Inhibition of vascular contractions to alpha-adrenoceptor agonists by polymyxin B: impact of heart failure state.

In this study, the effects of polymyxin B (a protein kinase C inhibitor) on alpha-adrenoceptor stimulation of the canine dorsal pedal artery and saphenous vein were examined. In addition, the question was asked, whether these effects could be altered by the impact of a heart failure state? Blood vessels were obtained at three time points during the development of pacing-induced heart failure in the dog; control (non-paced), 1 week paced and end-stage heart failure. Concentration-effect curves were constructed to the alpha-adrenoceptor agonists, namely, noradrenaline and phenylephrine in the absence and presence of polymyxin B (2 x 10(-5) and 10(-4) M). Responses to noradrenaline and phenylephrine were enhanced in the saphenous vein, but not in the dorsal pedal artery, following the onset of heart failure. In the dorsal pedal artery, polymyxin B was found to inhibit the contractions developed to noradrenaline and phenylephrine to a significant degree (P < 0.05) at control and end-stage heart failure. In contrast, in the saphenous vein, polymyxin B inhibited responses developed to noradrenaline and phenylephrine at all time points studied. This inhibition was always more marked against noradrenaline compared to phenylephrine and, similar to the dorsal pedal artery, became more pronounced at end-stage heart failure. Furthermore, the vein was always more sensitive compared to the artery. Interestingly, as heart failure developed, a non-classical broad concentration-effect curve was evident. The high affinity component was more sensitive to inhibition by polymyxin B. This component was absent at end-stage heart failure in response to phenylephrine.(ABSTRACT TRUNCATED AT 250 WORDS)