Release and effects of calcitonin gene-related peptide in myocardial ischaemia
Author: Källner, Göran
Date: 1998-09-11
Location: Thoraxklinikens aula, Karolinska sjukhuset
Time: 9.00
Department: Institutionen för kirurgisk vetenskap / Department of Surgical Science
Abstract
A proportion of sensory C-fibres is characterized by sensitivity to the
pungent agent in hot peppers, capsaicin. Upon stimulation by capsaicin,
co-stored peptides including calcitonin gene-related peptide (CGRP), are
released from the peripheral terminals of these fibres. In addition to
capsaicin, other noxious/painful stimuli and conditions such as low pH,
ischaemia, nicotine and bradykinin can cause release of CGRP from
capsaicin-sensitive afferent nerves. CGRP-immunoreactive nerve fibres
occur throughout the cardiovascular system, including the heart where the
highest amounts of CGRP have been detected along coronary arteries and in
the atria. In various species and experimental models, CGRP has proven to
be the most potent vasodilator yet discovered. The main objective of the
present study was to investigate the release, and possible effects of
CGRP in association with myocardial ischaemia.
Since ischaemia-induced metabolic disturbances correlate well with
ischaemia-induced myocardial acidosis, we have studied release of CGRP
evoked by perfusion with low pH buffers in the isolated guinea-pig heart.
This model was also used to study the possible involvement of
prostacyclin (PGI2) and various ion channels in CGRP-release. Perfusion
with buffer at pH 7, 6 and 5, and perfusion with lactic acid evoked a
reproducible and concentration-dependent release of CGRP from the
isolated heart. In addition, low pH caused formation of PGI2, which also
evoked release of CGRP from the heart. Both the formation of PGI2 and the
release of CGRP evoked by low pH were attenuated by cyclo-oxygenase
inhibition. The outflow of CGRP caused by low pH, but not that caused by
capsaicin or erogenous PGI2, was dependent on an intact endothelium. The
axonal Na+ conduction blocker tetrodotoxin attenuated the release of CGRP
evoked by low concentrations of capsaicin, indicating involvement of an
axon reflex mechanism in the local release of CGRP. We detected common
features in the outflow of CGRP evoked by capsaicin and low pH, including
sensitivity to the capsaicin antagonist capsazepine, and to the blocker
of N-type Ca2+-channels, [omega]-conotoxin.
Cardiovascular effects of CGRP, of the CGRP antagonist CGRP(8-37) and of
capsaicin pretreatment (which causes desensitization of C-fibres) in
association with myocardial ischaemia and -infarction were studied in the
pig in vivo. Exogenous CGRP caused a marked reduction of systemic
vascular resistance. This effect was attenuated by CGRP(8-37). Local
administration of CGRP augmented the myocardial hyperaemia observed after
45 minutes of occlusion of the left anterior descending coronary artery.
CGRP(8-37) had no effect on post-occlusive hyperaemia. Forty-eight hours
after systemic capsaicin pretreatment, myocardial levels of CGRP were
decreased, and infarcted myocardium contained less CGRP than
non-infarcted myocardium. Exogenous CGRP, or CGRP(8-37) had no effect on
the extent of myocardial infarction. Capsaicin pretreated animals had
larger myocardial infarctions than controls, indicating a protective
effect of intact C-fibre activation and endogenous peptide release.
In patients undergoing coronary bypass surgery without the use of
cardiopulmonary bypass, 10-20 minutes of local ischaemia (as evidenced by
a net production of lactate) was associated with increased levels of CGRP
in coronary sinus blood.
In summary, the present findings suggest that cardiac C-fibre activation
and local release of CGRP observed in animal studies may function as an
endogenous physiological protective response to myocardial ischaemia also
in man.
Issue date: 1998-08-21
Publication year: 1998
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