Differences in the vascular selectivity and tolerance between the NO donor/beta-blocker PF9404C and nitroglycerin.
The vascular selectivity of PF9404C ((2'S),(2S)-3-isopropylamine,1-[4-(2,3-dinitroxy)propoxymethyl]-phenoxy-2'-propanol), a new beta-blocker with nitric oxide (NO)-donor and vasodilator properties, was studied in different rabbit arteries and veins. Phenylephrine (10(-6) M) or 35 mM K+ were used to pre-contract the arteries and veins prior to study the relaxant effects of PF9404C and nitroglycerin. The potency of both drugs to depress the phenylephrine-induced contraction was greater than that shown in the blockade of the K(+)-evoked contraction in most of the vessels studied, with the exception of the central ear artery. PF9404C exhibited about three-fold higher potency than nitroglycerin to relax the majority of the vessels studied, especially when they were contracted with K+, and showed a certain selectivity of action for the renal artery. PF9404C produced autotolerance but this effect was about 20-fold less pronounced than that observed with nitroglycerin. Cross-tolerance in those preparations pre-exposed to PF9404C that were relaxed later on with nitroglycerin was much greater than autotolerance. The tolerance for nitroglycerin was practically abolished in the presence of N-acetylcysteine. However, this was not the case for PF9404C. These results indicate that, although sharing the property of being NO donors, PF9404C and nitroglycerin show a different profile in causing vasodilation; furthermore, the tolerance to this effect is lesser for PF9404C and seems to be mediated by a mechanism different to that of nitrates. This makes PF9404C a nice pharmacological tool to further develop novel NO-donor compounds with a lesser degree of vascular tolerance than those now available.
Ruiz-Nuño
Ana
A
Instituto Teófilo Hernando, Departamento de Farmacología y Terapéutica, Facultad de Medicina, Universidad Autónoma de Madrid, C/ Arzobispo Morcillo, 4. 28029 Madrid, Spain.
Rosado
Arancha
A
García
Antonio G
AG
López
Manuela G
MG
Villarroya
Mercedes
M
D000319:Adrenergic beta-Antagonists / Q000494:pharmacology*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000502:physiology; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D004423:Ear / Q000098:blood supply; D005263:Femoral Artery / Q000187:drug effects / Q000502:physiology; D066298:In Vitro Techniques; D008297:Male; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D009574:Nitro Compounds / Q000494:pharmacology*; D005996:Nitroglycerin / Q000494:pharmacology*; D050198:Phenoxypropanolamines; D010656:Phenylephrine / Q000494:pharmacology; D011169:Portal Vein / Q000187:drug effects / Q000502:physiology; D011188:Potassium / Q000494:pharmacology; D011412:Propanolamines / Q000494:pharmacology*; D011817:Rabbits; D051381:Rats; D017207:Rats, Sprague-Dawley; D012077:Renal Artery / Q000187:drug effects / Q000502:physiology; D012501:Saphenous Vein / Q000187:drug effects / Q000502:physiology; D014661:Vasoconstriction / Q000187:drug effects*; D014662:Vasoconstrictor Agents / Q000494:pharmacology
C404199:3-isopropylamino-1-(4-(2,3-dinitroxy)propoxymethyl)phenoxy-2'-propanol; D000319:Adrenergic beta-Antagonists; D020030:Nitric Oxide Donors; D009574:Nitro Compounds; D050198:Phenoxypropanolamines; D011412:Propanolamines; D014662:Vasoconstrictor Agents; D010656:Phenylephrine; D005996:Nitroglycerin; D011188:Potassium