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Clinical Science (1997) 93 (Suppl. 37),I~-3lp (Printed in Great Britain) MEDICAL RESEARCH SOCIETY Communicationsfor the Spring Meeting of the Medical Research Society on IS May 1997 at the Royal College of Physicians, London MRS Communications MI-MS Spoken MbNSB Posten MRS/Glaxo Wellcome Young InvestigatorAward Finalists YI-Y6 Spoken MRS/Glaxo WellcomeYoung InvestigatorCommunications V-Y9 Spoken YlC-Y46 Posten Communications MI-M58 agents is not established. P2 receptor stimulation has functional effects in human atrium but P2-mediated effects on human ventricular myocardium iu vivo have notbeen described. The aim of this study was to examine the effects of P2-adrenoceptor stimulation on ventricular repolarisation. 22 patients with coronary artery disease (CAD: 16 males, mean age 60) were compared to 12 patients with normal coronary arteries (NCA: 9 males, mean age 58). Patients were appropriately stratified for e.g. LV function, previous myocardial infarction etc. QT dispersion (QTd), defined as the difference between the maximum and minimum QT interval on the surface electrocardiogram, was calculated using standard protocols. Incremental doses of salbutamol (S, 10-30 pg min") or isoprenaline (I, 1.25-3.75 pg min'l) were infused through a central vein. --t IlC*Ol Heart rate was maintained constant with atrial pacing. +S ICADI Increases in QTd were 0 IINCA) significant in both CAD (p<O.OOl; ANOVA) and 130 - - 0 - SINCA) NCA (p=0.002) patients with both salbutamol and isoprenaline but occurred at lower doses in CAD patients. In a separate group of patients intra-coronary in,jection of salbutamol resulted in shortening of right ventricular monophasic action potential duration indicating a direct action on cardiac 10 20 30(S) repolarisation. M I ADENOVIRALTRANSFER OF THE MARKER GENE FOR p GALACTOSIDASE TO THE PIG CORONARY ARTERY THE EFFECT OF PRE-ESISTING LESIONS. W ANDREWS, L PACKWOOD, CM DOLLERY, P YIU. A McCLELLAND, SE HUMPHRIES, JR McEWAN Department of Medicine (Division of Cardiology), University College London Hospitals Medical School, London, WClE 6DB. England and Genetic Therapy Inc, Gaitersbury, MD, USA The application of local gene transfer to the investigation or therapy of coronary vascular disease will require high efficiency of gene transfer in vivo. This is a function of the technique of local drug delivery, the vector employed and the underlying vascular disease. We employed an adenoviral vector carrying the gene for p Galactosidase driven by the rous sarcoma virus promoter (Avl.PGal) and showed 80% of cultured pig vascular smooth muscle cells expressing the transgene (MOI 200). 4 large white landrace pigs (15-20 kg) underwent angioplasty of a single coronary artery, (left anterior descending (LAD), circumflex (Cx)) with a 3 m m balloon catheter (balloon to artery ratio 1.3). They were allowed to recover for 14 - 21 days. Further angioplasty at the same angiographic site (3mm balloon, balloon to artery ration 1.3) and also of the proximal segment of the previously uninjured left coronary branch. Immediately after angioplasty approximately 1.5ml of a suspension of 4 x 108 pfu A v l . p a l was delivered to the site using a 2.75mm double skinned microporous balloon, the MIC2 catheter (Cordis). Three days later the animals were killed and the coronary arteries retrieved and placed in X-Gal prior to processing for histology. Previously injured vessels showed neointimal hyperplasia. Four of 7 vessels examined showed successful gene transfer as evidenced by prussian blue nuclear staining. Three of these four positive vessels had sustained a primary injury prior to gene transfer, the fourth had a pre-existing neointimal lesion. In three of the vessels medial nuclear staining was sparse and seen in relationship to angioplasty-induced dissection. In the pre-injured vesssel sparse neointima cells showed positive staining. In the fourth vessel, a primary injury with extensive dissection, the adventitial fibromyoblasts showed evidence of approximately 25% gene transfer. Vessels without evidence of gene transfer were generally larger, suggesting poor apposition of the delivery catheter. Distal myocyte staining (with myositis) implied that intralumenal delivery had occurred. -- - I ug!min 1.25 2.5 3.75(1) Increases in QTd with both salbutamol and isoprenaline are consistent with P2-adrenoceptor stimulation having important electrophysiological effects in human ventricle. M3 MEASUREMENT OF CELL PROLIFERATION IN MAN WITH STABLE ISOTOPES BY ENDOGENOUS LABELLING OF DNA DC MACALLAN, CA FULLERTON, RA NEESE and MK HELLERSTEm Dept of Nutritional Sciences, University of California Berkeley, CA94720 USA &Division of Infectious Diseases, St George's Hospital Medical School, London SW17 ORE. UK Current methods for measuring cell proliferation by incorporation of nucleosides (eg. 'H-thymidine, bromodeoxyuridine) are inapplicable in man because of toxicity. We have developed a method for quantitation of cell proliferation in vivo from incorporation of *H-labelled glucose into deoxyribose of newly synthesised DNA via pentose phosphate and ribonucleotide reductase pathways. Genomic DNA is isolated, hydrolysed enzymatically to nucleosides and analysed by gas chromatography mass spectrometry of the trimethylsilyl derivatives. Labelling of deoxyadenosine (dA)is detected as enrichment of m/z 469/467. In pilot M 2 P2-ADRENOCEPTOR STIMULATION INCREASES DISPERSION OF CARDIAC REPOLARISATION MD LOWE, PF LUDMAN, E ROWLAND and AA GRACE Department of Cardiology, Papworth Hospital; Department of Cardiological Sciences, St. George's Hospital Medical School P-adrenoceptor blockers reduce risk in some patients with cardiac disease, but the optimal use of pl-selective versus non-selective IP