In vivo effects of the controlled NO donor/scavenger ruthenium cyclam complexes on blood pressure.
Ruthenium(II/III) complexes able to bind and release NO* were tested in vivo, in conscious Wistar rats instrumented for continuous blood pressure (BP) measurement and administration of in bolus injections (5 to 100 nmol/Kg i.v.) of trans-[Ru(II)Cl(NO+)(cyclam)](PF6)2 (cyclam-NO) or sodium nitroprusside (SNP). For normotensive rats, cyclam-NO produced a sustained 10% BP reduction of basal MAP during 7 +/- 0.4 to 11 +/- 0.3 min. In acute hypertensive rats, cyclam-NO produced BP reduction 3-fold larger than in normotensive rats and similar to that of SNP (maximal effect: 41 +/- 1.3 vs. 45 +/- 2.2 mmHg, respectively). However, the duration of the effect of cyclam-NO was 13 to 21-fold longer than that of SNP. The hypotensive effect of cyclam-NO was fully blocked in presence of continuous infusion of a NO* scavenger, carboxy-PTIO (6 mmol/Kg/min), or of the inhibitor of cGMP activation, methylene blue (83 nmol/Kg/min), or of the cyclam-NO precursor, trans-[RuCl(tfins)(cyclam)](tfms) (cyclam-tfms) (500 mmol/Kg/min). The long lasting BP reduction of cyclam-NO can be interpreted in terms of a slower rate of NO* release (k-NO = 2.2 x 10(-3) S(-1) at 35 degrees C) following chemical reduction (E(0') = 0.10 V vs NHE). In summary, cyclam-NO showed an hypotensive effect around 20 times longer than SNP in either normotensive or hypertensive rats, which was completely inhibited by methylene blue or carboxy-PTIO. Continuous infusion of cyclam-tfms completely blocked the hypotensive effect of cyclam-NO by scavenging the NO* released by the reduced cyclam-NO.
Marcondes
Fabiana G
FG
Departamento de Fisiologia e Biofisica, Instituto de Biologia UNICAMP, Barão Geraldo, Campinas-SP, Brazil.
Ferro
Alessander A
AA
Souza-Torsoni
Adriana
A
Sumitani
Marie
M
Clarke
Michael J
MJ
Franco
Douglas W
DW
Tfouni
Elia
E
Krieger
Marta H
MH
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002455:Cell Division / Q000187:drug effects; D003497:Cyclic N-Oxides / Q000494:pharmacology; D016166:Free Radical Scavengers / Q000494:pharmacology; D006571:Heterocyclic Compounds / Q000494:pharmacology*; D006973:Hypertension / Q000378:metabolism*; D007022:Hypotension / Q000188:drug therapy*; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D008751:Methylene Blue / Q000494:pharmacology; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D009569:Nitric Oxide / Q000378:metabolism / Q000494:pharmacology*; D009599:Nitroprusside / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D012428:Ruthenium / Q000494:pharmacology*
D003497:Cyclic N-Oxides; D016166:Free Radical Scavengers; D006571:Heterocyclic Compounds; D007093:Imidazoles; D009599:Nitroprusside; C079391:2-phenyl-4,4,5,5-tetramethylimidazoline-1-oxyl-3-oxide; C024560:cyclam; D009569:Nitric Oxide; D012428:Ruthenium; D008751:Methylene Blue; D019331:NG-Nitroarginine Methyl Ester