sodium-nitrite and Heart-Diseases

Metabolic syndrome (MetS) reduces endothelial nitric oxide (NO) bioavailability and exacerbates vascular dysfunction in patients with preexisting vascular diseases. Nitrite, a storage form of NO, can mediate vascular function during pathological conditions when endogenous NO is reduced. The aims of the present study were to characterize the effects of severe MetS and obesity on dyslipidemia, myocardial oxidative stress, and endothelial NO synthase (eNOS) regulation in the obese Ossabaw swine (OS) model and to examine the effects of a novel, sustained-release formulation of sodium nitrite (SR-nitrite) on coronary vascular reactivity and myocardial redox status in obese OS subjected to critical limb ischemia (CLI). After 6 mo of an atherogenic diet, obese OS displayed a MetS phenotype. Obese OS had decreased eNOS functionality and NO bioavailability. In addition, obese OS exhibited increased oxidative stress and a significant reduction in antioxidant enzymes. The efficacy of SR-nitrite therapy was examined in obese OS subjected to CLI. After 3 wk of treatment, SR-nitrite (80 mg · kg(-1) · day(-1) bid po) increased myocardial nitrite levels and eNOS function. Treatment with SR-nitrite reduced myocardial oxidative stress while increasing myocardial antioxidant capacity. Ex vivo assessment of vascular reactivity of left anterior descending coronary artery segments demonstrated marked improvement in vasoreactivity to sodium nitroprusside but not to substance P and bradykinin in SR-nitrite-treated animals compared with placebo-treated animals. In conclusion, in a clinically relevant, large-animal model of MetS and CLI, treatment with SR-nitrite enhanced myocardial NO bioavailability, attenuated oxidative stress, and improved ex vivo coronary artery vasorelaxation.

Topics: Animals; Coronary Vessels; Delayed-Action Preparations; Disease Models, Animal; Dose-Response Relationship, Drug; Dyslipidemias; Female; Heart Diseases; Male; Metabolic Syndrome; Myocardium; Nitric Oxide Synthase Type III; Obesity; Oxidation-Reduction; Oxidative Stress; Peripheral Vascular Diseases; Severity of Illness Index; Sodium Nitrite; Swine; Vasodilation

We evaluated the role of SH-groups in improvement of endothelial dysfunction with ACE-inhibitors in experimental heart failure. To this end, we compared the vasoprotective effect of chronic treatment with zofenopril (plus SH-group) versus lisinopril (no SH-group), or N-acetylcysteine (only SH-group) in myocardial infarcted (MI) heart failure rats. After 11 weeks of treatment, aortas were obtained and studied as ring preparations for endothelium-dependent and -independent dilatation in continuous presence of indomethacin to avoid interference of vasoactive prostanoids, and the selective presence of the NOS-inhibitor L-NMMA to determine NO-contribution. Total dilatation after receptor-dependent stimulation with acetylcholine (ACh) was attenuated (-49%, P<0.05) in untreated MI (n=11), compared to control rats with no-MI (n=8). This was in part due to impaired NO-contribution in MI (-50%, P<0.05 versus no-MI). At the same time the capacity for generation of biologically active NO after receptor-independent stimulation with A23187 remained intact. Chronic treatment with n-acetylcysteine (n=8) selectively restored NO-contribution in total dilatation to ACh. In contrast, both ACE-inhibitors fully normalized total dilatation to ACh, including the part mediated by NO (no significant differences between zofenopril (n=10) and lisinopril (n=8)). Zofenopril, but not lisinopril, additionally potentiated the effect of endogenous NO after A23187-induced release from the endothelium (+100%) as well as that of exogenous NO provided by nitroglycerin (+22%) and sodium nitrite (+36%) (for all P<0.05 versus no-MI). We conclude that ACE-inhibition with a SH-group has a potential advantage in improvement of endothelial dysfunction through increased activity of NO after release from the endothelium into the vessel wall. Furthermore, this is the first study demonstrating the selective normalizing effect of N-actylcysteine on NO-contribution to ACh-induced dilatation in experimental heart failure.

Topics: Acetylcholine; Acetylcysteine; Angiotensin-Converting Enzyme Inhibitors; Animals; Aorta, Thoracic; Blood Pressure; Body Weight; Calcimycin; Captopril; Endothelium, Vascular; Heart Diseases; In Vitro Techniques; Lisinopril; Male; Myocardial Infarction; Nitrates; Nitrites; Nitroglycerin; omega-N-Methylarginine; Rats; Rats, Wistar; Sodium Nitrite; Sulfhydryl Compounds; Vasodilation; Vasodilator Agents

The diuretic drug hydrochlorothiazide was administered to 24 male and 24 female F344 rats as a mixture of 0.1% in powdered food. A parallel group of the same size was given 0.1% hydrochlorothiazide plus 0.2% sodium nitrite in the food. A third group received 0.2% sodium nitrite in the food and there was a similar group of untreated controls. The treatments were well tolerated and there was no significant life shortening. A majority of the rats given hydrochlorothiazide, with or without nitrite, developed chronic progressive nephropathy, which was more severe in males than in females. Associated with this were diffuse parathyroid hyperplasia in both groups receiving the drug, also more severe in males than in females, and parallel increases in lesions of the blood vessels (mural thrombosis of the heart and polyarteritis). The few adenomas of the parathyroid and tubular cell adenomas of the kidney in rats ingesting hydrochlorothiazide were not statistically significant.

Topics: Animals; Arteritis; Carcinogens; Female; Heart Diseases; Hydrochlorothiazide; Kidney Diseases; Male; Nitrites; Parathyroid Diseases; Rats; Rats, Inbred F344; Sodium Nitrite; Thrombosis

Quinacrine hydrochloride is toxic for the heart of F-344 rats. Rats treated with 500 ppm quinacrine hydrochloride in the diet all developed a high incidence of left atrial thrombosis. The lesion was associated with cardiac hypertrophy and dilatation and focal myocardial degeneration. Rats died from cardiac hypertrophy with severe acute and chronic congestion of the lungs, liver, and other organs. Seventy percent of rats given 250 ppm quinacrine hydrochloride and 1,000 ppm sodium nitrite simultaneously in the diet had thrombosis of the atria of the heart, while untreated control rats in this laboratory did not have atrial thrombosis. Sodium nitrite in combination with quinacrine hydrochloride appeared to have no additional effect.

Topics: Animals; Cardiomyopathies; Chemical and Drug Induced Liver Injury; Female; Heart Atria; Heart Diseases; Lung Diseases; Male; Quinacrine; Rats; Rats, Inbred F344; Sex Factors; Sodium Nitrite; Thrombosis; Time Factors

Topics: Catalase; Heart Diseases; Nitrites; Sodium Nitrite; X-Rays