THE EFFECT OF SOME ANTIPROLIFERATIVE AGENTS ON PORCINE CORONARY ARTERY FUNCTION AND GROWTH OF VSMCs IN VITRO. Simon Kennedy, Brendan Clarke, Roger M. Wadsworth 8 Chewy L. Wainwright. Department of Physiology 8 Pharmacology, University of Strathclyde, Glasgow, U.K.

The use of antiproliferative drugs is a promising strategy lo combat the problem of restenosis after balloon angioplasty (Work et a/ 2001). In this study we investigated whether the antiproliferative agents paclitaxel. famesyl protein transferase inhibitor Ill (FPT Ill), perillyl alcohol (PA) or Van1014 (Strathclyde University patented fucopyranoside) have any effect on vascular contraction or endothelium- dependent relaxation in the porcine coronary artery. Artery rings were incubated short-term (30mins) or long-term (20hrs) with FPT Ill, Van 1 O/4 (10 and 25pM), paclitaxel (10 and 50pM) or PA (1 and 2mM), precontracted with U46619 or 5-HT and relaxed by cumulative addition of calcimycin (lnm-1pM). With the exception of PA, which abolished contractility, short-term incubation had no effect on endotheliumdependent relaxation or contraction. Long- term incubation with the higher concentration of FPT III, paclitaxel and Van 10/4 attenuated relaxation while this concentration of Van 10/4 also reduced contractility. At the concentrations studied, these agents decreased ‘H- thymidine uptake in cultured porcine coronary SMCs. In conclusion, short-term application of Van 10/4, paclitaxel and FPT Ill at antiproliferative concentrations has no detrimental effect on vascular contraction or relaxation. Work L.M., McPhaden A.R., Pyne N.J. el a/ (2001) Circulation 104; 1538-l 543.

IMPAIRED MlTOCHONDRlAL OXIDATIVE METABOLISM IN HEART FAILURE Janos Kerner, Edwm Vazquez, Margaret Chandler, Ham Sabbah. Willlam Stanley, Charles Hoppel Dept Nutrition Med. 8 Pharm and Dept Physiol 8 Biophysics, Case Western Resen/e Unlv Henry Ford Vascular Institute. Detrott. Ml &, VA Med Res Ctr Cleveland, OH. USA

Mltochondnal fatty acid oxldatlon (FAO) has been shown to be Increased and carbohydrate oxldatlon decreased In compensated heart failure (HF). To address the metabolic basis of this swatch tn fuel use In HF, we determIned lipld (palmitoyl-CoA and palmltoylcarnitine) and carbohydrate (pyruvate) oxtdation In mitochondna Isolated from healthy and microembolism induced HF dogs (LV ejection fraction ~30%) We also determined the acttvity and regulatory properties of carnitlne palmitoyltransferase-I (CPT-I), the rate controlling enzyme In mitochondnal FAO Our data show that the oxidation of both lipid and carbohydrate substrates IS decreased by 40% In mitochondna Isolated from HF animals as compared to control animals. Furthermore no signiftcant differences were found In CPT-I actlvlty or regulatory properties of the enzyme These data do not support the notlon that in HF there IS a change in mltochondnal fuel selection Since the magnitude of glutamate oxidation IS decreased to the same extent as that of ltpld and carbohydrate substrates. It is likely that the decreased mltochondnal oxtdative capacity IS due to a defect In one or more component(s) of the electron transport chain

ENDOTHELIAL REGENERATION AND INCREASED NOS EXPRESSION IN BALLOON INJURED ARTERIES. Simon Kennedy, Allan R. McPhaden’. Ashley M. Miller, Anthony Preston. Cherry L. Wainwright & Roger M. Wadsworth. Dept. of Physiology & Pharmacology, University of Strathclyde & ‘Department of Pathology, Royal Infirmary, Glasgow, U.K.

Nitric oxide may influence the extent of restenosis by reducing platelet aggregation, leukocyte chemotaxis and smooth muscle cell migration and proliferation. The aim of this study was to simultaneously examine vessel morphology and immunohistochemical expression of iNOS and eNOS in the vessel wall between 2 hours and 28 days after balloon injury to the rabbit left subclavian artery (Hadoke et a/ 1995). Early after injury, haematoxylin and eosin staining revealed endothelial denudation, thrombus formation, medial necrosis and inflammatory cell infiltrate. 28 days after injury arteries showed neointimal formatlon associated with medial and adventitial fibrosis. lmmunostaining for iNOS was elevated between 48 hours and 8 days after injury, largely in the regenerated endothelium and neointima. Staining for eNOS was raised only at 28 days in the regenerated endothelium. These results demonstrate that increased expression of NOS isoforms correlates with endothelial regeneration and the development of neointima. Upregulation of NOS may serve to limit the extent of neointima formation after balloon injury. Hadoke P.W., Wainwright C.L., Wadsworth R.M. et al (1995). Coron. Artery. Dis. 6; 403-415.

REGULATION OF PROCOLLAGEN C-PROTEINASE (PCP) AND ITS ENHANCER PROTEIN (PCPE) IN THE REMODELING MYOCARDIUM Gania Kessler-I&son, Hadassa Schlesinger, Sarit Freimaaa, Efrat Kessler. Sackler Faculty of Medicine, Tel-Avi\ University, Tel-Aviv, Israel

A critical step rn collagen deposition IS the processmg of procollagen by procollagen C-proteinase (PCP) PCP activlt! IS stimulated by the PCP enhancer protem (PCPE) We have previously shown, in cultured heart fibroblasts, that PCPE evprcsslon and PCP a&v@ arc enhanced by aldostcrone, In coordination with collagen production. In the current study WC examined whether aldostcronc regulates PCPE and PCP exprcsslon during cardiac remodeling VI V(VO Twenty Wlstar rats were subjected to acute myocardial infarction (MI) or sham operated (control, n=6). and allowed a 5-week recovq period. The aldosterone receotor-antanonist. solronolactonc i-p )

- . 5 I , was given to half of the MI rats (25mg/Kg/day), starting

on dav 7 nest MI (MVsoi) In Mllsm rats. infarct scars . . ‘I

appeared smaller than in MI rats In situ hybridization localized both PCPE and collagen mRNA to fibroblasts surrounding the scar rqlon, around blood vessels, and occasionally, within the scar of MI rats. Northern blot and RT-PCR analyses of RNA from the surviving myoc.ar&um of MI rats revealed a marked mcrcasc m PCPE and collagen mRNA. as compared to controls, whereas the lcvcl of PCP mRNA increased only slightly and ins~gmficantly. SPI inhibIted the increase in PCPE and collagen mRNAs wnh IntIc effect on the level of PCP transcripts. WC conclude that, m the remodeling myocardlum. aldostcrone coordinately uprcplatcs the cvprcssion of PCPE and collagen but not that of PCP