Locally administered antiproliferative drugs inhibit hypercontractility to serotonin in balloon-injured pig coronary artery.
Although drugs such as sirolimus and paclitaxel are effective in reducing restenosis, their effects on vascular function are often overlooked. In this study, we have examined the effects of local delivery of several anti-restenotic drugs given in vivo after balloon injury on in vitro vascular contraction and relaxation 28 days after injury. Paclitaxel (50 microM), the farnesyl protein transferase inhibitor L744 (25 microM), sirolimus (25 microM) and Van 10/4 (decahydro-1,1,4,7-tetramethyl-1H-cycloprop[e]azulen-4-o-[2-(3-methylpent-2-enoyl)-fucopyranoside]; 25 microM) were delivered to porcine coronary arteries in vivo and the arteries removed 28 days later. Contractions to KCl and 5-hydroxytryptamine (5-HT) and relaxations to calcimycin and 3-morpholinosydnonimine (SIN-1) were measured in control (LCx) and balloon-injured (LAD) rings. In vehicle-infused coronary arteries, contraction to KCl and 5-HT was significantly enhanced 28 days after balloon injury, while the response to calcimycin had recovered fully, indicating endothelial regrowth. The response to SIN-1 was unchanged. None of the four drugs tested had any effect on the enhanced response to KCl 28 days after injury or on recovery of the calcimycin response. The hyper-responsiveness to 5-HT was eliminated by sirolimus, Van 10/4 and L744, but not paclitaxel. This study demonstrates that local drug infusion with structurally different antiproliferative drugs at the time of balloon angioplasty does not affect endothelial recovery and may in some cases prevent hyper-responsiveness to constrictor agents.
Department of Physiology and Pharmacology, Strathclyde Institute of Biological Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, Scotland, UK. simon.kennedy@strath.ac.uk
Simon
S
Kennedy
Roger M
RM
Wadsworth
Cherry L
CL
Wainwright
D015906:Angioplasty, Balloon, Coronary; D000818:Animals; D052176:Azulenes / Q000008:administration & dosage / Q000494:pharmacology; D000001:Calcimycin; D003331:Coronary Vessels / Q000187:drug effects* / Q000293:injuries / Q000503:physiopathology; D005643:Fucose / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D006131:Growth Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008715:Methionine / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology; D023421:Models, Animal; D012701:Serotonin; D020123:Sirolimus / Q000008:administration & dosage / Q000494:pharmacology; D013552:Swine; D014661:Vasoconstriction; D014662:Vasoconstrictor Agents; D014664:Vasodilation; D014665:Vasodilator Agents
D052176:Azulenes; D006131:Growth Inhibitors; C096898:L 744832; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C488457:decahydro-1,1,4,7-tetramethyl-1H-cycloprop(e)azulen-4-o-(2-(3-methylpent-2-enoyl)fucopyranoside); D005643:Fucose; D012701:Serotonin; D000001:Calcimycin; D008715:Methionine; D020123:Sirolimus