CHF 2206, a new potent vasodilating and antiaggregating drug as potential nitric oxide donor.
The effects of the new 3,4-disubstituted furoxan, CHF 2206, on vascular tone, platelet aggregation and platelet cyclic 3',5'-guanosine monophosphate (cGMP) levels were investigated. The compound was a potent inhibitor of rabbit aortic ring contraction induced by norepinephrine, the stable prostaglandin F2 alpha analogue, U-46619, and KCl; this activity was independent of endothelium integrity. When pre-incubated with platelet-rich plasma, CHF 2206 potently reduced in a dose-dependent manner the aggregation induced by the threshold aggregating concentration of collagen, ADP or platelet activating factor (PAF). In the same experimental conditions, the test compound increased the platelet cGMP levels and this rise was clearly associated with the inhibition of platelet aggregation. Moreover, 3-isobutyl-1-methyl-xanthine (IBMX) 5 microM potentiated the antiaggregating activity of CHF 2206. These results indicate that the increase in cGMP plays a key role in the CHF 2206-elicited responses. Oxyhemoglobin reduced all the pharmacological actions of the test compound. This evidence, along with the capacity of CHF 2206 to cause inorganic nitrite production in the presence of platelet-rich plasma, strongly suggests that nitric oxide (NO) may be a common reactive intermediate responsible for the effects induced by the drug. In conclusion, the furoxan derivative CHF 2206 exerts a potent antiaggregating and vasodilating activity with a pharmacological profile similar to the one described for NO-donating pro-drugs.
Civelli
M
M
Department of Pharmacology, Chiesi Farmaceutici S.p.A., Parma, Italy.
Caruso
P
P
Giossi
M
M
Bergamaschi
M
M
Razzetti
R
R
Bongrani
S
S
Gasco
A
A
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D006152:Cyclic GMP / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006801:Humans; D066298:In Vitro Techniques; D008297:Male; D009129:Muscle Tonus / Q000187:drug effects; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D009569:Nitric Oxide / Q000378:metabolism*; D009599:Nitroprusside / Q000494:pharmacology; D010069:Oxadiazoles / Q000494:pharmacology*; D010108:Oxyhemoglobins / Q000378:metabolism; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology*; D011817:Rabbits; D014665:Vasodilator Agents / Q000494:pharmacology*
D010069:Oxadiazoles; D010108:Oxyhemoglobins; D010975:Platelet Aggregation Inhibitors; D014665:Vasodilator Agents; D009599:Nitroprusside; D009569:Nitric Oxide; C088213:4-phenyl-3-phenylsulfonylfuroxan; D006152:Cyclic GMP; D015056:1-Methyl-3-isobutylxanthine