Compensatory effect by sigma1 (sigma1) receptor stimulation during alcohol withdrawal in mice performing an object recognition task.

Chronic alcohol consumption (CAC) provokes intense neurobiological alterations, which lead, notably, to an important abstinence syndrome upon withdrawal with deleterious cognitive consequences. We here examined the effect of activation or inactivation of the sigma(1) receptor during CAC withdrawal on the cognitive abilities of Swiss mice. Animals consumed an alcohol 10%/sucrose 30 g/l solution during 4 months. Control groups consumed only the sucrose vehicle solution. Then, animals experienced a progressive, 16 days long, CAC withdrawal, during which they were administered once daily with saline, igmesine (10 mg/kg i.p.), a sigma(1) receptor agonist, or BD1047 (10 mg/kg i.p.), a sigma(1) antagonist. Mice were then tested using an object exploration task, to evaluate their locomotor and exploratory activities and reactions to object habituation, spatial change or novel object presentation. CAC-treated animals showed augmentation of locomotion, anxiety and object exploration, which impeded correct reaction to object habituation, spatial change or novelty. Treatment with the sigma(1) ligands, ineffective in control groups, resulted in decrease of the hyper-responsiveness and restored habituation. However, correct reactions to spatial change and novelty were only produced by the sigma(1) agonist treatment. Moreover, the sigma(1) receptor hippocampal expression was increased in CAC-treated mice. Treatments with both sigma(1) ligands regulated its expression, but subcellular fractionation experiments revealed that the agonist treatment increased [(3)H](+)-pentazocine binding to sigma(1) sites in the plasma membrane fraction, while the antagonist maintained it only in the microsomal, putatively endoplasmic reticulum, fraction. In conclusion, CAC increased the sigma(1) receptor expression in the hippocampus of mice. Regulation of its expression during withdrawal, notably using a selective agonist, allowed not only to attenuate the CAC-induced hyper-responsiveness, but also to restore correct cognitive abilities.

ERK1/2-mediated vasoconstriction normalizes wall stress in small mesenteric arteries during NOS inhibition in vivo.

As in essential hypertension, chronic nitric-oxide synthase (NOS) inhibition leads to hypertrophic remodeling in conduit and muscular arteries and inward eutrophic remodeling in small resistance arteries with activation of extracellular signal-regulated kinases 1 and 2 (ERK1/2) in both vessel types. The authors tested the hypothesis that this remodeling heterogeneity could be related to distinct vasoreactivity patterns in small and larger arteries, with a vessel-specific function of ERK1/2 signaling. Using intravital microscopy in rats we have demonstrated that acute NOS inhibition (l-NA injection, 100 mg/kg) produced vasoconstriction of small mesenteric arteries. Consequently, the calculated in vivo wall stress was not significantly modified, despite the local rise in pressure. This could explain the lack of vascular protein synthesis elevation in vivo, an early index of hypertrophy. Inhibition of ERK1/2 activation with PD98059 blunted mesenteric artery contractions. Femoral arteries did not contract and were thus submitted to an enhanced wall stress and underwent hypertrophic remodeling in chronic conditions. In conclusion, the heterogeneous vascular remodeling in the l-NAME model is associated with a heterogeneous vasoconstriction response to acute NOS inhibition. Indeed, in contrast to larger arteries, l-NA-induced vasoconstriction in small arteries normalized wall stress and prevented early signs of hypertrophy. The results also suggest that ERK1/2 is a signaling element in NOS inhibition-induced vasoconstriction of small arteries in vivo.

Comparison of the cardiovascular protection by omapatrilat and lisinopril treatments in DOCA-salt hypertension.

OBJECTIVE: To compare the cardiovascular protection provided by omapatrilat and lisinopril in an experimental model of hypertension. METHODS: Four-week deoxycorticosterone acetate (DOCA)-salt hypertensive (HT) and age-matched normotensive (NT) rats were treated either with omapatrilat (40 mg/kg per day) or lisinopril (20 mg/kg per day) for 2 weeks before sacrifice, and compared with untreated HT and NT rats sacrificed at ages corresponding to either before or after the drug regimens. RESULTS: Systolic arterial pressure (SAP) of 2 and 4 week HT rats was increased in comparison to age-matched NT rats (P <0.05). Treatment with omapatrilat or lisinopril reduced SAP in HT (P <0.05) similarly by about 10%. Cardiac interstitial collagen, perivascular collagen and media/lumen ratio of coronary arterioles were increased in HT rats. Both treatments partially prevented the rise in perivascular collagen and completely corrected the increased media/lumen ratio in small arterioles from HT (P <0.05). In contrast to NT rats, only a weak coronary dilatation to bradykinin was observed in Langendorff hearts isolated from untreated-HT. This response was slightly improved by lisinopril and markedly improved by omapatrilat (P <0.05). The coronary dilatation to SNP which was reduced in 4-week HT (P <0.05), was partially improved by omapatrilat treatment but not by lisinopril. The enhanced superoxide anion production in aorta from HT rats was partially corrected with omapatrilat and lisinopril. Finally, omapatrilat, unlike lisinopril, markedly reduced mortality in a more severe form of DOCA-salt hypertension. CONCLUSIONS: Omapatrilat and lisinopril regressed coronary remodelling and cardiac collagen deposition, and reduced vascular oxidative stress in DOCA-salt hypertensive rats. However, despite similar antihypertensive efficacy, omapatrilat was superior to lisinopril in improving the endothelial-dependent coronary dilatation, suggesting a better vascular protection in the DOCA-salt model of hypertension.

Vessel-specific stimulation of protein synthesis by nitric oxide synthase inhibition: role of extracellular signal-regulated kinases 1/2.

Although conduit arteries develop hypertrophy after chronic NO synthesis blockade, resistance arteries remodel without hypertrophy under the same conditions. Similar findings have been described in essential hypertension. We postulated that this regional difference may be related to a heterogeneous effect of endogenous NO on proliferation along the vascular tree. Newly synthesized proteins were radiolabeled in vivo with [(3)H]L-leucine in basal conditions and during NO synthase inhibition, with or without PD98059 (inhibitor of the extracellular signal-regulated kinases [ERK] 1/2). Blocking the generation of NO by 3 different L-arginine analogues increased protein synthesis by an average of 75% in the aorta, in association with enhanced ERK 1/2 phosphorylation. PD98059 significantly reduced L-arginine analogue-induced protein synthesis and ERK 1/2 phosphorylation, confirming the involvement of ERK 1/2 as an important signaling element. In small arteries, L-arginine analogues did not influence the extent of protein synthesis, although phosphorylation of ERK 1/2 was also enhanced. To determine the role of NO in a condition of enhanced protein synthesis, angiotensin II was infused for 24 hours. Angiotensin II augmented protein synthesis in mesenteric arteries and the aorta, and was additive to NO synthase blockade in the aorta. In conclusion, endogenous NO exerts a tonic inhibitory influence on aortic growth, with limited impact on small arteries in basal and hypertrophic conditions. This heterogeneous role of NO on vascular growth may explain the heterogeneity of vascular remodeling observed in essential hypertension, a condition associated with endothelial dysfunction.