ACTIVITY OF AMYLIN AT CGRP(1)-PREFERRING RECEPTORS COUPLED TO POSITIVE CONTRACTILE RESPONSE IN RAT VENTRICULAR CARDIOMYOCYTES

Calcitonin gene-related peptide (CGRP) exerts a positive contractile r esponse directly in rat ventricular cardiomyocytes. This response is m ediated by receptors of the CGRP(1)-subtype. Amylin is 46% homologous with CGRP and binds to receptors selective for CGRP in a range of tiss ues. The ability of amylin to influence ventricular contractility has been assessed using cardiomyocytes isolated from the ventricles of adu lt rats, Cardiomyocytes were subjected to biphasic electrical stimulat ion at 0.5 Hz. CGRP produced a concentration-dependent positive contra ctile response which became maximal 4 min after initial stimulation, C GRP increased the contractile amplitude maximally at 1 nM and to a val ue which was 23.3% greater than in the absence of peptide (EC(50) valu e = 21 pM). Amylin increased the contractile amplitude maximally at 20 nM and to a value which was 17.3% greater than in the absence of pept ide (EC(50) value = 216 pM). In the presence of amylin (20 nM), the co ncentration-dependence of the contractile response to CGRP was shifted to the left, so that the response became maximal when CGRP was presen t at 50 pM. In the presence of CGRP(8-37) (100 nM), a selective antago nist at CGRP(1)-preferring receptors, the concentration-dependence of the contractile response to CGRP was shifted to the right (dose ratio = 54). Similarly, in the presence of CGRP(8-37) (100 nM), the contract ile response to amylin was inhibited significantly (P less than or equ al to 0.01). Amylin(8-37) (100 nM) did not inhibit the concentration-d ependence of the contractile responses to CGRP and amylin significantl y (dose ratios = 4.2 and 2.4, respectively). In conclusion, these data indicate that amylin exerts a contractile response directly in rat ve ntricular cardiomyocytes via CGRP(1)-preferring receptors, This effect could assume greater significance in non-insulin-dependent diabetes m ellitus and in hypertensive states, in which the concentration of amyl in is elevated in plasma.