PAPAVERIVE ABOLISHES ENDOTHELIUM‐DEPENDENT DILATATION OF HUMAN INTERNAL MAMMARY ARTERIES IN VITRO

Abstract

1. The purpose of the present study was to examine the effects of papaverine-HCl, administered into the lumen of the human internal mammary artery (IMA) during harvesting of this vessel, on vascular reactivity in vitro and to specifically test the hypothesis that intraluminal administration of papaverine-HCl impairs endothelium-dependent vasodilation. 2. The present study measured in vitro dilator and constrictor responses of terminal segments of human IMA. Internal mammary artery segments were obtained either prior to routine administration of intraluminal papaverine (pre-P) or after papaverine administration (post-P) in patients undergoing coronary artery bypass grafting. In addition, the viability of cultured human saphenous vein endothelial cells exposed to papaverine-HCl was examined. 3. Cumulative concentrations of U46619, 5-hydroxytryptamine and phenylephrine (PE) produced active contractions in post-P IMA rings. Contractile responses to low concentrations of endothelin-1 were significantly enhanced in post-PIMA compared with pre-P IMA segments. 4. Maximal endothelium-dependent vasodilator responses of pre-P IMA segments to cumulative concentrations of acetylcholine (ACh) and the calcium ionophore A23187 were 49 +/- 7 and 66 +/- 4%, respectively, of the initial active tension induced by PE (1 mumol/L). 5. Maximal endothelium-dependent vasodilator responses were markedly attenuated in post-P IMA (6 +/- 6 and 11 +/- 10% for ACh and A23187, respectively; P< 0.0001 for both vasodilators compared with pre-P). Post-P IMA relaxed completely to the endothelium-independent vasodilator sodium nitroprusside. 6. Exposure of cultured human saphenous vein endothelial cells to papaverine-HCl (1.2 and 12.0 mg/mL) for 1 h resulted in the reduced viability of these cells. 7. The loss of endothelium-dependent relaxation could dangerously predispose the IMA graft to vasospasm in the postoperative period.

In vitro comparison of glyceryl trinitrate‐verapamil with other dilators of human saphenous vein

“…Schyvens et al . showed that the clinical use of intraluminal papaverine as a dilator of the internal mammary artery caused loss of endo­thelium‐dependent vasodilatory capacity, and the exposure of ­cultured human saphenous vein endothelial cells to papaverine resulted in the reduced viability of these cells 24 …”

S‐Nitrosothiols cause prolonged, nitric oxide‐mediated relaxation in human saphenous vein and internal mammary artery: therapeutic potential in bypass surgery

“…Incubation of vessels with S‐nitrosothiols may be sufficient to inhibit vasospasm for a number of hours after implantation, due to their prolonged dilator effects. In the post‐operative management of patients, prevention of graft spasm is vital because conduits like SV and IMA are hyper‐reactive to a variety of vasoconstrictors ( Cross et al ., 1994 ; He et al ., 1989 ) and high pressure distention or papaverine treatment, normally used to overcome spasm, cause further damage to the endothelium, and may compromise patency ( Roubos et al ., 1995 ; Schyvens et al ., 1997 ). Application of S‐nitrosothiols might improve the outcome of coronary artery bypass grafting (CABG) by reducing the need for high pressure distention or papaverine treatment.…”

“…Therefore, reduced NO production from vessels with damaged or dysfunctional endothelium predisposes graft vessels to spasm and thrombosis and might be responsible for the development of accelerated atherosclerosis, resulting in reduced patency ( Motwani & Topol, 1998 ; Verrier & Boyle, 1996 ). Recent studies have revealed that both high‐pressure distention of SV, and intraluminal treatment of IMA with papaverine in an effort to prevent spasm, cause loss of endothelium and markedly reduce endothelium‐dependent relaxation ( Roubos et al ., 1995 ; Schyvens et al ., 1997 ; Yang & He, 1997 ). Furthermore, there is recent experimental evidence that, even in the absence of either of these treatments, the maximal rate of generation of NO is intrinsically low in veins ( Nishioka et al ., 1998 ), and a marked variability of endothlium‐dependent relaxations is observed among IMAs ( Huraux et al ., 1999 ).…”

Vasorelaxant effect of iloprost on isolated human internal mammary artery

“…This relaxant effect of papaverine was stronger than that of diltiazem or iloprost. The clinical use of intraluminal papaverine as a dilator of the IMA graft may result in the loss of endothelium-dependent vasodilatory capacity [27]. Confirming its effectiveness, papaverine has been used as a vasodilator agent in clinical medicine for almost a century.…”

“…Papaverine solutions are highly acidic and acidic solutions have been implicated in structural damage to vascular endothelium [26]. The clinical use of intraluminal papaverine as a dilator of the IMA graft may result in the loss of endothelium-dependent vasodilatory capacity [27].…”