Abstract 5535: In Vivo Activation Of Myocardial At2 Receptor Expression By Endogenous No And Pentaerythritol Tetranitrate

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Thao-Vi V Dao ◽  
Vera Balz ◽  
Marc Oppermann ◽  
Tatsiana Suvorava ◽  
Georg Kojda
Keyword(s):  
Blood Pressure ◽  
Left Ventricular ◽  
Receptor Expression ◽  
Left Ventricular Myocardium ◽  
Myocardial Tissue ◽  
At2 Receptor ◽  
Dependent Manner ◽  
Pentaerythritol Tetranitrate ◽  
At2 Receptors

There are many vascular signaling interactions between the vascular endothelial NO system and the renin-angiotensin-system. We hypothesized that endothelial NO might impact on the expression of angiotensin (AT) type 1 (AT1) and type 2 (AT2) receptors. We generated mice with an endothelial-specific overexpression of endothelial NO • -synthase (eNOS) using the Tie-2 promotor. Two of these lines were characterized by eNOS-Western blot analyses and blood pressure measurements in comparison to transgene negative controls. In addition, C57Bl/6 mice were fed with either 6 or 60 mg pentaerythritol tetranitrate (PETN) for 4 weeks and characterized as well. Analysis of line 1 of transgenic eNOS mice (1-eNOS) showed a 2.3±0.15 fold higher aortic expression of eNOS and a reduction of blood pressure to 109.6±2.0 mmHg (P<0.01, n=4–6). Line 2 of transgenic eNOS mice (2-eNOS) showed a 3.3±0.3 fold higher aortic expression of eNOS and a reduction of blood pressure to 105.0±3.0 mmHg (n=6, P<0.01). Treatment of 2-eNOS with the NOS-inhibitor L-nitroarginine (L-NAME) for 30 days inhibited the difference in blood pressure suggesting that this effect is due to increased bioavailability of endogenous nitric oxide (NO). In lungs and left ventricular myocardium of 2-eNOS the expression of AT1 receptors was similar to the controls (121.6±14.77%, and 100.1±12.43%, respectively, n=8, P>0.05). In striking contrast, the expression of AT2 receptors was increased by endothelial overexpression of eNOS in a gene-dose-dependent manner in the myocardium. In 1-eNOS the increase was 134.3±10.66% (P<0.05) and in 2-eNOS the increase was 177.7±20.93% (P<0.05). In lung tissue the increase of AT2 receptor expression in line 2 amounted to 139.3±13.73% (P<0.05) and to 131.8±.7 in line 1 of eNOS transgenic mice suggesting a vascular rather than a cardiomyocyte effect. Furthermore, preliminary experiments showed a significant increase of AT2 receptor expression in myocardial tissue of PETN-fed mice and a significant decrease in myocardial tissue of L-NAME-fed mice (respectively, n=4, P<0.05). These results show that NO can upregulate vascular AT2 receptor expression in the lung and in the myocardium in-vivo. This newly discovered regulation might contribute to vasoprotective effects of NO.

Upregulation of angiotensin II type 2 receptor expression in estrogen-induced pituitary hyperplasia

2004 ◽  
Vol 286 (5) ◽  
pp. E786-E794 ◽  
Author(s):  
Cecilia Suarez ◽  
Graciela Díaz-Torga ◽  
Arturo González-Iglesias ◽  
Carolina Cristina ◽  
Damasia Becu-Villalobos
Keyword(s):  
Angiotensin Ii ◽  
Receptor Expression ◽  
Receptor Subtype ◽  
At2 Receptor ◽  
Ang Ii ◽  
Pituitary Hyperplasia ◽  
Releasing Effect ◽  
At2 Receptors

Recent evidence shows that reexpression and upregulation of angiotensin II (ANG II) type 2 (AT2) receptor in adult tissues occur during pathological conditions such as tissue hyperplasia, inflammation, and remodeling. In particular, expression of functional AT2 receptors in the pituitary and their physiological significance and regulation have not been described. In this study, we demonstrate that chronic in vivo estrogen treatment, which induces pituitary hyperplasia, enhances local AT2 expression (measured by Western blot and RT-PCR) concomitantly with downregulation of ANG II type 1 (AT1) receptors. In vivo progesterone treatment of estrogen-induced pituitary hyperplasia did not modify either the ANG II receptor subtype expression pattern or octapeptide-induced and AT1-mediated calcium signaling. Nevertheless, an unexpected potentiation of the ANG II prolactin-releasing effect was observed in this group, and this response was sensitive to both AT1 and AT2 receptor antagonists. These data are the first to document that ANG II can act at the pituitary level through the AT2 receptor subtype and that estrogens display a differential regulation of AT1 and AT2 receptors at this level.

β-blockade abolishes the augmented cardiac tPA release induced by transactivation of heterodimerised bradykinin receptor-2 and β2-adrenergic receptor in vivo

2014 ◽  
Vol 112 (11) ◽  
pp. 951-959 ◽  
Author(s):  
Morten Eriksen ◽  
Arnfinn Ilebekk ◽  
Alessandro Cataliotti ◽  
Cathrine Rein Carlson ◽  
Torstein Lyberg ◽  
...  
Keyword(s):  
Adrenergic Receptor ◽  
Sympathetic Nerves ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Adrenergic Stimulation ◽  
Β2 Adrenergic Receptor ◽  
Β Blocker

SummaryBradykinin (BK) receptor-2 (B2R) and β2-adrenergic receptor (β2AR) have been shown to form heterodimers in vitro. However, in vivo proofs of the functional effects of B2R-β2AR heterodimerisation are missing. Both BK and adrenergic stimulation are known inducers of tPA release. Our goal was to demonstrate the existence of B2R-β2AR heterodimerisation in myocardium and to define its functional effect on cardiac release of tPA in vivo. We further investigated the effects of a non-selective β-blocker on this receptor interplay. To investigate functional effects of B2R-β2AR heterodimerisation (i. e. BK transactivation of β2AR) in vivo, we induced serial electrical stimulation of cardiac sympathetic nerves (SS) in normal pigs that underwent concomitant BK infusion. Both SS and BK alone induced increases in cardiac tPA release. Importantly, despite B2R desensitisation, simultaneous BK infusion and SS (BK+SS) was characterised by 2.3 ± 0.3-fold enhanced tPA release compared to SS alone. When β-blockade (propranolol) was introduced prior to BK+SS, tPA release was inhibited. A persistent B2R-β2AR heterodimer was confirmed in BK-stimulated and nonstimulated left ventricular myocardium by immunoprecipitation studies and under non-reducing gel conditions. All together, these results strongly suggest BK transactivation of β2AR leading to enhanced β2AR-mediated release of tPA. Importantly, non-selective β-blockade inhibits both SS-induced release of tPA and the functional effects of B2R-β2AR heterodimerisation in vivo, which may have important clinical implications.

Abstract 71: Novel Bach1 Modulators Increase HMOX1 and Suppress Hypertension in the Goldblatt Model of Renovascular Hypertension

Hypertension ◽  
2013 ◽  
Vol 62 (suppl_1) ◽  
Author(s):  
Matthew Kostura ◽  
Otis Attucks ◽  
Jareer Kassis ◽  
Suparna Gupta ◽  
Samuel Victory ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Enzyme Activity ◽  
Renovascular Hypertension ◽  
Transcriptional Repressor ◽  
Plasma Aldosterone ◽  
Lung Fibroblasts ◽  
Left Renal Artery ◽  
Dependent Manner ◽  
Sprague Dawley

We report for the first time a novel class of compounds that specifically modulate the Bach1 transcriptional repressor pathway. In cellula, the compounds selectively inhibit the activity of the transcriptional repressor Bach1 resulting in transcription of a network of antioxidant and cytoprotective genes including HMOX1. HPP-1971, a member of this class, is a potent and selective Bach1 inhibitor that induces HMOX1 > 40-fold with a potency of 408 nM in human lung fibroblasts. To assess activity in vivo, we tested HPP-1971 in the Goldblatt model of renovascular hypertension. Sprague Dawley rats were implanted with in dwelling pressure telemeter probes and subsequently underwent sham surgery or placement of a 0.25 mm silver clip around the left renal artery. HPP-1971 treatment, dosed orally at 1,3,10 and 30 mpk, commenced three days following clip surgery, and continued for 18 days. At study completion, blood pressure, clipped kidney weight, renal HMOX1 enzyme activity and plasma aldosterone levels were measured (see Table). HPP-1971 attenuated both kidney atrophy and the increase in blood pressure in a dose dependent manner with significant differences seen at 3, 10 and 30 mpk (p<.0001). HMOX1 enzyme activity in the clipped kidney increased with treatment, reaching a maximum of 5.7 ± 0.9 nM/hr/mg at 30 mpk relative to sham operated animals (p<.0001). Plasma aldosterone levels increased in 2K1C animals compared to sham controls but were reduced by HPP-1971 treatment. These findings define a novel role for Bach1 suppressors in counteracting the influence of the RAAS system on hypertension and kidney atrophy in the 2K1C model of renovascular hypertension.

5-HT2B-receptor antagonist LY-272015 is antihypertensive in DOCA-salt-hypertensive rats

1999 ◽  
Vol 276 (3) ◽  
pp. H944-H952 ◽  
Author(s):  
Stephanie W. Watts ◽  
Gregory D. Fink
Keyword(s):  
Blood Pressure ◽  
Receptor Antagonist ◽  
High Blood Pressure ◽  
Reduce Blood Pressure ◽  
Receptor Expression ◽  
Hypertensive Rats ◽  
Arterial Blood ◽  
Salt Hypertension

We previously demonstrated a change in the receptors mediating 5-hydroxytryptamine (5-HT)-induced contraction in arteries of deoxycorticosterone acetate (DOCA)-salt-hypertensive rats. Specifically, contraction to 5-HT is mediated primarily by 5-HT2A receptors in arteries from normotensive sham rats and by both 5-HT2A and 5-HT2B receptors in arteries from hypertensive rats. We hypothesized that the 5-HT2B receptor may play a role in maintaining the high blood pressure of DOCA-salt-hypertensive rats, and herein we provide data connecting in vitro and in vivo findings. The endothelium-denuded isolated superior mesenteric artery of DOCA-salt rats displayed a marked increase in maximum contraction to the newly available 5-HT2B-receptor agonist BW-723C86 compared with that of arteries from sham rats, confirming that the 5-HT2B receptor plays a greater role in 5-HT-induced contraction in arteries from DOCA-salt rats. In chronically instrumented rats, the 5-HT2B-receptor antagonist LY-272015 (0.3, 1.0, and 3.0 mg/kg iv at 30-min intervals) was given cumulatively 1 time/wk during 4 wk of continued DOCA-salt treatment. LY-272015 did not reduce blood pressure of the sham-treated rats at any time or dose. However, LY-272015 (1.0 and 3.0 mg/kg) significantly reduced mean blood pressure in a subgroup of week 3 (−20 mmHg) and week 4 DOCA-salt (−40 mmHg) rats that had extremely high blood pressure (mean arterial blood pressure ∼200 mmHg). Blockade of 5-HT2Breceptors by in vivo administration of LY-272015 (3.0 mg/kg) was verified by observing reduced 5-HT-induced contraction in rat stomach fundus, the tissue from which the 5-HT2B receptor was originally cloned. These data support the novel hypothesis that 5-HT2B-receptor expression is induced during the development of DOCA-salt hypertension and contributes to the maintenance of severe blood pressure elevations.

P121 Pressure overload-induced functional and metabolic impairments in type 2 diabetic hearts are ameliorated by inhibition of xanthine oxidase

2020 ◽  
Vol 41 (Supplement_1) ◽  
Author(s):  
Y Igaki ◽  
M Tanno ◽  
H Kouzu ◽  
Y Tatekoshi ◽  
T Yano ◽  
...  
Keyword(s):  
Diastolic Dysfunction ◽  
Xanthine Oxidase ◽  
Pressure Overload ◽  
Ventricular Myocardium ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Dependent Manner ◽  
Phenylephrine Infusion ◽  
Type 2 Diabetic

Abstract Funding Acknowledgements SANWA KAGAKU KENKYUSHO Co., Ltd. Background   We have recently demonstrated that AMP deaminase (AMPD) is upregulated in OLETF, obese type 2 diabetic (T2DM) rats, and that the upregulated AMPD contributes to depletion of myocardial ATP at the time of pressure overload, leading to diastolic dysfunction.  On the other hand, AMPD promotes the formation of IMP from AMP, and IMP is in turn further converted to hypoxanthine and xanthine, substrates of xanthine oxidase (XO), which produces uric acid with ROS as a byproduct.  Based on these findings, we tested the hypothesis that inhibition of XO ameliorates the pressure overload-induced diastolic dysfunction in T2DM rats.  Methods and results Metabolomic analyses of the left ventricular myocardium revealed that levels of myocardial hypoxanthine and xanthine were significantly higher by 30% and 28%, respectively, in OLETF than in LETO, non-diabetic control rats, under the condition of pressure overloading (200-230 mmHg) induced by phenylephrine infusion. Myocardial XO activity in OLETF was 57.9% higher than that in LETO, and the activity was significantly attenuated by oral administration of topiroxostat, an XO inhibitor, at 0.1-0.5 mg/kg/day for 14 days in a dose-dependent manner.  Pressure volume loop analyses showed that the pressure overloading induced by phenylephrine infusion resulted in significantly higher LVEDP in OLETF than in LETO (18.3 ± 1.5 vs. 12.2 ± 1.3 mmHg, p &lt; 0.05, n = 7), though LVEDPs at baseline were comparable in OLETF and LETO (5.6 ± 0.4 vs. 4.7 ± 0.7 mmHg).  Treatment with topiroxostat significantly suppressed the pressure overload-induced elevation of LVEDP in OLETF (18.3 ± 1.5 vs. 11.3 ± 1.1 mmHg, p &lt; 0.05) but not in LETO.  Tau, the time constant of LV pressure decay, was significantly prolonged to 14.7 ± 0.7 ms (p &lt; 0.05) by pressure overloading in OLETF but not in LETO, though baseline Tau values were similar in LETO and OLETF (6.1 ± 0.2 vs. 8.0 ± 0.4 ms).  The prolongation of Tau by pressure overloading in OLETF was significantly attenuated by treatment with topiroxostat.  Ea/Ees, an index for ventricular-arterial coupling, was higher in OLETF than in LETO (2.3 ± 0.3 vs. 1.6 ± 0.3, p &lt; 0.05) under the condition of pressure overloading, and it was also improved by topiroxostat in OLETF (1.2 ± 0.2, p &lt; 0.05).  Myocardial ATP content was lower in OLETF than in LETO under the condition of pressure overloading (2966 ± 400 vs. 1818 ± 171 nmol/g wet tissue, p &lt; 0.05), but treatment with topiroxostat significantly restored the ATP level (2629 ± 307 nmo/g wet tissue). Conclusion:  In T2DM hearts, not only XO activity but also XO substrates are upregulated and upregulated AMPD may be involved in the upregulation.  Inhibition of XO ameliorates pressure overload-induced diastolic dysfunction and improves ventricular-arterial coupling most likely through augmented ATP preservation.

Alterations in cardiac [14C]deoxyglucose uptake induced by two renal afferent stimuli

1986 ◽  
Vol 251 (5) ◽  
pp. R867-R877
Author(s):  
N. L. Herman ◽  
D. R. Kostreva
Keyword(s):  
Blood Pressure ◽  
Heart Rate ◽  
Nerve Stimulation ◽  
Ventricular Myocardium ◽  
Venous Occlusion ◽  
Left Ventricular ◽  
Left Ventricular Myocardium ◽  
Renal Nerve ◽  
Vein Occlusion ◽  
Renal Nerve Stimulation

The reflex effects of renal afferents on the heart were studied in pentobarbital-anesthetized rats (400-425 g) using 2-[14C]deoxyglucose (DG). Three groups of rats were given a single bolus injection of DG (100 mu Ci/kg) 1) six controls, 2) four with periodic electrical stimulation of the proximal end of a cut renal nerve (2 Hz, 0.5-ms width) and 1-mA current, and 3) six with intermittent renal venous occlusion (unilateral). Forty-five minutes after injection the heart was removed, cooled quickly, and frozen-sectioned. Sections 20 micron thick were exposed to film for 12 days. The resulting autoradiographs were scanned using a computerized densitometer, and these densities were converted to relative glucose utilization (GlU, mumol X 100 g-1 X min-1) using the lumped constant for rat brain. Both renal venous occlusion and renal afferent nerve stimulation resulted in a decrease in blood pressure of 6.7 +/- 0.6 mmHg (P less than 0.001) and 7.3 +/- 0.7 mmHg (P less than 0.001) and heart rate-blood pressure product of 5.6 +/- 0.7% (P less than 0.001) and 8.8 +/- 0.8% (P less than 0.001), respectively, and afferent renal nerve stimulation induced a decrease in heart rate of 7.2 +/- 0.9 beats/min (P less than 0.01). However, when compared with control, renal venous occlusion induced a significant increase in GlU in left ventricular myocardium (LV myo, P less than 0.05), endocardium (LV endo, P less than 0.001), and papillary muscle (LV pap, P less than 0.001), whereas afferent renal nerve stimulation induced a significant increase in GlU in LV endo (P less than 0.05) and LV pap (P less than 0.002) only. This study shows both a reflex increase in GlU for the rat heart and a decrease in heart rate with either renal vein occlusion or afferent renal nerve stimulation.

scholarly journals CD4+CD25+ regulatory T cells inhibit natural killer cell functions in a transforming growth factor–β–dependent manner

2005 ◽  
Vol 202 (8) ◽  
pp. 1075-1085 ◽  
Author(s):  
François Ghiringhelli ◽  
Cédric Ménard ◽  
Magali Terme ◽  
Caroline Flament ◽  
Julien Taieb ◽  
...  
Keyword(s):  
Growth Factor ◽  
Natural Killer ◽  
Cell Activation ◽  
Transforming Growth Factor ◽  
Nk Cell ◽  
Killer Cell ◽  
Receptor Expression ◽  
Dependent Manner ◽  
Cell Functions

Tumor growth promotes the expansion of CD4+CD25+ regulatory T (T reg) cells that counteract T cell–mediated immune responses. An inverse correlation between natural killer (NK) cell activation and T reg cell expansion in tumor-bearing patients, shown here, prompted us to address the role of T reg cells in controlling innate antitumor immunity. Our experiments indicate that human T reg cells expressed membrane-bound transforming growth factor (TGF)–β, which directly inhibited NK cell effector functions and down-regulated NKG2D receptors on the NK cell surface. Adoptive transfer of wild-type T reg cells but not TGF-β−/− T reg cells into nude mice suppressed NK cell–mediated cytotoxicity, reduced NKG2D receptor expression, and accelerated the growth of tumors that are normally controlled by NK cells. Conversely, the depletion of mouse T reg cells exacerbated NK cell proliferation and cytotoxicity in vivo. Human NK cell–mediated tumor recognition could also be restored by depletion of T reg cells from tumor-infiltrating lymphocytes. These findings support a role for T reg cells in blunting the NK cell arm of the innate immune system.

High altitude hypoxia and blood pressure dysregulation in adult chickens

2012 ◽  
Vol 4 (1) ◽  
pp. 69-76 ◽  
Author(s):  
E. A. Herrera ◽  
C. E. Salinas ◽  
C. E. Blanco ◽  
M. Villena ◽  
D. A. Giussani
Keyword(s):  
Blood Pressure ◽  
High Altitude ◽  
Arterial Blood Pressure ◽  
Cardiovascular Function ◽  
Dependent Manner ◽  
Cardiovascular Development ◽  
Placental Perfusion ◽  
Arterial Blood ◽  
Increased Risk

Although it is accepted that impaired placental perfusion in complicated pregnancy can slow fetal growth and programme an increased risk of cardiovascular dysfunction at adulthood, the relative contribution of reductions in fetal nutrition and in fetal oxygenation as the triggering stimulus remains unclear. By combining high altitude (HA) with the chick embryo model, we have previously isolated the direct effects of HA hypoxia on embryonic growth and cardiovascular development before hatching. This study isolated the effects of developmental hypoxia on cardiovascular function measured in vivo in conscious adult male and female chickens. Chick embryos were incubated, hatched and raised at sea level (SL, nine males and nine females) or incubated, hatched and raised at HA (seven males and seven females). At 6 months of age, vascular catheters were inserted under general anaesthesia. Five days later, basal blood gas status, basal cardiovascular function and cardiac baroreflex responses were investigated. HA chickens had significantly lower basal arterial PO2 and haemoglobin saturation, and significantly higher haematocrit than SL chickens, independent of the sex of the animal. HA chickens had significantly lower arterial blood pressure than SL chickens, independent of the sex of the animal. Although the gain of the arterial baroreflex was decreased in HA relative to SL male chickens, it was increased in HA relative to SL female chickens. We show that development at HA lowers basal arterial blood pressure and alters baroreflex sensitivity in a sex-dependent manner at adulthood.

Deterioration of kidney function by the (pro)renin receptor blocker handle region peptide in aliskiren-treated diabetic transgenic (mRen2)27 rats

2014 ◽  
Vol 306 (10) ◽  
pp. F1179-F1189 ◽  
Author(s):  
Luuk te Riet ◽  
Mieke van den Heuvel ◽  
Carine J. Peutz-Kootstra ◽  
Joep H. M. van Esch ◽  
Richard van Veghel ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Diabetic Nephropathy ◽  
Natriuretic Peptide ◽  
Partial Agonist ◽  
Receptor Expression ◽  
Plasminogen Activator Inhibitor 1 ◽  
Independent Manner ◽  
Beneficial Effects ◽  
Renin Inhibition

Dual renin-angiotensin system (RAS) blockade in diabetic nephropathy is no longer feasible because of the profit/side effect imbalance. (Pro)renin receptor [(P)RR] blockade with handle region peptide (HRP) has been reported to exert beneficial effects in various diabetic models in a RAS-independent manner. To what degree (P)RR blockade adds benefits on top of RAS blockade is still unknown. In the present study, we treated diabetic TGR(mREN2)27 rats, a well-established nephropathy model with high prorenin levels [allowing continuous (P)RR stimulation in vivo], with HRP on top of renin inhibition with aliskiren. Aliskiren alone lowered blood pressure and exerted renoprotective effects, as evidenced by reduced glomerulosclerosis, diuresis, proteinuria, albuminuria, and urinary aldosterone levels as well as diminished renal (P)RR and ANG II type 1 receptor expression. It also suppressed plasma and tissue RAS activity and suppressed cardiac atrial natriuretic peptide and brain natriuretic peptide expression. HRP, when given on top of aliskiren, did not alter the effects of renin inhibition on blood pressure, RAS activity, or aldosterone. However, it counteracted the beneficial effects of aliskiren in the kidney, induced hyperkalemia, and increased plasma plasminogen activator-inhibitor 1, renal cyclooxygenase-2, and cardiac collagen content. All these effects have been linked to (P)RR stimulation, suggesting that HRP might, in fact, act as a partial agonist. Therefore, the use of HRP on top of RAS blockade in diabetic nephropathy is not advisable.

scholarly journals New Therapeutic Insight into the Effect of Ma Huang Tang on Blood Pressure and Renal Dysfunction in the L-NAME-Induced Hypertension

2021 ◽  
Vol 2021 ◽  
pp. 1-13
Author(s):  
Mi Hyeon Hong ◽  
Hye Yoom Kim ◽  
Youn Jae Jang ◽  
Se Won Na ◽  
Byung Hyuk Han ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Renal Function ◽  
Intima Media Thickness ◽  
Dependent Manner ◽  
Vascular Relaxation ◽  
Sprague Dawley ◽  
Induced Hypertension ◽  
Ma Huang

In this study, we evaluated the effect of a traditional herbal formula, Ma Huang Tang (MHT), on blood pressure and vasodilation in a rat model of NG‐nitro‐L‐arginine methylester- (L-NAME-) induced hypertension. We found that MHT-induced vascular relaxation in a dose-dependent manner in rat aortas pretreated with phenylephrine. However, pretreatment of endothelium-intact aortic rings with L‐NAME, an inhibitor of nitric oxide synthesis (NOS), or 1H‐[1, 2, 4]‐oxadiazole‐[4, 3‐α]‐quinoxalin‐1‐one (ODQ), an inhibitor of soluble guanylyl cyclase, significantly abolished vascular relaxation induced by MHT. MHT also increased the production of guanosine 3′,5′-cyclic monophosphate (cGMP) in the aortic rings pretreated with L-NAME or ODQ. To examine the in vivo effects of MHT, Sprague Dawley rats were treated with 40 mg/kg/day L-NAME for 3 weeks, followed by administration of 50 or 100 mg/kg/day MHT for 2 weeks. MHT was found to significantly normalize systolic blood pressure and decreased intima-media thickness in aortic sections of rats treated with L-NAME compared to that of rats treated with L-NAME alone. MHT also restored the L-NAME-induced decrease in vasorelaxation response to acetylcholine and endothelial nitric oxide synthase (eNOS) and endothelin-1 (ET-1) expression. Furthermore, MHT promoted the recovery of renal function, as indicated by osmolality, blood urea nitrogen (BUN) levels, and creatinine clearance. These results suggest that MHT-induced relaxation in the thoracic aorta is associated with activation of the nitric oxide/cGMP pathway. Furthermore, it provides new therapeutic insights into the regulation of blood pressure and renal function in hypertensive patients.

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