UMLS:C0020538 - FACTA Search

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Query: UMLS:C0020538 (hypertension)
170,190 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

To identify the mechanism of cyclosporine-induced hypertension, we studied the effect of cyclosporine on the catecholamine synthetic pathway in rats. We administered cyclosporine (10 mg/kg per day, s.c.) for 3 days to 10-week-old male Wistar rats. Systolic blood pressure increased significantly in the cyclosporine-treated group in comparison to that in the control group. Norepinephrine and epinephrine levels in the adrenal medulla and plasma of cyclosporine-treated rats were also significantly higher than levels in the control rats. Moreover, tyrosine hydroxylase (TH) activity and TH mRNA expression in the adrenal medulla of cyclosporine-treated rats were significantly elevated. Administration of the TH inhibitor alphamethyl-p-tyrosine (200 mg/kg, b.i.d., s.c.) for 3 days significantly suppressed cyclosporine-induced increases in systolic blood pressure. Phosphorylation of cyclic AMP responsive element-binding protein (CREB) and its binding activity to DNA in the nuclear fraction from the adrenal medulla of cyclosporine-treated rats were much higher than that of the control rats. Calcineurin protein expression of cyclosporine-treated rats was less than that of the control rats. These results suggest that cyclosporine increased blood pressure via activation of the catecholamine synthetic pathway due to the activation of transcription factor CREB.
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PMID:Involvement of tyrosine hydroxylase upregulation in cyclosporine-induced hypertension. 1132 24

This study examined the mechanisms linking different biochemical and clinical phenotypes of pheochromocytoma in multiple endocrine neoplasia type 2 (MEN 2) and von Hippel-Lindau (VHL) syndrome to underlying differences in the expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis, and of phenylethanolamine N-methyltransferase (PNMT), the enzyme that converts norepinephrine to epinephrine. Signs and symptoms of pheochromocytoma, plasma catecholamines and metanephrines, and tumor cell neurochemistry and expression of TH and PNMT were examined in 19 MEN 2 patients and 30 VHL patients with adrenal pheochromocytomas. MEN 2 patients were more symptomatic and had a higher incidence of hypertension (mainly paroxysmal) and higher plasma concentrations of metanephrines, but paradoxically lower total plasma concentrations of catecholamines, than VHL patients. MEN 2 patients all had elevated plasma concentrations of the epinephrine metabolite, metanephrine, whereas VHL patients showed specific increases in the norepinephrine metabolite, normetanephrine. The above differences in clinical presentation were largely explained by lower total tissue contents of catecholamines and expression of TH and negligible stores of epinephrine and expression of PNMT in pheochromocytomas from VHL than from MEN 2 patients. Thus, mutation-dependent differences in the expression of genes controlling catecholamine synthesis represent molecular mechanisms linking the underlying mutation to differences in clinical presentation of pheochromocytoma in patients with MEN 2 and the VHL syndrome.
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PMID:Pheochromocytomas in von Hippel-Lindau syndrome and multiple endocrine neoplasia type 2 display distinct biochemical and clinical phenotypes. 1134 98

We investigated the effect of antisense oligodeoxynucleotides (AS ODN) against tyrosine hydroxylase (TH) on hypertension and sympathetic nervous system activity in spontaneously hypertensive rats (SHR). Systolic blood pressure (SBP) in SHR treated with TH AS ODN (50, 200 microg/rat, i.v.) was significantly lower than that of control SHR. Epinephrine and norepinephrine levels, TH activity, and TH protein levels in the adrenal medulla of SHR were reduced concomitant with TH AS ODN treatment-induced changes in SBP. In contrast, TH AS ODN (200 microg/rat) had no effect on SBP in Wistar-Kyoto rats (WKY), despite significantly decreased catecholamine levels, TH activity, and TH protein levels. These findings suggest that peripheral systemic injection of TH AS ODN may be effective as hypotensive therapy in SHR.
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PMID:Tyrosine hydroxylase antisense gene therapy causes hypotensive effects in the spontaneously hypertensive rats. 1159 96

We previously showed that CGP 42112 (an angiotensin type 2 [AT(2)] agonist) markedly reduces catecholamine biosynthesis by decreasing cGMP production mediated by AT(2), a subtype of Ang II receptor that is dominantly expressed in cultured porcine chromaffin cells. To elucidate the relationship of the 2 types of Ang II receptors, angiotensin type 1 (AT(1)) and AT(2), in the synthesis of catecholamine in adrenal medullary cells, we have examined the effect of Ang II plus CV-11974 (an AT(1) antagonist that selectively simulates AT(2) stimulation) and the effect of Ang II plus PD 123319 (an AT(2) antagonist that selectively simulates AT(1) stimulation) on catecholamine synthesis. We found that Ang II reduced cGMP production via AT(2), in a similar manner to that found with CGP 42112. Stimulation of AT(1) significantly upregulated protein kinase C activity. Tyrosine hydroxylase (TH) is a rate-limiting enzyme involved in the biosynthesis of catecholamine, and this catecholamine synthesis depends both on TH enzyme activity and on the levels of TH protein after TH gene transcription. We found that AT(2) stimulation significantly inhibited TH enzyme activity, whereas AT(1) stimulation significantly upregulated TH enzyme activity. The stimulatory effect of AT(1) was completely inhibited by Ro-32-0432 (a protein kinase C inhibitor) and PD 98059 (a MAP kinase kinase-1 [MEK-1] inhibitor). Pretreatment of cells with either 8-Br-cGMP (a membrane-permeable cGMP analog) or Zaprinast (a phosphodiesterase inhibitor) abolished the inhibitory effect of AT(2) on TH enzyme activity, indicating that the stimulatory effect of AT(2) may be mediated through a reduction in cGMP concentration. Similar to the effect on TH enzyme activity, AT(2) stimulation significantly reduced TH mRNA and protein levels and net catecholamine content below basal levels, whereas AT(1) stimulation increased them. We confirmed these findings by gel mobility shift assay. Our results show that stimulation of AT(2) reduces catecholamine biosynthesis via a decrease in cGMP levels. In contrast, stimulation of AT(1) stimulates catecholamine biosynthesis through activation of PKC. Thus, we conclude that AT(1) and AT(2) have counter-regulatory roles in the synthesis of catecholamine in adrenal medullary chromaffin cells.
Hypertension 2002 Jan
PMID:Angiotensin II type 2 receptor counter-regulates type 1 receptor in catecholamine synthesis in cultured porcine adrenal medullary chromaffin cells. 1179 93

The activation of the sympathetic nervous system is a common feature of arterial hypertension and other cardiovascular diseases. This activation might be dependent on an altered baroreflex control of vascular resistance of which the inhibitory response on sympathetic activity appears impaired. The aim of the study was to monitor during the natural course of arterial hypertension in spontaneously hypertensive (SHR) and age-matched Wistar Kyoto (WKY) rats (5, 16, 30, and 54 weeks of age) the peripheral sympathetic activity expressed as interstitial norepinephrine (NE) release and as tyrosine hydroxylase (TH) activity, the rate-limiting enzyme of NE synthesis, in the differently baroreflex-controlled subcutaneous adipose tissues and skeletal muscles. Blood pressure and plasma NE in SHR were similar to WKY at 5 weeks of age but increased at all other ages. Body weight was similar in both 5-week-old rats but reduced in SHR at all other ages. The interstitial NE levels were greater in both SHR tissues at all ages as compared with WKY. In adipose tissue of SHR, TH activity was higher at all ages as compared with WKY, whereas TH activity in skeletal muscle was higher only after the development of hypertension. These data show that in both SHR tissues, an increase of interstitial NE release is always present during its lifespan. This suggests that increased sympathetic activation in the SHR model is not specific to baroreflex-controlled tissues such as skeletal muscle but involves also subcutaneous adipose tissue, the sympathetic efferents of which are independent from baroreflexes.
Hypertension 2002 Feb
PMID:Sympathetic activation in adipose tissue and skeletal muscle of hypertensive rats. 1188 26

Activation of alpha-2-adrenergic and neuropeptide Y (NPY) receptors in the nucleus tractus solitarii (NTS) induces hypotension and bradycardia. On the contrary, activation of angiotensin II (Ang II) receptors leads to hypertension. Acute changes in binding parameters of alpha-2-adrenergic, NPY and Ang II receptors were evaluated in the NTS and paraventricular hypothalamic nucleus (PVN) of rats after a hypertensive stimulus employing quantitative receptor autoradiography. Saturation experiments showed a decrease in the number (Bmax) of alpha-2-adrenergic binding sites in the NTS 6 hours after coarctation-induced hypertension. Furthermore, the affinity of NPY receptors was diminished as seen by the increase in the KD value of 125I-PYY. Tyrosine hydroxylase and NPY immunoreactivities were increased in the NTS and ventral medulla. Binding of 125I-Ang II was not changed in the NTS. Binding of all ligands analyzed was not altered in the PVN. The results suggest an acute down-regulation of alpha-2-adrenergic and NPY receptors involved with hypotension in response to hypertensive stimulus, which might be related to an increased availability of catecholamines and NPY in the NTS.
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PMID:Acute changes in 3H-PAC and 125I-PYY binding in the nucleus tractus solitarii and hypothalamus after a hypertensive stimulus. 1188 80

Loss of von Hippel-Lindau (VHL) gene function leads to VHL disease, which is characterized by vascular tumors of the central nervous system, renal clear cell carcinomas, and pheochromocytomas. Pheochromocytomas express high levels of tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine biosynthesis. PC12 cells that express VHL antisense RNA had 5-10-fold reduced levels of endogenous pVHL and 2-3-fold increased levels of TH protein and mRNA. Nuclear run-on analysis revealed an augmentation of TH gene transcription with enhanced efficiency of transcript elongation in the 3' region of the gene. Transient coexpression of the VHL antisense RNA with a TH promoter reporter construct increased TH promoter activity by 2-3-fold. A decrease in pVHL accumulation also resulted in an increase in TH mRNA accumulation and transcription of the TH gene during hypoxia. This is the first evidence that endogenous pVHL is a physiological regulator of the catecholaminergic phenotype. Thus, loss of pVHL function may be causative in pheochromocytoma-associated hypercatecholaminemia and arterial hypertension.
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PMID:Endogenous von Hippel-Lindau tumor suppressor protein regulates catecholaminergic phenotype in PC12 cells. 1191 40

Gender-specific differences in susceptibility to a number of disorders related to catecholaminergic systems, including depression and hypertension, have been postulated to be mediated, at least in part, by estrogens. In this study, we examined if estrogens may regulate gene expression of norepinephrine biosynthetic enzymes. Administration of five injections of 15 or 40 microg/kg estradiol benzoate to ovariectomized (OVX) female rats elicited a dose-dependent elevation in mRNA levels of tyrosine hydroxylase (TH) in locus coeruleus, to as great as 3-fold over control. Dopamine beta-hydroxylase (DBH) mRNA levels were also similarly increased. To examine the mechanism, PC12 cells were cotransfected with luciferase reporter constructs under control of DBH or TH promoters [pDBH/Luc(-2,236/+21) or pTH/Luc(-272/+27 or -773/+27)] with an expression vector for estradiol receptor alpha. The cells were treated with 17beta-estradiol (E(2)) for 12-36 h. E(2) triggered a several fold increase in luciferase activity under control of the DBH promoter in a dose-dependent fashion. Omission of estrogen receptor alpha or addition of the estrogen receptor antagonist ICI 182,780 prevented the DBH promoter-driven increase in luciferase. When E(2) was given with 0.2 mM CPT-cAMP, reporter activity with pDBH/Luc(-2,236/+21) was increased greater than with either treatment alone. In contrast, addition of E(2) to cells transfected with pTH/Luc(-272/+27) elicited no change in basal luciferase activity nor in the response to 0.2 mM CPT-cAMP. These findings are the first to reveal that estrogen can stimulate DBH gene expression. Differing mechanisms may underlie the regulation of TH and DBH gene expression by estrogens.
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PMID:Estradiol stimulates gene expression of norepinephrine biosynthetic enzymes in rat locus coeruleus. 1191 91

Von Euler characterised the sympathetic neurotransmitter noradrenaline (NA) and postulated that excessive neural tone was a cause of primary hypertension (PH). Thirty years ago, we found raised NA levels in 30-40% of young patients with PH. Laragh found plasma renin activity (PRA) a risk marker for coronary artery disease. With Esler, Miura, and Campese, a close association was found of plasma NA with PRA. We found raised tyrosine hydroxylase activity (AC) in the hearts of a rabbit model of sinoaortic denervated hypertension and in PH with raised plasma NA. Esler utilised titrated NA infusion and described increased spillover of NA from heart, kidney and subcortical areas of brain of patients with PH. With Eide we found raised cerebrospinal fluid (CSF) NA in PH (not secondary hypertension) and with Kolloch and Miura, we found raised plasma/CSF NA in conjunction with reduced dopaminergic tone. With Shkvatsabaya, Yurenev and Davison, we found that relaxation therapy improved the anger ambience and blood pressure of PH with raised plasma NA vs those with normal NA levels. Campese found a hypothalamic source of raised blood pressure in two rat models - microphenol treated and ischaemic kidney. The resulting hypertension was associated with raised NA turnover of their hypothalamic centres. Finally, with Hsueh and Hodis, we found raised plasma NA in association with insulin resistance increased left ventricular mass and intimal medial hypertrophy in Mexican-American diabetics and their yet unaffected offspring. Reliable estimates of human sympathetic AC, including levels of plasma NA in the effluent of selected organs and peripheral venous and arterial sites, may eventually be displaced by techniques using genetic analysis and molecular biology. Never the less, the sympathetic nervous system appears to play an important role in the pathogenesis, sequelae and therapy of PH.
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PMID:The sympathetic nervous system: the muse of primary hypertension. 1198 98

This study investigated the incidence of cafeteria-diet induced hypertension on hypothalamic tyrosine hydroxylase (TH) and alpha(2)-adrenoceptor subtype gene expression in male, female, and neonatally testosterone-imprinted female rats. After 10 weeks of cafeteria diet, all these rats were hyperleptinemic. In contrast, males and testosterone-treated females developed hypertension, whereas intact females remained normotensive. In these rats, cafeteria diet up-regulated TH gene expression only in males and testosterone-treated females. On the other hand, cafeteria diet differentially affected hypothalamic gene expression of alpha(2)-adrenoceptor subtypes. In fact, this diet increased alpha(2A)-adrenoceptor mRNA levels only in intact normotensive females. In contrast, gene expression of the alpha(2B)-adrenoceptor was up-regulated only in male and testosterone-treated female cafeteria-fed rats. Furthermore, an alpha(2C)-adrenoceptor gene over-expression was also induced, but only in male cafeteria-fed rats. If one assumes that the up-regulations in TH and alpha(2B)-adrenoceptor gene expression are indicative of increased sympathetic nervous activity, then, these altered gene expressions could be responsible for the maintenance of high blood pressure in male and testosterone-treated female cafeteria-fed rats. Conversely, in intact females, the absence of these over-expressions and the up-regulation of the alpha(2A)-adrenoceptor gene expression could reflect an adaptive response to the diet and, consequently, could be protective against cafeteria diet-induced hypertension. Moreover, neonatal testosterone imprinting in females could have induced an irreversible android susceptibility to the cafeteria diet, leading to the onset of hypertension.
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PMID:Gender differences in hypothalamic tyrosine hydroxylase and alpha(2)-adrenoceptor subtype gene expression in cafeteria diet-induced hypertension and consequences of neonatal androgenization. 1213 Jul 11

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