Effects of CRL 41034 on the adrenergic neuroeffector interaction in the canine saphenous vein

Summary— Experiments were designed to determine the effect of CRL 41034, a buflomedil analogue, on the adrenergic responsiveness of canine veins. Rings of saphenous vein (without endothelium) were suspended for isometric tension recording in modified Krebs‐Ringer bicarbonate solution at 37°C. CRL 41034 produced a concentration‐dependent inhibition of the contractions evoked by the alpha adrenergic agonists norepinephrine, phenylephrine and UK 14304 which was insensitive to the blockade of neuronal uptake by cocaine. CRL 41034 was more potent in inhibiting the concentration‐dependent contractions evoked by UK 14304 than those by phenylephrine and the antagonism it caused against the response to UK 14304 fulfilled the criteria for competitivity. CRL 41034, at 10⁻⁵ M significantly depressed, and at 10⁻⁴ M abolished the contractions induced by electrical stimulation of the adrenergic nerves and those evoked by the indirect sympathomimetic amine tyramine. Strips of canine saphenous vein were superfused after incubation with [³H] norepinephrine. During sympathetic nerve activation, CRL 41304 increased the stimulation‐evoked overflow of [³H] norepinephrine and 3‐methoxy‐4‐dihydroxyphenylglycol; in the presence of rauwolscine the compound only increased the stimulation‐evoked overflow of 3,4‐dihydroxyphenylglycol. These experiments suggest that the major vascular effects of CRL 41034 in canine veins are blockade of alpha₂‐adrenoceptors on vascular smooth muscle, and inhibition of prejunctional alpha₂‐adrenoceptors on adrenergic nerve endings. 1990 Société Française de Pharmacologie et de Thérapeutique