cyclic-gmp and cumene-hydroperoxide

The Mediterranean diet, which is abundant in antioxidants, is associated with a relatively low incidence of coronary heart disease. Olive oil and olives, which contain the antioxidants hydroxytyrosol, oleuropein, and tyrosol, are important components of this diet. In this study, the effects of oxidative stress on the nitric oxide radical (NO(*))-mediated relaxation of rat aorta and the protection by these antioxidants were determined. Cumene hydroperoxide (CHP) was used to mimic oxidative stress induced by lipid hydroperoxides, which is mediated by the formation of hydroxyl radicals (OH(*)). CHP (300 microM) impaired the NO(*)-mediated relaxation of rat aorta by the acetylcholine receptor agonist carbachol (P < 0.05). This was due to a reduction in NO(*) production. A diminished NO(*)-mediated relaxation disturbs the vascular tone and leads to a rise in blood pressure, which is a well-established risk factor for coronary heart disease. Hydroxytyrosol (10 microM) efficiently protected the aorta against the CHP-induced impairment of the NO(*)-mediated relaxation (P < 0.05). Oleuropein, tyrosol, and homovanillic alcohol, a major metabolite of hydroxytyrosol, did not show protection. Moreover, hydroxytyrosol was found to be a potent OH(*) scavenger, which can be attributed to its catechol moiety. Because of its amphiphilic characteristics (octanol-water partitioning coefficient = 1.1), hydroxytyrosol will readily cross membranes and provide protection in the cytosol and membranes, including the water-lipid interface. The present study provides a molecular basis for the contribution of hydroxytyrosol to the benefits of the Mediterranean diet.

Topics: Animals; Antioxidants; Aorta; Benzene Derivatives; Cyclic GMP; Diet, Mediterranean; Free Radical Scavengers; Hydroxyl Radical; In Vitro Techniques; Male; Olive Oil; Oxidants; Oxidative Stress; Phenylethyl Alcohol; Plant Oils; Rats; Rats, Inbred Lew

STUDY OBJECTIVE - The aim of the study was to determine whether cumene hydroperoxide, a substance known to induce lipid peroxidation through free radical action, and 4-hydroxy-2,3-nonenal (4-hydroxynonenal), a major aldehyde formed during lipid peroxidation, induce coronary vasodilatation by changing cyclic nucleotide levels. DESIGN - The study involved Langendorff perfused rat hearts, using different concentrations of cumene hydroperoxide and 4-hydroxynonenal, with sodium nitroprusside for comparison. Coronary flow was measured indirectly as retrograde aortic flow, with constant perfusion pressure. Information about the precise localisation of cyclic guanosine monophosphate (cGMP) in the heart was obtained by immunocytochemistry, using a new cGMP antiserum. EXPERIMENTAL MATERIAL - Hearts were from male Wistar rats, body weight 200-250 g. MEASUREMENTS and RESULTS - Both cumene hydroperoxide and 4-hydroxynonenal caused a dose dependent and reversible increase in coronary flow comparable with sodium nitroprusside. With sodium nitroprusside there was a good correlation between extent of vasodilatation and total heart cGMP concentration. Vasodilatation induced by cumene hydroperoxide or 4-hydroxynonenal was not accompanied by increase in total heart cGMP or cAMP (cyclic adenosine monophosphate) concentration. Isoprenaline was used as a positive control for cAMP. cGMP immunostaining was found in coronary vascular smooth muscle after vasodilatation with sodium nitroprusside, but no immunostaining was found in vascular smooth muscle after vasodilatation with cumene hydroperoxide or 4-hydroxynonenal. CONCLUSIONS - Cumene hydroperoxide and 4-hydroxynonenal can provoke reversible coronary vasodilatation in isolated perfused rat hearts by a cyclic nucleotide independent mechanism.

Topics: Aldehydes; Animals; Benzene Derivatives; Blood Flow Velocity; Coronary Circulation; Coronary Vessels; Cyclic AMP; Cyclic GMP; Dose-Response Relationship, Drug; In Vitro Techniques; Isoproterenol; Lipid Peroxidation; Male; Myocardium; Rats; Rats, Inbred Strains; Vasodilation