In this study the primary objective is to investigate whether activation of TRPV1, TRPA1 and TRPM3 by selective channel agonists induces vasodilation in human dermal arteries. If the primary objective is achieved, the secondary objective is to…
ID
Source
Brief title
Condition
- Maternal complications of pregnancy
- Obstetric and gynaecological therapeutic procedures
- Vascular hypertensive disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Endpoints:
- Contractions and relaxations induced by the agonists studied.
- Inhibition of these contractions and relaxations by the antagonists studied.
With the current in vitro study, we hope to substantiate these target
engagement biomarker models as some scientific questions remain unanswered:
1) Which vasodilatory mediators are released upon activation of TRPV1 and TRPA1
with capsaicin and cinnamaldehyde, respectively?
2) Does activation of TRPM3 by pregnenolone sulfate and/or CIM0216 induce
vasodilation and if so, which mediators are involved in this response?
In an attempt to answer these questions, we want to evaluate the effect of
capsaicin, cinnamaldehyde, pregnenolone sulfate and CIM0216 on human dermal
arteries, the vessels targeted in the biomarker models in vivo. Different
experimental conditions will be applied, e.g. in the presence or absence of
specific channel antagonists as well as antagonists of possible mediators
involved (e.g. CGRP-, NK1-, COX-inhibitors*).
Secondary outcome
In addition, as an exploratory objective, we want to compare the vasodilatory
responses resulting from TRPV1, TRPA1 and TRPM3 activation between dermal
arteries obtained from both normotensive pregnant women and preeclamptic women
undergoing a caesarean section. TRPV1 has recently been pointed out as one of
the receptors dysregulated in preeclampsia [5]. Furthermore, calcitonin-gene
related peptide (CGRP), a potent vasodilatory peptide and possible mediator
released upon TRP activation, has been suggested to play a role in the vascular
tone of the placenta.
Background summary
Transient receptor potential (TRP) ion channels are expressed in almost all
mammalian cell types, where they contribute to a variety of physiological
functions including vision, hearing, taste perception and thermosensation. In
addition, several members of the TRP ion channel family have been implicated in
nociception and are believed to play a role in different chronic pain
conditions including neuropathic pain and migraine, making them appealing drug
targets. Of particular interest are TRP Vanilloid 1 (TRPV1), Ankyrin 1 (TRPA1)
and Melastin 3 (TRPM3), all pursued to develop novel analgesics [4,8].
To get a better understanding of the (patho)physiological role of these
channels in human, in vivo target engagement biomarker models can be developed.
The principle behind these models is that the topical application of a
selective agonist will activate the specific TRP channel of interest and
subsequently result in the release of vasoactive neuropeptides, producing a
measurable increase in dermal blood flow. Such target engagement biomarker
models have been developed for TRPV1, using capsaicin as a selective agonist
[6] and for TRPA1, using cinnamaldehyde [1]. In the future, we plan to set up a
similar model for TRPM3 using pregnenolone sulfate and the synthetic compound
CIM0216 as chemical agonists [3,7].
We have ample experience in studying human arteries in our laboratory with
myograph experiments, including subcutaneous fat arteries obtained from
pregnancies [e.g., 9].
References:
[1] Buntinx L, Chang L, Amin A, Morlion B, de Hoon J. Development of an in
vivo target-engagement biomarker for TRPA1 antagonists in humans. Br. J. Clin.
Pharmacol. 2017;83:603-611.
[2] Gupta S, Lozano-Cuenca J, Villalón CM, de Vries R, Garrelds IM, Avezaat
CJJ, van Kats JP, Saxena PR, MaassenVanDenBrink A. Pharmacological
characterisation of capsaicin-induced relaxations in human and porcine isolated
arteries. Naunyn. Schmiedebergs. Arch. Pharmacol. 2007;375:29-38.
[3] Held K, Kichko T, De Clercq K, Klaassen H, Van Bree R, Vanherck J-C,
Marchand A, Reeh PW, Chaltin P, Voets T, Vriens J. Activation of TRPM3 by a
potent synthetic ligand reveals a role in peptide release. Proc. Natl. Acad.
Sci. 2015;112:E1363-E1372.
[4] Kaneko Y, Szallasi A. Transient receptor potential (TRP) channels: a
clinical perspective. Br. J. Pharmacol. 2014;171:2474-2507.
[5] Martínez N, Abán CE, Leguizamón GF, Damiano AE, Farina MG. TPRV-1
expression in human preeclamptic placenta. Placenta 2016;40:25-28.
[6] Van der Schueren BJ, de Hoon JN, Vanmolkot FH, Van Hecken A, Depre M, Kane
SA, De Lepeleire I, Sinclair SR. Reproducibility of the capsaicin-induced
dermal blood flow response as assessed by laser Doppler perfusion imaging. Br.
J. Clin. Pharmacol. 2007;64:580-590.
[7] Vriens J, Held K, Janssens A, Tóth BI, Kerselaers S, Nilius B, Vennekens
R, Voets T. Opening of an alternative ion permeation pathway in a nociceptor
TRP channel. Nat. Chem. Biol. 2014;10:188-95.
[8] Vriens J, Voets T. Sensing the heat with TRPM3. Pflügers Arch. - Eur. J.
Physiol. 2018.
[9] Gupta S, Hanff LM, Visser W, Steegers EA, Saxena PR, Vulto AG,
MaassenVanDenBrink A. Functional reactivity of 5-HT receptors in human
umbilical cord and maternal subcutaneous fat arteries after normotensive or
pre-eclamptic pregnancy. J Hypertens. 2006;24:1345-53.
Study objective
In this study the primary objective is to investigate whether activation of
TRPV1, TRPA1 and TRPM3 by selective channel agonists induces vasodilation in
human dermal arteries. If the primary objective is achieved, the secondary
objective is to examine the mediators involved in this response. As an
additional objective, the functionality of TRPV1, TRPA1 and TRPM3 will be
compared between normotensive and preeclamptic pregnant women.
Study design
After arrival at the laboratory, segments of the dermal arteries will be
mounted in organ baths for isometric contraction measurements. The tromboxane
A2 analogue U46619 will be administered to the segments as internal standard
for the contractile force developed by the segment. Also the endothelial
quality will be studied by assessing relaxations to bradykinin/substance P.
We will study vasodilation to selective TRPV1 (capsaicin), TRPA1
(cinnamaldehyde) and TRPM3 (pregnenolone sulfate and CIM0216) agonists in the
presence or absence of a precontraction induced by a threshold concentration of
U46619, as well as after addition of specific TRPV1 (capsazepine), TRPA1
(HC030031) and TRPM3 (isosakuranetin) channel antagonists and antagonists of
possible mediators involved (CGRP, COX, NK1*).
Study burden and risks
We expect no (or minimal) risks associated with participation.
Wytemaweg 80
Rotterdam 3015CE
NL
Wytemaweg 80
Rotterdam 3015CE
NL
Listed location countries
Age
Inclusion criteria
Both, normotensive and preeclamptic subjects must meet the following inclusion
criteria:
- Women >= 18 years old
- Capable of understanding the purpose and (minimal) risks of the study, fully
informed and given written informed consent (signed Informed Consent Form had
been obtained)
- Subjects undergoing elective caesarean section
Moreover, at least 1.5 cm of tissue of both, normotensive and preeclamptic
subjects, should be available for our study.
Exclusion criteria
A potential normotensive subject who meets any of the following criteria will
be excluded from participation in this study:
- Admission to an Intensive Care Unit (ICU) for any reason
- Subjects undergoing an emergency caesarean section
A potential preeclamptic subject who meets any of the following criteria will
be excluded from participation in this study:
- Admission to an Intensive Care Unit (ICU) for any reason
- Subjects diagnosed with the HELLP syndrome (Hemolysis, Elevated Liver enzymes
and Low Platelets)
- Subjects undergoing an emergency caesarean section
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| CCMO | NL68891.078.19 |