A molecular pathway revealing a genetic basis for human cardiac and craniofacial defects.
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Microdeletions of chromosome 22q11 are the most common genetic defects associated with cardiac and craniofacial anomalies in humans. A screen for mouse genes dependent on dHAND, a transcription factor implicated in neural crest development, identified Ufd1, which maps to human 22q11 and encodes a protein involved in degradation of ubiquitinated proteins. Mouse Ufd1 was specifically expressed in most tissues affected in patients with 22q11 deletion syndrome. The human UFD1L gene was deleted in all 182 patients studied with 22q11 deletion, and a smaller deletion of approximately 20 kilobases that removed exons 1 to 3 of UFD1L was found in one individual with features typical of 22q11 deletion syndrome. These data suggest that UFD1L haploinsufficiency contributes to the congenital heart and craniofacial defects seen in 22q11 deletion. (+info)
The cyclo-oxygenase-dependent regulation of rabbit vein contraction: evidence for a prostaglandin E2-mediated relaxation.
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1. Arachidonic acid (0.01-1 microM) induced relaxation of precontracted rings of rabbit saphenous vein, which was counteracted by contraction at concentrations higher than 1 microM. Concentrations higher than 1 microM were required to induce dose-dependent contraction of vena cava and thoracic aorta from the same animals. 2. Pretreatment with a TP receptor antagonist (GR32191B or SQ29548, 3 microM) potentiated the relaxant effect in the saphenous vein, revealed a vasorelaxant component in the vena cava response and did not affect the response of the aorta. 3. Removal of the endothelium from the venous rings, caused a 10 fold rightward shift in the concentration-relaxation curves to arachidonic acid. Whether or not the endothelium was present, the arachidonic acid-induced relaxations were prevented by indomethacin (10 microM) pretreatment. 4. In the saphenous vein, PGE2 was respectively a 50 and 100 fold more potent relaxant prostaglandin than PGI2 and PGD2. Pretreatment with the EP4 receptor antagonist, AH23848B, shifted the concentration-relaxation curves of this tissue to arachidonic acid in a dose-dependent manner. 5. In the presence of 1 microM arachidonic acid, venous rings produced 8-10 fold more PGE2 than did aorta whereas 6keto-PGF1alpha and TXB2 productions remained comparable. 6. Intact rings of saphenous vein relaxed in response to A23187. Pretreatment with L-NAME (100 microM) or indomethacin (10 microM) reduced this response by 50% whereas concomitant pretreatment totally suppressed it. After endothelium removal, the remaining relaxing response to A23187 was prevented by indomethacin but not affected by L-NAME. 7. We conclude that stimulation of the cyclo-oxygenase pathway by arachidonic acid induced endothelium-dependent, PGE2/EP4 mediated relaxation of the rabbit saphenous vein. This process might participate in the A23187-induced relaxation of the saphenous vein and account for a relaxing component in the response of the vena cava to arachidonic acid. It was not observed in thoracic aorta because of the lack of a vasodilatory receptor and/or the poorer ability of this tissue than veins to produce PGE2. (+info)
Enantioselective inhibition of the biotransformation and pharmacological actions of isoidide dinitrate by diphenyleneiodonium sulphate.
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1. We have shown previously that the D- and L- enantiomers of isoidide dinitrate (D-IIDN and L-IIDN) exhibit a potency difference for relaxation and cyclic GMP accumulation in isolated rat aorta and that this is related to preferential biotransformation of the more potent enantiomer (D-IIDN). The objective of the current study was to examine the effect of the flavoprotein inhibitor, diphenyleneiodonium sulphate (DPI), on the enantioselectivity of IIDN action. 2. In isolated rat aortic strip preparations, exposure to 0.3 microM DPI resulted in a 3.6 fold increase in the EC50 value for D-IIDN-induced relaxation, but had no effect on L-IIDN-induced relaxation. 3. Incubation of aortic strips with 2 microM D- or L-IIDN for 5 min resulted in significantly more D-isoidide mononitrate formed (5.0 +/- 1.5 pmol mg protein(-1)) than L-isoidide mononitrate (2.1 +/- 0.7 pmol mg protein(-1)) and this difference was abolished by pretreatment of tissues with 0.3 microM DPI. DPI had no effect on glutathione S-transferase (GST) activity or GSH-dependent biotransformation of D- or L-IIDN in the 105,000 x g supernatant fraction of rat aorta. 4. Consistent with both the relaxation and biotransformation data, treatment of tissues with 0.3 microM DPI significantly inhibited D-IIDN-induced cyclic GMP accumulation, but had no effect on L-IIDN-induced cyclic GMP accumulation. 5. In the intact animal, 2 mg kg(-1) DPI significantly inhibited the pharmacokinetic and haemodynamic properties of D-IIDN, but had no effect L-IIDN. 6. These data suggest that the basis for the potency difference for relaxation by the two enantiomers is preferential biotransformation of D-IIDN to NO, by an enzyme that is inhibited by DPI. Given that DPI binds to and inhibits NADPH-cytochrome P450 reductase, the data are consistent with a role for the cytochromes P450-NADPH-cytochrome P450 reductase system in this enantioselective biotransformation process. (+info)
Effect of acute and long-term treatment with 17-beta-estradiol on the vasomotor responses in the rat aorta.
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1. This study sought to evaluate whether the effects of acute and long-term treatment with 17-beta-estradiol on the vasomotor responses in rat aortic rings are mediated through the same mechanism. 2. Ovariectomized rats were treated daily with either 17-beta-estradiol-3-benzoate (100 microg kg(-1)) or vehicle for 1 week. 3. The effect of long-term 17-beta-estradiol treatment on the responses to cumulative doses of phenylephrine, 5-HT, calcium, potassium and 17-beta-estradiol was determined in aortic rings. In the same rings, the effect of acute exposure to 17-beta-estradiol (5 and 10 microM) on the dose response curves for phenylephrine, 5-HT, calcium, potassium and acetylcholine were estimated. The measurements were made in rings with and without intact endothelium. The tone-related basal release of nitric oxide (NO) was measured in rings with intact endothelium. 4. Long-term 17-beta-estradiol treatment reduced the maximum developed contraction to all contracting agents studied. This effect was abolished in endothelium denuded vessels. Acute 17-beta-estradiol treatment also reduced maximal contraction. This effect, however, was independent of the endothelium. 5. Long-term 17-beta-estradiol treatment significantly increased the ability of the rings to dilate in response to acetylcholine whereas acute exposure to 17-beta-estradiol had no effect. The tone-related release of NO was significantly increased after long-term exposure to 17-beta-estradiol. 6. In conclusion, this study indicate that the acute and long-term effects of 17-beta-estradiol in the rat aorta are mediated through different mechanisms. The long-term effect is mediated through the endothelium most likely by increasing NO release. In contrast, the acute effect of 17-beta-estradiol seems to be through an effect on the vascular smooth muscle cells. (+info)
Studies of the role of endothelium-dependent nitric oxide release in the sustained vasodilator effects of corticotrophin releasing factor and sauvagine.
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1. The mechanisms of the sustained vasodilator actions of corticotrophin-releasing factor (CRF) and sauvagine (SVG) were studied using rings of endothelium de-nuded rat thoracic aorta (RTA) and the isolated perfused rat superior mesenteric arterial vasculature (SMA). 2. SVG was approximately 50 fold more potent than CRF on RTA (EC40: 0.9 +/- 0.2 and 44 +/- 9 nM respectively, P < 0.05), and approximately 10 fold more active in the perfused SMA (ED40: 0.05 +/- 0.02 and 0.6 +/- 0.1 nmol respectively, P < 0.05). Single bolus injections of CRF (100 pmol) or SVG (15 pmol) in the perfused SMA caused reductions in perfusion pressure of 23 +/- 1 and 24 +/- 2% that lasted more than 20 min. 3. Removal of the endothelium in the perfused SMA with deoxycholic acid attenuated the vasodilatation and revealed two phases to the response; a short lasting direct action, and a sustained phase which was fully inhibited. 4. Inhibition of nitric oxide synthase with L-NAME (100 microM) L-NMMA (100 microM) or 2-ethyl-2-thiopseudourea (ETPU, 100 microM) had similar effects on the vasodilator responses to CRF as removal of the endothelium, suggesting a pivotal role for nitric oxide. However the selective guanylate cyclase inhibitor 1H-[l,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ, 10 microM) did not affect the response to CRF. 5. High potassium (60 mM) completely inhibited the vasodilator response to CRF in the perfused SMA, indicating a role for K channels in this response. 6. Compared to other vasodilator agents acting via the release of NO, the actions of CRF and SVG are strikingly long-lasting, suggesting a novel mechanism of prolonged activation of nitric oxide synthase. (+info)
Protective effect of dietary tomato against endothelial dysfunction in hypercholesterolemic mice.
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The effects of dietary ingestion of tomato were studied in mice that had been made hypercholesterolemic by feeding atherogenic diets. Mice which had been fed on the atherogenic diet without tomato for 4 months had significantly increased plasma lipid peroxide, and the vaso-relaxing activity in the aorta induced by acetylcholine (ACh) was harmed when compared with mice fed on a common commercial diet. On the other hand, mice which had been fed on the atherogenic diet containing 20% (w/w) lyophilized powder of tomato showed less increase in the plasma lipid peroxide level, and ACh-induced vaso-relaxation was maintained at the same level as that in normal mice. These results indicate that tomato has a preventive effect on atherosclerosis by protecting plasma lipids from oxidation. (+info)
Effects of docosahexaenoic and eicosapentaenoic acid on lipid metabolism, eicosanoid production, platelet aggregation and atherosclerosis in hypercholesterolemic rats.
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Exogenously hypercholesterolemic (ExHC) rats were fed on an atherogenic diet supplemented with 1% each of either ethyl ester docosahexaenoic acid [EE-DHA, 22:6(n-3)], ethyl ester eicosapentaenoic acid [EE-EPA, 20:5(n-3)] or safflower oil (SO) for 6 months. The rats fed on the diets containing EE-EPA or EE-DHA, compared with those fed on SO, had lower serum cholesterol and triacylglycerol levels, less aggregation of platelets and slower progress of intimal thickening in the ascending aorta. Relative to the SO-fed rats, both of the (n-3) fatty acid-fed rats had a significantly reduced proportion of arachidonic acid in the platelet and aortic phospholipids, and lower production of thromboxane A2 by platelets and of prostacyclin by the aorta. These results suggest that EPA and DHA are similarly involved in preventing atherosclerosis development by reducing hypercholesterolemia and modifying the platelet functions. (+info)
Modulation of temperature-induced tone by vasoconstrictor agents.
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One of the primary cardiovascular adjustments to hyperthermia is a sympathetically mediated increase in vascular resistance in the viscera. Nonneural factors such as a change in vascular tone or reactivity may also contribute to this response. Therefore, the aim of this study was to determine whether vascular smooth muscle tone is altered during heating to physiologically relevant temperatures >37 degrees C. Gradually increasing bath temperature from 37 degrees C (normothermia) to 43 degrees C (severe hyperthermia) produced graded contractions in vascular ring segments from rat mesenteric arteries and thoracic aortae. In untreated rings these contractions were relatively small, whereas hyperthermia elicited near-maximal increases in tension when rings were constricted with phenylephrine or KCl before heating. In phenylephrine-treated mesenteric arterial rings, the contractile responses to heating were markedly attenuated by the Ca2+ channel antagonists nifedipine and diltiazem. Diltiazem also blocked the contractile responses to heating in thoracic aortic rings. These results demonstrate that hyperthermia has a limited effect on tension generation in rat vascular smooth muscle in the absence of vascular tone. However, in the presence of agonist-induced tone, tension generation during heating is markedly enhanced and dependent on extracellular Ca2+. In conclusion, these data suggest that local regulation of vascular tone can contribute to the hemodynamic adjustments to hyperthermia. (+info)