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University of Illinois at Urbana-Champaign ~aai¢ Sdanc~ ~ng 2031 S~ud~ ~n¢~In Urb~a, ~ 61801 217 333-2~05 May 17, 1988 Dr. Harmon McAllister Research Director Council for Tobacco Research 900 Third Avenue New York, NY I0022 RE: "Preliminary Outline of a Research Study" Dear Dr. McAllister: In accordance with your guidelines, I have prepared a brief preliminary outline of a research study titled "Nicotine and organ/tissue perfusion during exercise" for your consideration for potential support by the Council for Tobacco Research--USA, Inc. Also enclosed are a copy of my curriculum vita (NIH format) and reprints of three related papers. A line in acknow]edgement of the receipt of these materials at your end will be highly appreciated. With best regards, Sincerely, Murli Manohar, BVSc, PhD Professor of Cardiopulmonary Physiology Enclosures Iib:859 50571

BRIEF GUTLI~E OF THE PROPOSED STUDY Title: NICOTINE AND ORE~N/TISSUE PERFUSION DURING EXERCISE. Investigator: Dr. M. Manohar, Professor of Cardiopulmonary Physiology, Department of Veterinary Biosciences, College of Veterinary Medicine, University of Illinois, Urbana, IL 61801. Objectives: I, TO STUDY THE ACUTE EFFECTS OF NICOTINE ADMINISTRATION ON SYSTEHIC HEMODYNAMICS AND REGIONAL DISTRIBUTION OF BLOOD FLON DURING REST AND GRADED TREADMILL EXERCISE. II. TO CHARACTERIZE THE EFFECTS OF NICOTINE ADMINISTRATION ON BLOOD-GAS VARIABLES DURING GRADED TREADMILL EXERCISE. Rationale: Nicotine has diverse cardiovascular actions including stimulation of autonomic nicotinic ganglia, cardiopulmonary mechanoreceptors, and chemoreceptors. It is well known that vascular effects of nicotine are mediated via sympathetic and parasympathetic stimulation of vascular smooth muscle. It is, however, not known how nicotine administration would affect systemic and pulmonary hemodynamics, as well as distri.bution of cardiac output during exercise of varying intensity. Also, it is not known how blood-gas variables are affected by nicotine during exercise. These are pertinent questions to ascertain the effects of nicotine on exercise performance. The proposed experiments will utillze an animal model, swine, whose cardiopulmonary responses to exercise is similar to that of human beings, and organ/tissue perfusion will be studied using a very reliable technique-- 15-pm-diameter radiolabeled microspheres. Contemplated Approach: Experiments will be carried out on 3 groups of healthy miniature swine (n = lO each). Group I swine ~il] serve as controls, whlle group 11 and III 50571870

- 2 - swine will be used to study the effects of a lo~ (5 Fg/kg) and ~ high (10 ~g/kg) dose of nicotine, respectively. A11 s~ine wi11 be instrumented with fluid-filled catheters in the ascending aorta, left atrium, and the pulmonary artery 4 to 6 weeks before the study using general anesthesia induced and maintained with iso?lurane vaporized in 02. At this surgery, hi-fidelity miniature pressure transducers wi11 also be implanted in the le?t ventricle, aorta, and the pulmonary artery. A period of 15 days will be allowed for recuperation from the surgery. Thereafter, the animals will be trained to run on a motor-driven treadmill and will be accustomed to laboratory surroundings and personnel. [He have considerable experience in surgical instrumentation of swine in this manner for hemodynamic studies.] Each group of swine will be studied at rest and during 3 different treadmill work intensities (namely, exercise at 507° of the maximal whole body 02 utilization [902max], exercise at 75% of the 902max and exercise at 902max). Measurements will be made of arterial as well as mixed-venous 02 and C02 tensions, pH, 02 saturation of hemoglobin, hemoglobin concentration, and 02 content at every step of the protocol. Also, we will determine dye-dilution cardiac output, pressures in the aorta, pulmonary artery and left ventricle along with LV dP/dt, and whole body distribution of cardiac output using radionuclide-labeled 15-~m-diameter microspheres injected into the left atrium. All measurements will be made under steady-state conditions. Data analysis will be done using a split-plot design analysis of variance followed by orthogonal contrast comparisons to determine the significant effects of various treatments. A probability level of P < 0.05 will be ~egarded as stat~sticall~ significant. Anticipated Duration: 18 ~nths 50571871

-3- Annual Direct Costs: Year 01: Research Technician (50%, salary + f.b.) Animals (24 miniature swine g $185 per animal) Animal care/feed (24 swine x $2 per day x 65 days) Radionuclide-labe]ed 15-pm-diameter microspheres Radioactive carcass disposal Anesthetic and surgical supplies ($45 per animal x 24 swine) Miscellaneous items: Cardiogreen, recorder paper, calibration materials for blood-gas/pH analyzer, scintillation vials, catheter materials, heparin, nicotine, saline, etc. Computer costs TOTAL $ 8,500 4,440 3,120 2,785 575 1,080 2,895 480 $23,875 Year 02: Research Technician (25% salary + f.b.) Animals (12 miniature swine @ $185 per animal) Animal care/feed (12 swine x $2 per day x 65 days) Radionuclide-labeled 15-~m-diameter microspheres Radioactive carcass disposal Anesthetic/surgical supplies ($45 per animal x 12 swine) Miscellaneous ~tems: Cardiogreen, recorder paper, calibration materials for blood-gas/pH, analyzer, scintillation vials, catheter materials, heparin, nicotine, saline, etc. Computer costs Publication costs ($35 per page x 15 pages) TOTAL $ 4,250 2,220 1,560 1,500 300 540 1,500 250 525 $12,645 MM:bcbJ84 11b:05117/88 50571872