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Release and effects of calcitonin gene-related peptide in myocardial ischaemia

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posted on 2024-09-02, 16:40 authored by Göran Källner

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.

History

Defence date

1998-09-11

Department

  • Department of Molecular Medicine and Surgery

Publication year

1998

Thesis type

  • Doctoral thesis

Language

  • eng

Original publication date

1998-08-21

Author name in thesis

Källner, Göran

Original department name

Department of Surgical Science

Place of publication

Stockholm

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