xt76dj58d94c https://exploreuk.uky.edu/dips/xt76dj58d94c/data/mets.xml Lexington, Kentucky University of Kentucky 19830410 minutes English University of Kentucky Contact the Special Collections Research Center for information regarding rights and use of this collection. Minutes of the University of Kentucky Board of Trustees Minutes of the University of Kentucky Board of Trustees, 1983-04-mar10-ec. text Minutes of the University of Kentucky Board of Trustees, 1983-04-mar10-ec. 1983 2011 true xt76dj58d94c section xt76dj58d94c
Minutes of the Special Called Meeting of the Executive
Committee of the Board of Trustees of the University of Kentucky,
Thursday, March 10, 1983.
The Executive Committee of the Board of Trustees of the
University of Kentucky met in a Special Called Meeting in the
Board Room on the 18th floor of the Patterson office Tower on the
Lexington Campus at 11 a.m. (Eastern Standard Time) on Thursday,
March 10, 1983.
A. Meeting opened and Roll Called
Mr. William B. Sturgill, Chairman, called the meeting to
order at 11:10 a.m. and the invocation was pronounced by Mr.
William R. Black.
The following members of the Executive Committee of the Board
of Trustees answered the call of the roll: Mr. William B.
Sturgill (Chairmany, Mr. William R. Black, Mr. Tracy Farmer, and
Mr. John C. Darsie (Assistant Secretary, ex officio, of the
Executive Committee). Absent from the meeting were Mr. Albert G.
Clay and Mr. A. Stevens Miles. Members of the Board of Trustees
attending the meeting were Mr. James W. Dinkle, Mrs. Edythe Jones
Hayes, Mr. W. Terry McBrayer, and Professor William F. Wagner.
The University administration was represented by President Otis
A. Singletary; Dr. Donald B. Clapp, Vice President for
Administration; Chancellors Peter P. Bosomworth, Art Gallaher,
and Charles T. Wethington; Dr. Raymond R. Hornback, Vice
President for University Relations; Mr. Henry Clay Owen,
Controller and Treasurer; Mr. David I. Carter, Special Assistant
for Business and Financial Affairs; Dr. Paul G. Sears, Special
Assistant for Academic Affairs; and Dr. Wimberly C. Royster, Vice
Chancellor for Research and Dean of the Graduate School. Members
of the various news media were also in attendance. The Secretary
reported a quorum present, and the Chairman declared the meeting
officially open for the conduct of business at 11:13 a.m.
B. Adoption of Resolution Accepting the Successful Bid for
the University of Kentucky Consolidated Educational Buildings
Revenue Bonds, Series H (PR 3A)
Thereupon, a motion was made by Mr. Farmer and seconded by
Mr. Black that the following titled Resolution, which was read in
summary form to the Executive Committee, be adopted:
A RESOLUTION RELATING TO THE $8,500,000 UNIVERSITY OF
KENTUCKY CONSOLIDATED EDUCATIONAL BUILDINGS REVENUE
BONDS, SERIES H.
(The full Resolution being attached to these Minutes as
Exhibit 1.)
-2-
Upon a vote being taken on the motion, the result was as
follows:
Yeas Nays
William B. Sturgill None
William R. Black
Tracy Farmer
Thereupon, the Chairman declared that the motion had carried
and that the Resolution had been passed and adopted and directed
that the same be recorded in the Minutes of the Executive
Committee of the Board of Trustees. (See PR 3A at the end of the
Minutes.)
C. Scientific Advisory Committee Report, Tobacco and Health
Research Institute
President Singletary reminded the Trustees of the appointment
several months ago of a Scientific Advisory Committee, Tobacco
and Health Research Institute. The Committee has submitted its
first report and President Singletary said he wished to share it
with members of the Board. He then called on Chancellor Gallaher
who made introductory comments and introduced Dr. Layten Davis,
Director of the Tobacco and Health Research Institute. Dr. Davis
summarized the report, a copy of which is appended to the
Minutes.
The Chairman indicated the Board's approval and support of
the Institute and complimented President Singletary, Dr. Davis,
and the administration on the progress being made at the
Institute. Mr. Sturgill then accepted the report of the
Scientific Advisory Committee, Tobacco and Health Research
Institute.
D. Meeting Adjourned
There being no further business to come before the meeting,
the Chairman declared the meeting officially adjourned at 11:35
a.m.
Respectfully s mitted,
ohn C. Darsie
Assistant Secretary, Ex Officio
Executive Committee
Board of Trustees
(PR 3A (Exhibit 1) and the THRI Scientific Advisory
Committee Report which follow are official parts of the Minutes
of the meeting.)
(EXHIBIT 1)
Office of the President
March 10, 1983
Members, Executive Committee, Board of Trustees:
RESOLUTION ACCEPTING THE SUCCESSFUL BID
FOR THE
UNIVERSITY OF KENTUCKY CONSOLIDATED
EDUCATIONAL BUILDINGS REVENUE BONDS, SERIES H
Recommendation: That the Executive Committee approve a Resolution
accepting the bid of Seasongood and Mayer with a net interest cost
of 8.435319% for the purchase of $8,500,000 Consolidated
Educational Buildings Revenue Bonds, Series H, dated March 1, 1983.
Action: Approved X
Disapproved
Other
Date: March 10
, 198 3
EXHIBIT 1
RESOLUTION RELATING TO THE
$8,500,000 UNIVERSITY OF KENTUCKY
CONSOLIDATED EDUCATIONAL BUILDINGS
REVENUE BONDS, SERIES H
WHEREAS, the Executive Committee of the Board of
Trustees of the University of Kentucky ("the Board") at
its meeting on January 25, 1983, passed and adopted two
Resolutions, entitled, respectively,
A RESOLUTION AUTHORIZING THE ISSUANCE OF
$8,500,000 UNIVERSITY OF KENTUCKY CONSOLIDATED
EDUCATIONAL BUILDINGS REVENUE BONDS, SERIES H, OF
THE BOARD OF TRUSTEES OF THE UNIVERSITY OF KEN-
TUCKY
- and -
A RESOLUTION AUTHORIZING THE ISSUANCE OF
$8,500,000 UNIVERSITY OF KENTUCKY CONSOLIDATED
EDUCATIONAL BUILDINGS REVENUE BONDS, SERIES H, OF
THE BOARD OF TRUSTEES OF THE UNIVERSITY OF KEN-
TUCKY AND THE ISSUANCE OF $8,500,000 UNIVERSITY OF
KENTUCKY CONSOLIDATED EDUCATIONAL BUILDINGS
REVENUE BOND ANTICIPATION NOTES, SERIES H, OF THE
BOARD OF TRUSTEES OF THE UNIVERSITY OF KENTUCKY IN
ANTICIPATION OF THE ULTIMATE ISSUANCE OF SAID
SERIES H BONDS,
said Resolutions being referred to herein, respec-
tively, as "the Series H Resolution" and "the Alternate
Series H Resolution;" and
WHEREAS, pursuant to Section 5.3 of the Alternate
Series H Resolution, on or about February 15, 1983, the
Treasurer of the Board duly polled each member of the
Finance Committee of the Board, all of whom preferred
the issuance of the Series H Bonds authorized by the
Series H Resolution to the issuance of the Series H
Notes authorized by the Alternate Series H Resolution;
and
WHEREAS, pursuant to Section 2.10 of the Series H
Resolution, the Treasurer has caused to be published a
Notice of Bond Sale with respect to the Series H Bonds
for the information of potential bidders and has
furnished copies of an Official Statement and Official
Terms and Conditions of Bond Sale to interested persons
requesting the same; and
WHEREAS, under the terms of the Notice of Bond Sale and
the Official Terms and Conditions of Bond Sale, it is
provided that proposals for purchase of the Series H
Bonds would be received by the Board until 10:30 a.m.
on March 10, 1983; and
WHEREAS, the following proposals for purchase of the
Series H Bonds have been received in due time and
acceptable form:
Seasongood & Mayer
Cincinnati, Ohio
- Aggregate
Principal
Amount
Sought
$1,255 ,000
310,000
340,000
365,000
400,000
435,000
475,000
525,000
575 ,000
630,000
3,190,000
Coupon
Rate
Offered
6.75%
7.00%
7.20%
7.40%
7.60%
7.80%
8.00%
8.20%
8.40%
8.60%
8.70%
Net
Interest
Cost
8.435319%
B. Bidder: Smith Barney, Harris Upham & Co.,
New York, New York
Aggregate
Bonds Principal
Maturing
May 1,
1986-1990
1991
1992
1993
1994
1995
1996
1997-1998
1999-2000
200 1-2003
Amount
Sought
$1,255,000
310,000
340,000
365,000
400,000
435,000
475,000
1, 100,000
1,320,000
2,500,000
Incorporated
Coupon
Rate
Offered
7.00%
7. 20%
7 .40%
7.70%
8.00%
8.20%
8.40%
8.60%
8.75%
9.00%
2
A. Bidder:
Bonds
Maturing
May 1,
1986-1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000-2003
Net
Interest
Cost
8.699996%
C. Bidder: Blyth Eastman Paine Webber, Inc.
New York, New York
Bonds
Maturing
May 1,
1986-1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999-2003
Aggregate
Principal
Amount
Sought
$ 700,000
265,000
290,000
310,000
340,000
365,000
400,000
435,000
475,000
525,000
575,000
3,820,000
D. Bidder: Johnston, Brown, Burnett
Inc., Prudential - BachE
Lexington, Kentucky
Bonds
Maturing
May 1,
1986-1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000-2003
Aggregate
Principal
Amount
Sought
$ 965,000
290,000
310,000
340,000
365,000
400,000
435,000
475,000
525,000
575,000
630,000
3,190,000
& Knight, Inc., John Nuveen & Co.,
e Securities, Inc. and Associates
Coupon
Rate
Offered
6.65%
6.90%
7.15%
7.40%
7.65%
8.00%
8.20%
8.40%
8.60%
8.75%
9.00%
9.10%
Net
Interest
Cost
8.7934%
3
Net
Interest
Cost
8.7376%
Coupon
Rate
Offered
6.40%
6.70%
6.90%
7. 10%
7.40%
7.70%
7.90%
8.20%
8.40%
8.60%
8.80%
9.00%
E. Bidder: Morgan Guaranty Trust Company of New York
New York, New York
Bonds
Maturing
May 1,
1986-2003
Aggregate
Principal
Amount
Sought
$8,500,000
Coupon
Rate
Offered
8.75%
Net
Interest
Cost
8.&8154%
WHEREAS, the Executive Committee has considered
the matter of which bid is most advantageous to
the Board;
NOW, THEREFORE, THE EXECUTIVE COMMITTEE HEREBY
RESOLVES AS FOLLOWS:
1. that the proposal of Seasongood & Mayer, as
follows, for the purchase of the $8,500,000
"University of Kentucky Consolidated Educational
Buildings Revenue Bonds, Series H," dated March 1,
1983 ("the Series H Bonds") is hereby accepted as
the highest and best bid:
Bonds
Maturing
May 1
1986
1987
1988
1989
1990
1991
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
Coupon
Rate
6. 75%
6. 75%
6. 75%
6. 75%
6. 75%
7 . 00%
7 . 20%
7. 40%
7 . 60%
7. 80%
8. 00%
8.20%
8 . 40%
8.60%
8. 70%
8. 70%
8. 70%
8. 70%
Aggregate
Principal
Amount
$215,000
235,000
250,000
265,000
290,000
310,000
340,000
365,000
400,000
435,000
475,000
525,000
575,000
630,000
690,000
755,000
830,000
915,000
Net Interest Cost = 8.435319%
4
2. that the interest rates on the Series H Bonds
are hereby fixed at the rates set out in the said
accepted proposal;
3. that the Series H Bonds as identified in the
Series H Resolution shall be delivered by the
officers of the Board in accordance with the terms
of the Series H Resolution as soon as ready;
4. that the confirmation of the said accepted
proposal subjects the Board to no liability if it
is unable to obtain the final approving legal
opinion of Wyatt, Tarrant & Combs, Louisville,
Kentucky, Bond Counsel, or if the interest on the
Series H Bonds should become subject to federal or
Kentucky income taxation, or if the Series H Bonds
should become subject to Kentucky ad valorem
taxation, prior to the delivery of the Series H
Bonds; but also that the purchaser shall not be
required to take up the Series H Bonds without the
final approving legal opinion of Bond Counsel
aforesaid or if the Series H Bonds or interest
thereon should become so subject to taxation;
5. that this Resolution shall be in full force
and effect from and after its adoption.
5
SCIENTIFIC ADVISORY COMMITTEE REPORT, TOBACCO AND HEALTH RESEARCH INSTITUTE
Submitted to: Dr. D. Layten Davis, Director. University of Kentucky
Tobacco and Health Research Institute
Subject: Report of the Scientific Advisory Committee, Tobacco and
Health Institute concerning site visit held December 15-16,
1982 at the University of Kentucky, Lexington, Kentucky
Scientific Advisory Committee:
Leo G. Abood, Professor, Center for Brain Research, University
of Rochester Medical Center, Rochester, NY 14642
Donald Heistad, Professor of Medicine, University Hospital,
Iowa City, IA 52242
Aaron Janoff, Professor of Pathology, State University of New
York at Stony Brook, Stony Brook, NY 11794
Fred Bock, Senior Scientist, Papanicolaou Cancer Research
Institute, Miami, FL 33101
Thurston J. Mann, Assistant Director, North Carolina
Agricultural Research Service, North Carolina University,
Raleigh, NC 27650
SUMMARY OF THE REVIEW
It was the Committee's view that the aims of the research program of the
University of Kentucky Tobacco and Health Research Institute (THRI) address
many timely and important issues relating to tobacco and the health
consequences of smoking. The program is a broad-based one involving a number
of capable investigators from numerous departments throughout the University
of Kentucky whose interests range from the neurobehavioral and cardiovascular-
pulmonary effects of smoking to matters dealing with product modification and
passive exposure to the constituents of smoke. In addition to contributing to
a better understanding of the basic mechanisms associated with the health
consequences of smoking, the investigations were appropriately directed
towards the missions of 1) identifying and reducing the health hazards in
both the smoking and non-smoking population, 2) emphasizing numan studies,
and 3) attempting to develop appropriate animal models for research on
smoking. The research program is unique in its scope and the concentration of
qualified investigators devoted to research on smoking.
In summary, the Committee concluded that the research program of the THRI
is comprised of a number of projects of high scientific merit, is clearly
relevant to the issues of tobacco health, and is being effectively
administered.
COMMENTS ON THE INDIVIDUAL RESEARCH PROJECTS
The majority of the research projects were highly meritorious,
particularly 1) The involvement of elastase-antielastase in emphysema, 2) the
chemistry and function of a1 -protease inhibitor;3ithe neurobehavioral projects
dealing with multiple nicotine receptors and their neuroanatomical loci of
action; 4) the cardiovascular program, particularly the studies on ventilatory
mechanisms, the studies on the use of non-invasive techniques to evaluate
high-risk cardiovascular patients, the studies on drug disposition, and those
on thromboxane-prostacyclin production; 5) a number of the projects dealing
with passive smoking-smoke components, particularly those on nicotine-derived
nitrosamines, the role of methylation in nicotine toxicity, and on the growth
and coagulation of tobacco smoke aerosols; 6) the projects on product
modification within the College of Agriculture, particularly those on nicotine
metabolism on modification of the tobacco plant and on viral gene expression
in tobacco cells. All of the principal investigators responsible for these
projects were considered to be highly competent and productive, while the
projects themselves were in the forefront of research on smoking and tobacco
health.
There were some projects that were considered to be satisfactory but
could be improved by a revision of experimental procedures. Included in this
group were the projects 1) aimed at developing a model of lung injury induced
by chronic exposure to cigarette smoke coupled with steroid treatment, 2)
examining the relationship between the accumulation of tobacco smoke and
pulmonary emphysema, 3) determining the effects of passive smoking on
interferon production, and 4) determining the effect of cigarette smoking and
age on drug disposition in man.
2
Other projects were somewhat less promising and/or productive. Included
in this group were the projects on the early detection of and susceptibility
to smoking-related emphysema, at the treatment of emphysema, the studies
attempting to develop a smoking induced model of lung injury, the project on
cutaneous blood flow in man, the project on the tissue distribution of smoke
carcinogens, and the project concerned with the cholinergic system of brain
synaptosomes. Some of the projects were often lacking in tenable hypotheses,
originality, and potential for disclosing new, significant findings.
I. Pulmonary Program
1. The underlying hypothesis behind one study is that amines in. cigarette
smoke are avidly bound by lung cells or extracellular receptors, leading to
phospholipid accumulation in pulmonary macrophages. Macrophage
phospholipidosis, in turn, is thought to cause cell death with attendant
release of elastase and destruction of adjacent pulmonary tissue. No
mechanism is suggested for the accumulation of phospholipids in macrophages
due to amine-binding in the lung, nor is it made clear why such accumulations
should cause macrophage death. Some data were presented showing that labelled
imipramine, preloaded into animal lungs, is partly displaced following
subsequent in vivo exposure of these animals to cigarette smoke inhalation,
thus supporting the suggestion that amines in smoke may bind to amine
receptors in lung tissue.
(a) The bulk of the data are derived from an in-vitro isolated lung
perfusion model, in which amine-containing fractions of smoke-condensate are
3
added to the perfusate and efflux of labelled imipramine is then measured.
The physiological relevance of such experiments is questionable, since uptake
of smoke amines by pulmonary endothelium in the investigator's model may be
very different from uptake by pulmonary epithelium in smoking animals or man.
Why not ventilate the isolated, perfused lung with cigarette smoke so as to
bring the in vitro and in vivo experiments onto a common footing?
(b) If phospholipid accumulation in macrophages (or some other
effect of amine-binding on these cells) causes macrophage death and
dissolution, this is unlikely to lead to significant elastase release in the
lung. Macrophages do not store elastase in their lysosomes, rather they
continuously synthesize and secrete it into their medium. Therefore,
macrophage death is associated with decreased, not increased, elastase
production. It was shown that alveolar macrophages sequester neutorphil
elastase and that this enzyme is released by injured macrophages (e.g.,
severely anoxic cells). Is this the mechanism of lung injury proposed by one
of the investigators? A more detailed exposition of the working hypothesis is
needed to help clarify these and other questions.
2. A second project proposes to synthesize 14C-labelled carbamates to be
used as elastase-specific substrates and to use such reagents in a screening
program to detect smokers at risk of developing emphysema. The rationale is
that high-risk smokers may have increased lung elastolytic activity.
Aerosolizations of the labelled substrate into the lung, then, may permit
detection of such individuals by measurement of exhaled 14CO2. Alternatively,
the assay may be used to measure elastase activity in plasma.
4
(a) Smokers with emphysema are likely to have derangements in
ventilation, such that the inhaled substrate-aerosol may not be adequately
exposed to lung regions where higher than normal elastase activity is present
(diseased regions).
(b) Detection of increased plasma or serum elastase activity in
high-risk smokers is very unlikely, because of the overwhelming concentration
of al-croteinase inhibitor in plasma. It is more feasible to measure
neurtroph1il elastase in plasma by immunological techniques, since neutrophil
elastase retains its antigenicity in a 1-proteinase inhibitor complex.
Indeed, screening of smoking populations using such measurements (RIA, other)
are already in progress in several laboratories.
(c) Other non-invasive chemical tests are currently being developed
and have already been reported in the literature, which may be more promising
for detection of high-risk smokers. These tests include ELISA for elastin-
peptides in serum (Darnule et al., Anal. Biochem. 1982, 122:302) and RIA for
desmosine in urine (Harel et al., Am. Rev. Respir. Dis. 1980, 122:769).
3. A third study seeks to develop desmosine analogues to inhibit monocyte
chemotactic responses to desmosine-containing elastin-peptides. Such drugs
would hopefully blunt the further recruitment of monocytes (macrophages?) to
regions of smokers' lungs containing degraded elastin, thus reducing the risk
of developing emphysema.
This work is largely based on earlier published work by Senior et al.
5
showing that elastin-peptides are chemotactic for monocytes and suggesting
that the chemotactic fragments were enriched in desmosine cross-links (J.
Clin. Invest., 1980, 66:859). Recently, however, Senior has observed that
non-cross-linked tropoelastin and also desmosine-free synthetic peptides (with
amino acid sequences characteristic of repeating peptides in elastin) are
chemotactic for human monocytes. He mentions these observations in a second
paper (Senior et al., J. Olin. invest., 1982, 70:614) and concludes: 'tit
appears that cross links are not necessary for chemotactic activity of elastin
peptides. t
4. A fourth study of the Pulmonary Program is conducting an extensive
correlation designed to evaluate the protease-antiDrotease imbalance
hypothesis of pulmonary emphysema. Parameters being explored include:
smoking history, individual smoking habits (puff-volume, puff-duration, etc.)
plasma thiocyanate and carboxyhemoglobin levels, number of
polymorphonucleocytes (PMN) in the circulation, elastase and myeloperoxidase
contents of PMN, total plasma a 1-proteinase inihibitor (immunological assay),
ratio of trypsin-inhibitory to elastase-inhibitory activities of plasma
(functional assay of al-proteinase inhibitor), complement levels in plasma,
neutrophil chemotactic responses to zymosan-activated plasma and to n-formyl-
methionyl-peptides, and pulmonary function tests including spirometry and
single-breath nitrogen washout.
Preliminary results on 50 matched subject pairs (smokers vs. non-smokers)
were presented at the visit. Statistically significant negative correlations
were found between pulmonary function and levels of complement,, neutrophil
6
myeloperoxidase and numbers of circulating neutrophils. These data suggest
that increased inflammatory mediators and attendant increases in total
neutrophil protease "burden" may be important pathogenetic determinants of
lung injury in smokers. Of special interest is the observation of increased
neutrophil myeloperoxidase in high-risk smokers, since this enzyme has been
implicated by other workers in the oxidative inactivation of a 1-proteinase
inhibitor.
The group working on protease-antiprotease imbalance is a hard-working,
impressive one, who is fully competitive with the best in its field at other
lung research centers. Moreover, the group has made an exensive effort to
characterize their smoking subjects in terms of mg tar per cigarette, depth of
inhalation, puff retention time, puff volume and number of puffs per
cigarette, in addition to the usual indices of packs per day x years of
smoking. They should now take greater advantage of available statistical
resources at THRI to examine possible correlations between parameters of
inflammation, protease-antiprotease balance, and Individual smoking habits.
5. Another study seeks to develop a model of lung-injury induced by chronic
cigarette smoke exposure coupled with steroid treatment to suppress the
pulmonary macrophage response to cigarette smoke. In the absence of the
normal macrophage pool in the lung, cigarette smoke exposure is observed to
cause severe accumulation of phospholipid-protein complexes (tubular myelin
arrays) in the alveoli, resembling those seen in human alveolar proteinosis.
It is clear that emphysematous (destructive) changes also take place in this
model. It was hypothesized that, in the absence of normal numbers of
7
phagocytic macrophages, secretory products (perhaps augmented in smoking
animals) cannot be properly removed from the alveoli.
(a) The dose of steroid employed to produce the above effect in
animals is extraordinarily high and has no physiological relevance. The dose
corresponds to 35,000 mg/day/70 kg man as opposed to the usual clinical dose
of 100-200 mg/day. (The lazter is, itself, a pharmacological dose as opposed
to a physiological dose.) At the dose level- used in the animal studies, there
is a 30% mortality from the steroid alone. Under these conditions, little can
be said regarding the mechanism of action of the steroid-smoke combination,
since steroids have wide-ranging effects even at physiologic doses.
(b) In view of these potential problems in data interpretation, a
recent study has initiated experiments using lower doses of the drug combined
with smoking. However, even this current dose is about 1Ox higher
(corresponding to 1,750 mg/day/70 kg man) than the usual clinical dosage.
Data on lung effects of this modified regimen were not available at the time
of the site-visit.
6. A study is being undertaken on the in vitro and in vivo studies of the
chemical and biological changes in alPi induced by oxidizing agents and by
cigarette smoke. Data were summarized at the site-visit showing that 4 out of
6 tyrosine residues in the free inhibitor molecule are normally suscpetible to
nitrosylation with resultant loss of pancreataic elastase-inhibitory activity.
However, a lPi complexed to trypsin or to pancreataic elastase appears
conformationally altered, so that these same 4 tyrosine residues are no longer
8
susceptible to nitrosylation. Furthermore, and perhaps of greater relevance
to the smoking and health issue, mild oxidation of a lPi converts 2 of 8
methionine residues in the inhibitor to their sulfoxides with loss of
elastase-inhibitory activity (as observed by others); whereas stronger
oxidizing conditions lead to conversion of 4 methionine residues to
methionine-sulfoxide. Under these conditions, reductants cannot reactivate
clPi , but they can do so when only 2 methionine sulfoxides are present. This
information is new and potentially of great importance, since chronic
cigarette smoking has been reported to convert half of the a lPi in the lung
to an oxidized form containing 4 methionine sulfoxide residues per molecule
(Carp et al., PNAS, 1982, 79:2041).
Studies are now in progress dealing with chemical changes and activity
measurements for a lPi treated with cigarette smoke fractions in vitro, as
well as for inhibitor recovered from lung fluids and plasma of animals
following acute cigarette smoke inhalation. Longer-range plans include
structure-function studies of lPi obtained from chronic smoking animals and
humans.
The studies of ventilatory mechanics in unanesthetized dogs is certainly
an appropriate preparation. Preliminary observations that nicotine may
stimulate airway receptors are provocative and potentially important. It will
be important in those studies 1) to obtain simple hemodynamic measurements,
such as arterial pressure, which may have important effects on ventilation,
and 2) to perform systematic pharmacological evaluation to determine whether
the airway receptors that are activated are indeed nicotinic receptors.
9
II. Neurobehavioral Program
The main objective of this program is to explore the mechanisms and the
various sites of action of nicotine in rats and dogs with a view toward
elucidating the role of nicotine in smoking health and behavior. The group is
attempting to characterize the physiologic and pharmacologic nature of the
various receptors for nicotine within the central and peripheral nervous
system employing an extensive battery of pharmacodynamic, electrophysiologic,
psychophysical, and biochemical techniques.
The overall objectives of the program were well-delineated and addressed
important issues related to tobacco health, while the experimental design and
protocol was well-conceived and appropriate. During a relatively short
period, many experimental procedures were developed and refined, which were
required to accomplish the objectives, and also significant data was generated
concerning the nature and function of multiple nicotine binding sites within
the brain. Among the significant findings were those demonstrating that low
concentrations of nicotine may enhance nicotine binding and that the analgetic
action of nicotine involved the medulla oblongata rather than the opioid
system.
Convincing data was presented showing that nicotine is self-administered
(i.e., reinforcing) when administered directly into rat lateral hypothalamus,
while being adversive when administered into the pons-medulla. Although other
studies have demonstrated that nicotine is reinforcing when given
systemically, this study is the first to show that it is self-administered
10
into a brain area, specifically the lateral hypothalamus. Such studies
contribute to our knowledge of why people smoke and help elucidate the brain
sites and mechanisms involved in nicotine's action.
In summary, the projects have considerable relevance to the stated
objectives of THRI and are in competent, experienced hands. The progress to
date has been very good and is expected to continue to be so.
Neurochemical Studies:
This project dealt with the effects of chronic nicotine administration on
the cholinergic system of synaptosomes isolated from rat and mouse brain and
on the transport of 14C-isoaminobutyric acid (AI) transport across the mouse
placenta. The likelihood that the synaptosomal studies will result in
significant new findings concerning mechanism of the action of nicotine is not
great, since this approach has been used by innumerable investigators in the
past and to little avail. Although effects of chronic nicotine on placental
transport are worth investigating, the rationale behind the studies on AIB
transpor