Norvaline reduces blood pressure and induces diuresis in rats with inherited stress-induced arterial hypertension

AbstractGrowing evidence suggests that increased arginase activity affects vital bioprocesses in various systems and universally mediates the pathogenesis of numerous metabolic diseases. The adverse effects of arginase are associated with a severe decline in L-arginine bioavailability, which leads to nitric oxide synthase substrate insufficiency, uncoupling, and, eventually, to superoxide anion generation and substantial reduction of nitric oxide (NO) synthesis. In cooperation, it contributes to chronic oxidative stress and endothelial dysfunction, which might lead to hypertension and atherosclerosis.Recent preclinical investigations point to arginase as a promising therapeutic target in ameliorating metabolic and vascular dysfunctions. In the present study, adult rats with inherited stress-induced arterial hypertension (ISIAH) were used as a model of hypertension. Wistar rats served as normotensive controls. Experimental animals were intraperitoneally administered for seven days with non-proteinogenic amino acid L-norvaline (30 mg/kg/day), which is a potent arginase inhibitor, or with the vehicle. Blood pressure (BP), body weight, and diuresis were monitored. The changes in blood and urine levels of creatinine, urea, and NO metabolites were analyzed.We observed a significant decline in BP and induced diuresis in ISIAH rats following the treatment. The same procedure did not affect the BP of control animals. Remarkably, the treatment had no influence upon glomerular filtration rate in two experimental groups, just like the daily excretion of creatinine and urea. Conversely, NO metabolites levels were amplified in normotonic but not in hypertensive rats following the treatment.The data indicate that L-norvaline is a potential antihypertensive agent, and deserves to be clinically investigated. Moreover, we suggest that changes in blood and urine are causally related to the effect of L-norvaline upon the BP regulation.

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Norvaline Reduces Blood Pressure and Induces Diuresis in Rats with Inherited Stress-Induced Arterial Hypertension

BioMed Research International ◽

10.1155/2020/4935386 ◽

2020 ◽

Vol 2020 ◽

pp. 1-10

Author(s):

Michael A. Gilinsky ◽

Yulia K. Polityko ◽

Arkady L. Markel ◽

Tatyana V. Latysheva ◽

Abraham O. Samson ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Arterial Hypertension ◽

Metabolic Diseases ◽

Substantial Reduction ◽

Adult Rats ◽

Chronic Oxidative Stress ◽

Promising Therapeutic Target ◽

Daily Excretion ◽

Oxide Synthase

Growing evidence suggests that increased arginase activity affects vital bioprocesses in various systems and universally mediates the pathogenesis of numerous metabolic diseases. The adverse effects of arginase are associated with a severe decline in L-arginine bioavailability, which leads to nitric oxide synthase substrate insufficiency, uncoupling, and, eventually, superoxide anion generation and substantial reduction of nitric oxide (NO) synthesis. In cooperation, it contributes to chronic oxidative stress and endothelial dysfunction, which might lead to hypertension and atherosclerosis. Recent preclinical investigations point arginase as a promising therapeutic target in ameliorating metabolic and vascular dysfunctions. In the present study, adult rats with inherited stress-induced arterial hypertension (ISIAH) were used as a model of hypertension. Wistar rats served as normotensive controls. Experimental animals were intraperitoneally administered for seven days with nonproteinogenic amino acid L-norvaline (30 mg/kg/day), which is a potent arginase inhibitor, or with the vehicle. Blood pressure (BP), body weight, and diuresis were monitored. The changes in blood and urine levels of creatinine, urea, and NO metabolites were analyzed. We observed a significant decline in BP and induced diuresis in ISIAH rats following the treatment. The same procedure did not affect the BP of control animals. Remarkably, the treatment had no influence upon glomerular filtration rate in two experimental groups, just like the daily excretion of creatinine and urea. Conversely, NO metabolite levels were amplified in normotonic but not in hypertensive rats following the treatment. The data indicate that L-norvaline is a potential antihypertensive agent and deserves to be clinically investigated. Moreover, we suggest that changes in blood and urine are causally related to the effect of L-norvaline upon BP regulation.

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Faculty Opinions recommendation of UVA irradiation of human skin vasodilates arterial vasculature and lowers blood pressure independently of nitric oxide synthase.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.718245328.793497119 ◽

2014 ◽

Author(s):

Robert Knobler

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Nitric Oxide Synthase ◽

Human Skin ◽

Uva Irradiation ◽

Oxide Synthase

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Vascular Endothelin-1 Gene Expression and Effect on Blood Pressure of Chronic ET A Endothelin Receptor Antagonism After Nitric Oxide Synthase Inhibition With L- NAME in Normal Rats

Circulation ◽

10.1161/01.cir.95.1.240 ◽

1997 ◽

Vol 95 (1) ◽

pp. 240-244 ◽

Cited By ~ 38

Author(s):

Pavol Sventek ◽

Andre´ Turgeon ◽

Ernesto L. Schiffrin

Keyword(s):

Gene Expression ◽

Nitric Oxide ◽

Blood Pressure ◽

Nitric Oxide Synthase ◽

Endothelin Receptor ◽

Receptor Antagonism ◽

Endothelin 1 ◽

Oxide Synthase

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Neural Nitric Oxide Synthase in the Renal Medulla and Blood Pressure Regulation

Hypertension ◽

10.1161/01.hyp.28.2.297 ◽

1996 ◽

Vol 28 (2) ◽

pp. 297-303 ◽

Cited By ~ 66

Author(s):

David L. Mattson ◽

Thomas G. Bellehumeur

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Nitric Oxide Synthase ◽

Renal Medulla ◽

Blood Pressure Regulation ◽

Pressure Regulation ◽

Neural Nitric Oxide Synthase ◽

Oxide Synthase

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Effects of AGXT2 variants on blood pressure and blood sugar among 750 older Japanese subjects recruited by the complete enumeration survey method

BMC Genomics ◽

10.1186/s12864-021-07612-3 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Yuta Yoshino ◽

Hiroshi Kumon ◽

Takaaki Mori ◽

Taku Yoshida ◽

Ayumi Tachibana ◽

...

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Blood Sugar ◽

Vascular Diseases ◽

Survey Method ◽

Nucleotide Polymorphisms ◽

Complete Enumeration ◽

Plasma Adma ◽

Oxide Synthase ◽

Japanese Subjects

Abstract Background Alanine:glyoxylate aminotransferase 2 (AGXT2; EC 2.6.1.44) is the only enzyme that degrades the R-form of 3-aminoisobutyrate, an intermediate metabolite of thymine. AGXT2, as well as diaminoarginine dimethylaminohydrolase 1 (DDAH1; EC 3.5.3.18), works as an enzyme that degrades asymmetric dimethylarginine (ADMA), which competitively inhibits the nitric oxide synthase family. Thus, these two enzyme activities may change vascular vulnerability for a lifetime via the nitric oxide (NO) system. We investigated the association between vascular conditions and diseases such as hypertension and diabetes mellitus and polymorphisms of these two genes in 750 older Japanese subjects (mean age ± standard deviation, 77.0 ± 7.6 years) recruited using the complete enumeration survey method in the Nakayama study. Demographic and biochemical data, such as blood pressure (BP) and casual blood sugar (CBS), were obtained. Four functional single nucleotide polymorphisms (SNPs; rs37370, rs37369, rs180749, and rs16899974) of AGXT2 and one functional insertion/deletion polymorphism in the promotor region with four SNPs (rs307894, rs669173, rs997251, and rs13373844) of DDAH1 were investigated. Plasma ADMA was also analyzed in 163 subjects. Results The results of multiple regression analysis showed that a loss of the functional haplotype of AGXT2, CAAA, was significantly positively correlated with BP (systolic BP, p = 0.034; diastolic BP, p = 0.025) and CBS (p = 0.021). No correlation was observed between DDAH1 and either BP or CBS. ADMA concentrations were significantly elevated in subjects with two CAAA haplotypes compared with subjects without the CAAA haplotype (p = 0.033). Conclusions Missense variants of AGXT2, but not DDAH1, may be related to vulnerability to vascular diseases such as hypertension and DM via the NO system.

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Selective neuronal nitric oxide synthase inhibition blocks furosemide-stimulated renin secretion in vivo

AJP Renal Physiology ◽

10.1152/ajprenal.1995.269.1.f134 ◽

1995 ◽

Vol 269 (1) ◽

pp. F134-F139 ◽

Cited By ~ 31

Author(s):

W. H. Beierwaltes

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Nitric Oxide Synthase ◽

Perfusion Pressure ◽

Renal Perfusion ◽

Macula Densa ◽

Renin Secretion ◽

Renal Perfusion Pressure ◽

Neuronal Nos ◽

Oxide Synthase

The macula densa is a regulatory site for renin. It contains exclusively the neuronal isoform of nitric oxide synthase (NOS), suggesting NO could stimulate renin secretion through the macula densa pathway. To test whether neuronal NOS mediates renin secretion, renin was stimulated by either the renal baroreceptor or the diuretic furosemide (acting through the macula densa pathway). Renin secretion rate (RSR) was measured in 12 Inactin-anesthetized rats at normal (104 +/- 3 mmHg) and reduced renal perfusion pressure (65 +/- 1 mmHg), before and after selective blockade of the neuronal NOS with 7-nitroindazole (7-NI, 50 mg/kg ip). 7-NI had no effect on basal blood pressure (102 +/- 2 mmHg) or renal blood flow (RBF). Decreasing renal perfusion pressure doubled RSR from 11.8 +/- 3.3 to 22.9 +/- 5.7 ng ANG I.h-1.min-1 (P < 0.01) (ANG I is angiotensin I). Similarly, in 7-NI-treated rats, reduced perfusion doubled RSR from 8.5 +/- 1.8 to 20.5 +/- 6.2 ng ANG I.h-1.min-1 (P < 0.01). Renal hemodynamics and RSR were measured in response to 5 mg/kg iv furosemide in 12 control rats and 11 rats treated with 7-NI. Blocking neuronal NOS did not alter blood pressure (102 +/- 2 mmHg), RBF (5.8 +/- 0.4 ml.min-1.g kidney wt-1), or renal vascular resistance (18.7 +/- 1.4 mmHg.ml-1.min.g kidney wt).(ABSTRACT TRUNCATED AT 250 WORDS)

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Systemic and regional hemodynamics after nitric oxide synthase inhibition: role of a neurogenic mechanism

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.1994.267.1.r84 ◽

1994 ◽

Vol 267 (1) ◽

pp. R84-R88 ◽

Cited By ~ 2

Author(s):

M. Huang ◽

M. L. Leblanc ◽

R. L. Hester

Keyword(s):

Nitric Oxide ◽

Blood Pressure ◽

Cardiac Output ◽

No Synthase ◽

Before And After ◽

Regional Hemodynamics ◽

Autonomic Blockade ◽

Infusion Of Norepinephrine ◽

Oxide Synthase

The study tested the hypothesis that the increase in blood pressure and decrease in cardiac output after nitric oxide (NO) synthase inhibition with N omega-nitro-L-arginine methyl ester (L-NAME) was partially mediated by a neurogenic mechanism. Rats were anesthetized with Inactin (thiobutabarbital), and a control blood pressure was measured for 30 min. Cardiac output and tissue flows were measured with radioactive microspheres. All measurements of pressure and flows were made before and after NO synthase inhibition (20 mg/kg L-NAME) in a group of control animals and in a second group of animals in which the autonomic nervous system was blocked by 20 mg/kg hexamethonium. In this group of animals, an intravenous infusion of norepinephrine (20-140 ng/min) was used to maintain normal blood pressure. L-NAME treatment resulted in a significant increase in mean arterial pressure in both groups. L-NAME treatment decreased cardiac output approximately 50% in both the intact and autonomic blocked animals (P < 0.05). Autonomic blockade alone had no effect on tissue flows. L-NAME treatment caused a significant decrease in renal, hepatic artery, stomach, intestinal, and testicular blood flow in both groups. These results demonstrate that the increase in blood pressure and decreases in cardiac output and tissue flows after L-NAME treatment are not dependent on a neurogenic mechanism.

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