Impairment Of Nitric Oxide Release Research Articles

Role of glucocorticoid receptor in the inhibitory effect of medroxyprogesterone acetate on the estrogen-induced endothelial nitric oxide synthase phosphorylation in human umbilical vein endothelial cells

We aimed to clarify which steroid receptor is involved in the inhibitory effect of medroxyprogesterone acetate (MPA) on estrogen-induced endothelial nitric oxide synthase (eNOS) phosphorylation in human umbilical vein endothelial cells (HUVEC). The progesterone/glucocorticoid receptor (GR) antagonist RU-486 and introduction of GR siRNA caused attenuation of the inhibitory effect of MPA on the estrogen-induced eNOS phosphorylation and eNOS activity in HUVEC.

Characterization of nitrergic function in monkey penile erection in vivo and in vitro

The nitrergic nerve appears to have a major role in the neuronal regulation of penile erection. Cholinergic innervation has been shown histochemically in penile cavernous tissues, but its functional role is not well understood. This study was aimed at examining the functional properties of the nitrergic nerve and the possible involvement of cholinergic function in the regulation of monkey penile erection in vivo and in vitro. In anesthetized Japanese monkeys, electrical stimulation of the cavernous nerve caused a frequency-dependent increase in intracavernous pressure and penile erection, and atropine enhanced the pressure response. Intravenous injections of N(G)-nitro-L-arginine (L-NA) markedly inhibited the stimulation-induced pressure increase and the erectile response, and L-arginine partially restored the pressure response. In some monkeys, the intracavernous pressure increase caused by nerve stimulation was reversed by treatment with L-NA; however, L-arginine restored the pressor response. In addition, hexamethonium suppressed the pressure increase that resulted from the nerve stimulation. In corpus cavernosum isolated from monkeys, transmural electrical stimulation elicited frequency-dependent relaxation. The relaxation was attenuated by physostigmine, and was potentiated by atropine. Relaxation was markedly inhibited by treatment with L-NA. It appears that nitric oxide (NO) released from inhibitory nerves, even at low frequencies, has a pivotal role in the initiation and maintenance of intracavernous pressure increase and penile erection in monkeys. Prejunctional muscarinic receptors in nitrergic nerves are expected to participate in the impairment of NO release. Nitrergic nerves responsible for penile erection may originate from ganglia close to the corpus cavernosum.

Lack of impairment of nitric oxide-mediated responses in a rat model of high-renin hypertension.

1. Angiotensin (Ang) II triggers the expression of a pro- oxidant phenotype in the vascular wall, suggesting that activation of the renin-angiotensin system (RAS) causes endothelial dysfunction in various pathological situations, such as hypertension. However, this hypothesis has been mostly tested in a setting of exogenous administration of AngII. 2. We tested the hypothesis of a role for endogenous activation of the RAS leading to oxidant stress and endothelial dysfunction in a high-renin model of hypertension (i.e. two-kidney, one-clip hypertension) in rats. One month after clipping or sham surgery, aorta were isolated from untreated rats or rats treated by the angiotensin AT1 receptor antagonist irbesartan (10 mg/kg per day). Mesenteric artery segments were also isolated from normotensive or hypertensive rats. 3. Hypertension reduced the relaxations to acetylcholine but did not affect the ratio of contractions to phenylephrine in the presence compared with the absence of a nitric oxide (NO) synthase inhibitor, used as an index of basal release of NO. 4. The free radical scavenger tempol reduced the contractions to phenylephrine in the absence, but not in the presence, of an inhibitor of NO synthesis. This index of free radical-mediated degradation of NO was not affected by hypertension. In parallel, hypertension did not affect the expression of p22phox, a component of the free radical generating enzyme reduced nicotinamide adenine dinucleotide phosphate oxidase. 5. Chronic treatment with the AT1 receptor antagonist decreased blood pressure, moderately improved the response to acetylcholine, but did not affect basal NO release in hypertensive rats, although it did increase basal NO release in normotensive rats. 6. Thus, this model of hypertension is characterized by an impaired stimulated NO release but not of basal NO release in isolated arteries. Furthermore, there was no functional evidence of an increased oxidative stress-mediated impairment of NO release. This is not in favour of a direct link between activation of the RAS and development of endothelial dysfunction in experimental hypertension.

Agonist-induced release of nitric oxide during acute exposure to nicotine

While we have shown that acute infusion of nicotine impairs agonist-induced dilatation of resistance arterioles (Am.J.Physiol. 272:H2337–H2342, 1997), no studies have examined the release of nitric oxide in response to these agonists before and during treatment with nicotine. Thus, the first goal of the present study was to examine agonist-induced release of nitric oxide by the hamster cheek pouch microcirculation under control conditions and during acute infusion of nicotine. We measured the release of nitric oxide (Sievers NO analyzer) in response to repeated topical application of acetylcholine (1.0 uμM) and 5′-adenosine diphosphate (ADP; 1.0 μM) during infusion of vehicle and during infusion of nicotine (2.0 μg/kg/min iv for 30 minutes followed by a maintenance dose of 0.35 μg/kg/min). In hamsters treated with vehicle, topical application of acetylcholine and ADP elicited reproducible increases in nitric oxide release. In contrast, in hamsters treated with nicotine, there was a marked inhibition of nitric oxide release in response to acetylcholine and ADP. In a previous study (J.Appl.Physiol. 85:1292–1298, 1998) we found that treatment of the hamster cheek pouch microcirculation with superoxide dismutase restored unpaired agonist-induced vasodilatation during acute infusion of nicotine. Thus, our second goal was to examine whether Superoxide dismutase would restore agonist-induced release of nitric oxide during infusion of nicotine. We found that treatment of the hamster cheek pouch microcirculation with superoxide dismutase prior to infusion of nicotine prevented nicotine-induced impairment of nitric oxide release in response to acetylcholine and ADP. We suggest that nicotine alters dilatation of arterioles via an increased release of superoxide anion and subsequent inactivation of nitric oxide.

3.P.201 Impairment of nitric oxide release and endothelium-dependent arterial relaxation by cholesterol oxides

3.P.201 Impairment of nitric oxide release and endothelium-dependent arterial relaxation by cholesterol oxides

Fosinopril improves regulation of vascular tone in mesenteric bed of diabetic rats.

Because diabetes mellitus leads to vascular dysfunction, we examined the microvascular endothelial and smooth muscle function in long-term diabetes and a possible influence of fosinopril treatment (10 mg/kg). We investigated isolated perfused mesenteric beds of diabetic rats (4 groups: control, control + fosinopril, diabetes, diabetes + fosinopril; diabetes of 6-month duration, induced by streptozotocin, STC) were investigated using computer-assisted microvideoangiometry. Vascular diameter of four different vascular regions [classified as conductive (G1, 303 +/- 6.5 mu m and G2, 239 +/- 6.3 mu m) and resistance (G3, 192 +/- 4.5 mu m and G4, 124 +/- 2.6 mu m) vessel generations; resting conditions, control group] were increased in diabetes by approximately 20%. However, the endothelium-dependent relaxation in response to 1 mu M acetylcholine (ACh) was reduced from 38-44% to 20-25% (diabetes mellitus) with maximal impairment in G4 vessels. This could be significantly antagonized by fosinopril treatment. Similarly, vasodilation in response to 1 mu M glyceroltrinitrate (GTN) was reduced from 50-58 to 20-30%, but was partially prevented by fosinopril (32-38%), whereas potassium chloride (KCl)-induced vasoconstriction did not show differences between the groups. Inhibition of nitric oxide (NO) synthesis by 3 mu M L-NG-nitro arginine (L-NNA) resulted in a slight vasoconstriction of all vessels (12-25%), with maximum response in G3/G4. This was not altered by disease or treatment. We conclude that (a) long-term diabetes leads to endothelial and smooth muscle dysfunction with reduced capability of vasodilation and either an impairment of NO release or a reduced smooth muscle responsiveness to and (b) a predominant impairment of NO-dependent regulation in small resistance vessels, and (c) that fosinopril treatment can at least partially prevent this vascular dysfunction.