Effect of aging and hypertension on contractility of resistance arteries: modulation by endothelial factors

1995 ◽  
Vol 269 (3) ◽  
pp. H837-H844 ◽  
Author(s):  
M. G. Lang ◽  
G. Noll ◽  
T. F. Luscher
Keyword(s):  
Isometric Tension ◽  
No Production ◽  
Ang Ii ◽  
Resistance Arteries ◽  
Spontaneously Hypertensive ◽  
Thromboxane Receptor ◽  
Increased Sensitivity ◽  
Wistar Kyoto ◽  
Thromboxane Receptor Antagonist ◽  
Effects Of Aging

The effects of aging and hypertension on contraction were examined in rat mesenteric resistance arteries of 12- and 74-wk-old Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). The vessels were suspended in myographs (37 degrees C, 95% O2-5% CO2) filled with modified Krebs-Ringer bicarbonate solution. Isometric tension was measured. Contractions to KCl (100 mM) were similar in adult WKY and SHR; they increased in senescent WKY (P < 0.05) but decreased in senescent SHR (P < 0.05). Responses to norepinephrine (% of KCl) were comparable in all four groups. However, blockade of nitric oxide (NO) production with NG-nitro-L-arginine methyl ester (L-NAME) enhanced the sensitivity to norepinephrine in senescent animals, particularly in SHR. Inhibition of cyclooxygenase with indomethacin prevented increased sensitivity to norepinephrine after NO blockade. Responses to angiotensin (ANG) II were not affected by aging and hypertension, but the thromboxane receptor antagonist SQ-30741 reduced ANG II-induced contractions only in SHR of both ages (P < 0.05). Aging increased responses to ANG I in SHR but decreased it in WKY (P < 0.05). In quiescent rings with endothelium, acetylcholine caused contractions in the presence of L-NAME in adult and senescent SHR but not in WKY (P < 0.05). SQ-30741 prevented these contractions (P < 0.05). Contractions to the thromboxane analogue U-46619 were reduced only in senescent SHR (P < 0.05). Thus aging increases and hypertension decreases contractility of smooth muscle in rat mesenteric resistance arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II inhibits DDAH1–nNOS signaling via AT1R and μOR dimerization to modulate blood pressure control in the central nervous system

2019 ◽  
Vol 133 (23) ◽  
pp. 2401-2413 ◽  
Author(s):  
Gwo-Ching Sun ◽  
Tzyy-Yue Wong ◽  
Hsin-Hung Chen ◽  
Chiu-Yi Ho ◽  
Tung-Chen Yeh ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Drug Targets ◽  
Nucleus Tractus Solitarius ◽  
Pressure Control ◽  
No Production ◽  
Ang Ii ◽  
Spontaneously Hypertensive ◽  
Extracellular Signal ◽  
Wistar Kyoto

Abstract G protein-coupled receptors (GPCRs) are important drug targets. Blocking angiotensin II (Ang II) type 1 receptor signaling alleviates hypertension and improves outcomes in patients with heart failure. Changes in structure and trafficking of GPCR, and desensitization of GPCR signaling induce pathophysiological processes. We investigated whether Ang II, via induction of AT1R and μ-opioid receptor (μOR) dimerization in the nucleus tractus solitarius (NTS), leads to progressive hypertension. Ang II signaling increased μOR and adrenergic receptor α2A (α2A-AR) heterodimer levels and decreased expression of extracellular signal-regulated kinases 1/2T202/Y204, ribosomal protein S6 kinaseT359/S363, and nNOSS1416 phosphorylation. Dimethylarginine dimethylaminohydrolase 1 (DDAH1) expression was abolished in the NTS of adult spontaneously hypertensive rats (SHRs). Endomorphin-2 was overexpressed in NTS of adult SHRs compared with that in 6-week-old Wistar-Kyoto rats (WKY). Administration of μOR agonist into the NTS of WKY increased blood pressure (BP), decreased nitric oxide (NO) production, and decreased DDAH1 activity. μOR agonist significantly reduced the activity of DDAH1 and decreased neuronal NO synthase (nNOS) phosphorylation. The AT1R II inhibitor, losartan, significantly decreased BP and abolished AT1R-induced formation of AT1R and μOR, and α2A-AR and μOR, heterodimers. Losartan also significantly increased the levels of nNOSS1416 phosphorylation and DDAH1 expression. These results show that Ang II may induce expression of endomorphin-2 and abolished DDAH1 activity by enhancing the formation of AT1R and μOR heterodimers in the NTS, leading to progressive hypertension.

scholarly journals Aging Additively Influences Insulin- and Insulin-Like Growth Factor-1-Mediated Endothelial Dysfunction and Antioxidant Deficiency in Spontaneously Hypertensive Rats

Biomedicines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 676
Author(s):  
Kunanya Masodsai ◽  
Yi-Yuan Lin ◽  
Sih-Yin Lin ◽  
Chia-Ting Su ◽  
Shin-Da Lee ◽  
...  
Keyword(s):  
Growth Factor ◽  
Endothelial Dysfunction ◽  
Spontaneously Hypertensive Rats ◽  
No Production ◽  
Organ Bath ◽  
Insulin Like Growth Factor ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Nos Inhibitors ◽  
Wistar Kyoto

This study aimed to investigate the aging-related endothelial dysfunction mediated by insulin and insulin-like growth factor-1 (IGF-1) and antioxidant deficiency in hypertension. Male spontaneously hypertensive rats (SHRs) and age-matched normotensive Wistar–Kyoto rats (WKYs) were randomly divided into 24-week-old (younger) and 48-week-old (older) groups, respectively. The endothelial function was evaluated by the insulin- and IGF-1-mediated vasorelaxation of aortic rings via the organ bath system. Serum levels of nitric oxide (NO), malondialdehyde (MDA), catalase, and total antioxidant capacity (TAC) were examined. The insulin- and IGF-1-mediated vasorelaxation was significantly impaired in both 24- and 48-week-old SHRs compared with age-matched WKYs and was significantly worse in the 48-week-old SHR than the 24-week-old SHR. After pretreatments of phosphoinositide 3-kinase (PI3K) or NO synthase (NOS) inhibitors, the insulin- and IGF-1-mediated vasorelaxation became similar among four groups. The serum level of MDA was significantly increased, while the NO, catalase, and TAC were significantly reduced in the 48-week-old SHR compared with the 24-week-old SHR. This study demonstrated that the process of aging additively affected insulin- and IGF-1-mediated endothelial dysfunction in SHRs, which could be partly attributed to the reduced NO production and antioxidant deficiency.

Renal cytochrome P-450-arachidonic acid metabolism: localization and hormonal regulation in SHR

1992 ◽  
Vol 262 (4) ◽  
pp. F591-F599 ◽  
Author(s):  
K. Omata ◽  
N. G. Abraham ◽  
M. L. Schwartzman
Keyword(s):  
Hormonal Regulation ◽  
Distribution Patterns ◽  
Arachidonic Acid Metabolism ◽  
Proximal Tubules ◽  
Ang Ii ◽  
Spontaneously Hypertensive ◽  
Nephron Segments ◽  
Wistar Kyoto ◽  
Cytochrome P 450 ◽  
Stimulation Of

Epoxygenase and omega- and omega-1-hydroxylases are the major cytochrome P-450-arachidonate (P-450-AA) metabolizing enzymes in renal tissues. We measured P-450-AA metabolism in single nephron segments and determined the tubular localization of this activity in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Formation of 20-hydroxyeicosatetraenoic acid (20-HETE), the product of AA omega-hydroxylase was specifically localized in the entire proximal tubules (S1, S2, and S3 segments), whereas formation of 19-HETE, the product of omega-1-hydroxylase and epoxyeicosatrienoic acids (EETs), products of AA epoxygenase, was demonstrable throughout the tubule. Although distribution patterns were similar in SHR and WKY, formation of 19- and 20-HETE in the proximal tubules was higher in SHR, whereas the formation of EETs was not different between the two strains. In the proximal tubules, angiotensin II (ANG II) significantly stimulated epoxygenase activity (EETs formation), whereas parathyroid hormone (PTH) and epidermal growth factor (EGF) had no effect on epoxygenase but significantly stimulated omega-hydroxylase activity (20-HETE formation). Because P-450-AA metabolites have a wide and contrasting spectrum of biological and renal effects, from vasodilation to vasoconstriction and from inhibition to stimulation of Na(+)-K(+)-adenosinetriphosphatase, their localization to the specific nephron segments and differential stimulation of their formation by ANG II, PTH, and EGF may contribute not only to renal hemodynamics and blood pressure regulation but also to the regulation of renal sodium and water balance.

Contractile responses and signal transduction of endothelin-1 in aorta and mesenteric vasculature of adult spontaneously hypertensive rats

1993 ◽  
Vol 71 (7) ◽  
pp. 473-483 ◽  
Author(s):  
Paul V. Nguyen ◽  
Xiao-Ping Yang ◽  
Guo Li ◽  
Li Yuan Deng ◽  
Jean-Pierre Flückiger ◽  
...  
Keyword(s):  
Inositol Phosphates ◽  
Second Messengers ◽  
Resistance Arteries ◽  
Hypertensive Rats ◽  
Contractile Responses ◽  
Spontaneously Hypertensive ◽  
Wky Rats ◽  
Mesenteric Arterial Bed ◽  
Mesenteric Vessels ◽  
Wistar Kyoto

The contractile responses and generation of intracellular second messengers in response to endothelin-1 (ET-1), a potent vasoconstrictor peptide released locally by endothelial cells and involved in the regulation of vascular tone, were investigated in different segments of the vascular tree of adult 18-week-old spontaneously hypertensive rats (SHR) as compared with age-matched Wistar–Kyoto (WKY) rats. Aorta rings of SHR showed lower maximum response to ET-1 in comparison with WKY rats. Rings of the main superior mesenteric artery of SHR and WKY showed similar responses to ET-1. Small mesenteric resistance arteries of SHR, mounted on a wire myograph, developed similar tension to those of WKY rats in response to ET-1. The dose–response of inositol phosphates to ET-1 was significantly blunted in thoracic aorta of SHR compared with WKY rats, whereas it was similar in the mesenteric arterial bed. Baseline 1,2-diacylglycerol content was higher in thoracic aorta of SHR than WKY, while it was similar in the mesenteric arterial bed of the two strains. The response of 1,2-diacylglycerol to ET-1 was blunted in aorta of SHR, whereas no significant differences in diacylglycerol accumulation could be found in mesenteric vessels between SHR and WKY. In small mesenteric arteries, the dose–response to ET-1 of cytosolic free calcium, measured with the fluorescent dye Fura 2-AM, was similar in the two groups of rats. We conclude that in the aorta of 18-week-old SHR there is reduced generation of second messengers (inositol phosphates and diacylglycerol), which underlies its decreased response to ET-1 In mesenteric vessels (both proximal and distal) signal transduction is similar in SHR and WKY, and as a result contractile responses in both species are comparable. The responses to ET-1 of the arterial tree in terms of contractility and second messenger generation may reflect the adaptive processes taking place as a consequence of elevated blood pressure within the arterial wall of different segments of the vasculature of SHR.Key words: inositol phosphate, phospholipids, diacylglycerol, cytosolic calcium, second messengers, conduit and resistance arteries, Wistar–Kyoto rats.

Enhanced ANG II activity in anterior pituitary cell aggregates from hypertensive rats

1988 ◽  
Vol 255 (3) ◽  
pp. R407-R411
Author(s):  
W. Robberecht ◽  
C. Denef
Keyword(s):  
Defined Medium ◽  
Pituitary Cell ◽  
Pituitary Cells ◽  
Cell Aggregates ◽  
Ang Ii ◽  
Hypertensive Rats ◽  
Spontaneously Hypertensive ◽  
Wistar Kyoto ◽  
Dose Dependent ◽  
Perifusion System

Pituitary cell reaggregates from 14-day-old and adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were cultured in serum-free, chemically defined medium supplemented with the thyroid hormone triiodothyronine and the glucocorticoid dexamethasone. After 1 wk in culture, aggregates were transferred into a perifusion system, and the effect of angiotensin II (ANG II) on prolactin (PRL) and growth hormone (GH) release was studied. In aggregates from adult SHR, ANG II displayed a significant and dose-dependent GH releasing activity, whereas a negligible effect or no effect was seen in aggregates from adult WKY. In contrast, no difference in the stimulation of PRL release by ANG II was found. To exclude the possibility that the enhanced GH responsiveness was secondary to longstanding hypertension, aggregates from animals in the prehypertensive stage were studied. Both the GH and PRL responses to ANG II were significantly higher in aggregates from 14-day-old SHR than in aggregates from 14-day-old WKY. These data indicate that abnormal GH and PRL responses to ANG II exist in pituitary cell aggregates from SHR long before hypertension develops. Because these differences were found in pituitary cells maintained in culture for 1 wk, they do not seem to be secondary to changes in brain regulation of pituitary function but rather are caused by factors intrinsic to the pituitary.

Interactions of cAMP-mediated vasodilators with angiotensin II in rat kidney during hypertension

1993 ◽  
Vol 265 (6) ◽  
pp. F845-F852 ◽  
Author(s):  
C. Chatziantoniou ◽  
X. Ruan ◽  
W. J. Arendshorst
Keyword(s):  
Angiotensin Ii ◽  
G Protein ◽  
Rat Kidney ◽  
Control Period ◽  
Ang Ii ◽  
Dibutyryl Camp ◽  
Renal Vasculature ◽  
Spontaneously Hypertensive ◽  
Electromagnetic Flowmetry ◽  
Wistar Kyoto

In previous studies [C. Chatziantoniou and W.J. Arendshorst. Am. J. Physiol. 263 (Renal Fluid Electrolyte Physiol. 32): F573-F580, 1992], we reported that vasodilator prostaglandins (PGs) are defective in buffering the angiotensin II (ANG II)-induced vasoconstriction in the renal vasculature of spontaneously hypertensive rats (SHR). The purpose of the present study was to determine whether this defect in SHR kidneys is specific to PGs or generalized to the action of vasodilators and to gain insight into which intracellular signal(s) mediates this abnormality. Renal blood flow (RBF; electromagnetic flowmetry) was measured in 7 wk-old anesthetized, euvolemic SHR and normotensive Wistar-Kyoto (WKY) rats pretreated with indomethacin to avoid interactions with endogenous PGs. ANG II (2 ng) was injected into the renal artery before and during continuous intrarenal infusion of fenoldopam [DA1 receptor agonist and G protein-dependent stimulator of adenosine 3',5'-cyclic monophosphate (cAMP)], forskolin (G protein-independent stimulator of cAMP), dibutyryl-cAMP (soluble cAMP), and acetylcholine (cGMP stimulator). Each vasodilator was infused at a low dose that did not affect baseline arterial pressure or RBF. In the control period, ANG II reduced RBF by 50% in both strains. Infusion of fenoldopam significantly blunted the ANG II-induced vasoconstriction in WKY, but not in SHR. In contrast, forskolin, dibutyryl-cAMP, and acetylcholine effectively buffered the vasoconstriction due to ANG II in both SHR and WKY. These results suggest that renal vasodilators acting through receptor binding to stimulate the cAMP signaling pathway are ineffective in counteracting the ANG II-induced vasoconstriction in SHR kidneys. (ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Effect of AT1 receptor blockade on hepatic redox status in SHR: possible relevance for endothelial function?

2003 ◽  
Vol 285 (3) ◽  
pp. R674-R681 ◽  
Author(s):  
Eva Cediel ◽  
David Sanz-Rosa ◽  
M. Pilar Oubiña ◽  
Natalia de las Heras ◽  
Francisco R. González Pacheco ◽  
...  
Keyword(s):  
Systolic Arterial Pressure ◽  
Redox System ◽  
Redox Status ◽  
Ang Ii ◽  
Spontaneously Hypertensive ◽  
Enos Mrna ◽  
Malonyl Dialdehyde ◽  
Wistar Kyoto ◽  
Oxide Synthase ◽  
Endothelial Nitric Oxide

The study investigated whether the amelioration of endothelial dysfunction by candesartan (2 mg·kg-1·day-1; 10 wk) in spontaneously hypertensive rats (SHR) was associated with modification of hepatic redox system. Systolic arterial pressure (SAP) was higher ( P < 0.05) in SHR than in Wistar-Kyoto rats (WKY) and was reduced ( P < 0.05) by candesartan in both strains. Acetylcholine (ACh) relaxations were smaller ( P < 0.05) and contractions induced by ACh + NG-nitro-l-arginine methyl ester (l-NAME) were greater ( P < 0.05) in SHR than in WKY. Treatment with candesartan enhanced ( P < 0.05) ACh relaxations in SHR and reduced ( P < 0.05) ACh + l-NAME contractions in both strains. Expression of aortic endothelial nitric oxide synthase (eNOS) mRNA was similar in WKY and SHR, and candesartan increased ( P < 0.05) it in both strains. Aortic mRNA expression of the subunit p22phox of NAD(P)H oxidase was higher ( P < 0.05) in SHR than in WKY. Treatment with candesartan reduced ( P < 0.05) p22phox expression only in SHR. Malonyl dialdehyde (MDA) levels were higher ( P < 0.05), and the ratio reduced/oxidized glutathione (GSH/GSSG) as well as glutathione peroxidase activity (GPx) were lower ( P < 0.05) in liver homogenates from SHR than from WKY. Candesartan reduced ( P < 0.05) MDA and increased ( P < 0.05) GSH/GSSG ratio without affecting GPx. Vessel, lumen, and media areas were bigger ( P < 0.05) in SHR than in WKY. Candesartan treatment reduced ( P < 0.05) media area in SHR without affecting vessel or lumen area. The results suggest that hypertension is not only associated with elevation of vascular superoxide anions but with alterations of the hepatic redox system, where ANG II is clearly involved. The results further support the key role of ANG II via AT1 receptors for the functional and structural vascular alterations produced by hypertension.

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