Enhanced contraction to 5-hydroxytryptamine is not due to "unmasking" of 5-hydroxytryptamine(1b) receptors in the mesenteric artery of the deoxycorticosterone acetate-salt rat.
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5-Hydroxytryptamine(1B) (5-HT(1B)) receptors have been implicated in mediating arterial contraction to 5-HT. Additionally, the 5-HT(1B) receptor has been reported to be "unmasked" by depolarizing stimuli. We hypothesized that 5-HT(1B) receptors in arteries from hypertensive animals, arteries reported to have a depolarized resting membrane potential in smooth muscle cells, are unmasked and participate in the supersensitivity observed to 5-HT in hypertension. We used the isolated tissue bath apparatus and examined the response of superior mesenteric arteries from normotensive sham and hypertensive deoxycorticosterone acetate (DOCA)-salt rats. The 5-HT(1B) agonists CP93129 and sumatriptan (10(-9) to 10(-5) mol/L) caused a maximal contraction (50+/-12% of phenylephrine [10(-5) mol/L] contraction) in arteries from DOCA-salt rats; no contraction was observed in arteries from normotensive rats. The 5-HT(1B) receptor antagonist GR55562 (100 nmol/L) inhibited both the 5-HT- (4-fold rightward shift) and CP93129-induced (11-fold rightward shift) contractions in mesenteric arteries from hypertensive DOCA-salt rats. In other experiments, arteries from normotensive rats were incubated with 15 mmol/L KCl, as a depolarizing stimulus, and then exposed to 5-HT and CP93129. In the presence of KCl, a small leftward shift to 5-HT was observed. However, the presence of a depolarizing stimulus was unable to produce changes in the 5-HT maximal response to resemble that of arteries from DOCA-salt rats, nor was contraction to CP93129 observed. These data support the conclusions that 5-HT(1B) receptors mediate contraction in mesenteric arteries from hypertensive rats and that this enhanced response to 5-HT is not due to membrane depolarization alone. (+info)
Effects of centrally administered losartan on deoxycorticosterone-salt hypertension rats.
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To investigate whether brain AT1 receptor stimulation contributes as a hypertensive mechanism to deoxycorticosterone acetate (DOCA)-salt hypertension, losartan (1 mg/4 microL) or artificial cerebrospinal fluid (aCSF) was injected into the lateral cerebral ventricle in conscious control uninephrectomized Wistar rats or rats with DOCA-salt for 2 or 4 weeks, and mean arterial pressure (MAP) and heart rates (HR) were recorded. In rats with DOCA-salt treatment, resting MAP increased to 144+/-6 mmHg after 2 weeks and to 170+/-5 mmHg after 4 weeks versus 115- 120 mmHg in controls. In rats with 2 week DOCA-salt treatment, MAP started declining at 4 hr after intracerebroventricular (icv) injection of losartan, and significant decreases in MAP were found at 18 and 24 hr. In rats with 4 week DOCA-salt treatment, MAP was significantly decreased at 4, 18 and 24 hr. In both groups MAP decreased to that of control rats. In control rats, icv losartan had no effect on MAP and HR. Icv aCSF did not significantly change MAP and HR in either DOCA-salt hypertensive rats or control rats. Normalization of MAP after icv administration of the AT1 receptor antagonist suggests a significant role for brain AT1 receptor stimulation in the development and maintenance of hypertension in the DOCA-salt hypertensive rat model. (+info)
Antihypertensive effects of chicken extract against deoxycorticosterone acetate-salt-induced hypertension in rats.
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We investigated the antihypertensive effect of Brand's Essence of Chicken (BEC), a popular chicken extract used as a traditional remedy, using deoxycorticosterone acetate (DOCA)-salt hypertensive rats. Animals were unilaterally nephrectomized, and then separated into a sham-operated group (sham group) and a DOCA-salt-treated group. The latter was further separated into a normal diet group and a BEC (freeze-dried powder, 0.1 w/w%)-containing diet group. Systolic blood pressure of the normal diet group progressively increased in comparison with that of the sham group. The DOCA-salt-induced hypertension was markedly suppressed by feeding a BEC-containing diet. Systolic blood pressure after 5 weeks was 128+/-2 mmHg in sham group, 181+/-4 mmHg in the DOCA-salt-treated normal diet group and 139+/-5 mmHg in the DOCA-salt-treated BEC diet group, respectively. The treatment with DOCA and salt for 5 weeks significantly increased the weights of heart and left ventricle, but these increases were significantly suppressed in the BEC group. When the degree of vascular hypertrophy of the aorta was histochemically evaluated, DOCA-salt-induced increases in wall thickness and wall area of the vessels were significantly decreased by the BEC-feeding. Histopathological renal damage of fibrinoid-like necrosis in glomeruli, thickening of small arteries and tubular dilatation were observed in the DOCA-salt-treated normal diet group, but this damage was efficiently reduced by the BEC-feeding. In addition, BEC-feeding decreased urinary excretion of protein, which was elevated by the treatment with DOCA and salt. Thus, BEC seems to be useful as a prophylactic treatment in the development of hypertension and related tissue injuries. (+info)
Endothelin antagonist reduces hemodynamic responses to vasopressin in DOCA-salt hypertension.
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The contribution of endothelin to the changes in blood pressure, cardiac output, and total peripheral resistance evoked by arginine vasopressin and angiotensin II was investigated in deoxycorticosterone acetate (DOCA)-salt hypertensive rats by infusing the peptides intravenously before and after pretreatment with the endothelin receptor antagonist bosentan. Blood pressure was recorded with radiotelemetry devices and cardiac output was recorded with ultrasonic transit time flow probes in conscious unrestrained animals. The dose-related decreases in cardiac output induced by vasopressin and angiotensin II were unaffected by bosentan. In contrast, the dose-related increases in total peripheral resistance evoked by vasopressin were blunted in both DOCA-salt hypertensive and sham normotensive rats, but this effect of bosentan was greater in the DOCA-salt hypertensive group. In contrast with vasopressin, bosentan failed to change hemodynamic responses to angiotensin II. The exaggerated vascular responsiveness (total peripheral resistance) of the DOCA-salt hypertensive group to vasopressin was largely abolished by bosentan. These results suggest that endothelin contributes to the hemodynamic effects of vasopressin but not angiotensin II in the DOCA-salt model of hypertension. (+info)
NADH/NADPH oxidase and enhanced superoxide production in the mineralocorticoid hypertensive rat.
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We previously reported increased aortic reactive oxygen species (ROS) production in mineralocorticoid (deoxycorticosterone acetate [DOCA]-salt) hypertensive rats. In the present study, we tested the hypothesis that NADH/NADPH oxidase is responsible for increased ROS production, namely superoxide (O(2-)), in aorta from the DOCA-salt rat. Treatment of aortic rings from DOCA-salt rats with the NO synthase inhibitor N-nitro-L-arginine and the xanthine oxidase inhibitor allopurinol did not significantly change O(2-) production. Furthermore, de-endothelialization of aorta from DOCA-salt rats did not affect O(2-) production compared with that of sham-operated rats. Thus, xanthine oxidase and uncoupled endothelial NO synthase were not responsible for increased O(2-) production in the DOCA-salt rats. In contrast, treatment with the NADPH oxidase inhibitor apocynin significantly decreased O(2-) production in aortic rings from DOCA-salt rats compared with sham-operated rats. Moreover, long-term administration of apocynin (in drinking water, 1.5 mmol/L, 28 days) to DOCA-salt rats significantly decreased systolic blood pressure compared with that of rats treated with DOCA-salt alone. Furthermore, O(2-) production in aortic rings from DOCA-salt rats treated with apocynin for 28 days was reduced compared with that of untreated DOCA-salt rats. Reverse transcriptase-polymerase chain reaction (RT-PCR) analysis demonstrated that DOCA-salt rats have significantly greater mRNA levels of the NADPH oxidase subunit p22phox than do sham-operated rats. These findings suggest that NADPH oxidase is increased and is responsible for increased O(2-) production and possibly contributes to increased blood pressure in the DOCA-salt hypertensive rat. (+info)
An increased reactivity in hypertensive rats unaffected by prolonged antihypertensive therapy.
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1. Isolated perfused mesenteric arteries obtained from chronic experimental hypertensive rats (deoxycorticosterone/NaCl) exhibited an increased reactivity to noradrenaline, 5-hydroxytryptamine and adenosine 5'-triphosphate (ATP) when compared with similar preparations from age-matched normotensive animals. 2. The dose-response curves to all three vasoconstrictor agents obtained from hypertensive animals exhibited a steeper slope, and higher maximum without any significant change in the threshold dose suggesting that adaptive/structural changes in the blood vessels had taken place. 3. Ten week treatments with antihypertensive combinations of hydrallazine, hydrochlorothiazide and reserpine or hydrallazine and mecamylamine lowered the systolic blood pressures of the hypertensive rats to those of normotensive animals and also reversed secondary changes such as periarteritis nodosa of the mesentery and cardiac hypertrophy. 4. The reactivity of these blood vessels to all these vasoconstrictor agents from the hypertensive rats with a normalized blood pressure was similar to those obtained with untreated hypertensive animals. 5. The persistent increased reactivity in the hypertensive rats after long-term anti-hypertensive treatment suggests that the hyperresponsiveness is secondary to the elevated blood pressures and that the adaptive/structural changes of the blood vessels in chronic hypertensive rats cannot be reversed by prolonged antihypertensive therapy. (+info)
Glucocorticoids manifest androgenic activity in a cell line derived from a metastatic prostate cancer.
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The pathophysiological mechanism(s) by which androgen independence develops in prostate cancer remains to be determined. The identification in many prostate cancer specimens of a mutant androgen receptor, T877A, with altered ligand specificity has provided an explanation for some treatment failures. The T877A mutant androgen receptor recognizes a number of nonandrogenic compounds, including certain estrogens, progestins, and even antiandrogens as androgens. However, a comprehensive screen for hormonal agents which display agonist activity on this mutant has not been performed. In this study, we characterized this clinically important receptor mutant further and found that it can be activated by a wide range of compounds, including a number of endogenous glucocorticoids. Among the most clinically relevant compounds identified are DOC and corticosterone, both of which can effectively activate the mutant receptor at concentrations normally found in blood. Dexamethasone, a synthetic glucocorticoid frequently used in various contexts for prostate cancer therapy, is also recognized as an androgen by the mutant receptor. These unexpected findings suggest the need to: (a) reassess the role of adrenally derived glucocorticoids in prostate cancer disease progression; and (b) recognize the potential for iatrogenic stimulation of disease progression with certain glucocorticoid interventions. (+info)
Epidermal growth factor (EGF) causes contraction in arteries from deoxycorticosterone acetate (DOCA)-salt hypertensive rats but not in normotensive sham rats. We hypothesized that an increase in the number of EGF receptors (EGFRs) in arteries from DOCA-salt rats enables the observed contraction to EGF to occur. DOCA-salt rats had a systolic blood pressure >170 mm Hg, whereas all sham rats had a systolic blood pressure <125 mm Hg. Thoracic aorta were removed for measurement of isometric force, EGFR mRNA levels, and EGFR protein levels. EGF caused a significant contraction in endothelium-denuded aorta from DOCA-salt rats (38+/-7% of maximal phenylephrine-induced [10 micromol/L] contraction) compared with aorta from sham rats (4+/-2%). The EGFR tyrosine kinase-specific inhibitors 4,5-dianilinophthalimide (10 micromol/L) and AG1478 (250 nmol/L) reduced contraction in aorta from DOCA-salt by 85+/-14% and 65+/-10%, respectively. EGFR mRNA in DOCA-salt aorta was increased 4.2-fold compared with that in sham aorta. However, Western analyses of membrane-enriched and whole-tissue lysate of aorta from sham and DOCA-salt revealed no statistical difference in the density of EGFR protein between sham and DOCA-salt aorta. These data refute our hypothesis and suggest that a change downstream of EGFR is responsible for enabling EGF-induced contraction in hypertension. (+info)