Specific N-terminal CGRP fragments mitigate chronic hypoxic pulmonary hypertension in rats.
Chronic hypoxic pulmonary hypertension (HPH) is characterized by elevated pulmonary arterial pressure (P(PA)), right ventricular hypertrophy (RVH), pulmonary vascular remodeling, pulmonary edema and polycythemia. Currently, there is no safe and effective treatment for HPH. Calcitonin gene-related peptide (CGRP) is the most potent peptide vasodilator discovered thus far. We previously demonstrated that exogenous CGRP reversed HPH in rats. However, the CGRP1 receptor antagonist CGRP(8-37) and smaller inhibitory C-terminal CGRP fragments that can be formed by enzymatic cleavage in vivo may compromise the beneficial effects of endogenous or exogenous CGRP. We here examine the agonistic efficacy of N-terminal rat alpha-CGRP peptides containing the disulfide bridge (Cys(2)-Cys(7)) with amidated C-terminal in prevention of HPH. Chronic infusion of CGRP(1-8), CGRP(1-13), or CGRP(1-14) at 7 nmol/h/rat via the right jugular vein during 14 days of hypobaric hypoxia (10% inspired O(2)) significantly decreased the P(PA), RVH and pulmonary arterial medial thickness in comparison with controls, suggesting that these CGRP sequences can mitigate chronic HPH in rats. Systemic pressure was unchanged by infused peptides indicating no carry-over effect. In conclusion, N-terminal CGRP fragments (CGRP(1-8), CGRP(1-13) and CGRP(1-14)) may have a protective role in hypoxic pulmonary hypertension.
Qing
Xin
X
Department of Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin-Madison, AHABS Building, 1656 Linden Drive, Madison, WI 53706, USA.
Wimalawansa
Sunil J
SJ
Keith
Ingegerd M
IM
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002908:Chronic Disease; D006352:Heart Ventricles / Q000187:drug effects; D006976:Hypertension, Pulmonary / Q000150:complications / Q000188:drug therapy* / Q000473:pathology; D017380:Hypertrophy, Right Ventricular / Q000188:drug therapy / Q000209:etiology; D000860:Hypoxia / Q000150:complications / Q000188:drug therapy / Q000473:pathology; D008168:Lung / Q000098:blood supply / Q000187:drug effects; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009929:Organ Size / Q000187:drug effects; D010446:Peptide Fragments / Q000494:pharmacology*; D011651:Pulmonary Artery / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D016896:Treatment Outcome
D010446:Peptide Fragments; D015740:Calcitonin Gene-Related Peptide