Y27632, a Rho-activated kinase inhibitor, normalizes dysregulation in alpha1-adrenergic receptor-induced contraction of Lyon hypertensive rat artery smooth muscle.

RhoA-activated kinase (ROK) is involved in the disorders of smooth muscle contraction found in hypertension model animals and patients. We examined whether the alpha1-adrenergic receptor agonist-induced ROK signal is perturbed in resistance small mesentery artery (SMA) of Lyon genetically hypertensive (LH) rats, using a ROK antagonist, Y27632. Smooth muscle strips of SMA and aorta were isolated from LH and Lyon normotensive (LN) rats. After Ca(2+)-depletion and pre-treatment with phenylephrine (PE), smooth muscle contraction was induced by serial additions of CaCl(2). In LH SMA Ca(2+) permeated cells to a lesser extent as compared with LN SMA, while CaCl(2)-induced contraction of LH SMA was greater than that of LN SMA, indicating a higher ratio of force to Ca(2+) in LH SMA contraction (Ca(2+) sensitization). No hyper-contraction was observed in LH aorta tissues. Treatment of LH SMA with Y27632 restored both Ca(2+) permeability and Ca(2+)-force relationship to levels seen for LN SMA. In response to PE stimulation, phosphorylation of CPI-17, a phosphorylation-dependent myosin phosphatase inhibitor protein, and MYPT1 at Thr853, the inhibitory phosphorylation site of the myosin phosphatase regulatory subunit, was increased in LN SMA, but remained unchanged in LH SMA. These results suggest that the disorder in ROK-dependent Ca(2+) permeability and Ca(2+)-force relationship is responsible for LH SMA hyper-contraction. Unlike other hypertensive models, the ROK-induced hyper-contractility of LH SMA is independent of MYPT1 and CPI-17 phosphorylation, which suggests that ROK-mediated inhibition of myosin phosphatase does not affect SMA hyper-contractility in LH SMA cells

Low molecular mass dinitrosyl nonheme-iron complexes up-regulate noradrenaline release in the rat tail artery

BACKGROUND: Dinitrosyl nonheme-iron complexes can appear in cells and tissues overproducing nitric oxide. It is believed that due to their chemical nature these species may be implicated in certain pathophysiological events. We studied the possible role of low molecular mass dinitrosyl iron complexes in the control of noradrenaline release in electrically stimulated rat tail artery. RESULTS: A model complex, dinitrosyl-iron-thiosulfate (at 1–10 μM) produced a concentration-dependent enhancement of electrical field stimulated [(3)H]noradrenaline release (up to 2 fold). At the same time, dinitrosyl-iron-thiosulfate inhibited neurogenic vasoconstriction, consistent with its nitric oxide donor properties. A specific inhibitor of cyclic GMP dependent protein kinase, Rp-8pCPT-cGMPS, partially inhibited the effect of dinitrosyl-iron-thiosulfate on neurogenic vasoconstriction, but not on [(3)H]noradrenaline release. Another model complex, dinitrosyl-iron-cysteine (at 3 μM) elicited similar responses as dinitrosyl-iron-thiosulfate. Conventional NO and NO+ donors such as sodium nitroprusside, S-nitroso-L-cysteine or S-nitroso-glutathione (at 10 μM) had no effect on [(3)H]noradrenaline release, though they potently decreased electrically-induced vasoconstriction. The "false complex", iron(II)-thiosulfate showed no activity. CONCLUSIONS: Low molecular mass iron dinitrosyl complexes can up-regulate the stimulation-evoked release of vascular [(3)H]noradrenaline, apparently independently of their NO donor properties. This finding may have important implications in inflammatory tissues

Role of Endothelium on the Effects of Neuropeptide Y in Mesenteric Resistance Arteries of Spontaneously Hypertensive and Wistar-Kyoto Normotensive Rats1

ABSTRAC

A pertussis toxin-insensitive calcium influx mediated by neuropeptide Y2 receptors in a human neuroblastoma cell line

Stimulation of neuropeptide Y (NPY) Y-2 receptors induced an intracellular free Ca2+ ([Ca2+](i)) increase in a human neuroblastoma cell line, CHP-234. When NPY in a Ca2+-free solution was applied, this increase was abolished. Depolarization with high KC1 evoked no response, suggesting that the responses were not mediated by voltage-gated Ca2+ channels. There was no evidence that the NPY response consisted of a capacitative Ca2+ entry sensitive to internal Ca2+ store levels. The [Ca2+](i) elevation was diminished by Ni2+, a blocker of Ca2+ entry. Mn2+ induced a quench of the fura-2 fluorescence, which ceased promptly upon the removal of NPY, indicating that Ca2+ entry was linked tightly to receptor activation. Although thapsigargin- and ryanodine-sensitive Ca2+ stores were present, NPY induced responses were not impaired by pretreatment with either drug. Further-more, NPY had no effect on the thapsigargin sensitive store. Pertussis toxin did not affect the NPY-stimulated [Ca2+](i) increase, although it abolished the NPY-dependent inhibition of cAMP production. It is concluded that the Y-2 receptors couple directly to receptor-operated Ca2+ channels without the involvement of intracellular Ca2+ stores. The results also indicate that Y-2 receptors can activate both pertussis toxin-sensitive and -insensitive mechanisms in the same cell

MECANISME DE L'HYPERREACTIVITE BRONCHIQUE A L'ADENOSINE INDUITE PAR UNE PROVOCATION ALLERGENIQUE CHEZ DES RATS BROWN NORWAY ACTIVEMENT SENSIBILISES

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

CARACTERISATION PHARMACOLOGIQUE DES MECANISMES DE LA VASOCONSTRICTION NORADRENERGIQUE DANS LES ARTERES DE RESISTANCE DE RAT ET DE SA MODULATION PAR LE GMP CYCLIQUE

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF

Implication de la s-nitrosation des résidus cystéine dans les effets des donneurs de no dans les vaisseaux (formation de stocks de no)

L'OBJECTIF GENERAL DE CE TRAVAIL A ETE D'ETUDIER LE ROLE DE LA FORMATION DE S-NITROSOTHIOLS DANS LES EFFETS VASCULAIRES DU NO. L'INFORMATION MAJEURE QUE NOUS AVONS OBTENUE EST QUE L'INHIBITION PERSISTANTE DE LA CONTRACTION VASCULAIRE INDUITE PAR CERTAINS " DONNEURS DE NO " EST LIEE A LA FORMATION DE STOCKS MOBILISABLES DE NO DANS LA PAROI VASCULAIRE, SOUS FORME DE S-NITROSOTHIOLS. NOUS AVONS EGALEMENT MONTRE DES DIFFERENCES IMPORTANTES ENTRE LES DIVERSES FAMILLES DE DONNEURS DE NO, ET MEME A L'INTERIEUR D'UNE MEME FAMILLE DE COMPOSES, QUANT A LEUR CAPACITE A INDUIRE OU NON DES EFFETS PERSISTANTS SUR LE TONUS ARTERIEL PAR S-NITROSATION DE RESIDUS CYSTEINE. EN SE BASANT SUR LES PROPRIETES PHYSICO-CHIMIQUES DE CES COMPOSES, NOUS AVONS PU PROPOSER QUE CEUX SUSCEPTIBLES D'INDUIRE DES EFFETS PROLONGES SONT LES PORTEURS DE NO SOUS FORME REDOX DE L'ION NITROSONIUM (NO+) ET SUFFISAMMENT STABLES EN SOLUTION PHYSIOLOGIQUE POUR PERMETTRE LE TRANSFERT DE NO+ SUR DES RESIDUS CYSTEINE DANS LE TISSU VASCULAIRE. EN CE QUI CONCERNE LA STABILITE DES S-NITROSOTHIOLS EN SOLUTION ET LES RELATIONS ENTRE STABILITE ET PROPRIETES VASORELAXANTES, NOUS AVONS MONTRE LE ROLE PREPONDERANT DES IONS FER DANS LE PROCESSUS DE DECOMPOSITION ET DE LIBERATION DE NO A PARTIR DE LA S-NITROSOCYSTEINE. ENFIN, NOUS AVONS EGALEMENT APPORTE DES ARGUMENTS SUGGERANT LA PARTICIPATION DE COMPLEXE DINITROSYLE DE FER DANS LE PROCESSUS DE DECOMPOSITION ET DANS L'EFFET RELAXANT DE LA S-NITROSOCYSTEINE. DE TELS MECANISMES SERAIENT INTERESSANTS A EXPLOITER POUR COMPENSER LA DEFICIENCE DE LA PRODUCTION ENDOGENE DE NO PAR L'ENDOTHELIUM QUI EST ASSOCIEE A DIVERS FACTEURS DE RISQUE ET PATHOLOGIES CARDIOVASCULAIRES.STRASBOURG ILLKIRCH-Pharmacie (672182101) / SudocPARIS-BIUP (751062107) / SudocSudocFranceF

APPROCHE PHARMACOLOGIQUE DU ROLE DU MONOXYDE D'AZOTE DANS LES DOMMAGES PROVOQUES PAR ISCHEMIE-REPERFUSION CARDIAQUE (DOCTORAT (PHARMACOLOGIE MOLECULAIRE ET CELLULAIRE))

STRASBOURG ILLKIRCH-Pharmacie (672182101) / SudocSudocFranceF

Evolution des mécanismes de contrôle de la vasomotricité au cours du vieillissement et dans un modèle d'hypertension artérielle gravidique

STRASBOURG-Sc. et Techniques (674822102) / SudocSudocFranceF