Effects of omega-toxins on noradrenergic neurotransmission in beating guinea pig atria.
The effects of four omega-toxins, known to block various subtypes of neuronal voltage-activated Ca2+ channels, on the beating guinea pig left atrium have been analyzed. Atria were suspended in oxygenated Krebs-bicarbonate solution at 32 degrees C and driven with electrical pulses delivered by a stimulator at 1 Hz, 1 ms, 4 V. A 10-fold increase of voltage caused a potent and rapid enhancement of the size of contractions (about 3- to 4-fold above basal), which reflects the release of endogenous noradrenaline from sympathetic nerve terminals. omega-Conotoxin MVIIC, omega-conotoxin MVIIA and omega-conotoxin GVIA inhibited the inotropic responses to 10 x V stimulation with IC50 values of 191, 44 and 20.4 nM, respectively. omega-Agatoxin IVA did not affect the contractile responses. The inotropic responses to exogenous noradrenaline were unaffected by the toxins. The potent blocking effects of omega-conotoxin GVIA were present even in conditions in which the release of noradrenaline was strongly facilitated by presynaptic alpha 2-adrenoceptor blockade by phenoxybenzamine. These effects were not reversed upon repeated washing of the tissue with toxin-free medium. In contrast, the blockade induced by omega-conotoxin MVIIC and omega-conotoxin MVIIA were fully reversed, with t1/2 of 13.5 and 31.2 min, respectively. omega-Conotoxin MVIIC (1 microM) protected against the irreversibility of the blockade induced by omega-conotoxin GVIA (100 nM).(ABSTRACT TRUNCATED AT 250 WORDS)
Vega
T
T
Departamento de Farmacología, Facultad de Medicina, Universidad Autónoma de Madrid, Spain.
De Pascual
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R
Bulbena
O
O
García
A G
AG
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D004558:Electric Stimulation; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects / Q000294:innervation*; D006325:Heart Atria / Q000187:drug effects / Q000294:innervation; D066298:In Vitro Techniques; D008297:Male; D008978:Mollusk Venoms / Q000494:pharmacology*; D009200:Myocardial Contraction / Q000187:drug effects; D009411:Nerve Endings / Q000187:drug effects / Q000378:metabolism; D009638:Norepinephrine / Q000378:metabolism / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000187:drug effects* / Q000378:metabolism; D009435:Synaptic Transmission / Q000187:drug effects*
D002121:Calcium Channel Blockers; D008978:Mollusk Venoms; D009638:Norepinephrine