Effects of inhibition of alpha-CGRP receptors on cardiac and peripheral vascular dynamics in conscious dogs with chronic heart failure.
Whether endogenous calcitonin gene-related peptide (CGRP) plays a role in heart failure is unclear. Seven dogs were instrumented with left ventricular (LV) pressure gauges, pacers, coronary occluder and aortic, atrial, and coronary sinus catheters. Hemodynamic recordings and response to alpha-CGRP challenge were obtained for baseline in the conscious state. Rapid pacing (240 beats/min) was then initiated. The coronary artery was occluded for 90 minutes followed by reperfusion after 2 weeks of pacing. After 6 weeks of pacing, LV pressure (-11 +/- 6%), LV dP/dt (-53 +/- 5%), and mean arterial pressure (-15 +/- 4%) decreased (P < 0.01), while left atrial pressure (+19 +/- 3 mm Hg from 7 +/- 1 mm Hg) and heart rate (+53 +/- 16%) increased (P < 0.01). Infusion of the alpha-CGRP receptor antagonist alpha-CGRP[8-37] (30 microg/kg/min, i.v.), which blocked the exogenous alpha-CGRP challenge, did not affect any of these indices. Regional blood flow, as measured by the microsphere technique, in the nonischemic myocardium, as well as cerebral and renal vasculatures were unaltered during the infusion of alpha-CGRP[8-37]. Plasma concentrations of CGRP from both arterial and coronary sinus samples were unchanged after 6 weeks of pacing as compared with control. Thus, we conclude that endogenous alpha-CGRP does not appear to play a major role in the regulation of cardiac and peripheral vascular dynamics in the late stage of heart failure.
Department of Pharmacology, Merck Research Laboratories, West Point, Pennsylvania 19486, USA. you-tang_shen@merck.com
You-Tang
YT
Shen
John J
JJ
Mallee
Laurence K
LK
Handt
David B
DB
Gilberto
Joseph J
JJ
Lynch
Richard J
RJ
Hargreaves
Kenneth S
KS
Koblan
Robert J
RJ
Gould
Stefanie A
SA
Kane
D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D002560:Cerebrovascular Circulation / Q000187:drug effects / Q000502:physiology; D002908:Chronic Disease; D004285:Dogs; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D018015:Receptors, Calcitonin Gene-Related Peptide / Q000502:physiology; D012039:Regional Blood Flow / Q000187:drug effects / Q000502:physiology; D012079:Renal Circulation / Q000187:drug effects / Q000502:physiology; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology*
D000077221:Calcitonin Gene-Related Peptide Receptor Antagonists; D010446:Peptide Fragments; D018015:Receptors, Calcitonin Gene-Related Peptide; C058636:calcitonin gene-related peptide (8-37); D015740:Calcitonin Gene-Related Peptide