摘要:

Abstract—Less nitric oxide (NO)-dependent vasodilation and excess formation of reactive oxygen species could explain poor placenta perfusion in preeclampsia, but the pathways involved are unknown. We tested the hypothesis that reduced NO activity and increased oxidative stress in preeclamptic placenta is related to a low bioavailability of l-arginine. Placental endothelial NO synthase (ecNOS) expression (by immunoperoxidase) and activity (by diaphorase and [3H]L-citrulline formation) were comparable in normotensive pregnancy and in preeclampsia, whereas nitrotyrosine staining, a marker of peroxynitrite, was stronger in preeclamptic villi, confirming previously reported data. Oxidative tissue damage was documented in preeclamptic villi by strong 4-hydroxynonenal-lysine staining (by immunoperoxidase), which closely colocalized with nitrotyrosine. Concentration of the NO precursor l-arginine (by HPLC) in umbilical blood and in villous tissue was lower in preeclampsia than in normotensive pregnancy. This was not caused by a defective l-arginine transport, because gene expression of the CAT-1, 4F2hc, and LAT-1 cationic amino acid transporters (by real-time reverse-transcription polymerase chain reaction [RT-PCR]) was normal. Instead, gene expression (by real-time RT-PCR) and protein tissue content (by immunoperoxidase and Western blot) of arginase II—the enzyme that degrades arginine to ornithine—were higher in preeclamptic villi than in normotensive pregnancy. These results provide a biochemical explanation for defective NO activity and increased oxidative stress in preeclamptic placenta. In normal placenta, adequate concentration of l-arginine orients ecNOS toward NO. In preeclampsia, a lower than normal l-arginine concentration caused by arginase II overexpression redirects ecNOS toward peroxynitrite.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—The present study tested the hypothesis that cytochrome P-450 (CYP) metabolites of arachidonic acid (AA) are involved in mediating hypertension and renal vasoconstriction during chronic reductions in uterine perfusion pressure (RUPP) in pregnant rats. 1-aminobenzotriazole (ABT), a CYP enzyme inhibitor (25 mg/kg per day), or vehicle (saline 0.9%) was administered for 7 days to normal pregnant (NP) rats and to pregnant rats with chronic RUPP. RUPP rats infused with vehicle showed significantly (P<0.01) higher mean arterial pressure (MAP) (130±2 versus 106±1 mm Hg), renal vascular resistance (RVR) (22.6±1.8 versus 16.3±1.1 mm Hg/mL per minute) and lower (P<0.05) glomerular filtration rate (GFR) (1.6±0.1 versus 2.3±0.1 mL/min) than NP rats. ABT decreased (P<0.01) MAP in RUPP rats (111±1 mm Hg), whereas it had no effect in NP rats (108±2 mm Hg). CYP inhibition also attenuated the differences in renal hemodynamics observed between NP and RUPP rats. After treatment with ABT, RVR and GFR were similar in RUPP rats (19.3±1.5 mm Hg/mL per minute and 2.0±0.2 mL/min, respectively) and NP rats (16.3±2.4 mm Hg/mL per minute and 2.4±0.2 mL/min). The effects of CYP enzymes inhibitor in RUPP rats were associated with a reduction (P<0.05) of 20-HETE formation (32%) and a decreased (P<0.05) expression (33%) of CYP4A protein in renal cortex. In contrast, renal epoxygenase activity did not change in these animals. These results suggest that 20-HETE contributes to hypertension and renal vasoconstriction induced by chronic RUPP in pregnant rats.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—This study examined the role of arterial baroreceptors in mediating the relationship between changes in the mean level and the amplitude of slow oscillations of renal sympathetic nerve activity (RSNA) during environmental stress. In 7 sham-operated (control) and 7 chronically (2 weeks before study) sinoaortic baroreceptor denervated (SAD) conscious rats, arterial pressure (AP) and RSNA were simultaneously recorded during two 15-minute periods, before and during the application of a mild environmental stressor (jet of air). Air-jet stress induced a similar degree of sympathoexcitation in both groups of rats. During stress in control rats, AP and RSNA spectral power in the mid-frequency (MF) range (0.27 to 0.74 Hz) increased, mainly as a consequence of an amplification of strongly coherent oscillations of ≈0.4 Hz frequency. In SAD rats, MF fluctuations of AP and RSNA were reduced but not abolished before stress, tended to increase during stress, and were linearly related under both experimental conditions. However, in the MF range, there was no well-defined oscillation at any specific frequency. At the peak coherence frequency (≈0.4 Hz), the gain of the transfer function from RSNA to AP did not change during stress in control rats and was similar to that measured in SAD rats, indicating that it mainly reflected the properties of the feedforward effect of RSNA on AP (ie, vascular reactivity). In summary, the parallelism between stress-induced changes in the mean level of RSNA and the amplitude of slow RSNA oscillations requires the functional integrity of the baroreceptor reflex, which is consistent with the hypothesis that slow AP and RSNA rhythms are resonant oscillations within the baroreceptor reflex loop.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—We determined whether the sympathetic excitatory responses to environmental stressors and the sympathoinhibitory responses to rilmenidine are altered by renovascular hypertension. Rabbits were made hypertensive with a clip on the right renal artery, and a left renal nerve recording electrode was implanted. After 3 or 6 weeks, the animals were given air-jet stress and loud noise stress before and after intravenous rilmenidine. Three and 6 weeks after renal clipping, mean arterial pressure was 28% and 36% greater than preclip values. Air-jet stress elicited a marked increase in renal sympathetic nerve activity, mean arterial pressure, and heart rate. Renal sympathetic nerve activity responses were much greater in hypertensive rabbits, but the pressor responses were similar to those observed in normotensive animals. Acute administration of rilmenidine decreased blood pressure more in hypertensive animals but with a much lesser inhibition of sympathetic activity. Rilmenidine markedly reduced increased sympathetic activity during air-jet stress in 3-week clipped rabbits but to a lesser extent in the other groups. These studies show that while sympathetic responses to stress were markedly enhanced in renal clip hypertensive rabbits, they did not result in greater pressor responses, thus suggesting that vascular neuroeffector mechanisms were not altered. By contrast, the increased effects of rilmenidine suggest a much greater contribution to the hypertension by the sympathetic nervous system, but one that is caused by an enhanced “nonvascular” neuroeffector mechanism. As such, sympathoinhibitory agents such as rilmenidine are very suitable and very effective agents for the treatment of renovascular hypertension.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—This study investigated the effects of angiotensin II “slow pressor” hypertension on structure and function of nerves supplying the renal vasculature. Low-dose angiotensin II (10 ng/kg per minute, initially sub-pressor) or saline vehicle was infused intravenously for 21 days in rats, and the effects were compared in renal and mesenteric arteries. Mean arterial pressure averaged 12±2 mm Hg higher than in vehicle-infused rats at 21 days. Using electron microscopy, the innervation density of renal arcuate, but not mesenteric arteries of equivalent size, was significantly higher in angiotensin II-infused than in vehicle-infused rats. Functional testing on a pressure myograph revealed that constrictions evoked by nerve stimulation in arcuate arteries were 2.3±0.7-fold greater in vessels from angiotensin II-infused compared with vehicle-infused rats (P<0.0001), whereas there was no significant difference in nerve-induced constrictions in mesenteric arteries. Sensitivity to and maximum amplitude of constrictions evoked by phenylephrine were not different in renal or mesenteric arteries between groups, suggesting that the increased neurally evoked constriction in renal arcuate arteries was not caused by postsynaptic changes. Endothelium-dependent vasorelaxation and the vessel wall physical properties were not different between the two groups in either artery. Thus, angiotensin II infusion appeared to evoke renal-specific increases in vessel innervation and increased vasoconstriction to nerve stimulation. These changes appear early and occur before changes in renal endothelial function are apparent. Thus, “slow pressor” angiotensin II hypertension is associated with increased renal innervation, compatible with a pathogenetic role.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—A fluorescent nitric oxide (NO) indicator, 4,5-diaminofluorescein diacetate, and the calcium indicator, indo-1, with 488 nm and 364 nm UV confocal laser scanning microscopy were used to detect NO and calcium concentration in rabbit macula densa (MD) cells challenged by angiotensin II (Ang II). Glomeruli with attached thick ascending limbs with the MD plaque were isolated and perfused. Ang II concentration from 10−9to 10−5progressively increased MD cell calcium and NO to peak values at 10−6and 10−7, respectively. Ang II (10−6M) caused the cytosolic calcium concentration ([Ca2+]i) to increase by 125.8±16.3 nM (n=17) from the bath and by 52.3±11.5 nM (n=18) from the lumen. AT1antagonist CV-11974 (10−6M) blocked the Ang II-induced calcium responses from bath and lumen, but AT2antagonist PD-123319 (10−6M) did not. AT2agonist CGP-42112A (10−6M) did not affect [Ca2+]iin MD cells from either side. Ang II (10−6M) increased the NO production by 16%±3.4% (n=26) from the bath and by 18%±3.1% (n=24) from the lumen. CV-11974 (10−6M) blocked the NO responses from both sides, but PD-123319 (10−6M) did not on either side. CGP-42112A (10−6M) had no effect on NO in MD cells. In calcium-free experiments there was no difference from the result in normal calcium solutions. In conclusion, we found that Ang II increased [Ca2+]iand stimulated NO production in MD cells from the basolateral and luminal sides through AT1receptors.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—Dopamine plays a role in the regulation of blood pressure by inhibition of sodium transport in renal proximal tubules (RPTs) and relaxation of vascular smooth muscles. Because dopamine receptors can regulate and interact with each other, we studied the interaction of D1and D3receptors in immortalized RPT cells and mesenteric arteries from Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHRs), and in human coronary artery smooth muscle cells (CASMCs). In WKY rats, the D1-like agonist, fenoldopam, increased D3receptor protein in a time-dependent and concentration-dependent manner (EC50=4.5×10−9M, t1/2=15.8 hours). In SHRs, fenoldopam (10−5M) actually decreased the expression of D3receptors. D1and D3receptor co-immunoprecipitation was increased by fenoldopam (10−7M/24 h) in WKY rats but not in SHRs. The effects of fenoldopam in CASMCs were similar as those in WKY RPT cells (ie, fenoldopam increased D1and D3receptor proteins). Both D3(PD128907, Emax=80%±6%, pED50=5±0.1) and D1-like receptor (fenoldopam, Emax=81%±8%, pED50=5±0.2, n=12) agonists relaxed mesenteric arterial rings. Co-stimulation of D1and D3receptors led to additive vasorelaxation in WKY rats, but not in SHRs. D1and D3receptors interact differently in WKY and SHRs. Altered interactions between D1and D3receptors may play a role in the pathogenesis of genetic hypertension, including human hypertension, because these receptors also interact in human vascular smooth muscle cells.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—The peroxisome proliferator activated receptor (PPAR&ggr;) agonist rosiglitazone has been reported to yield cardiovascular benefits in patients by a mechanism that is not completely understood. We tested whether oral rosiglitazone (25 mg/kg per day, 21 days) treatment improves blood pressure and vascular function in a transgenic mouse expressing both human renin and human angiotensinogen transgenes (R+A+). Rosiglitazone decreased systolic (138±5 versus 128±5 mm Hg) and mean blood pressure (145±5 versus 126±7 mm Hg) of R+A+mice as measured by tail-cuff and indwelling carotid catheters, respectively. Relaxation of carotid arteries to acetylcholine and authentic nitric oxide, but not papaverine, was impaired in R+A+mice when compared with littermate controls (RA−). There were no effects of rosiglitazone on RA−mice; however, relaxation to acetylcholine (49±10 versus 82±9% at 100 &mgr;mol/L) and nitric oxide (51±11 versus 72±6% at 10 &mgr;mol/L) was significantly improved in treated R+A+mice. Rosiglitazone treatment of R+A+mice did not alter the expression of genes, including endothelial nitric oxide synthase (eNOS), angiotensin 1 receptors, and preproendothelin-1, nor did it alter the levels of eNOS or soluble guanylyl cyclase protein. In separate studies, carotid arteries from R+A+and RA−mice relaxed in a concentration-dependent manner to rosiglitazone, suggesting possible PPAR&ggr;-independent effects in the vasculature. This response was not inhibited with the nitric oxide synthase inhibitorN&ohgr;-nitro-l-arginine methyl ester (200 &mgr;mol/L) or the PPAR&ggr; antagonist bisphenol A diglycidyl ether; 4,4′-isopropylidenediphenol diglycidyl ether (100 &mgr;mol/L). These data suggest that in addition to potential genomic regulation caused by PPAR&ggr; activation, the direct effect of rosiglitazone in blood vessels may contribute to the improved blood pressure and vessel function.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—Hyperinsulinemia and insulin resistance are closely associated with hypertension in humans and in animal models. Gender differences have been found in the development of hypertension in fructose-fed rats. The objectives of the present study were, first, to clarify whether androgens are required in the development of hyperinsulinemia, insulin resistance, and hypertension in fructose-fed rats, and second, to determine if cyclooxygenase-1 and cyclooxygenase-2 are also increased in the arteries of these rats. Male rats were gonadectomized or sham-operated and fed a 60% fructose diet beginning at age 7 weeks. Blood pressure was measured by a tail-cuff method, and an oral glucose tolerance test was performed to assess insulin sensitivity after 8 weeks of fructose feeding. Cyclooxygenase-1 and cyclooxygenase-2 mRNA expression was also assessed in the thoracic aortae and mesenteric arteries. Gonadectomy prevented hypertension from developing in the fructose-fed rats, but hyperinsulinemia and insulin resistance developed. There was an increase in cyclooxygenase-2 expression in the thoracic aortae and mesenteric arteries of the fructose-fed sham-operated rats while the expression of cyclooxygenase-1 remained unchanged. Gonadectomy prevented the mRNA overexpression of vascular cyclooxygenase-2 in the fructose-fed rats. These results suggest that the presence of androgens is necessary for the development of fructose-induced hypertension. Androgens apparently act as a link between hyperinsulinemia/insulin resistance and hypertension in fructose-hypertensive rats. Furthermore, an increase in the expression of cyclooxygenase-2 is implicated in the development of hypertension. The mechanisms involved require further study.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID

摘要:

Abstract—Dopamine is an important modulator of blood pressure, in part, by regulating vascular resistance. To test the hypothesis that D1and D3receptors interact in vascular smooth muscle cells, we studied A10 cells, a rat aortic smooth muscle cell line, and rat mesenteric arteries that express both dopamine receptor subtypes. Fenoldopam, a D1-like receptor agonist, increased both D1and D3receptor protein in a time-dependent and a concentration-dependent manner in A10 cells. The effect of fenoldopam was specific because a D1-like receptor antagonist, SCH23390 (10−7M/24 h), completely blocked the stimulatory effect of fenoldopam (10−7M/24 h) (D3receptor: control=21±1 density units [DU]); SCH23390=23±2 DU; fenoldopam=33±2 DU; fenoldopam+SCH23390=23±2 DU; n=10). D1and D3receptors physically interacted with each other because fenoldopam (10−7M/24 h) increased D1/D3receptor coimmunoprecipitation (35±5 versus 65±5 DU; n=8). A D3receptor agonist, PD128907, relaxed mesenteric arterial rings independent of the endothelium, effects that were blocked by a D3receptor antagonist, U99194A. Costimulation of D1and D3receptors led to additive vasorelaxation. We conclude that the D1receptor regulates the D3receptor by physical interaction and receptor expression. D1receptor stimulation augments D3receptor vasorelaxant effects. An interaction of D1and D3receptors may be involved in the regulation of blood pressure.

ISSN:0194-911X    

出版商:OVID    

年代:2004

数据来源: OVID