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 IICl(NO +)(cyclam)](PF 6) 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(tfms)(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 × 10 −3 s −1 at 35 °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.