Inotropic and lusitropic effects of calcitonin gene-related peptide in the heart

Previous studies have demonstrated positive-inotropic effects of calcitonin gene-related peptide (CGRP), but the mechanisms remain unclear. Therefore, two experiments were performed to determine the physiological correlates of the positive-inotropic effects of CGRP. Treatments designed to antagonize the effects of physiologically active CGRP(1-37) included posttreatment with CGRP(8-37) and pretreatment with LY-294002 (LY, an inhibitor of phosphatidylinositol 3-kinase), 17 beta-estradiol (E), and progesterone (P) were also used to modulate the effects of CGRP(1-37). Experiment 1 was in vitro studies on sarcomeres and cells of isolated adult rat cardiac myocytes. CGRP(1-37), alone and in combination with E and P, decreased sarcomere shortening velocities and increased shortening percentages, effects that were antagonized by CGRP(8-37), but not by LY. CGRP(1-37) increased resting intracellular calcium ion concentrations and Ca2+ influxes, effects that were also antagonized by both CGRP(8-37) and LY. Experiment 2 was in vivo studies on left ventricular pressure-volume (PV) loops. CGRP(1-37) increased end-systolic pressure, ejection fraction, and velocities of contraction and relaxation while decreasing stroke volume, cardiac output, stroke work, PV area, and compliance. After partial occlusion of the vena cava, CGRP(1-37) increased the slope of the end-systolic PV relationship. CGRP(8-37) and LY attenuated most of the CGRP-induced changes. These findings suggest that CGRP-induced positive-inotropic effects may be increased by treatments with estradiol and progesterone and inhibited by LY. The physiological correlates of CGRP-induced positive inotropy observed in rat sarcomeres, cells, and intact hearts are likely to reveal novel mechanisms of heart failure in humans.