Perinatal development influences mechanisms of bradykinin-induced relaxations in pulmonary resistance and conduit arteries differently.
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 (approximately 5 min), newborn (60-84 h) and adult pigs (> or =6 months) were isolated, mounted for in vitro isometric force recording, activated with PGF(2alpha) (30 micromol/l) and relaxed with BYK (10 pmol/l-1 micromol/l), SP (10 pmol/l-0.1 micromol/l) or ACH (1 nmol/l-1 mmol/l).


RESULTS
(i) BYK: L-NAME (100 micromol/l) attenuated relaxations in foetal EPA ( approximately 55%) but nearly abolished them in the adult ( approximately 80%). In RPA, L-NAME nearly abolished ( approximately 90%) relaxations in the foetus and this effect diminished progressively with age to approximately 20% in the adult. Indomethacin (IND, micromol/l) attenuated relaxations in neonatal (approximately 25%), new-born and adult EPA (both approximately 45%). Together, L-NAME and IND abolished relaxations in all EPA and in neonatal RPA but not in older RPA. SKF525a (100 micromol/l) attenuated relaxations in foetal RPA ( approximately 4%), diminishing in the adult RPA to approximately 10%. Together, SKF52Sa and L-NAME largely abolished relaxations in postnatal RPA (approximately 80%). Activation with K(+)=125 mmol/l attenuated relaxations in adult EPA (approximately 80%), foetal RPA ( approximately 45%) and neonatal RPA (approximately 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.
Boels
P J
PJ
Vascular Biology & Pharmacology Unit Institute of Child Health, University College London, 3-Guilford Street, London, UK. pboels@ich.uck.ac.uk
Deutsch
J
J
Gao
B
B
Haworth
S G
SG
D000109:Acetylcholine / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D000831:Animals, Newborn; D001920:Bradykinin / Q000494:pharmacology*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D065607:Cytochrome P-450 Enzyme Inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors; D011335:Proadifen / Q000494:pharmacology; D011651:Pulmonary Artery / Q000187:drug effects / Q000196:embryology* / Q000254:growth & development; D013373:Substance P / Q000494:pharmacology; D013552:Swine; D014655:Vascular Resistance / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D016861:Cyclooxygenase Inhibitors; D065607:Cytochrome P-450 Enzyme Inhibitors; D004791:Enzyme Inhibitors; D014665:Vasodilator Agents; D013373:Substance P; D011335:Proadifen; D019001:Nitric Oxide Synthase; D000109:Acetylcholine; D001920:Bradykinin; D019331:NG-Nitroarginine Methyl Ester; D007213:Indomethacin