MINIREVIEW
The Role of Endogenous Lung Neuropeptides in Regulation of the Pulmonary
Circulation
I. M. KEITH
Department of Comparative Biosciences, School of Veterinary Medicine,
University of Wisconsin, Madison, USA
Received February 29, 2000
Accepted April 3, 2000
Summary
Vascular resistance in the mammalian pulmonary circulation is
affected by many endogenous agents that influence vascular smooth muscle, right
ventricular myocardium, endothelial function, collagen and elastin deposition,
and fluid balance. When the balance of these agents is disturbed, e.g. by airway
hypoxia from high altitude or pulmonary obstructive disorders, pulmonary
hypertension ensues, as characterized by elevated pulmonary artery pressure (PPA).
Among neuropeptides with local pulmonary artery pressor effects are endothelin-1
(ET-1), angiotensin II (AII), and substance P, and among mitigating peptides are calcitonin gene-related peptide (CGRP), adrenomedullin (ADM), atrial natriuretic
peptide (ANP), vasoactive intestinal peptide (VIP) and ET-3. Moreover,
somatostatin28 (SOM28) exacerbates, whereas SOM14
decreases PPA in hypoxic rats, with lowering and increasing of lung CGRP levels, respectively. Pressure can also be modulated by increasing or
decreasing plasma volume (VIP and ANP, respectively), or by induction or
suppression of vascular tissue remodeling (ET-1 and CGRP, respectively). Peptide
bioavailability and potency can be regulated through hypoxic up- and down-
regulation of synthesis or release, activation by converting enzymes (ACE for AII and ECE for ET-1), inactivation by neutral endopeptidase and proteases, or
by interaction with nitric oxide (NO). Moreover, altered receptor density and
affinity can account for changed peptide efficacy. For example, upregulation of
ETA receptors and ET-1 synthesis occurs in the hypoxic lung
concomitantly with reduced CGRP release. Also, receptor activity modifying
protein 2 (RAMP2) has been shown to confer ADM affinity to the pulmonary calcitonin-receptor-like receptor (CRLR). We recently detected the mRNA encoding
for RAMP2, CRLR, and the CGRP receptor RDC-1 in rat lung. The search for an
effective, lung selective treatment of pulmonary hypertension will likely
benefit from exploring the imbalance and restoring the balance between these
native modulators of intrapulmonary pressure. For example, blocking of the ET-1
receptor ETA and vasodilation by supplemental CGRP delivered i. v. or
via airway gene transfer, have proven to be useful experimentally.
Key words
Pulmonary hypertension · Hypoxia · Monocrotaline · Vasoconstriction ·
Vasodilatation · Receptors · Neuropeptide interactions
Reprint requests
Ingegerd M. Keith, PhD, Professor, Department of Comparative
Biosciences, School of Veterinary Medicine, University of Wisconsin, 2015 Linden
Drive West, Madison, WI 53706, USA, fax: (608) 263 3926, e-mail:
keithi@svm.vetmed.wisc.edu
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