CGRP-alpha responsiveness of adult rat ventricular cardiomyocytes from normotensive and spontaneously hypertensive rats.
Calcitonin gene-related peptide (CGRP)-alpha is expressed in heart ventricles in sensory nerves and cardiomyocytes. It modifies inotropism and induces ischaemic preconditioning. This study investigates the effect of CGRP-alpha on the contractile responsiveness of isolated adult ventricular rat cardiomyocytes and the effect of chronic hypertension on this interaction. Cardiomyocytes were isolated and paced at 0.5-2.0 Hz. Cell shortening was recorded via a line camera with a reading frame of 500 Hz. CGRP-alpha exerted a dual effect on cardiomyocytes with a positive contractile effect at 10nM and a negative contractile effect at 10 pM. CGRP-alpha(8-37), a calcitonin receptor-like receptor (CRLR) antagonist, attenuated the positive contractile effect. H89, a protein kinase A antagonist, converted the positive contractile effect into a negative contractile effect. The negative contractile effect was converted again back to a positive contractile effect in the presence of l-nitro arginine. In cardiomyocytes isolated from spontaneously hypertensive rats (SHR) the mRNA expression of CRLR and the receptor-associated modifier protein (RAMP)-2 were lower. However, on the protein level CLRL was up-regulated, RAMP2 expression remained unchanged, and eNOS expression was down-regulated in these cells. These cells responded with a pure positive contractile response. In Langendorff preparations, CGRP-alpha slightly reduced the rate pressure product in hearts from normotensive rats but it caused an increase in hearts from SHR. In conclusion, it is shown that CGRP-alpha exerts dual effects on cardiomyocytes favouring the negative contractile effect at very low concentrations. This effect is compensated in chronic pressure-overloaded hearts and converted into a positive inotropism.
Schlier
Alexander
A
Physiologisches Institut, Justus-Liebig-Universität, Aulweg 129, D-35392 Giessen, Germany.
Schreckenberg
Rolf
R
Abdallah
Yaser
Y
Krasteva
Gabriela
G
Piper
Hans Michael
HM
Pfeil
Uwe
U
Kummer
Wolfgang
W
Schlüter
Klaus-Dieter
KD
D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000494:pharmacology*; D058286:Calcitonin Receptor-Like Protein; D002118:Calcium / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D006352:Heart Ventricles / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D066298:In Vitro Techniques; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D007546:Isoquinolines / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism; D009200:Myocardial Contraction / Q000187:drug effects* / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000378:metabolism / Q000502:physiology; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051381:Rats; D011918:Rats, Inbred SHR; D017208:Rats, Wistar; D058263:Receptor Activity-Modifying Protein 2; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin / Q000037:antagonists & inhibitors; D013449:Sulfonamides / Q000494:pharmacology; D016276:Ventricular Function / Q000187:drug effects* / Q000502:physiology
D058286:Calcitonin Receptor-Like Protein; C545580:Calcrl protein, rat; D047908:Intracellular Signaling Peptides and Proteins; D007546:Isoquinolines; D008565:Membrane Proteins; D010446:Peptide Fragments; D047428:Protein Kinase Inhibitors; C545509:Ramp2 protein, rat; D058263:Receptor Activity-Modifying Protein 2; D058261:Receptor Activity-Modifying Proteins; D018003:Receptors, Calcitonin; D013449:Sulfonamides; C058636:calcitonin gene-related peptide (8-37); D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D017868:Cyclic AMP-Dependent Protein Kinases; D015740:Calcitonin Gene-Related Peptide; C063509:N-(2-(4-bromocinnamylamino)ethyl)-5-isoquinolinesulfonamide; D002118:Calcium