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Cardiovascular Research 2001 51(1):140-150; doi:10.1016/S0008-6363(01)00275-9
© 2001 by European Society of Cardiology
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Copyright © 2000, European Society of Cardiology

Perinatal development influences mechanisms of bradykinin-induced relaxations in pulmonary resistance and conduit arteries differently

P.J Boelsa,*, J Deutscha, B Gaob and S.G Hawortha

aVascular Biology & Pharmacology Unit Institute of Child Health, University College London, 3-Guilford Street, London WC1N 1EH, UK
bPharmacology Royal Free Hospital School of Medicine University College London Rowland Hill Street, London NW3 2PF, UK

* Corresponding author. Tel.: +44-20-7905-2348; fax: +44-20-7905-2370 pboels{at}ich.ucl.ac.uk

Objective: As bradykinin (BYK) relaxes conduit (EPA) and resistance (RPA) pulmonary arteries from both perinatal and adult lungs, we investigated whether this vasodilator's relaxation-mechanisms were altered during perinatal development, differed between EPA and RPA and differed with other endothelium-dependent vasodilators, acetyicholine (ACH) and substance P (SP). Methods: Arteries from mature foetal (5 days), neonatal ({approx}5 min), newborn (60–84 h) and adult pigs (≥6 months) were isolated, mounted for in vitro isometric force recording, activated with PGF2{alpha} (30 µmol/l) and relaxed with BYK (10 pmol/l–1 µmol/l), SP (10 pmol/l–0.1 µmol/l) or ACH (1 nmol/l–1 mmol/l). Results: (i) BYK: L-NAME (100 µmol/l) attenuated relaxations in foetal EPA ({approx}55%) but nearly abolished them in the adult ({approx}80%). In RPA, L-NAME nearly abolished ({approx}90%) relaxations in the foetus and this effect diminished progressively with age to {approx}20% in the adult. Indomethacin (IND, µmol/l) attenuated relaxations in neonatal ({approx}25%), new-born and adult EPA (both {approx}45%). Together, L-NAME and IND abolished relaxations in all EPA and in neonatal RPA but not in older RPA. SKF525a (100 µmol/l) attenuated relaxations in foetal RPA ({approx}4%), diminishing in the adult RPA to {approx}10%. Together, SKF52Sa and L-NAME largely abolished relaxations in postnatal RPA ({approx}80%). Activation with K+=125 mmol/l attenuated relaxations in adult EPA ({approx}80%), foetal RPA ({approx}45%) and neonatal RPA ({approx}75%) and abolished relaxations in RPA from older ages. (ii) ACH: L-NAME abolished relaxations in new-born EPA and RPA. In adult EPA, combined L-NAME and IND moderately attenuated relaxations. (iii) SP: Combined application of L-NAME and IND attenuated relaxations to a similar degree in new-born and adult EPA and RPA. Conclusions: In postnatal EPA, BYK-relaxations depend completely on prostaglandin- and NO-synthesis whereas those to SP (at all ages) and ACH (in the adult) do not. In RPA, BYK-relaxations develop from being completely dependant on the sole release of NO (foetus) to being almost completely independent of it (adult), a situation mimicked partially by SP but not by ACH, which, in new-born RPA is completely dependent on NO. BYK-relaxations in postnatal RPA depend on the release of a hyperpolarising factor generated through an SKF525a-sensitive pathway in conjunction with NO. The mechanisms of endothelium-dependent BYK-relaxations in the pulmonary vascular bed undergo diverging alterations, depending on the stage of development and arterial size/function. These changes are specific for BYK as they differ from those obtained from ACH or SP.

KEYWORDS ACH, acetylcholine; AD, adult (≥6 months old); BYK, bradykinin; CCRR, cumulative concentration response-relation; COX, cyclo-oxygenase; EDHF, endothelium-derived hyperpolarising factor; EDNO, endothelium-derived nitric oxide; EDPG, endothelium-derived prostaglandins; EPA, elastic conduit-type large intrapulmonary arteries; FT, mature foetal (5 days to term); NB, newborn, adapted to extrauterine life (60–84 h old); NE, neonatal with partially inflated lungs (≤5 min old); NO, nitric oxide; NOS, nitric oxide synthase; PG, prostaglandins; RPA, muscular resistance-type small intrapulmonary arteries; SP, substance P


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