Nitric oxide pathway in hypertrophied heart: new therapeutic uses of nitric oxide donors.
Left ventricular hypertrophy (LVH) is regarded as a complication common to a number of cardiovascular diseases, including hypertension, myocardial infarction and ischaemia associated with coronary artery disease. Initially LVH is a compensatory mechanism, but in the long term cardiac hypertrophy predisposes individuals to heart failure, myocardial infarction and sudden death. Alteration of the nitric oxide (NO) pathway is believed to play an important role in the haemodynamically overloaded heart and pathological cardiac remodelling. Although re-establishment of the physiological NO pathway could be considered an important therapeutic target, the use of conventional nitrates is limited in the clinical setting by the development of tissue resistance and tolerance and by the shortage of large-scale clinical trials unequivocally confirming the beneficial impact of NO donors on cardiovascular morbidity and mortality. The aim of this review is to present current therapeutic options for dealing with changes in the L-arginine-NO pathway. The most promising therapeutic approach is represented by a new neutral sugar organic nitrate, LA-419, the thiol group of which seems to protect NO from degradation, thereby increasing its bioavailability. In a model of aortic stenosis-induced pressure overload, LA-419 has been found to restore the complete NO signalling cascade and reduce left ventricular remodelling, but without restoring the original pressure gradient, indicating a possible direct antiproliferative effect. Future studies are needed to confirm this therapeutic benefit in other animal models of hypertension and in the clinical setting.
Ruiz-Hurtado
Gema
G
Departamento de Farmacología, Facultad de Medicina, Universidad Complutense, Madrid, Spain.
Delgado
Carmen
C
D001120:Arginine / Q000627:therapeutic use; D001708:Biopterins / Q000031:analogs & derivatives / Q000627:therapeutic use; D006332:Cardiomegaly / Q000188:drug therapy / Q000201:enzymology / Q000378:metabolism*; D006152:Cyclic GMP / Q000378:metabolism; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism*; D020030:Nitric Oxide Donors / Q000627:therapeutic use*; D019001:Nitric Oxide Synthase / Q000378:metabolism
D020030:Nitric Oxide Donors; D001708:Biopterins; D009569:Nitric Oxide; D001120:Arginine; D019001:Nitric Oxide Synthase; C003402:sapropterin; D006152:Cyclic GMP