title: Calcitonin gene-related peptide in vivo positive inotropy is attributable to regional sympatho-stimulation and is blunted in congestive heart failure.
abstract: Calcitonin gene-related peptide (CGRP) is a nonadrenergic/noncholinergic (NANC) peptide with vasodilatative/inotropic action that may benefit the failing heart. However, precise mechanisms for its in vivo inotropic action remain unclear. To assess this, dogs with normal or failing (sustained tachypacing) hearts were instrumented for pressure-dimension analysis. In control hearts, CGRP (20 pmol/kg per minute) enhanced cardiac contractility (eg, +33+/-4.2% in end-systolic elastance) and lowered afterload (-14.2+/-2% in systemic resistance, both P<0.001). The inotropic response was markedly blunted by heart failure (+6.5+/-2%; P<0.001 versus control), whereas arterial dilation remained unaltered (-19.3+/-5%). CGRP-positive inotropy was not attributable to reflex activation because similar changes were observed in the presence of a ganglionic blocker. However, it was fully prevented by the beta-receptor antagonist (timolol), identifying a dominant role of sympatho-stimulatory signaling. In control hearts, myocardial interstitial norepinephrine assessed by microdialysis almost doubled in response to CGRP infusion, whereas systemic plasma levels were unchanged. In addition, CGRP receptors were not observed in ventricular myocardium but were prominent in coronary arteries and the stellate ganglia. Ventricular myocytes isolated from normal and failing hearts displayed no inotropic response to CGRP, further supporting indirect sympatho-stimulation as the primary in vivo mechanism. In contrast, the peripheral vasodilatative capacity of CGRP was similar in femoral vascular rings from normal and failing hearts in dogs. Thus, CGRP-mediated positive inotropy is load-independent but indirect and attributable to myocardial sympathetic activation rather than receptor-coupled stimulation in canine hearts. This mechanism is suppressed in heart failure, so that afterload reduction accounts for CGRP-enhanced function in this setting.
authors.affiliation: Division of Cardiology, Department of Medicine, Johns Hopkins Medical Institutions; Baltimore, Md, USA.
authors.forename: Tatsuo
authors.initials: T
authors.lastname: Katori
authors.forename: Donald B
authors.initials: DB
authors.lastname: Hoover
authors.forename: Jeffrey L
authors.initials: JL
authors.lastname: Ardell
authors.forename: Robert H
authors.initials: RH
authors.lastname: Helm
authors.forename: Diego F
authors.initials: DF
authors.lastname: Belardi
authors.forename: Carlo G
authors.initials: CG
authors.lastname: Tocchetti
authors.forename: Paul R
authors.initials: PR
authors.lastname: Forfia
authors.forename: David A
authors.initials: DA
authors.lastname: Kass
authors.forename: Nazareno
authors.initials: N
authors.lastname: Paolocci
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002304:Cardiac Pacing, Artificial; D002316:Cardiotonic Agents / Q000494:pharmacology*; D004285:Dogs; D045604:Extracellular Fluid / Q000737:chemistry; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism / Q000503:physiopathology; D006439:Hemodynamics / Q000187:drug effects; D006801:Humans; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects / Q000502:physiology; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000502:physiology; D009638:Norepinephrine / Q000032:analysis / Q000097:blood; D010446:Peptide Fragments / Q000494:pharmacology*; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology*; D013564:Sympathetic Nervous System / Q000502:physiology; D013610:Tachycardia / Q000150:complications; D013999:Timolol / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002316:Cardiotonic Agents; D010446:Peptide Fragments; D011943:Receptors, Adrenergic, beta; D018015:Receptors, Calcitonin Gene-Related Peptide; C058636:calcitonin gene-related peptide (8-37); D013999:Timolol; D015740:Calcitonin Gene-Related Peptide; D007545:Isoproterenol; D009638:Norepinephrine