title: Inotropic and lusitropic effects of calcitonin gene-related peptide in the heart.
abstract: 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 CGRP₁₋₃₇ included posttreatment with CGRP₈₋₃₇ and pretreatment with LY-294002 (LY, an inhibitor of phosphatidylinositol 3-kinase), 17β-estradiol (E), and progesterone (P) were also used to modulate the effects of CGRP₁₋₃₇. Experiment 1 was in vitro studies on sarcomeres and cells of isolated adult rat cardiac myocytes. CGRP₁₋₃₇, alone and in combination with E and P, decreased sarcomere shortening velocities and increased shortening percentages, effects that were antagonized by CGRP₈₋₃₇, but not by LY. CGRP₁₋₃₇ increased resting intracellular calcium ion concentrations and Ca(2+) influxes, effects that were also antagonized by both CGRP₈₋₃₇ and LY. Experiment 2 was in vivo studies on left ventricular pressure-volume (PV) loops. CGRP₁₋₃₇ 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, CGRP₁₋₃₇ increased the slope of the end-systolic PV relationship. CGRP₈₋₃₇ 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.
authors.affiliation: Department of Physiology and Biophysics, College of Medicine, Howard University, Washington, DC 20059, USA.
authors.forename: Mustafa
authors.initials: M
authors.lastname: Al-Rubaiee
authors.forename: Pandu R
authors.initials: PR
authors.lastname: Gangula
authors.forename: Richard M
authors.initials: RM
authors.lastname: Millis
authors.forename: Robin K
authors.initials: RK
authors.lastname: Walker
authors.forename: Nsini A
authors.initials: NA
authors.lastname: Umoh
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Cousins
authors.forename: Miara A
authors.initials: MA
authors.lastname: Jeffress
authors.forename: Georges E
authors.initials: GE
authors.lastname: Haddad
mesh_terms: D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling / Q000187:drug effects; D002316:Cardiotonic Agents; D002469:Cell Separation; D004958:Estradiol / Q000494:pharmacology; D012739:Gonadal Steroid Hormones / Q000502:physiology; D006321:Heart / Q000187:drug effects*; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects*; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D010446:Peptide Fragments / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011374:Progesterone / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012518:Sarcomeres / Q000187:drug effects; D013318:Stroke Volume / Q000187:drug effects; D016277:Ventricular Function, Left / Q000187:drug effects
chemical_list: D002316:Cardiotonic Agents; D012739:Gonadal Steroid Hormones; D010446:Peptide Fragments; D011374:Progesterone; D004958:Estradiol; D019869:Phosphatidylinositol 3-Kinases; D015740:Calcitonin Gene-Related Peptide; D002118:Calcium
keywords: PI3K; calcitonin gene-related peptide; cardiac; estrogen; progesterone