scholarly journals Reconstitution of autophagy ameliorates vascular function and arterial stiffening in spontaneously hypertensive rats

2019 ◽  
Vol 317 (5) ◽  
pp. H1013-H1027 ◽  
Author(s):  
Cameron G. McCarthy ◽  
Camilla F. Wenceslau ◽  
Fabiano B. Calmasini ◽  
Nicole S. Klee ◽  
Michael W. Brands ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Spontaneously Hypertensive Rats ◽  
Cellular Aging ◽  
Experimental Hypertension ◽  
Dependent Manner ◽  
Vascular Aging ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Autophagic Activity

Insufficient autophagy has been proposed as a mechanism of cellular aging, as this leads to the accumulation of dysfunctional macromolecules and organelles. Premature vascular aging occurs in hypertension. In fact, many factors that contribute to the deterioration of vascular function as we age are accelerated in clinical and experimental hypertension. Previously, we have reported decreased autophagy in arteries from spontaneously hypertensive rats (SHRs); however, the effects of restoring autophagic activity on blood pressure and vascular function are currently unknown. We hypothesized that reconstitution of arterial autophagy in SHRs would decrease blood pressure and improve endothelium-dependent relaxation. We treated 14- to 18-wk-old Wistar rats ( n = 7 vehicle and n = 8 trehalose) and SHRs ( n = 7/group) with autophagy activator trehalose (2% in drinking water) for 28 days. Blood pressure was measured by radiotelemetry, and vascular function and structure were measured in isolated mesenteric resistance arteries (MRAs) using wire and pressure myographs, respectively. Treatment with trehalose had no effect on blood pressure in SHRs; however, isolated MRAs presented enhanced relaxation to acetylcholine, in a cyclooxygenase- and reactive oxygen species-dependent manner. Similarly, trehalose treatment shifted the relaxation to the Rho kinase (ROCK) inhibitor Y-27632 to the right, indicating reduced ROCK activity. Finally, trehalose treatment decreased arterial stiffness as indicated by the slope of the stress-strain curve. Overall these data indicate that reconstitution of arterial autophagy in SHRs improves endothelial and vascular smooth muscle function, which could synergize to prevent stiffening. As a result, restoration of autophagic activity could be a novel therapeutic for premature vascular aging in hypertension. NEW & NOTEWORTHY This work supports the concept that diminished arterial autophagy contributes to premature vascular aging in hypertension and that therapeutic reconstitution of autophagic activity can ameliorate this phenotype. As vascular age is a new clinically used index for cardiovascular risk, understanding this mechanism may assist in the development of new drugs to prevent premature vascular aging in hypertension. Listen to this article’s corresponding podcast at https://ajpheart.podbean.com/e/behind-the-bench-episode-one-cam-squared/ .

Abstract P241: Autophagic Flux is Diminished in Mesenteric Resistance Arteries of Spontaneously Hypertensive Rats

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Cameron G McCarthy ◽  
Camilla F Wenceslau ◽  
R. Clinton Webb
Keyword(s):  
Blood Pressure ◽  
High Blood Pressure ◽  
Spontaneously Hypertensive Rats ◽  
Cellular Aging ◽  
Experimental Hypertension ◽  
Autophagic Flux ◽  
Vascular Aging ◽  
Resistance Arteries ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive

Autophagy is the constitutively active catabolic process regulating protein quality control and energy homeostasis. However, dysregulation of this process can have detrimental effects on cellular function. In particular, insufficient autophagy has been proposed as a mechanism of cellular aging, as this leads to the accumulation of damaged macromolecules and organelles. Hypertension is a condition of vascular aging. In fact, many factors that contribute to the deterioration of vascular function as we age are exacerbated in clinical and experimental hypertension. Nonetheless, whether high blood pressure per se is the cause or effect of diminished autophagy remains to be clarified. We hypothesized that mesenteric resistance arteries (MRA) from spontaneously hypertensive rats (SHR) would have decreased autophagic flux as measured by conversion of microtubule-associated protein light chain 3 (LC3-I to LC3-II) compared to normotensive Wistar Kyoto rats (WKY). We observed that MRA from male 12-15 week old SHR have decreased basal expression both cytosolic LC3 (LC3-I) and phosphatidylethanolamine conjugated LC3 (LC3-II), and expression of these proteins are similarly decreased in SHR chronically treated with hydrochlorothiazide and reserpine (SHR+HCTZ/Res) [Arbitrary units (AU), LC3-1: WKY: 1.4±0.1, SHR: 1.1±0.1*, and SHR+HCTZ/Res: 0.7±0.1*; LC3-II: WKY: 1.4±0.1, SHR: 1.1±0.1*, and SHR+HCTZ/Res: 0.7±0.1*, *p<0.05 vs. WKY]. To understand autophagic flux, some MRA were incubated with lysosomal inhibitor chloroquine (CQ; 30 μM) for 2 hours. CQ incubation significantly increased LC3-II expression to a similar magnitude in WKY, SHR, and SHR+HCTZ/Res MRA (all *p<0.05 vs. basal). However, the percent increase in LC3-II expression after CQ incubation was significantly less in SHR compared to WKY, and SHR+HCTZ/Res was not different from either WKY or SHR (% increase from basal LC3-II, WKY: 546±187, SHR: 156±38*, and SHR+HCTZ/Res: 273±106, *p<0.05 vs. WKY). Overall, these data suggest that SHR have impaired autophagosome-lysosomal fusion, and this is not solely attributable to high blood pressure. Therefore, reconstituting autophagic activity could be a novel prophylactic or therapeutic measure against vascular aging in hypertension.

Altered Cardiac β-adrenoreceptors in Spontaneously Hypertensive Rats Receiving Salt Excess

1980 ◽  
Vol 59 (s6) ◽  
pp. 169s-170s ◽  
Author(s):  
A. A. MacPhee ◽  
H. L. Blakesley ◽  
Karen A. Graci ◽  
E. D. Frohlich ◽  
F. E. Cole
Keyword(s):  
Blood Pressure ◽  
Spontaneously Hypertensive Rats ◽  
Tap Water ◽  
Heart Weight ◽  
Experimental Hypertension ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Age Related ◽  
Clinical Hypertension ◽  
Logarithmic Relationship

1. Altered adrenergic responsiveness of hearts and blood vessels occurs in both experimental and clinical hypertension. 2. Since salt excess aggravates both types of hypertension, we investigated β-adrenoreceptor properties in the hearts of spontaneously hypertensive and normotensive rats drinking 1% NaCl or tap water for 3 weeks. 3. Sodium loading increased heart weight in both spontaneously hypertensive and normotensive rats. 4. In spontaneously hypertensive rats excess salt attenuated the age-related decrease in β-adrenoreceptor number observed in spontaneously hypertensive and normotensive rats drinking tap water and in normotensive rats drinking 1% NaCl. 5. Unlike the normotensive rats, which did not show a relationship between β-adrenoreceptor number and blood pressure, spontaneously hypertensive rats on tap water and 1% NaCl showed a significant negative logarithmic relationship between these two variables. These data provide further evidence implicating sodium excess as an aggravating factor in this model of experimental hypertension.

scholarly journals Hemin and L-arginine regulation of blood pressure in spontaneous hypertensive rats.

1991 ◽  
Vol 2 (6) ◽  
pp. 1078-1084 ◽  
Author(s):  
P Martasek ◽  
M L Schwartzman ◽  
A I Goodman ◽  
K B Solangi ◽  
R D Levere ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cytochrome P450 ◽  
Heme Oxygenase ◽  
Spontaneously Hypertensive Rats ◽  
Dependent Manner ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Heme Oxygenase Activity ◽  
Oxygenase Activity ◽  
Heme Arginate

Perturbation in heme metabolism is known to affect the level and activity of hemoproteins, including cytochrome P450-dependent arachidonic acid metabolism. The latter has been associated with elevation in blood pressure seen in spontaneously hypertensive rats. The effect of heme arginate and its components, arginine and heme, on cytochrome P450 levels and blood pressure in spontaneously hypertensive rats were studied. Administration of heme arginate or heme alone at doses of 9 to 30 mg/kg body wt/day for 4 days resulted in a marked decrease of blood pressure in spontaneously hypertensive rats, whereas blood pressure in rats receiving the vehicle control was not affected. Similarly, L-arginine, but not D-arginine, in a dose-dependent manner decreased blood pressure in spontaneously hypertensive rats. The maximal change in blood pressure was achieved at 100 mg/kg body wt of arginine and was associated with a significant increase in heme oxygenase activity. A higher concentration (500 mg/kg) did not cause an additional decrease in blood pressure but further increased heme oxygenase activity. The arginine-induced heme oxygenase activity was suppressed by Sn-protoporphyrin. Administration of heme to spontaneously hypertensive rats resulted in an accumulation of heme oxygenase mRNA, which was accompanied by an increase in enzyme activity. The increase in heme oxygenase activity was also prevented by Sn-protoporphyrin. It is postulated that heme treatment resulted in an increase in heme oxygenase mRNA, which consequently led to a diminution of cellular heme and depletion of hemoproteins, such as the cytochrome P450 arachidonate metabolizing enzymes.(ABSTRACT TRUNCATED AT 250 WORDS)

Antihypertensive actions of angiotensin-(1-7) in spontaneously hypertensive rats

1995 ◽  
Vol 269 (1) ◽  
pp. H313-H319 ◽  
Author(s):  
I. F. Benter ◽  
C. M. Ferrario ◽  
M. Morris ◽  
D. I. Diz
Keyword(s):  
Blood Pressure ◽  
Prostaglandin E2 ◽  
Spontaneously Hypertensive Rats ◽  
Systolic Pressure ◽  
Experimental Hypertension ◽  
Electrolyte Balance ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Plasma Vasopressin

Observations that angiotensin-(1-7) [ANG-(1-7)] may oppose the vasoconstrictor actions of angiotensin II (ANG II) prompted an investigation of the effects of the heptapeptide on the maintenance of elevated blood pressure in spontaneously hypertensive rats (SHR). ANG-(1-7) (24 micrograms.kg-1.h-1) was infused into the jugular vein of 13-wk-old SHR (n = 64), Wistar-Kyoto (WKY, n = 50), and Sprague-Dawley (SD, n = 18) rats for 2 wk, with the use of osmotic minipumps. Blood pressure, fluid and electrolyte balance, plasma vasopressin, and urinary excretion of prostaglandin E2 and 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) were measured at days 2, 7, and 12 of the infusion. In SHR, ANG-(1-7) caused a sustained and significant reduction in plasma vasopressin concentration that was associated with an increase in urinary prostaglandin E2 and 6-keto-PGF1 alpha excretion at day 2 after the commencement of the infusion. These changes were accompanied by diuresis and natriuresis during the first 3 days of infusion in SHR but not in WKY or SD rats. Direct measurements of arterial pressure confirmed the lowering effect of ANG-(1-7) on systolic pressure of SHR on day 2 of treatment with a restoration of the pressure by days 7 and 12. These findings, along with our previous demonstration that ANG-(1-7) is an active depressor peptide in the intact animal, suggest that ANG-(1-7) may play a significant role as a vasodepressor system opposing the hemodynamic actions of ANG II in this genetic form of experimental hypertension.

Antibiotics attenuate experimental hypertension in rats

1985 ◽  
Vol 105 (3) ◽  
pp. 347-350 ◽  
Author(s):  
J. W. Honour ◽  
S. P. Borriello ◽  
U. Ganten ◽  
P. Honour
Keyword(s):  
Blood Pressure ◽  
Oral Administration ◽  
High Blood Pressure ◽  
Spontaneously Hypertensive Rats ◽  
Experimental Hypertension ◽  
Sprague Dawley ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Intramuscular Injections ◽  
Sprague Dawley Rats

ABSTRACT Hypertension was produced in Sprague–Dawley rats by intramuscular injections of either corticosterone or ACTH. Lower increases in blood pressure to these challenges were observed in Sprague–Dawley rats pretreated with neomycin or vancomycin which alone had no effect on blood pressure or growth. The development of high blood pressure in spontaneously hypertensive rats of a stroke-prone substrain was also attenuated by oral administration of neomycin. These results suggest that experimental hypertension can be modulated by the administration of antibiotics. J. Endocr. (1985) 105, 347–350

scholarly journals Combined antihypertensive effect of unripe Rubus coreanus Miq. and Dendropanax morbiferus H. Lév. Extracts in 1 kidney-1 clip hypertensive rats and spontaneously hypertensive rats

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Soyi Park ◽  
Ki Hoon Lee ◽  
Hakjoon Choi ◽  
Goeun Jang ◽  
Wan Seok Kang ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Function ◽  
Spontaneously Hypertensive Rats ◽  
Antihypertensive Activity ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Rat Models ◽  
Rubus Coreanus ◽  
Hypertensive Rat

Abstract Background We previously showed that enzymatically hydrolyzed Dendropanax morbiferus H. Lév. leaf (Hy-DP) and unripe Rubus coreanus Miq. (5-uRCK) extracts exhibit potent vasodilator effects on isolated aortic rings from rats partly through endothelium-dependent and endothelium-independent mechanisms. These two extracts have different mechanisms of action; however, their combined effect on antihypertensive activity has not been explored. Methods The present study aims to investigate the effect of a chronic optimized mixture (HDR-2, composed of Hy-DP and 5-uRCK in a 2:1 mass ratio) on vascular tension and blood pressure in two different hypertensive rat models. Results The results showed that HDR-2 concentration-dependently relaxed endothelium-intact and endothelium-denuded aortic rings precontracted with phenylephrine. Antihypertensive effects were assessed in vivo on a 1 kidney-1 clip (1 K-1C) rat model of hypertension and spontaneously hypertensive rats (SHRs). Acute HDR-2 treatment significantly decreased systolic blood pressure (SBP) 3 h posttreatment in both models. Chronic HDR-2 administration also significantly decreased SBP in the hypertensive rat models. Moreover, HDR-2 increased eNOS protein expression and phosphorylation levels in the aorta. Conclusion Chronic HDR-2 administration may effectively improve vascular function by decreasing plasma angiotensin-converting enzyme (ACE) activity and AngII levels. HDR-2 significantly improved acetylcholine (ACh)-induced aortic endothelium-dependent relaxation and affected sodium nitroprusside (SNP)-induced endothelium-independent relaxation in SHRs.

Cardiac hypertrophy and brain natriuretic peptide in experimental hypertension

1994 ◽  
Vol 266 (2) ◽  
pp. R451-R457 ◽  
Author(s):  
M. Kohno ◽  
T. Fukui ◽  
T. Horio ◽  
K. Yokokawa ◽  
K. Yasunari ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Brain Natriuretic Peptide ◽  
Natriuretic Peptide ◽  
Spontaneously Hypertensive Rats ◽  
Chronic Treatment ◽  
Experimental Hypertension ◽  
Acute Administration ◽  
Hypertensive Rats ◽  
Secretory Rate ◽  
Spontaneously Hypertensive

The blood pressure was decreased after chronic treatment with enalapril, MK-954, and hydralazine in deoxycorticosterone acetate (DOCA)-salt-induced malignant hypertension of spontaneously hypertensive rats (SHR); however, ventricular weight and plasma brain natriuretic peptide (BNP) concentration were decreased after enalapril and MK-954 but not after hydralazine. The BNP secretory rates from the ventricle in enalapril- and MK-954-treated DOCA-salt SHR were decreased to approximately 50% of those in untreated DOCA-salt SHR. The BNP secretory rate from the ventricle was positively correlated with ventricular weight in untreated and treated DOCA-salt SHR. In contrast, acute administration of captopril or MK-954 did not decrease the BNP secretory rate from the heart. Results suggest that the decrease in plasma BNP after enalapril and MK-954 is attributed to a decline in the secretion from the ventricle but not from the atrium. The reduction in ventricular mass appeared to be related to this decline.

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