability (Kvol) of liver cells. The enantiomers did not differ substantially in their ability to block the Ca(2+)-activated K+ permeability of rabbit red cells or in their effectiveness as blockers of the contractile response of depolarized smooth muscle to externally applied Ca2+. There was a clear difference in the muscarinic blocking activity of the enantiomers, as assessed by inhibition of the contractile response of intestinal smooth muscle to acetylcholine; (+)-cetiedil was 7.7 +/- 0.2 (s.d.) times more active than the (-) from. The enantiomers also differed in their potency as blockers of the increase in membrane conductance which occurs when liver cells swell. The concentration of (+)-cetiedil needed to reduce the conductance increase by 50% was 2.04 +/- 0.54 (s.d.) microM; (-)-cetiedil was 2.6 +/- 0.8 (s.d.) times less active (IC50 of 5.2 +/- 1.2 microM). Differences in the biological actions of the enantiomers of cetiedil indicate that a more extensive study could be rewarding in relation to the use of the enantiomers both in therapeutics and in the study of K+ channels.
2001 commission impossible?
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Health policy dilemmas related to high technology infertility services.
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Effects of cromakalim on the membrane potassium permeability of frog skeletal muscle in vitro.
1. The effects of the potassium channel opener, cromakalim, and its active enantiomer, lemakalim, have been investigated in frog skeletal muscle. 2. Cromakalim (30-300 microM) increased 86Rb efflux from muscles loaded with the isotope, hyperpolarized the fibres and reduced membrane resistance. 3. These effects were inhibited by the sulphonylureas, glibenclamide and tolbutamide. The IC50 for glibenclamide inhibition of 86Rb efflux was ca. 8 nM. 4. Phentolamine (300 microM) (which blocks responses to cromakalim in smooth muscle and inhibits ATP-sensitive K+ channels in pancreatic beta-cells) had no effect on the reduction in membrane resistance caused by 100 microM lemakalim. 5. Diazoxide (600 microM) had no effect on 86Rb efflux. 6. The similarities of the K+ channel activated by cromakalim in frog skeletal muscle to the channel acted on in smooth muscle and to the ATP-sensitive K+ channel of beta-cells are discussed.
Screening for undescended testes.
There is a general consensus among surgeons and paediatricians that cryptorchidism should be detected and treated by the age of 5 years, if not earlier. In reality, incomplete descent is often detected well beyond the age of 5. The effectiveness of local screening was assessed by reviewing the screening history and subsequent management of boys treated for undescended testes between 1983 and 1986. The detection rates for undescended testes in the boys under 5 years were low both for doctors and health visitors. In contrast, the school entry medical examination for 5 and 6 year olds had a higher screening yield. Over 40% of cases came to light as a result of parents recognising the condition and seeking medical opinion. Late detection had also occurred in some boys who had had previous genital surgery or examination. Methods to improve early detection and ways of monitoring proposed changes are discussed.
Synergistic antiviral effects of acyclovir and vidarabine on herpes simplex infection in newborn mice.
277 5-7-day-old white Swiss mice were infected intranasally with Herpes simplex virus type 2 (HSV2) to mimic disseminated herpetic infection in human newborns. The antiviral efficacy of acyclovir, vidarabine and specific antiserum (SAS) alone and in combination was assessed. A significant increase in survival rate (52%) was observed with the combination of acyclovir (80 mg/kg/day) and vidarabine (125 mg/kg/day) compared to either compound (24 and 6%, respectively) when therapy was begun 30 h after infection and continued daily for the next 4 days. Combinations of acyclovir, vidarabine and SAS had less protective effect (8%) than acyclovir with SAS (32%) or vidarabine with SAS (12%). No improvement was observed in survival rate of HSV2-infected mice treated with SAS as compared with controls (0% and 5%, respectively). These results suggest the enhanced antiherpes effect in newborn mice is due to synergism of acyclovir and vidarabine, a combination deserving further evaluation for the treatment of HSV2 infections in humans.
An agenda for change.
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