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We recently showed that diencephalic TRH may mediate the central leptin-induced pressor effect. Here, to study the role of TRH in obesity-induced hypertension (OIH), we used a model of OIH produced by a high-fat diet (HFD, 45 days) in male Wistar rats. After 4 wk, body weight and systolic arterial blood pressure (SABP) increased in HFD animals. Plasma leptin was correlated with peritoneal adipose tissue. Then, we treated OIH animals with an antisense oligodeoxynucleotide and small interfering (si)RNA against the prepro-TRH. Antisense significantly decreased diencephalic TRH content and SABP at 24 and 48 h posttreatment. Similar effects were observed with siRNA against prepro-TRH but for up to 4 wk. Conversely, vehicle, an inverted antisense sequence and siRNA against green fluorescence protein, produced no changes. SABP decrease seems to be owing to an inhibition of the obesity-enhanced sympathetic outflow but not to an alteration in thyroid status. Using a simple OIH model we demonstrated, for the first time, that central TRH participates in the hypertension induced by body weight gain probably through its well-known action on sympathetic activity. Thus the TRH-leptin interaction may contribute to the strong association between hypertension and obesity.

Background: Tumor necrosis factor-alpha (TNF-alpha) has been associated with obesity, obesity-related hypertension, and metabolic syndrome. We investigated the possible contribution of the G-308A TNF-alpha mutant to explain variables of the metabolic syndrome., Methods: Data and blood samples were used from the 175 adolescents that satisfied the criterion of having systolic or diastolic blood pressures (BP) more than the 80th or less than the 20th percentiles, out of a cross-sectional, population-based study of 934 high school students. Genotyping for the polymorphism was performed by polymerase chain reaction-based restriction fragment length polymorphism analysis., Results: In univariate analysis, we found that there was no difference between A allele carriers and noncarriers in most of the clinical characteristics of the metabolic syndrome such as body mass index (BMI), waist-to-hip ratio, plasma leptin levels, total cholesterol, HDL- and LDL-cholesterol, triglycerides, plasma fasting glucose, insulin, and homocysteine levels. However, we found a significantly (P = .015) higher age- and sex-adjusted systolic BP (Z score) in the A allele carriers, and A allele carriers also showed an elevated homeostasis model assessment of insulin resistance (HOMA) index with respect to noncarriers. Logistic regression analysis indicates that A allele carriers had a 2.8-fold higher probability of being hypertensive independent of BMI, waist-to-hip ratio, and HOMA index., Conclusions: In this report we found a positive association between the G-308A TNF-alpha variant and systolic arterial BP Z score and HOMA index in adolescents harboring features of metabolic syndrome. Therefore, the A allele may predispose to hypertension and insulin resistance in youth.

Thyrotropin (TSH)-releasing hormone (TRH) also known as thyroliberin was the first of a number of peptides exerting several roles as a hormone and as a neuropeptide. Its ubiquitous distribution in the hypothalamus and in the extrahypothalamic regions and its diverse pharmacological and physiological effects are all features of its dual functions. For this reason, TRH has been the subject of much research throughout the past 20 years, work that has examined the structure, function, distribution, and regulation of the tripeptide and it has been extensively reviewed elsewhere [O'Leary R., O'Connor B. Thyrotropin-releasing hormone. J Neurochem. 1995;65:953-963.; Nillni E., Sevarino K. The biology of pro-thyrotropin-releasing hormone-derived peptides. Endocrine Reviews, 1999;20:599-664.]. After a brief overview of its distribution, hypothalamic and extrahypothalamic functions, and receptors involved, this review discusses efforts devoted to support TRH role in cardiovascular regulation with a main focus on hypertension pathophysiology in experimental models and humans.

We have recently demonstrated that arterial PTHrP expression and cardiovascular responses to this protein are altered in SHR compared with normotensive animals, Wistar Kyoto (WKY) and Sprague-Dawley (SD) rats. To investigate whether the slightly, but significantly decreased, aortic PTHrP gene expression observed in SHR, compared to that of normotensive animals, may play a causative role in the maintenance of the elevated arterial blood pressure (ABP) of the SHR, we transfected a hepatic lobe with a PTHrP expression vector in a sense and antisense orientation. At 24 and 48 hours, sense pSV2neo-ECE induced a significant five-fold increase in PTHrP mRNA abundance with respect to antisense pSV2neo-ECE and vehicle. This increment in the PTHrP mRNA induced by the sense PTHrP expression vector was totally inhibited by the co-administration of the antisense PTHrP expression vector. At the same time, we observed a significant decrease of mean ABP (MABP) in SHR transfected with the sense pSV2neo-ECE to similar values as those obtained in the normotensive strain. Neither antisense PTHrP expression vector nor vehicle had any significant effect in any strain. Again, the effect of the sense PTHrP expression vector on MABP was blocked by the simultaneous treatment with the antisense PTHrP expression vector. At 48 hours, the hypotensive effect of the sense pSV2neo-ECE in SHR was reverted by the i.v. bolus injection of a specific competitive PTHrP receptor antagonist such as Nle8,18,Tyr34-bPTH(3-34)amide. We propose that a defect of this potent local vasodilator may contribute to the development and/or maintenance of arterial hypertension in SHR. This defect can be ameliorated by transfecting tissues with protein-exporting capabilities, such as the liver. Finally, our work adds additional data to a cumulative body of evidence suggesting that it might be possible to design an effective gene therapy to treat the common polygenic and multifactorial form of hypertension by increasing the activity of potent and physiological vasodilators.

Objective: Renin-angiotensin-aldosterone system component genes have been associated to essential hypertension. Thus, we studied the association of singe locus or multilocus interactions with young-onset essential hypertension., Setting and Design: This is a case-control study based on a population sample of adolescent at an inner city., Participants: We studied 54 adolescents with hypertension and 121 age-matched normotensives, recruited from a high-school student population of 934 interviewed individuals., Methods: Resting blood pressure was measured on three different days and normalized (Z-score) by sex and age. Genotypes of ACE (I/D) angiotensinogen (T174M and M235T), ATIR (A1166C), and CYP11B2 (C-344T) were determined by PCR/RFLP or ASO., Results: Although genotype frequencies were not different in both groups, we found a significant dominant effect of ACE D and angiotensinogen 235T alleles on normalized systolic arterial blood pressure in males. This effect was confirmed by sib-pair linkage analysis taking normalized blood pressure as a quantitative trait. We independently analyzed multilocus interactions in normotensive and hypertensive adolescents searching for multiple locus deviation from Hardy-Weinberg or linkage equilibrium. We found that from 63 multilocus combinations, 4 deviated significantly from equilibrium in hypertensive adolescents but none in the normotensives. Deviations from equilibrium may indicate that the combination of alleles at different loci affects susceptibility or resistance to the disease., Conclusion: In addition to the angiotensin-converting enzyme (ACE) and angiotensinogen (AGT) gene variants, gene-gene interactions may be important causative factors in a complex disease such as young-onset essential hypertension.

Background: Tumor necrosis factor-α (TNF-α) has been associated with obesity, obesity-related hypertension, and metabolic syndrome. We investigated the possible contribution of the G-308A TNF-α mutant to explain variables of the metabolic syndrome. Methods: Data and blood samples were used from the 175 adolescents that satisfied the criterion of having systolic or diastolic blood pressures (BP) more than the 80th or less than the 20th percentiles, out of a cross-sectional, population-based study of 934 high school students. Genotyping for the polymorphism was performed by polymerase chain reaction-based restriction fragment length polymorphism analysis. Results: In univariate analysis, we found that there was no difference between A allele carriers and noncarriers in most of the clinical characteristics of the metabolic syndrome such as body mass index (BMI), waist-to-hip ratio, plasma leptin levels, total cholesterol, HDL- and LDL-cholesterol, triglycerides, plasma fasting glucose, insulin, and homocysteine levels. However, we found a significantly (P = .015) higher age- and sex-adjusted systolic BP (Z score) in the A allele carriers, and A allele carriers also showed an elevated homeostasis model assessment of insulin resistance (HOMA) index with respect to noncarriers. Logistic regression analysis indicates that A allele carriers had a 2.8-fold higher probability of being hypertensive independent of BMI, waist-to-hip ratio, and HOMA index. Conclusions: In this report we found a positive association between the G-308A TNF-α variant and systolic arterial BP Z score and HOMA index in adolescents harboring features of metabolic syndrome. Therefore, the A allele may predispose to hypertension and insulin resistance in youth. [Copyright &y& Elsevier]

OBJECTIVE: Losartan, a dose of 25 mg/day, has been found to be effective in 50% of patients with portal hypertension without adverse effects. We evaluated the relationship between genetic polymorphisms of the renin-angiotensin system (A1166C angiotensin II type 1 receptor (AT1R), angiotensinogen T174M and M235T, and angiotensin-converting enzyme I/D) and the effects of losartan on portal and systemic hemodynamic in patients with cirrhosis and portal hypertension.METHODS: We performed a longitudinal study that included 23 consecutive patients with cirrhosis and esophageal varices who received 25 mg/day of losartan during 12 wk. Hepatic venous pressure gradient (HVPG) and systemic hemodynamic were measured at baseline and after treatment. Genomic DNA was extracted from peripheral blood leukocytes; genetic polymorphisms of the renin-angiotensin system were investigated by polymerase chain reaction and restriction fragment length polymorphisms.RESULTS: The homozygous patients for AT1R A allele showed higher pulmonary-wedged and free hepatic venous pressure on baseline. After treatment, they showed a higher decrease of HVPG (32.5%± 19.2) in comparison with patients with AC/CC genotype (2.4%±18.9),p<0.01. Ten of 15 patients with AA genotype were responders, while only one of eight with AC/CC genotype (p<0.002); genotype AA showed a positive predictive value of 66.6% and negative predictive value of 87.5%.CONCLUSIONS: These results suggest that there is a relationship between the AT1R A1166C polymorphisms and the therapeutic response to losartan. The genetic testing may be used as a predictive factor of this response.(Am J Gastroenterol 2005;100:636–642) [ABSTRACT FROM AUTHOR]

The neuropeptides arginine vasopressin (AVP) and oxytocin (OT) have been implicated in the genesis of hypertension due to deoxycorticosterone acetate (DOCA)-salt treatment of uninephrectomized rats. In this work, we studied if DOCA treatment of intact rats in doses arousing a salt appetite (a prehypertensive state), modulated mRNA for AVP and OT in the hypothalamus. Male Sprague-Dawley rats were offered both tap water and 3% NaCl in separate bottles and received vehicle or subcutaneous injections of 10 mg DOCA on alternate days for 7 days (4 injections) or 17 days (9 injections). They developed a preference for 3% NaCl solutions 24–48 h after treatment. Brain slices from rats killed on the 8th or 18th day were exposed to [sup 35] S-labeled probes encoding prepro-AVP mRNA or OT mRNA, respectively. Expression of these mRNAs was measured in the magnocellular and parvocellular divisions of the paraventricular nucleus (PVN) and magnocellular cells of the supraoptic nucleus (SON). No changes were obtained in neuropeptide mRNA levels in the parvocellular division of the PVN between control and the two groups of DOCA-treated rats. However, DOCA-treated animals presented an increased number of grains per cell for AVP mRNA in the magnocellular division of the PVN and in magnocellular cells of the SON, as shown by group mean comparisons and frequency histograms. No changes were detected for OT mRNA. In a second series of studies, control or DOCA-treated rats were offered 3% NaCl or water as the only choice. Animals drinking 3% NaCl showed increased AVP and OT mRNA levels, whether they received DOCA or not. However, AVP mRNA levels in both nuclei were higher in DOCA-treated rats drinking 3% NaCl than in controls drinking salt solution. In comparison, control and DOCA-treated rats drinking water showed lower levels of AVP mRNA. OT mRNA levels in the SON remained unchanged in the same groups. The results suggest that in the magnocellular cells of the PVN and SON, increments in AVP mRNA are obtained following increments in salt intake produced by either mineralocorticoid treatment or exclusive salt drinking. In rats offered salt solution and water to drink, DOCA effects on AVP mRNA developed before changes occurred in serum sodium levels. Because combined DOCA + salt treatment induced a higher response in terms of AVP mRNA expression, we suggest that AVP could be a target of the central effects of the mineralocorticoid. [ABSTRACT FROM AUTHOR]