NO-donating oximes relax corpora cavernosa through mechanisms other than those involved in arterial relaxation.
BACKGROUND
Erectile dysfunction (ED), as well as many cardiovascular diseases, is associated with impaired nitric oxide (NO) bioavailability. Recently, oxime derivatives have emerged as vasodilators due to their NO-donating capacities. However, whether these oximes offer therapeutic perspectives as an alternative NO delivery strategy for the treatment of ED is unexplored.


OBJECTIVE
This study aims to analyze the influence of formaldoxime (FAL), formamidoxime (FAM), and cinnamaldoxime (CAOx) on corporal tension and to elucidate the underlying molecular mechanisms.


METHODS
Organ bath studies were carried out measuring isometric tension on isolated mice corpora cavernosa (CC), thoracic aorta, and femoral artery. After contraction with norepinephrine (NOR), cumulative concentration-response curves of FAL, FAM, and CAOx (100 nmol/L-1 mmol/L) were performed.


METHODS
FAL-/FAM-induced relaxations were evaluated in the absence/presence of various inhibitors of different molecular pathways.


RESULTS
FAL, FAM, and CAOx relax isolated CC as well as aorta and femoral artery from mice. ODQ (soluble guanylyl cyclase-inhibitor), diphenyliodonium chloride (nonselective flavoprotein inhibitor), and 7-ethoxyresorufin (inhibitor of CYP450 1A1 and NADPH-dependent reductases) substantially blocked the FAL-/FAM-induced relaxation in the arteries but not in CC. Only a small inhibition of the FAM response in CC was observed with ODQ.


CONCLUSIONS
This study shows for the first time that NO-donating oximes relax mice CC. Therefore, oximes are a new group of molecules with potential for the treatment of ED. However, the underlying mechanism(s) of the FAL-/FAM-induced corporal relaxation clearly differ(s) from the one(s) involved in arterial vasorelaxation.
Department of Pharmacology, Ghent University, Ghent, Belgium.
Bart
B
Pauwels
Charlotte
C
Boydens
Kelly
K
Decaluwé
Johan
J
Van de Voorde
D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects; D005263:Femoral Artery / Q000187:drug effects; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D008297:Male; D051379:Mice; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology*; D010078:Oxazines / Q000494:pharmacology; D010091:Oximes / Q000494:pharmacology; D010413:Penis / Q000098:blood supply; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors; D000071756:Soluble Guanylyl Cyclase; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D020030:Nitric Oxide Donors; D010078:Oxazines; D010091:Oximes; D018160:Receptors, Cytoplasmic and Nuclear; D014665:Vasodilator Agents; D009569:Nitric Oxide; C484470:formaldoxime; C007649:ethoxyresorufin; C001250:formamidoxime; C041163:4-(N,N-dimethylamino)cinnamaldoxime; D006162:Guanylate Cyclase; D000071756:Soluble Guanylyl Cyclase
Cinnamaldoxime; Corpora Cavernosa; Erectile Function; Formaldoxime; Formamidoxime; Oxime