Paradoxical coronary microcirculatory constriction during ischemia: a synergic function for nitric oxide and endothelin.
A paradoxical microcirculatory constriction has been observed in hearts of patients with ischemia, secondary to coronary stenosis. Here, using the isolated mouse heart (Langendorff), we examined the mechanism of this response, assuming involvement of nitric oxide (NO) and endothelin-1 (ET-1) systems. Perfusion pressure was maintained at 65 mmHg for 70 min (protocol 1), or it was reduced to 30 mmHg over two intervals, between the 20- and 40-min marks (protocol 2) or from the 20-min mark onward (protocol 3). In protocol 1, coronary resistance (CR) remained steady in untreated heart, whereas it progressively increased during treatment with the NO synthesis inhibitor N(G)-nitro-l-arginine methyl ester (L-NAME) (2.7-fold) or the ET(A) antagonist BQ-610 (2.8 fold). The ET(B) antagonist BQ-788 had instead no effect by itself but curtailed vasoconstriction to BQ-610. In protocol 2, hypotension raised CR by 2.2-fold. This response was blunted by reactive oxygen species (ROS) scavengers (mannitol and superoxide dismutase plus catalase) and was converted into vasodilation by l-NAME, BQ-610, or BQ-788. Restoration of normal pressure was followed by vasodilation and vasoconstriction, respectively, in untreated and treated preparations. In protocol 3, CR progressively increased with hypotension in the absence but not presence of L-NAME or BQ-610. We conclude that the coronary vasculature is normally relaxed by two concerted processes, a direct action of NO and ET-1 curtailing an ET(B2)-mediated tonic vasoconstriction through ET(A) activation. The negative feedback mechanism on ET(B2) subsides during hypotension, and the ensuing vasoconstriction is ascribed to ET-1 activating ET(A) and ET(B2) and reactive nitrogen oxide species originating from ROS-NO interaction.
Kusmic
Claudia
C
Area della Ricerca CNR, Istituto di Fisiologia Clinica, Via Moruzzi, 1-56124 PISA, Italia. kusmic@ifc.cnr.it
Lazzerini
Guido
G
Coceani
Flavio
F
Barsacchi
Renata
R
L'Abbate
Antonio
A
Sambuceti
Gianmario
G
D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology; D001794:Blood Pressure / Q000502:physiology; D023921:Coronary Stenosis / Q000150:complications / Q000503:physiopathology*; D003331:Coronary Vessels / Q000503:physiopathology*; D016232:Endothelins / Q000502:physiology*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006439:Hemodynamics / Q000502:physiology; D007022:Hypotension / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008833:Microcirculation / Q000503:physiopathology; D008955:Models, Cardiovascular; D017202:Myocardial Ischemia / Q000209:etiology / Q000503:physiopathology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000502:physiology*; D009842:Oligopeptides / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D017382:Reactive Oxygen Species / Q000378:metabolism; D014661:Vasoconstriction / Q000187:drug effects / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology; D014666:Vasomotor System / Q000502:physiology
D000959:Antihypertensive Agents; D016232:Endothelins; D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010880:Piperidines; D017382:Reactive Oxygen Species; C087220:BQ 610; D009569:Nitric Oxide; C086539:BQ 788; D019331:NG-Nitroarginine Methyl Ester