Abstract
Adrenomedullin (AM) is a 52-amino acid peptide which is produced
in many tissues, including adrenal medulla, lung, kidney and heart.
Intravenous administration of AM causes a long-lasting hypotensive
effect, accompanied with an increase in the cardiac output in experimental
animals. This study was aimed to examine whether AM has any direct
effects on myocardial function. In addition to the myocardial contractility,
the effects of AM on coronary vascular tone and A-type natriuretic
peptide (ANP) release from atria and B-type natriuretic peptide
(BNP) gene expression in the ventricles were studied in the perfused
rat heart preparation.
In spontaneously beating hearts, AM had no effects on the
heart rate, but dose-dependently increased the developed tension
(DT) with an EC50 of 7 x 10-11 nmol/l,
reflecting a potent positive inotropic effect. The lower the initial
resting tension, the higher was the elevation in DT. In paced hearts,
a protein kinase A inhibitor, H-89, had no effect on AM-induced
inotropic effect, and AM did not increase the cAMP content of the
ventricular myocardium. In contrast, the inhibitors of sarcoplasmic
reticulum Ca2+ stores, ryanodine
and thapsigargin, as well as a protein kinase C inhibitor, staurosporine,
significantly attenuated the inotropic response to AM. L-type Ca2+ channel blocker,
diltiazem, also suppressed the AM-induced elevation in DT. Moreover,
AM increased the duration of myocyte action potentials between 10
mV and - 50 mV in isolated rat atria, consistent with an
increase in L-type Ca2+ channel
current during the plateau.
Inotropic effect of endothelin-1 (ET-1), another locally
acting peptide, was enhanced by inhibiting the myocardial nitric
oxide (NO) synthesis by Nω-nitro-L-arginine
methyl ester (L-NAME) in perfused rat heart. The AM-induced inotropic
action was unaltered by L-NAME treatment. When AM and ET-1 were
administrated in combined infusion, the inotropic response was significantly smaller
than that following the infusion of the peptides alone. This attenuated
response was more than overcome by infusion of L-NAME, although
the individual responses to AM and ET-1 were not modulated by L-NAME
at the doses used in the combination. Consistent with its vasodilator
action, AM dose-dependently dilated the coronary arteries of the
perfused heart. The effect of AM was not dependent on NO under basal
conditions or in coronary arteries constricted with ET-1. Furthermore, AM
enhanced the stretch-induced release of ANP from the right atrium,
but did not affect the ventricular BNP expression induced by ET-1.
In conclusion, AM exerts regulatory actions on the heart
by increasing cardiac contractility, dilating coronary arteries
and modulating stretch-induced ANP release. The inotropic effect
of AM was independent of cyclic AMP, but may involve activation
of protein kinase C, Ca2+ influx
through L-type Ca2+ channels
and the release of Ca2+ from
the sarcoplasmic reticulum. Endogenous NO production did not modulate
the inotropic effect of AM, although the effect of ET-1 was suppressed. Combined
administration of AM and ET-1 produced a weak inotropic response
most likely because of a potentiated synthesis of NO. Finally, AM
had a coronary vasodilator effect and augmented the stretch-induced
ANP release in the right atrium.
| Identifer | oai:union.ndltd.org:oulo.fi/oai:oulu.fi:isbn951-42-5675-1 |
| Date | 29 May 2000 |
| Creators | Kinnunen, P. (Pietari) |
| Publisher | University of Oulu |
| Source Sets | University of Oulu |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/doctoralThesis, info:eu-repo/semantics/publishedVersion |
| Format | application/pdf |
| Rights | info:eu-repo/semantics/openAccess, © University of Oulu, 2000 |
| Relation | info:eu-repo/semantics/altIdentifier/pissn/0355-3221, info:eu-repo/semantics/altIdentifier/eissn/1796-2234 |
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