scholarly journals Effects of Transgenic Expression of Dopamine Beta Hydroxylase (Dbh) Gene on Blood Pressure in Spontaneously Hypertensive Rats

2016 ◽  
pp. 1039-1044
Author(s):  
M. PRAVENEC ◽  
V. LANDA ◽  
V. ZÍDEK ◽  
P. MLEJNEK ◽  
J. ŠILHAVÝ ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Essential Hypertension ◽  
Spontaneously Hypertensive Rat ◽  
Reduce Blood Pressure ◽  
Left Ventricular ◽  
Brown Norway ◽  
Catecholamine Metabolism ◽  
Mrna Levels ◽  
Spontaneously Hypertensive ◽  
Dopamine Beta Hydroxylase

The spontaneously hypertensive rat (SHR) is the most widely used animal model of essential hypertension and left ventricular hypertrophy. Catecholamines play an important role in the pathogenesis of both essential hypertension in humans and in the SHR. Recently, we obtained evidence that the SHR harbors a variant in the gene for dopamine beta hydroxylase (Dbh) that is associated with reduced adrenal expression of Dbh mRNA and reduced DBH enzymatic activity which correlated negatively with blood pressure. In the current study, we used a transgenic experiment to test the hypothesis that reduced Dbh expression predisposes the SHR to hypertension and that augmentation of Dbh expression would reduce blood pressure. We derived 2 new transgenic SHR-Dbh lines expressing Dbh cDNA under control of the Brown Norway (BN) wild type promoter. We found modestly increased adrenal expression of Dbh in transgenic rats versus SHR non-transgenic controls that was associated with reduced adrenal levels of dopamine and increased plasma levels of norepinephrine and epinephrine. The observed changes in catecholamine metabolism were associated with increased blood pressure and left ventricular mass in both transgenic lines. We did not observe any consistent changes in brainstem levels of catecholamines or of mRNA levels of Dbh in the transgenic strains. Contrary to our initial expections, these findings are consistent with the possibility that genetically determined decreases in adrenal expression and activity of DBH do not represent primary determinants of increased blood pressure in the SHR model.

Catecholamines, Blood Pressure, Renin and Myocardial Function in the Spontaneously Hypertensive Rat

1976 ◽  
Vol 51 (s3) ◽  
pp. 455s-459s
Author(s):  
Suzanne Oparil ◽  
Lynda Erinoff ◽  
A. Cutilletta
Keyword(s):  
Blood Pressure ◽  
Left Ventricular Hypertrophy ◽  
Ventricular Hypertrophy ◽  
Myocardial Function ◽  
Spontaneously Hypertensive Rat ◽  
Plasma Renin ◽  
Left Ventricular ◽  
Ventricular Contractility ◽  
Spontaneously Hypertensive ◽  
6 Hydroxydopamine

1. Neither nerve-growth-factor antiserum (NGFAS) administered subcutaneously nor 6-hydroxydopamine administered intraventricularly to immature spontaneously hypertensive rats (SHR) inhibited the development of the hypertensive syndrome. In contrast, NGFAS did not affect blood pressure in normotensive Kyoto/Wistar rats. 2. Peripheral vascular resistance was increased and cardiac index decreased in both NGFAS and 6-hydroxydopamine-treated SHR despite preservation of normal blood pressure. 3. NGFAS treatment did not influence the development of left ventricular hypertrophy in SHR, despite the lowering of blood pressure. In contrast, 6-hydroxydopamine caused an attenuation in the development of left ventricular hypertrophy. 4. Indices of left ventricular contractility were depressed by NGFAS treatment but not by 6-hydroxydopamine. 5. Plasma renin activity was unaffected by NGFAS treatment and increased by 6-hydroxydopamine.

scholarly journals Endoplasmic reticulum stress inhibition blunts the development of essential hypertension in the spontaneously hypertensive rat

2019 ◽  
Vol 316 (5) ◽  
pp. H1214-H1223 ◽  
Author(s):  
Safaa Naiel ◽  
Rachel E. Carlisle ◽  
Chao Lu ◽  
Victor Tat ◽  
Jeffrey G. Dickhout
Keyword(s):  
Blood Pressure ◽  
Endoplasmic Reticulum ◽  
Essential Hypertension ◽  
Er Stress ◽  
Spontaneously Hypertensive Rat ◽  
Resistance Arteries ◽  
Spontaneously Hypertensive ◽  
Functional Changes ◽  
Hypertensive Rat ◽  
Hypertension Development

Essential hypertension is the leading cause of premature death worldwide. However, hypertension’s cause remains uncertain. endoplasmic reticulum (ER) stress has recently been associated with hypertension, but it is unclear whether ER stress causes hypertension. To clarify this question, we examined if ER stress occurs in blood vessels before the development of hypertension and if ER stress inhibition would prevent hypertension development. We used the spontaneously hypertensive rat (SHR) as a model of human essential hypertension and the Wistar-Kyoto (WKY) rat as its normotensive control. Resistance arteries collected from young rats determined that ER stress was present in SHR vessels before the onset of hypertension. To assess the effect of ER stress inhibition on hypertension development, another subset of rats were treated with 4-phenylbutyric acid (4-PBA; 1 g·kg−1·day−1) for 8 wk from 5 wk of age. Blood pressure was measured via radiotelemetry and compared with untreated SHR and WKY rats. Mesenteric resistance arteries were collected and assessed for structural and functional changes associated with hypertension. Systolic and diastolic blood pressures were significantly lower in the 4-PBA-treated SHR groups than in untreated SHRs. Additionally, 4-PBA significantly decreased the media-to-lumen ratio and ER stress marker expression, improved vasodilatory response, and reduced contractile responses in resistance arteries from SHRs. Overall, ER stress inhibition blunted the development of hypertension in the SHR. These data add evidence to the hypothesis that a component of hypertension in the SHR is caused by ER stress. NEW & NOTEWORTHY In this study, 4-phenylbutyric acid’s (4-PBA’s) molecular chaperone capability was used to inhibit endoplasmic reticulum (ER) stress in the small arteries of young spontaneously hypertensive rats (SHRs) and reduce their hypertension. These effects are likely mediated through 4-PBA's effects to reduce resistant artery contractility and increase nitric oxide-mediated endothelial vasodilation through a process preventing endothelial dysfunction. Overall, ER stress inhibition blunted the development of hypertension in this young SHR model. This suggests that a component of the increase in blood pressure found in SHRs is due to ER stress. However, it is important to note that inhibition of ER stress was not able to fully restore the blood pressure to normal, suggesting that a component of hypertension may not be due to ER stress. This study points to the inhibition of ER stress as an important new physiological pathway to lower blood pressure, where other known approaches may not achieve blood pressure-lowering targets.

Time-Dependent Effects of Individual and Combined Treatments With Nebivolol, Lisinopril, and Valsartan on Blood Pressure and Vascular Reactivity to Angiotensin II and Norepinephrine

2021 ◽  
pp. 107424842110018
Author(s):  
Diego Lezama-Martinez ◽  
Maria Elena Hernandez-Campos ◽  
Jazmin Flores-Monroy ◽  
Ignacio Valencia-Hernandez ◽  
Luisa Martinez-Aguilar
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Vascular Reactivity ◽  
Spontaneously Hypertensive Rat ◽  
Reduce Blood Pressure ◽  
Time Dependent ◽  
Spontaneously Hypertensive ◽  
Sympathetic Nervous Systems ◽  
Wistar Kyoto ◽  
Concentration Response Curve

Clinical guidelines suggest the combination of 2 drugs as a strategy to treat hypertension. However, some antihypertensive combinations have been shown to be ineffective. Therefore, it is necessary to determine whether differences exist between the results of monotherapy and combination therapy by temporal monitoring of the responses to angiotensin II and norepinephrine, which are vasoconstrictors involved in the development of hypertension. Thus, the purpose of this work was to determine the vascular reactivity to angiotensin II and norepinephrine in spontaneously hypertensive rat (SHR) aortic rings after treatment with valsartan, lisinopril, nebivolol, nebivolol-lisinopril, and nebivolol-valsartan for different periods of time. In this study, male SHR and Wistar Kyoto normotensive (WKY) rats were divided into 7 groups treated for 1, 2, and 4 weeks: (1) WKY + vehicle, (2) SHR + vehicle; (3) SHR + nebivolol; (4) SHR + lisinopril; (5) SHR + valsartan; (6) SHR + nebivolol-lisinopril; and (7) SHR + nebivolol-valsartan. Blood pressure was measured by the tail-cuff method, and vascular reactivity was determined from the concentration-response curve to angiotensin II and norepinephrine in aortic rings. The results showed that the combined and individual treatments reduced mean blood pressure at all times evaluated. All treatments decreased vascular reactivity to angiotensin II; however, in the case of lisinopril and nebivolol-lisinopril, the effect observed was significant up to 2 weeks. All treatments decreased the reactivity to norepinephrine up to week 4. These results show a time-dependent difference in vascular reactivity between the pharmacological treatments, with nebivolol-valsartan and nebivolol-lisinopril being both effective combinations. Additionally, the results suggest crosstalk between the renin-angiotensin and sympathetic nervous systems to reduce blood pressure and to improve treatment efficacy.

Renal renin activity is associated with alterations of the renin gene in recombinant inbred rat strains

1993 ◽  
Vol 84 (2) ◽  
pp. 129-132 ◽  
Author(s):  
Irena Pohlová ◽  
Josef Zicha ◽  
Vladimir Křen ◽  
Jaroslav Kuneš ◽  
Michal Pravenec
Keyword(s):  
Blood Pressure ◽  
Recombinant Inbred ◽  
Spontaneously Hypertensive Rat ◽  
Inbred Strains ◽  
Renin Activity ◽  
Recombinant Inbred Strains ◽  
Brown Norway ◽  
Spontaneously Hypertensive ◽  
Hypertensive Rat ◽  
Renin Gene

1. A structural alteration within the first intron of the renin gene in spontaneously hypertensive rats was demonstrated to co-segregate with blood pressure in some sets of F2 hybrids or recombinant inbred strains. There is no evidence as to whether restriction fragment length polymorphism of the renin gene is associated with any of the changes in the renin tissue level. For this reason we have determined renal renin activity in spontaneously hypertensive, Wistar-Kyoto and Brown Norway rats as well as in 22 recombinant inbred strains derived from F2 hybrids of spontaneously hypertensive and Brown Norway rats. 2. At the age of 4 months significantly lower renal renin activity was observed in spontaneously hypertensive rats than in both normotensive rat strains, Wistar-Kyoto and Brown Norway. The presence of the spontaneously hypertensive rat allele in recombinant inbred strains was associated with a substantially lower renal renin activity as compared with recombinant inbred strains bearing the Brown Norway rat allele. There was no relationship between renal renin activity and the polymorphism in either the angiotensinogen gene or the angiotensin-converting enzyme gene. 3. There was a borderline correlation between blood pressure and renal renin activity in recombinant inbred strains. Nevertheless, additional comparisons within recombinant inbred strains bearing the spontaneously hypertensive rat allele of the renin gene failed to reveal any significant relationship between blood pressure level and renal renin activity. 4. Our data suggest that the restriction fragment length polymorphism marking the renin gene of the spontaneously hypertensive rat is accompanied by an alteration in the renin-angiotensin system at the renal level. The mechanisms by which structural abnormalities of the renin gene might influence the renin level in the kidney remain to be investigated.

Chronic administration of hexarelin attenuates cardiac fibrosis in the spontaneously hypertensive rat

2012 ◽  
Vol 303 (6) ◽  
pp. H703-H711 ◽  
Author(s):  
Xiangbin Xu ◽  
Fan Ding ◽  
Jinjiang Pang ◽  
Xue Gao ◽  
Rong-Kun Xu ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Heart Disease ◽  
Cardiac Fibrosis ◽  
Spontaneously Hypertensive Rat ◽  
Therapeutic Potential ◽  
Heart Diseases ◽  
Hypertensive Heart Disease ◽  
Left Ventricular ◽  
Tissue Inhibitor Of Metalloproteinase ◽  
Spontaneously Hypertensive

Cardiac fibrosis is a hallmark of heart disease and plays a vital role in cardiac remodeling during heart diseases, including hypertensive heart disease. Hexarelin is one of a series of synthetic growth hormone secretagogues (GHSs) possessing a variety of cardiovascular effects via action on GHS receptors (GHS-Rs). However, the role of hexarelin in cardiac fibrosis in vivo has not yet been investigated. In the present study, spontaneously hypertensive rats (SHRs) were treated with hexarelin alone or in combination with a GHS-R antagonist for 5 wk from an age of 16 wk. Hexarelin treatment significantly reduced cardiac fibrosis in SHRs by decreasing interstitial and perivascular myocardial collagen deposition and myocardial hydroxyproline content and reducing mRNA and protein expression of collagen I and III in SHR hearts. Hexarelin treatment also increased matrix metalloproteinase (MMP)-2 and MMP-9 activities and decreased myocardial mRNA expression of tissue inhibitor of metalloproteinase (TIMP)-1 in SHRs. In addition, hexarelin treatment significantly attenuated left ventricular (LV) hypertrophy, LV diastolic dysfunction, and high blood pressure in SHRs. The effect of hexarelin on cardiac fibrosis, blood pressure, and cardiac function was mediated by its receptor, GHS-R, since a selective GHS-R antagonist abolished these effects and expression of GHS-Rs was upregulated by hexarelin treatment. In summary, our data demonstrate that hexarelin reduces cardiac fibrosis in SHRs, perhaps by decreasing collagen synthesis and accelerating collagen degradation via regulation of MMPs/TIMP. Hexarelin-reduced systolic blood pressure may also contribute to this reduced cardiac fibrosis in SHRs. The present findings provided novel insights and underscore the therapeutic potential of hexarelin as an antifibrotic agent for the treatment of cardiac fibrosis.

scholarly journals Transcriptome Analysis Reveals Downregulation of Urocortin Expression in the Hypothalamo-Neurohypophysial System of Spontaneously Hypertensive Rats

2021 ◽  
Vol 11 ◽  
Author(s):  
Andrew Martin ◽  
Andre S. Mecawi ◽  
Vagner R. Antunes ◽  
Song T. Yao ◽  
Jose Antunes-Rodrigues ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Essential Hypertension ◽  
Spontaneously Hypertensive Rat ◽  
Cumulative Risk ◽  
Pressure Control ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto Rat ◽  
Wistar Kyoto ◽  
Normotensive Strain

The chronically increased blood pressure characteristic of essential hypertension represents an insidious and cumulative risk for cardiovascular disease. Essential hypertension is a multifactorial condition, with no known specific aetiology but a strong genetic component. The Spontaneously Hypertensive rat (SHR) shares many characteristics of human essential hypertension, and as such is a commonly used experimental model. The mammalian hypothalamo-neurohypophyseal system (HNS) plays a pivotal role in the regulation of blood pressure, volume and osmolality. In order to better understand the possible role of the HNS in hypertension, we have used microarray analysis to reveal differential regulation of genes in the HNS of the SHR compared to a control normotensive strain, the Wistar Kyoto rat (WKY). These results were validated by quantitative reverse transcription-polymerase chain reaction (qRT-PCR). One of the genes identified and validated as being downregulated in SHR compared to WKY was that encoding the neuropeptide urocortin (Ucn). Immunohistochemical analyses revealed Ucn to be highly expressed within magnocellular neurons of the PVN and SON, with pronounced localisation in dendritic projections containing oxytocin and vasopressin. When Ucn was overexpressed in the PVN of the SHR by in vivo lentiviral mediated gene transfer, blood pressure was unaffected but there were significant, transient reductions in the VLF spectra of systolic blood pressure consistent with an action on autonomic balance. We suggest that Ucn may act, possibly via dendritic release, to subtly regulate neurohumoral aspects of arterial pressure control.

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