Differences between nitrates: role of isosorbide 2-mononitrate.
BACKGROUND
Nitrates are used in the treatment of coronary heart disease and heart failure. The major drawback of their therapeutic use is the rapid development of tolerance.


OBJECTIVE
To investigate the effect of different nitrates on isolated rabbit hearts and aortic strips and the mechanism responsible for nitrate tolerance, using nitroglycerine (NTG), isosorbide dinitrate (ISDN), 5-mononitrate (5MN) and 2-mononitrate (2MN).


METHODS
Preparations were stimulated by different spasmogenic agents: KCl, angiotensin II and noradrenaline; nitrates were administered on the plateau contraction, at the concentration of maximum inhibitory effect. In another series of experiments, preparations were preincubated with the maximum inhibitory concentration of each nitrate to evaluate the induction of tolerance.


RESULTS
Nitrates produced the following maximum inhibitions on noradrenaline-induced contraction: NTG 90% (10(-6) mol/l), ISDN 60% (10(-4) mol/l), 5MN 55% (10(-4) mol/l) and 2MN 80% (10(-4) mol/l). After incubation a loss of vasodilator effect of nearly 50-60% was observed for all the nitrates considered except 2MN, whose loss of effect was significantly lower (36%). The cyclic guanosine monophosphate (cGMP) levels measured in the preparations were lower in the presence of 2MN than the other compounds.


CONCLUSIONS
These data suggest that 2MN is able to induce a lower cGMP increase and less tolerance induction; since these observations seem to be correlated, the vasodilator effect of 2MN probably also involves mechanisms other than stimulation of guanylate cyclase.
Raddino
Riccardo
R
Dipartimento di Medicina sperimentale Applicata, Sezione di malattie cardiovascolari, Università degli studi di Brescia, Brescia, Italy. Riccardo.raddino@libero.it
Caretta
Giorgio
G
Bonadei
Ivano
I
Teli
Melissa
M
Vizzardi
Enrico
E
Cas
Livio Dei
LD
D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism; D006152:Cyclic GMP / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance; D005260:Female; D066298:In Vitro Techniques; D007548:Isosorbide Dinitrate / Q000031:analogs & derivatives* / Q000494:pharmacology; D008297:Male; D009131:Muscle, Smooth, Vascular / Q000187:drug effects; D005996:Nitroglycerin / Q000494:pharmacology; D010477:Perfusion; D011817:Rabbits; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology*
D014665:Vasodilator Agents; C030398:isosorbide-2-mononitrate; D005996:Nitroglycerin; D006152:Cyclic GMP; D007548:Isosorbide Dinitrate; C030397:isosorbide-5-mononitrate