Resting state block and use independence of rat vascular muscle Ca++ channels by Ro 40-5967
Mishra, S.K.; Hermsmeyer, K.
Journal of Pharmacology and Experimental Therapeutics 269(1): 178-183
1994
ISSN/ISBN: 0022-3565 PMID: 8169822 Document Number: 429401
Blocking actions of the novel Ca++ antagonist, Ro 40-5967 ((1S,2S)-2-(2((3-(2-benzimidazolylpropyl) methylamino)ethyl)-6-fluoro-1,2,3,4'-tetrahydro-1-isopropyl-2-naphthyl methoxyacetate dihydrochloride), on divalent inward currents were characterized in spontaneously active vascular muscle cells (VMC) of neonatal rat azygos veins. Ca++ channel currents (I-Ca) were reduced by Ro 40-5967 in a concentration range from 0.1 to 10 mu-M, effective within the first 5 min of exposure. I-Ca were decreased by up to 70% during the first stimulus test pulse and remained constant during subsequent pulses, and were not shifted along the voltage axis, as determined by peak current voltage plots. There was no change in apparent threshold or the voltage (+20 mV) at which maximum inward current occurred. Block of Ba++ currents through VMC Ca++ channels occurred independent of membrane potential, even when holding potential was as negative as -80 mV. I-Ca were blocked to the same absolute values from holding potential = -30 mV. Thus, I-Ca block occurred equally during the first pulse and at all subsequent time points, i.e., under conditions in which VMC Ca++ channels were in the resting state, inactive state, or open state. To search further for use-dependent effects of Ro 40-5967, we stimulated at higher frequencies (up to 0.3/sec), but there was no change in fractional block with frequency or stimulus repetition and thus no use dependence of the block of VMC Ca++ channels by Ro 40-5967. The blocking abilities of this new Ca++ antagonist at physiological resting potentials and under varying conditions of stimulation lead us to hypothesize that Ro 40-5967 causes an immediately maximal, tonic inhibition of VMC I-Ca making it unusual among Ca++ antagonists.