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1.
Br J Pharmacol ; 109(3): 802-6, 1993 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-7689405

RESUMO

1. The role of nitric oxide synthase and cyclo-oxygenase in the skin blood flow response to ultraviolet light B (u.v.B) irradiation was investigated in the rat in vivo. 2. Local skin blood flow changes were measured in the shaved dorsal skin of anaesthetized male Sprague-Dawley rats with a laser Doppler flow probe. 3. u.v.B irradiation caused delayed onset vasodilation and by 18 h basal blood flow increased by 125 +/- 25% (P < 0.05, n = 12 rats, mean +/- s.e. mean). 4. Indomethacin, 3 nmol per site, NG-nitro-L-arginine methyl ester (L-NAME) 100 nmol per site, but not D-NAME 100 nmol per site, injected locally 17.5 h after u.v.B irradiation abolished the 18 h increase in blood flow. 5. The nitric oxide synthase inhibitor L-NAME, NG-monomethyl-L-arginine (L-NMMA) and canavanine, 10 and 100 nmol per site injected at 17.5 h, suppressed significantly the u.v.B 18 h response in a dose-dependent manner. The order of potency was L-NAME > canavanine = L-NMMA. The effect of L-NAME was reversed partially by the co-injection of an excess of L-arginine. 6. Topical application of the corticosteroid, clobetasol 17-propionate, immediately after irradiation inhibited the 18 h u.v.B response in a dose-dependent manner. 7. The delayed onset microcirculatory vasodilation induced by u.v.B involves both nitric oxide synthase and cyclo-oxygenase in this in vivo model. Topical corticosteroids may attenuate the response by inhibiting both prostaglandin and nitric oxide synthesis pathways.


Assuntos
Aminoácido Oxirredutases/fisiologia , Pele/irrigação sanguínea , Vasodilatação/efeitos da radiação , Aminoácido Oxirredutases/antagonistas & inibidores , Animais , Arginina/análogos & derivados , Arginina/farmacologia , Canavanina/farmacologia , Clobetasol/análogos & derivados , Clobetasol/farmacologia , Inibidores de Ciclo-Oxigenase/farmacologia , Indometacina/farmacologia , Fluxometria por Laser-Doppler , Masculino , NG-Nitroarginina Metil Éster , Óxido Nítrico Sintase , Ratos , Ratos Sprague-Dawley , Fluxo Sanguíneo Regional/fisiologia , Fluxo Sanguíneo Regional/efeitos da radiação , Raios Ultravioleta , ômega-N-Metilarginina
2.
FASEB J ; 9(5): 411-8, 1995 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-7896012

RESUMO

Angiotensin converting enzyme inhibitors (ACEIs) are a cornerstone of treatment of hypertension and heart failure yet their mechanism of action is still debated. This study was designed to test whether the ACEI captopril increases skin microvascular blood flow by a bradykinin-dependent mechanism. Local changes in microvascular blood flow were measured in the skin of rabbits and of human volunteers using a laser Doppler flow probe. Captopril injected intradermally increased skin blood flow over the dose range of 10(-12)-10(-8) mol site in rabbits and humans. In both species the response was abolished by coinjecting either a nitric oxide synthase (NOS) inhibitor or a cyclooxygenase inhibitor. Intradermal bradykinin also increased rabbit skin microvascular blood flow; at 10(-11) mol site it increased mean +/- SE basal blood flow by 88 +/- 12%. The responses to bradykinin or captopril were abolished by coinjecting a bradykinin antagonist, a specific bradykinin B2 receptor antagonist, or inhibitors of NOS or cyclooxygenase. Injecting a specific angiotensin II receptor antagonist at a dose that antagonized the constrictor effects of exogenous angiotensin II did not cause a significant increase in rabbit skin blood flow. This suggests that endogenous angiotensin II does not influence microvascular blood flow in this model. The results indicate that captopril increases skin microvascular blood flow in rabbits and humans secondary to an increase in endogenous tissue bradykinin; this stimulates B2 receptors with subsequent release of prostaglandins and nitric oxide. ACEIs may increase microvascular perfusion by a bradykinin-dependent mechanism.


Assuntos
Bradicinina/fisiologia , Captopril/farmacologia , Óxido Nítrico/fisiologia , Prostaglandinas/fisiologia , Pele/irrigação sanguínea , Adulto , Animais , Antagonistas dos Receptores da Bradicinina , Humanos , Masculino , Coelhos , Fluxo Sanguíneo Regional/efeitos dos fármacos
3.
Am J Physiol ; 266(5 Pt 2): H1846-53, 1994 May.
Artigo em Inglês | MEDLINE | ID: mdl-7515584

RESUMO

We investigated the role of endogenous prostaglandins and NO in the blood flow response of skin microcirculation in vivo. Test agents were injected intradermally in anesthetized rabbits and changes in skin blood flow measured with a laser-Doppler flow probe. Skin blood flow increased 75% at 7.33, 6.77, 11.63, 10.30, 10.55, 8.20, and < 7 -log mol/site with acetylcholine, ATP, bradykinin, prostaglandin D2 (PGD2), prostaglandin E2 (PGE2), NO gas in solution, and nitroprusside respectively. Co-injection of indomethacin (3 x 10(-9) mol/site) or NG-nitro-L-arginine methyl ester (L-NAME; 10(-7) mol/site) with either acetylcholine or bradykinin abolished the effects. This suggests a link between NO and prostaglandin release. Arachidonic acid increased blood flow, which was inhibited by indomethacin, L-NAME, or the PGD2-receptor antagonist BW-A868C. Blood flow responses to either intradermal acetyl-choline or bradykinin, but not to NO in solution, were abolished by co-injection with BW-A868C. PGD2-mediated vasodilation was abolished by L-NAME or BW-A868C, but not by indomethacin. There was no evidence of a link between NO and prostaglandin release in precontracted rabbit aortic rings in vitro. The results suggest that, in the microcirculation of rabbit skin, acetylcholine- and bradykinin-mediated vasodilation involve the arachidonic acid-PGD2-NO pathway.


Assuntos
Microcirculação/fisiologia , Músculo Liso Vascular/fisiologia , Óxido Nítrico/fisiologia , Prostaglandina D2/fisiologia , Pele/irrigação sanguínea , Acetilcolina/farmacologia , Trifosfato de Adenosina/farmacologia , Aminoácido Oxirredutases/antagonistas & inibidores , Animais , Ácido Araquidônico/farmacologia , Arginina/análogos & derivados , Arginina/farmacologia , Bradicinina/farmacologia , Dinoprostona/farmacologia , Hidantoínas/farmacologia , Indometacina/farmacologia , Masculino , Microcirculação/efeitos dos fármacos , Modelos Cardiovasculares , Músculo Liso Vascular/efeitos dos fármacos , NG-Nitroarginina Metil Éster , Óxido Nítrico/farmacologia , Óxido Nítrico Sintase , Nitroprussiato/farmacologia , Inibidores da Agregação Plaquetária/farmacologia , Prostaglandina D2/farmacologia , Coelhos , Fluxo Sanguíneo Regional/efeitos dos fármacos
4.
FASEB J ; 7(14): 1394-400, 1993 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-7693536

RESUMO

Eight agents that increase the intracellular concentration of cyclic AMP were tested for their effect on edema formation. The specificity of the agents for vascular smooth muscle or the endothelium was determined by measuring vasodilation with a laser Doppler flow probe and cAMP production by endothelial cells and vascular smooth muscle cells in culture. The agents were injected intradermally in anesthetized rabbit skin and the local accumulation of 125I-labeled albumin in response to intradermal bradykinin was measured. Iloprost, prostaglandin E1, prostaglandin E2, pituitary adenylate cyclase activating polypeptide (PACAP), and vasoactive intestinal polypeptide (VIP) potentiated bradykinin-induced edema. These same agents also increased blood flow and vascular smooth muscle cAMP concentrations, but did not increase endothelial cell cAMP production. Albuterol suppressed edema formation, did not cause vasodilation, but did increase endothelial cell cAMP concentrations. The phosphodiesterase inhibitor rolipram did not cause vasodilation, but suppressed edema and potentiated the cAMP response to albuterol in cultured endothelial cells. L-Isoproterenol affected both cell types. At a lower concentration L-isoproterenol was a potent stimulus to endothelial cell cAMP production and inhibited edema formation; a higher dose had additional effects on vascular smooth muscle and significantly increased blood flow. These findings support the hypothesis that increasing intracellular cAMP concentrations in vascular smooth muscle promotes edema via increased blood flow. In contrast, increasing cAMP concentrations in endothelium may suppress edema by enhancing the permeability barrier.


Assuntos
Vasos Sanguíneos/efeitos dos fármacos , AMP Cíclico/biossíntese , Edema/metabolismo , Albuterol/farmacologia , Alprostadil/farmacologia , Animais , Vasos Sanguíneos/metabolismo , Bradicinina , Dinoprostona/farmacologia , Sinergismo Farmacológico , Edema/induzido quimicamente , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/metabolismo , Iloprosta/farmacologia , Isoproterenol/farmacologia , Masculino , Músculo Liso Vascular/efeitos dos fármacos , Músculo Liso Vascular/metabolismo , Neuropeptídeos/farmacologia , Polipeptídeo Hipofisário Ativador de Adenilato Ciclase , Pirrolidinonas/farmacologia , Coelhos , Rolipram , Peptídeo Intestinal Vasoativo/farmacologia
5.
Clin Sci (Lond) ; 87(2): 179-86, 1994 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-7523018

RESUMO

1. Endotoxin induces a shock-like syndrome with increased nitric oxide synthesis. To clarify the cellular source of NO in endotoxic shock we used immunohistochemistry and in situ hybridization to localize inducible NO synthase in rats given lipopolysaccharide or Corynebacterium parvum and lipopolysaccharide. Immunohistochemistry was carried out with an antibody raised against a synthetic peptide of mouse macrophage NO synthase. In situ hybridization was performed with 35S-labelled oligonucleotide probes corresponding to cDNA sequences common to mouse macrophage inducible NO synthase and rat vascular smooth inducible NO synthase. Monocytes and macrophages were identified by immunohistochemistry with the mouse monoclonal antibody ED1. 2. After lipopolysaccharide alone, the major site of NO synthase induction was monocytes and macrophages in multiple organs, principally liver and spleen. Bronchial, bile duct, intestinal and bladder epithelium and some hepatocytes also expressed inducible NO synthase. Expression peaked at 5 h and had returned to normal by 12 h except in spleen. 3. After priming with C. parvum, lipopolysaccharide led to a similar distribution of inducible NO synthase as lipopolysaccharide alone, but in addition there was more prominent hepatocyte staining, staining in macrophage granulomas in the liver and inducible NO synthase was present in some endothelial cells in the aorta. 4. These findings provide a direct demonstration of the cellular localization of inducible NO synthase after lipopolysaccharide.


Assuntos
Aminoácido Oxirredutases/análise , Fígado/enzimologia , Macrófagos/enzimologia , Monócitos/enzimologia , Choque Séptico/enzimologia , Baço/enzimologia , Sequência de Aminoácidos , Animais , Ductos Biliares/enzimologia , Brônquios/enzimologia , Epitélio/enzimologia , Imuno-Histoquímica , Hibridização In Situ , Mucosa Intestinal/enzimologia , Lipopolissacarídeos/farmacologia , Masculino , Dados de Sequência Molecular , Óxido Nítrico Sintase , Propionibacterium acnes , Ratos , Ratos Endogâmicos , Bexiga Urinária/enzimologia
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