Hedical Research Society
P3
showed a significantly greater incremental vasodilator response to
Ach (AUC 157214 vs 132+14 AU, ~'0.04). There was no
difference in response to SNP. The mechanism of Ach-induced
vasodilation in microvessels is unclear, and may not involve nitric
oxide. Since microvessels are less important in the development of
hypertension, the results of this study may be particularly relevant
to the changes in microvascular permeability associated with PE.
OPTlMlSATlON OF SENSITISER DOSE IN
ENDOVASCULAR PHOTODYNAMICTHERAPY.
R MANSFIELD+,A MOSS', G BUONACCORSI*,
A OPANUGA? J MCEWAN~,s BOW"
Cardiovascular Repair & Remodeling Groupt and National
Medical Laser Centre', Middlesex Hospital, London
Photodynamic therapy (PDT) has exciting potential in the
prevention of coronary restenosis. PDT utilises the activation
of a photosensitising drug by laser light. Optimal application
may require titration of drug dose. We have previously
shown in a pig model early (3 days) medial smooth muscle
cell (SMC) depletion, favourable vessel wall remodeling and
reduced neointima formation, using the photosensitising
agent 5-aminolaevulinic acid (5-AM).
Aim: To determine the optimal sensitiser dose for medial
SMC depletion at 3 days.
Methods: 6 juvenile pigs (20-30 Kg) received drug (5-AM)
and laser light <50J/cm2) delivered to the left anterior
descending artery as tabulated. Coronary arteries were
pressure perfusion fixed in 4% formaldehyde at 3 days. H&E
sections were Dreoared and medial SMC counts determined.
Results:
. .
15mgkg
and light
SMCs
106i13
meanisd p=O.19
Wmgkg
and light
120mgkg
and light
120mgkg
No light
Ugh1
Alone
33t13
p=O.002
22*5
p=O.OOOOE
86i3
102t11
p=O.19
p4.38
Control
No DNQ/NOlight
93t16
Both 60mgkg and 120mgkg of A M resulted in a significant
depletion of medial SMCs vs control when activated by light.
However,there was no significant difference between these
doses ( ~ 4 . 1 ) .There was no significant effect from light
alone, drug alone (120mgkg) or with 15mgkg and light.
Conclusion: 60mg/kg of 5-aminolaevulinic acid represents
the optimal sensitiser dose for endovascular PDT, resulting
in medial SMC depletion.
P4 ACETYLCHOLINE-MEDIATED VASODILATOR
RESPONSES OF MICROVESSELS ARE INCREASED IN
WOMEN WITH PRE-ECLAMPSIA
J PONNAMPALAM, KR DAVIS, R HAYMAN,
S ARLJLKUMARAN and R DONNELLY
Divisions of Vascular Medicine, and Obstetrics & Gynaecology,
University of Nottingham, and Southern Derbyshire Acute
Hospitals Trust, Derby, UK
Changes in endothelial cell permeability and vasodilator function
have been reported using in-vitro and ex-vivo models of preeclampsia (PE), but this clinical study is one of the first to compare
endothelial-dependent and independent vasodilator responses in
vivo in hypertensive and normotensive pregnancy. Vasodilator
responses of subcutaneous microvessels of the forearm were
evaluated in 13 women with PE (mean age 27.1 2 2 yrs, BP 151/93
+ 4/3 d g , gestation 35.6 wks, and proteinuria 1.1 2 0.2 g/24h)
and 16 normotensive pregnant controls of similar gestation using
laser doppler fluximetry (LDF) with incremental iontophoretic
administration of acetylcholine (Ach) and sodium nitroprusside
(SNP) to characterise dose-response curves for endothelialdependent and independent vasodilator function. Patients were
studied under controlled conditions of temperature, posture and
probe position using a LDF system coupled with iontophoresis unit
(DRT4, Moor Instruments, UK) automated software. Doseresponses were defined using incremental iontophoretic currents,
each applied for 10-20 secs, in the range 25-100pA, and the data
were compared between groups using a Mann-Whitney U-test.
Baseline flux was similar in the two groups, but women with PE
P5 EFFECTS OF ACUTE WPERHOMOCYSTEINAEMIA
ON MICROVASCULAR FUNCTION
KR DAVIS*, H PEARSON, J BONHAMS and R DONNELLY
Division of Vascular Medicine, University of Nottingham,
Derbyshire Royal Infirmary and §Department of Chemical
Pathology, Sheffield Children's Hospital
Raised homocysteine levels are associated with premature coronary
artery disease and endothelial dysfunction in large conduit vessels,
but the underlying mechanism and the extent to which smaller vessel
function is affected by homocysteine is unclear. This placebocontrolled crossover study evaluates the effects of acute
hyperhomocysteinaemia (induced by oral methionine loading) on
circulating Von Willibrand factor (vWf) activity and forearm
microvascular responses to acetylcholine (ACh) and sodium
nitroprusside (SNP)using laser doppler fluximetry (LDF).
Fourteen healthy, non-smoking male volunteers attended fasted on
two separate occasions. On each study day, LDF responses to
incremental iontophoretic administration of ACh and SNP were
measured at T=O, 3 and 8 hours after placebo or methionine 15g.
Dose-responses were evaluated using currents applied for 10 seconds
in the range 8-128pA.
Methionine loading raised plasma homocysteine levels from 8.7
pmol/L to 30.1 and 36.0 at 3 and 8 hours, respectively. This had no
effect on vWf activity levels (1.02fo.3U/mL v 0.99f0.3 at 8 hours;
correlation: A.975). Nor were there any significant effects on peak
vasodilator responses to ACh (129.8f15 v 123.8f14 at 3 hours and
139.6f15 v 143.7f13 at 8 hours) and SNP (165.1f15 v 176.4f12 at
3 hours and 176.8f16 \I 171.5f15 seen at 8 hours). However,
increased homocysteine was associated with a rise in pulse pressure
at 8 hours (52.7f5 v 45.5f8; p<0.05).
Although homocysteine is known to affect endothelial function in
larger conduit arteries, and in this study increased pulse pressure,
there appears to be no adverse effects of homocysteine on
endothelial cell activation or on microvascular vasodilator responses.
P6
TNF RECEPTOR 1 POLYMORPHISMS AND THE
RISK OF CORONARY ARTERY DISEASE (CAD)
RA ALLEN'.', EM LEE', DH ROBERTS', M P I R M O H A M E ~
and BK PARK*
lBlackpool Victoria Hospital, Whinney Hey Road, Blackpool FY3
*Department of Pharmacology and Therapeutics, The
University of Liverpool, Ashton Street, Liverpool L69 3GE. ' MRS
8NR.
member
Coronary artery disease is
know to have a significant
inflammatory component.
TNF Receptor 1 (p55) is
constitutively expressed on nucleated cells and is thought to
mediate many of the actions of the pro-inflammatory cytokine
TNF-a.
We have investigated the significance of two
in patients
polymorphisms in the TNF Receptor 1 (p55) gene
with angiographically characterised coronary arteries.
259
patients attending Blackpool were recruited: these included
patients with normal coronary arteries (n=79), those with single
vessel CAD (n=58) and multi-vessel CAD (n=,122). Genotyping
I IP