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At least 469 records · Page 26Linked to original sources
PubMed2005

Mechanisms of the protective effects of urocortin on coronary endothelial function during ischemia-reperfusion in rat isolated hearts.

1 Urocortin is a vasodilator peptide related to corticotrophin-releasing factor, which may protect endothelial function during coronary ischemia-reperfusion (I-R). The aim of this study was to study the mechanisms of this protective effect. 2 Hearts from Sprague-Dawley rats were isolated and perfused at constant flow and then exposed to 15 min global zero-flow ischemia, followed by 15 min reperfusion. The relaxation to acetylcholine (10 nM-10 microM) was recorded after pre-constriction of the coronary vasculature with U46619 (100-300 nM) in ischemic-reperfused or time-control hearts. 3 After I-R, the coronary relaxation to acetylcholine was reduced and this reduction was attenuated by treatment with urocortin (10 pM), administered before ischemia and during reperfusion. 4 This urocortin-induced improvement of the relaxation to acetylcholine was not modified by tetraethylammonium (10 mM), blocker of Ca2+ dependent-potassium channels; glibenclamide (10 microM), blocker of K(ATP) channels; N(w)-nitro-L-arginine methyl ester (L-NAME, 100 microM), blocker of nitric oxide synthesis; or meclofenamate (10 microM), blocker of cyclooxygenase, but it was abolished by chelerythrine (3 microM), blocker of protein kinase C (PKC). 5 These results suggest that urocortin may protect coronary endothelial function during I-R by activation of PKC.

Acetylcholine↗
PubMed1983

The influence of changes in tension on protein synthesis and prostaglandin release in isolated rabbit muscles.

Intermittent stretching of isolated rabbit muscles increased the rate of protein synthesis by 70% and prostaglandin-F2 alpha release by 105%. Both effects of intermittent stretching were blocked by indomethacin and meclofenamate; the absence of Ca2+ together with added EGTA also inhibited both processes. The residual influence of intermittent stretching on protein synthesis was closely correlated with prostaglandin-F2 alpha release, which may be the link between mechanical activity and protein synthesis in skeletal muscle.

Animals↗
PubMed1979

Effects of high salt intake and meclofenamate on arterial pressure and renal function in the spontaneously hypertensive rat.

1. The effects of prolonged high sodium intake (duration 3 months) and meclofenamate were studied in two groups of male spontaneously hypertensive (SH) rats. 2. Group 1 (eight rats) received 1% NaCl in water and served as controls, and group 2 received 1% NaCl in water plus meclofenamate (3.5-4.0 mg daily). 3. Group 2 rats developed higher arterial pressure, renal vascular resistance and left ventricular weight and greater renal histological changes, with lower effective renal plasma flow, renal blood flow and glomerular filtration rate, than group 1. No differences were observed between the two groups in heart rate, body weight, fluid intake, urine volume, UNaV, UKV and right ventricular weight. 4. The results suggest that the combination of high sodium intake and meclofenamate exerts a greater damaging effect on the arterial presssure and renal function of SH rats than salt alone.

Animals↗
PubMed1980

Inhibition of bradykinin of the vascular effects of pressor hormones in the canine kidney: relationship to prostaglandins.

1. Renal arterial injection of bolus doses of angiotensin II or noradrenaline, (0.06, 0.12 and 0.25 microgram) caused renal vasoconstriction and decreased blood flow to the kidney in a dose-related manner in dogs anaesthetized by sodium pentobarbital. 2. The effect of angiotensin II and noradrenaline in lowering renal blood flow was reduced during renal arterial infusion of either bradykinin (10 ng min-1 kg-1) or prostaglandin E2 (4 ng min-1 kg-1). 3. Pretreatment of the dogs with an inhibitor of prostaglandin synthesis, sodium meclofenamate (5 mg/kg), blunted the inhibitory action of bradykinin, but not that of prostaglandin E2, on renal vascular reactivity to angiotensin II and noradrenaline. 4. These results indicate that bradykinin reduces the renal vasoconstriction induced by angiotensin II and noradrenaline in the dog by a mechanism dependent upon synthesis of prostaglandins.

Angiotensin II↗
PubMed1981

The effects of meclofenamate, captopril and phentolamine on organ blood flow in the conscious rabbit.

1. Systemic and regional vascular changes were measured in conscious rabbits after intravenous sodium meclofenamate, captopril and phentolamine. These drugs were used respectively to inhibit prostaglandin synthesis and angiotensin-converting enzyme, and to block alpha-adrenoceptors. 2. Meclofenamate reduced renal and adrenal blood flow by 11 and 28% respectively, and doubled hepatic artery flow. The effect on renal and adrenal flow persisted in the presence of phentolamine. 3. Captopril decreased estimated peripheral resistance and increased cardiac output without changing arterial pressure. Kidney and adrenal flow increased by 70 and 21% respectively. 4. Phentolamine reduced arterial pressure and doubled flow to skeletal muscle and increased hepatic artery flow to the liver. 5. Splenic blood flow was unaffected by meclofenamate, captopril or phentolamine alone. Meclofenamate given after captopril caused a halving of splenic flow and a rise in arterial pressure; these effects were prevented by phentolamine. 6. The results point to a continuing effect of prostaglandin synthesis in maintaining blood flow to the kidney and adrenal gland independent of alpha-adrenoceptor activation in resting conscious rabbits. An important modulating effect of prostaglandins on sympathetic vascular tone in the spleen is suggested.

Adrenal Glands↗
PubMed1982

Effects of meclofenamate and captopril on renal and other regional vascular beds after mild haemorrhage in conscious rabbits.

1. The role of prostaglandins and angiotensin II in blood flow regulation was studied in conscious rabbits subjected to mild haemorrhage. 2. Haemorrhage caused a 13% fall in arterial pressure and a 21% fall in cardiac output, responses which were unchanged by sodium meclofenamate, an inhibitor of prostaglandin synthesis, or captopril, an inhibitor of the angiotensin converting enzyme. 3. Haemorrhage doubled plasma adrenaline and noradrenaline levels. Plasma renin activity trebled after haemorrhage and was further elevated by captopril. 4. Renal blood flow was maintained after haemorrhage alone. Meclofenamate given immediately after haemorrhage caused a 31% fall in renal blood flow. Captopril given immediately after haemorrhage caused renal vasodilation, but when given after meclofenamate augmented renal vasoconstriction. 5. Splenic vasoconstriction was seen after haemorrhage and meclofenamate, and subsequently was augmented by captopril. 6. Results suggest that prostaglandins variably modulate regional blood flow in conscious rabbits subjected to mild haemorrhage. Enhanced sympatho-adrenal activity increases renovascular and splenic dependence on vasodilator prostaglandins, but not that of coronary, cerebral, hepatic or adrenal circulations. Renal and splenic vasoconstriction seen with meclofenamate are not due to circulating angiotensin II.

Animals↗
PubMed1983

Dose-dependent effects of meclofenamate on peripheral vasculature of conscious rabbits.

1. Changes in systemic haemodynamics and organ blood flow were measured in conscious rabbits after various doses of intravenous sodium meclofenamate, an inhibitor of prostaglandin cyclo-oxygenase. 2. Meclofenamate had no effect on arterial pressure or cardiac output but caused a dose-dependent fall in renal blood flow. 3. Meclofenamate also reduced adrenal perfusion but, in contrast, caused a dose-dependent increase in blood flow to the brain, bronchial and hepatic circulation and to the testis. No effect was demonstrated on other organs studied. 4. The effect on the cerebral circulation was observed at the lowest dose of meclofenamate (0.75 mg/kg). Higher total doses were necessary for an effect on the renal and bronchial (3 mg/kg) and testicular and hepatic arteries (6 mg/kg). 5. The results suggest a variety of local vasomotor influences of renal and non-renal prostaglandins in conscious rabbits.

Animals↗
PubMed1987

Interaction between renal prostaglandins and angiotensin II in controlling glomerular filtration in the dog.

Although previous studies suggest that the renal vasoconstrictor effects of angiotensin II (ANG II) are normally confined to the efferent arterioles, the mechanisms that prevent ANG II from constricting preglomerular vessels are still unclear. In the present study, the role of prostaglandins (PG) in protecting preglomerular vessels from ANG II constriction was examined in dogs with normal or non-filtering kidneys in which ANG II formation was blocked with captopril and renal artery pressure was servo-controlled at 75-80 mmHg. Before PG blockade (n = 6), ANG II infusion (20 ng min-1 kg-1) decreased renal blood flow (RBF) by 54 +/- 4%, but did not change glomerular filtration rate (GFR) significantly. After PG blockade (n = 6), ANG II infusion decreased GFR by 37 +/- 7% and RBF by 56 +/- 6%, while increasing calculated preglomerular resistance much more than before PG blockade. In another group of dogs, secondary changes in renal resistances, due to tubuloglomerular feedback, were prevented by occluding the ureter during mannitol diuresis until glomerular filtration ceased. After inhibition of tubuloglomerular feedback in non-filtering kidneys (n = 7), ANG II decreased RBF by 40 +/- 3% and increased glomerular hydrostatic pressure, estimated from stop-flow ureteral pressure and plasma colloid osmotic pressure, by 8.7 +/- 1.7 mmHg. Postglomerular resistance increased by 91 +/- 12% while preglomerular resistance was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1999

O2 sensing is preserved in mice lacking the gp91 phox subunit of NADPH oxidase.

The rapid response to hypoxia in the pulmonary artery (PA), carotid body, and ductus arteriosus is partially mediated by O2-responsive K+ channels. K+ channels in PA smooth muscle cells (SMCs) are inhibited by hypoxia, causing membrane depolarization, increased cytosolic calcium, and hypoxic pulmonary vasoconstriction. We hypothesize that the K+ channels are not themselves "O2 sensors" but rather respond to the reduced redox state created by hypoxic inhibition of candidate O2 sensors (NADPH oxidase or the mitochondrial electron transport chain). Both pathways shuttle electrons from donors, down a redox gradient, to O2. Hypoxia inhibits these pathways, decreasing radical production and causing cytosolic accumulation of unused, reduced, freely diffusible electron donors. PASMC K+ channels are redox responsive, opening when oxidized and closing when reduced. Inhibitors of NADPH oxidase (diphenyleneiodonium) and mitochondrial complex 1 (rotenone) both inhibit PASMC whole-cell K+ current but lack the specificity to identify the O2-sensor pathway. We used mice lacking the gp91 subunit of NADPH oxidase [chronic granulomatous disease (CGD) mice] to assess the hypothesis that NADPH oxidase is a PA O2-sensor. In wild-type lungs, gp91 phox and p22 phox subunits are present (relative expression: macrophages > airways and veins > PASMCs). Deletion of gp91 phox did not alter p22 phox expression but severely inhibited activated O2 species production. Nonetheless, hypoxia caused identical inhibition of whole-cell K+ current (in PASMCs) and hypoxic pulmonary vasoconstriction (in isolated lungs) from CGD vs. wild-type mice. Rotenone vasoconstriction was preserved in CGD mice, consistent with a role for the mitochondrial electron transport chain in O2 sensing. NADPH oxidase, though a major source of lung radical production, is not the pulmonary vascular O2 sensor in mice.

Animals↗
PubMed1993

Moderate stress by cardiac pacing may induce both short term and long term cardioprotection.

OBJECTIVE: The aim was to investigate whether moderate ischaemic stress induced by brief periods of cardiac pacing to twice the normal heart rate protects the heart from the electrophysiological and haemodynamic consequences of subsequent periods of rapid pacing. METHODS: Conscious rabbits with implanted right ventricular electrodes and a permanent catheter in the left ventricular cavity were studied. Hearts were paced at a rate of 500.min-1 for 5 min. The resulting transient ST segment elevation in intracavital electrogram, the ventricular effective refractory period, and the left ventricular end diastolic pressure were measured. RESULTS: After discontinuation of pacing, a shortlasting ST segment elevation appeared in the endocardial electrogram, together with a transient rise in left ventricular end diastolic pressure. These changes were significantly reduced after a second pacing, provided that this was applied not later than 30 min after the first pacing; maximum protection occurred when there was a 5 min interval between these pacing periods. Serial stimulation (10 pacing periods with a 5 min interval between each) gave a similar protection to that resulting from a single pacing period. The protection was lost after 1 h; however, 24 h and 48 h (but not 72 h) after the end of serial stimulation there was again a reduction in postpacing ST segment and left ventricular end diastolic pressure elevation. At these times the ventricular effective refractory period was prolonged. The cyclo-oxygenase inhibitor sodium meclofenamate (1-2 mg.kg-1) prevented the early protection. CONCLUSIONS: The results suggest that brief periods of rapid pacing induce both short term and long term cardioprotection, as shown by reduced electrophysiological and haemodynamic consequences of subsequent pacing periods. Endogenous prostanoids might play a role in the short term cardioprotection.

Animals↗
PubMed2003

Pregnancy-induced alterations of vascular function in mouse mesenteric and uterine arteries.

Normal pregnancy involves dramatic changes to maternal vascular function, while abnormal vascular adaptations may contribute to pregnancy-associated diseases such as preeclampsia. Many genetic mouse models have recently emerged to study vascular pathologies of pregnancy. However, vascular adaptations to pregnancy in normal mice are not fully understood. Thus, we studied changes in vascular reactivity during normal mouse pregnancy. We hypothesized that pregnant mice will have enhanced endothelial-dependent vasodilation compared with nonpregnant mice, via an enhancement of the nitric oxide synthase (NOS) prostaglandin H synthase (PGHS), and other endothelial-derived hyperpolarizing pathways. Late pregnant (Day 17-18) C57BL/6J mice (n = 10) were compared with nonpregnant mice (n = 7). Uterine and mesenteric arteries were mounted on a wire myograph system and assessed for endothelium-dependent (methacholine) and -independent (sodium nitroprusside; SNP) relaxation responses. Endothelial-dependent relaxation was enhanced in pregnant uterine and mesenteric arteries, which was blunted after the addition of inhibitors of the PGHS or NOS pathways. In nonpregnant mice, these pathways had no effect in modulating relaxation in uterine arteries, whereas vasodilation in mesenteric arteries was reduced only by NOS inhibition. Both uterine and mesenteric vessels had nonnitric oxide- and nonprostaglandin-mediated relaxation, but this relaxation was not enhanced during pregnancy. Endothelial-independent relaxation was also enhanced in pregnant uterine but not mesenteric arteries. Our data indicate that uterine and mesenteric arteries from pregnant mice have enhanced vasodilation. Understanding vascular adaptations to normal mouse pregnancy is crucial for interpreting changes that may occur in genetic mouse models.

Animals↗
PubMed1988

Direct evidence for the local generation of vascular angiotensin II and its prostaglandin-mediated release from isolated hind legs in the rat.

We examined the effect of prostaglandin synthesis inhibitors (indomethacin and meclofenamate) on the release of immunoreactive angiotensins I (irAng I) and II (irAng II) from isolated perfused rat hind-leg vasculature in order to delineate the possible relevance of prostaglandins to the vascular renin-angiotensin system in vitro. Isolated rat hind-legs were perfused with Krebs-Ringer solution and release of irAng I and irAng II into the perfusate was directly measured by using a Sep-Pak C18 cartridge connected to the perfusion system. The spontaneous release of irAng I and irAng II was as high as 600-700 pg per 30 min and was stable for at least 3 h. Addition of indomethacin and meclofenamate (10(-8) to 2 X 10(-6) mol/l) to the perfusion medium suppressed the release of both irAng I and irAng II to a similar extent in a dose-dependent fashion (P less than 0.001); the maximal percentage inhibition of irAng II release that was evoked by these inhibitors (2 X 10(-6) mol) was 60 +/- 6% (P less than 0.001) for indomethacin and 50 +/- 4% (P less than 0.001) for meclofenamate. There was a highly significant positive correlation between the amount of irAng I released and the amount of irAng II that was altered by indomethacin (r = 0.91) or meclofenamate (r = 0.94). These results provide direct proof of the local generation and subsequent release of Ang II by peripheral vascular tissue and suggest that prostaglandin plays an important role in the regulation of vascular Ang II release.

Angiotensin I↗