The effects of strychnine on the regulation of voltage-dependent calcium channels by dihydropyridines in brain and heart.
The effects of strychnine (STR) were investigated on K(+)-stimulated 45Ca2(+)-uptake into mouse brain neurons, the contractile activity of spontaneously beating rat atria and on [3H]nitrendipine and [3H]BAY K 8644 binding to dihydropyridine calcium channel antagonist and agonist binding sites on brain and cardiac membranes. STR (10(-6)-10(-4) M) had no effect on neuronal 45Ca2(+)-uptake. When combined at equimolar concentrations (10(-5) M), STR and nifedipine produced a potent (nM) inhibition (40%) of neuronal 45Ca2(+)-uptake. In the spontaneously beating rat atria, STR produced a dose-dependent (10(-7)-3 x 10(-4) M) decrease in chronotropy but did not affect inotropy. STR (10(-4) M) completely inhibited the positive chronotropic, but did not affect the positive inotropic effects of (-)-S-BAY K 8644. [3H]Nitrendipine and [3H]BAY K 8644 binding to brain and cardiac membranes was enhanced by STR in a concentration-dependent manner (EC50 8 X 10(-6) M). Scatchard analysis revealed that STR increased the affinity (decreased the Kd) of [3H]BAY K 8644 to a greater degree than that of [3H]nitrendipine for dihydropyridine binding sites. STR decreased the Kd of [3H]nitrendipine binding by increasing and decreasing the microassociation and microdissociation constants respectively. STR enhanced [3H]nitrendipine binding to the same extent in the cerebral cortex, striatum, hippocampus, cerebellum, brainstem and spinal cord. The enhancement of [3H]nitrendipine binding in brain was completely inhibited by Ca2+ and partially inhibited by Na+ in a concentration-dependent manner. Glycine (10(-2) M) did not affect the STR enhancement of [3H]nitrendipine binding.(ABSTRACT TRUNCATED AT 250 WORDS)
O'Neill
S K
SK
Memorial University of Newfoundland, St. John's, Canada.
Bolger
G T
GT
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism* / Q000648:ultrastructure; D002118:Calcium / Q000378:metabolism / Q000494:pharmacology; D015220:Calcium Channels / Q000187:drug effects* / Q000378:metabolism; D004095:Dihydropyridines / Q000494:pharmacology*; D004347:Drug Interactions; D006321:Heart / Q000187:drug effects*; D008297:Male; D051379:Mice; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism*; D009543:Nifedipine / Q000378:metabolism / Q000494:pharmacology; D010622:Phencyclidine / Q000494:pharmacology; D011188:Potassium / Q000502:physiology; D051381:Rats; D011919:Rats, Inbred Strains; D012964:Sodium / Q000494:pharmacology; D013331:Strychnine / Q000494:pharmacology*
D015220:Calcium Channels; D004095:Dihydropyridines; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D012964:Sodium; D013331:Strychnine; D009543:Nifedipine; D010622:Phencyclidine; D011188:Potassium; D002118:Calcium