nitroarginine and Obesity

Erectile dysfunction frequently coexists with coronary artery disease and has been proposed as a potential marker for silent coronary artery disease in type 2 diabetes. In the present study, we comparatively assessed the structural and functional changes of both penile arteries (PAs) and coronary arteries (CAs) from a prediabetic animal model. PAs and CAs from 17- to 18-wk-old obese Zucker rats (OZRs) and from their control counterparts [lean Zucker rats (LZRs)] were mounted in microvascular myographs to evaluate vascular function, and stained arteries were subjected to morphometric analysis. Endothelial nitric oxide (NO) synthase (eNOS) protein expression was also assessed. The internal diameter was reduced and the wall-to-lumen ratio was increased in PAs from OZRs, but structure was preserved in CAs. ACh-elicited relaxations were severely impaired in PAs but not in CAs from OZRs, although eNOS expression was unaltered. Contractions to norepinephrine and 5-HT were significantly enhanced in both PAs and CAs, respectively, from OZRs. Blockade of NOS abolished endothelium-dependent relaxations in PAs and CAs and potentiated norepinephrine and 5-HT contractions in arteries from LZRs but not from OZRs. The vasodilator response to the phosphodiesterase 5 inhibitor sildenafil was reduced in both PAs and CAs from OZRs. Pretreatment with SOD reduced the enhanced vasoconstriction in both PAs and CAs from OZRs but did not restore ACh-induced relaxations in PAs. In conclusion, the present results demonstrate vascular inward remodeling in PAs and a differential impairment of endothelial relaxant responses in PAs and CAs from insulin-resistant OZRs. Enhanced superoxide production and reduced basal NO activity seem to underlie the augmented vasoconstriction in both PAs and CAs. The severity of the structural and functional abnormalities in PAs might anticipate the vascular dysfunction of the more preserved coronary vascular bed.

Topics: Acetylcholine; Animals; Arteries; Cholesterol; Coronary Vessels; Endothelium, Vascular; Enzyme Inhibitors; Erectile Dysfunction; Male; Nitric Oxide; Nitric Oxide Synthase Type III; Nitroarginine; Obesity; Penis; Piperazines; Prediabetic State; Purines; Rats; Rats, Zucker; Sildenafil Citrate; Sulfones; Superoxides; Triglycerides; Vasoconstriction; Vasodilation; Vasodilator Agents

Obesity is related to insulin resistance and hypertension, but the underlying mechanisms are unclear. Insulin exerts both vasodilator and vasoconstrictor effects on muscle resistance arteries, which may be differentially impaired in obesity.. To investigate whether vasodilator and vasoconstrictor effects of insulin are impaired in muscle resistance arteries of obese rats and the roles of Akt and endothelial NO synthase (eNOS).. Effects of insulin were studied in resistance arteries isolated from cremaster muscles of lean and obese Zucker rats. In arteries of lean rats, insulin increased activity of both NO and endothelin (ET-1), resulting in a neutral effect under basal conditions. In arteries of obese rats, insulin induced endothelin-mediated vasoconstriction (-15 +/- 5% at 1 nM, P < 0.05 vs. lean). Insulin induced vasodilatation during endothelin receptor blockade in arteries of lean rats (20 +/- 5% at 1 nM) but not in those of obese rats. Inhibition of NO synthesis increased vascular tone (by 12 +/- 2%) and shifted insulin-mediated vasoreactivity to vasoconstriction (-25 +/- 1% at 1 nM) in lean rats but had no effect in arteries of obese rats, indicating reduced NO activity. Protein analysis of resistance arteries revealed that insulin-mediated activation of Akt was preserved in obese rats, whereas expression of eNOS was markedly decreased.. Vasodilator but not vasoconstrictor effects of insulin are impaired in muscle resistance arteries of obese rats, and this selective impairment is associated with decreased protein levels of eNOS. These findings provide a new mechanism linking obesity to insulin resistance and hypertension.

Topics: Animals; Blotting, Western; Endothelin Receptor Antagonists; Endothelin-1; Enzyme Inhibitors; In Vitro Techniques; Insulin; Insulin Resistance; Muscle, Smooth, Vascular; Nitric Oxide Synthase Type III; Nitroarginine; Obesity; Oligopeptides; Oncogene Protein v-akt; Rats; Rats, Zucker; Receptors, Endothelin; Vasoconstriction; Vasodilation

The JCR:LA-corpulent rat is a unique animal model of human vascular disease that exhibits a profound insulin resistance, vasculopathy, and cardiovascular dysfunction. We tested the hypothesis that the defects affect endothelial and smooth muscle function of the coronary microvasculature as well as cardiac contractility. Coronary, myocardial and aortic function were assessed in obese (homozygous for the cp gene, cp/cp) and lean (heterozygous or homozygous normal, +/?) littermates aged 7 and 18 weeks.. Coronary endothelial relaxation was examined in isolated perfused hearts by determining the effect of bradykinin (0. 1-1000 nmol l(-1)) on coronary perfusion pressure (CPP), myocardial mechanical function was evaluated in terms of left-ventricular developed pressure (LVDevP), and aortic relaxation with the endothelium-dependent agonist, A 23187 (1-1000 nmol l(-1)).. In rats aged 7 weeks, bradykinin reduced CPP from 133+/-1 mmHg to 43+/-1 mmHg (-67%) in lean rats, but only to 64+/-3 mmHg (-52%) in corpulent rats (n=6, P<0.05). Similar differences were found in rats aged 18 weeks (n=8). Inhibition of NO synthase with N(G)-nitro-L-arginine (L-NNA; 0.2 mmol l(-1)) impaired, and tetrahydrobiopterin (0.1 mmol l(-1)), a NO synthase cofactor, restored relaxation in cp/cp rats. Spermine/NO equally reduced CPP in both groups (-58%). Mechanical function was similar in lean and corpulent rats, aortic endothelial relaxation was attenuated by approximately 30% and aortic smooth muscle function was normal (7 weeks) or improved (18 weeks) in the cp/cp genotype.. These results suggest that (i) there is a specific impairment of NO-mediated relaxation of the coronary resistance vessels in the JCR:LA-corpulent rat that is not associated with impaired baseline myocardial contractility, and (ii) exogenous tetrahydrobiopterin reversed the relaxation defects that are part of the vascular complications typical for the insulin resistance syndrome.

Topics: Animals; Antioxidants; Aorta, Thoracic; Biopterins; Bradykinin; Calcimycin; Dose-Response Relationship, Drug; Endothelium, Vascular; Enzyme Inhibitors; In Vitro Techniques; Insulin Resistance; Ionophores; Male; Microcirculation; Myocardial Contraction; Nitric Oxide Synthase; Nitroarginine; Obesity; Perfusion; Rats; Rats, Inbred Strains

The effects of NG-nitro-L-arginine, an inhibitor of brain nitric oxide (NO) synthase, on central serotoninergic system were studied in male obese Zucker rats and in their lean age-matched controls (FA/?; FA/FA), both groups aged 14 weeks. Acute injection of NG-nitro-L-arginine (50 mg/kg i.p.) or repeated administration of NG-nitro-L-arginine (50 mg/kg i.p. daily, for 7 days) reduced food intake and body weight in obese rats. Acute administration of NG-nitro-L-arginine reduced food intake in lean rats. However, lean rats showed tolerance to the NG-nitro-L-arginine effects after repeated administration. NG-Nitro-L-arginine administration significantly increased serotonin metabolism in the cortex, diencephalon and medulla-pons of obese Zucker rats after either acute or repeated administration of NG-nitro-L-arginine. In contrast, NG-nitro-L-arginine increased serotonin metabolism in lean rats only after acute administration, and the appearance of tolerance to NG-nitro-L-arginine anorectic effects paralleled the failure of NG-nitro-L-arginine to increase serotonin metabolism. The present data extend our previous findings indicating that NG-nitro-L-arginine possesses anorectic activity in obese Zucker rats, and clearly suggest that the central serotoninergic system mediates the anorexia induced by inhibitors of brain NO synthase.

Topics: Amino Acid Oxidoreductases; Animals; Appetite Depressants; Arginine; Body Weight; Brain; Eating; Hydroxyindoleacetic Acid; Male; Nitric Oxide Synthase; Nitroarginine; Obesity; Rats; Rats, Zucker; Serotonin; Tryptophan

We investigated the effects of NG-nitro-L-arginine (L-NO Arg) administration (12.5, 25 and 50 mg/kg i.p.) on food consumption and body weight of male obese Zucker rats (fa/fa) and in their lean age-matched controls (FA/?; FA/FA), both groups aged 14 weeks. Acute or repeated administration of L-NO Arg reduced food intake and body weight in both obese and lean rats. However the lean rats showed tolerance to the L-NO Arg effects after 5 days of treatment. L-NO Arg anorexia was suppressed by pretreatment with metergoline. These results suggest that L-NO Arg may represent a new anorectic drug.

Topics: Amino Acid Oxidoreductases; Animals; Appetite Depressants; Arginine; Body Weight; Brain; Eating; Male; Metergoline; Nitric Oxide Synthase; Nitroarginine; Obesity; Rats; Rats, Zucker; Ritanserin; Serotonin Antagonists