CGRP-α responsiveness of adult rat ventricular cardiomyocytes from normotensive and spontaneously hypertensive rats
Calcitonin gene-related peptide (CGRP)-α is expressed in heart ventricles in sensory nerves and cardiomyocytes. It modifies inotropism and induces ischaemic preconditioning. This study investigates the effect of CGRP-α 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-α exerted a dual effect on cardiomyocytes with a positive contractile effect at 10 nM and a negative contractile effect at 10 pM. CGRP-α(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-α 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-α 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.