Relaxation matters: comparison of in-vitro vasodilatory role of botulinum toxin-A and papaverine in human radial artery grafts

Abstract

Background: Radial artery (RA) is widely used in coronary artery bypass (CABG) surgery and the prevention of spasm is crucial for graft patency. Botulinum toxin A (BTX-A) and B are commonly used for aesthetic reasons and neuromuscular disorders. They are proven to raise blood flow and increase survival of ischemic skin flaps. In this study we evaluated and compared the vasodilator effects of BTX-A and papaverine on human RA grafts.

Methods: After resting 60 min in isolated organ baths, human RA grafts were examined. Contraction responses for different doses of serotonin (5-HT) and endothelin-1 (ET-1) were evaluated as a percent of maximum contraction response elicited by 80 mM potassium chloride (KCl). The inhibitory effects of BTX-A and papaverine on contraction responses taken at the 0th hour were compared with the 1st and 2nd hour responses. Inhibitory effects of BTX-A and papaverine against the contractile agent were evaluated by comparing the results of the first and last (0th and 2nd hour) application.

Results: In low concentrations, when we compared the effects of BTX-A (10^{- 8} M) and papaverine (10^{- 6} M) on 5-HT, papaverine was found to be more effective at both the 0th and 2nd hour (p < 0.05). Both BTX-A and papaverine inhibited the maximum contractile effect of ET-1 to the same extent at the 0th hour; but, the inhibitory effect of BTX-A was significantly stronger at the 2nd hour (p < 0.05). In high concentrations, when we compared the effects of BTX-A (10^{- 6} M) and papaverine (10^{- 4} M) on 5-HT, papaverine showed stronger inhibition (p < 0.05), whereas both agents had similar action of inhibition on ET-1 mediated maximum contraction responses.

Conclusion: BTX-A inhibits both ET-1 and 5-HT induced contractions and its effectiveness does not decrease over time as observed with papaverine. This study is the first in the literature using human RA for prevention of vasospasm by BTX-A.

Keywords: Botox; Botulinum toxin A; Coronary artery bypass graft surgery; Papaverine; Radial artery; Vasodilation.

Fig. 1

Operative view from radial artery harvesting. Note the fascia over the radial artery is peeled to prevent vasospasm

Fig. 2

Flow-chart of the experimental procedures. KCL: potassium chloride (80 mM), BTX-A: botulinum toxin A (10^− 8 M or 10^− 6 M), papaverine (10^− 6 M or 10^− 4 M), cumulative 5-HT (10^− 9 M - 10^− 6 M), cumulative ET-1 (10^− 12 M - 10^− 8 M)

Fig. 3

The effects of BTX-A pretreatment over the contraction responses of cumulative 5-HT. Results are % of KCl induced contractions, mean ± SD. *: p < 0.05 compared to control of each constrictor agent. ^§: p < 0.05 increas in inhibition, compared to 0th hour

Fig. 4

The effects of BTX-A pretreatment over the contraction responses of cumulative ET-1. Results are % of KCl induced contractions, mean ± SD. *: p < 0.05 compared to control of each constrictor agent. ^§: p < 0.05 increase in inhibition, compared to 0th hour

Fig. 5

The effects of Papaverine pretreatment over the contraction responses of cumulative 5-HT. Results are % of KCl induced contractions, mean ± SD. *: p < 0.05 compared to control of each constrictor agent. ^#: p < 0.05 decrease in inhibition compared to 0th hour

Fig. 6

The effects of Papaverine pretreatment over the contraction responses of cumulative ET-1. Results are % of KCl induced contractions, mean ± SD. *: p < 0.05 compared to control of each constrictor agent. ^#: p < 0.05 decrease in inhibition compared to 0th hour

Fig. 7

Histopathologic evaluation of papaverine (b-c) and Botulinum Toxin-A (d-e), made by Hematoxylene&Eosine stain under light microscopy (× 40 magnification) showed similar findings with the control group (a)