N-acetyl-L-cysteine potentiates depressor response to captopril and enalaprilat in SHRs

1994 ◽  
Vol 267 (3) ◽  
pp. R767-R772 ◽  
Author(s):  
F. J. Ruiz ◽  
M. G. Salom ◽  
A. C. Ingles ◽  
T. Quesada ◽  
E. Vicente ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Sulfhydryl Groups ◽  
Vascular Effects ◽  
Converting Enzyme Inhibitors ◽  
Depressor Response ◽  
Antihypertensive Response

Recently, in vivo and in vitro studies have implicated nitric oxide as a mediator of the vascular effects of angiotensin-converting enzyme inhibitors (ACEIs). In the present study we hypothesized that N-acetyl-L-cysteine (NAC), by increasing the availability of reduced sulfhydryl groups, would enhance the antihypertensive response to the ACEIs captopril and enalaprilat by a mechanism dependent on nitric oxide. The experiments were performed on instrumented, indomethacin-pretreated, awake spontaneously hypertensive rats (SHRs). Thirty minutes after a bolus of captopril (10 mg/kg iv) was administered, blood pressure decreased from 167 +/- 5 to 147 +/- 6 mmHg (n = 8). The pretreatment with the donor of thiol groups NAC (300 mg/kg iv) potentiated the depressor response to captopril because blood pressure decreased from 172 +/- 3 to 139 +/- 4 mmHg (n = 6). At the dose of 60 micrograms/kg iv, the ACEI enalaprilat did not acutely modify the blood pressure of SHRs (from 172 +/- 5 to 167 +/- 4 mmHg; n = 6). However, when the SHRs were pretreated with NAC, the same dose of enalaprilat significantly reduced blood pressure from 176 +/- 5 to 151 +/- 5 mmHg (n = 6). This potentiation of the depressor response to ACEIs, due to NAC, was not observed when SHRs were pretreated with the nitric oxide inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 50 micrograms.kg-1.min-1 iv). The results of this study suggest that NAC, a donor of sulfhydryl groups, potentiates the antihypertensive response to captopril and enalaprilat in SHR by a nitric oxide-dependent mechanism.

Distinction of NPY receptors in vitro and in vivo. II. Differential effects of NPY and NPY-(18-36)

1990 ◽  
Vol 259 (1) ◽  
pp. H174-H180 ◽  
Author(s):  
N. A. Scott ◽  
M. C. Michel ◽  
J. H. Boublik ◽  
J. E. Rivier ◽  
S. Motomura ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Receptor Subtypes ◽  
Base Line ◽  
Hemodynamic Effects ◽  
Vascular Effects ◽  
Inotropic Effects ◽  
Npy Receptor ◽  
Negative Inotropic Effects

We have studied the hemodynamic effects of neuropeptide Y (NPY) and its COOH-terminal fragment NPY-(18–36) in conscious rats. Intra-arterial injection of NPY rapidly elevated systemic vascular resistance (SVR), which remained high for greater than 30 min. Cardiac output (CO) decreased, and it remained low for greater than 30 min. Accordingly, blood pressure rose only transiently and returned to base-line values within 5 min. The reduction of CO could be attributed to a decreased stroke volume with an only marginal reduction of heart rate. Thus a direct cardiodepressive effect of NPY rather than baroreflex activation appears to be the major cause of the reduced CO. In vitro experiments excluded the possibility that NPY has direct negative inotropic effects and suggest that its cardiodepressive action is caused by coronary vasoconstriction or by presynaptic inhibition of norepinephrine release. Intra-arterial injections of NPY-(18-36) caused different hemodynamic effects. NPY-(18–36) decreased CO in a manner similar to that seen with NPY but initially did not elevate SVR, resulting overall in a reduced blood pressure. Only later, when blood pressure was reduced, was an elevation of SVR observed, which could be associated with increased plasma levels of catecholamines, angiotensin II, vasopressin, and NPY. Thus NPY-(18–36) mimics the cardiac effects of NPY but does not elicit its vascular effects. As NPY-(18–36) discriminates between NPY receptor subtypes in vitro, we conclude that the cardiac and vascular effects of NPY are mediated by distinct receptor subtypes.

Role of nitric oxide in regulation of vascular resistance in postnatal intestine

1995 ◽  
Vol 268 (6) ◽  
pp. G949-G958 ◽  
Author(s):  
C. A. Nankervis ◽  
P. T. Nowicki
Keyword(s):  
Nitric Oxide ◽  
Vascular Resistance ◽  
Age Groups ◽  
Calcium Ionophore ◽  
Similar Extent ◽  
Vascular Effects ◽  
A 23187

Studies were conducted to determine whether endothelial production of nitric oxide (NO) participates in the regulation of vascular resistance in postnatal swine intestine. In vivo, intra-arterial infusion of the arginine analogue NG-monomethyl-L-arginine (L-NMMA, 10(-4) M) increased intestinal vascular resistance 34% in 3-day-old animals and 9% in 35-day-old animals (P < 0.01); similar findings were noted during infusion of 10(-3) M L-NMMA. Mechanical augmentation of gut flow rate induced intestinal vasodilation in both age groups; L-NMMA eliminated this flow-induced dilation in intestine of 3- but not 35-day-old animals. In vitro, precontracted mesenteric artery rings from both age groups relaxed to a similar extent in response to the endothelium-independent nitrovasodilator sodium nitroprusside (SNP) and the calcium ionophore A-23187; the effect of A-23187, but not SNP, was eliminated by mechanical disruption of the endothelium. Acetylcholine (ACh) and substance P (SP), agents with vascular effects that are secondary to receptor-mediated activation of NO, caused greater relaxation of rings from younger than from older animals, and this effect was attenuated by L-NMMA or methylene blue. Unstimulated accumulation of guanosine 3',5'-cyclic monophosphate (cGMP) occurred to a similar extent in vessel segments from both groups. ACh and SP increased cGMP accumulation in segments from 3- but not from 35-day-old animals. We conclude that the NO-cGMP axis participates to a greater extent in regulation of intestinal vascular resistance in 3- than in 35-day-old swine.

scholarly journals The GPR18 Agonist PSB-KD-107 Exerts Endothelium-Dependent Vasorelaxant Effects

2021 ◽  
Vol 14 (8) ◽  
pp. 799
Author(s):  
Magdalena Kotańska ◽  
Monika Kubacka ◽  
Marek Bednarski ◽  
Noemi Nicosia ◽  
Małgorzata Szafarz ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Blood Vessels ◽  
Heart Function ◽  
Oxidative Potential ◽  
Antioxidant Power ◽  
Vascular Dilatation ◽  
Ferric Reducing Antioxidant Power

GPR18 is an orphan GPCR that is activated by the cannabinoid tetrahydrocannabinol (THC). Emerging evidence indicates its involvement in the control of cardiovascular functions, including heart rate, contractility, vascular tone, as well as blood pressure. Therefore, we investigated the effects of selective GPR18 receptor ligands, namely PSB-KD-107 (agonist) and PSB-CB-92 (antagonist), on blood pressure, electrocardiogram (ECG), and vascular dilatation in vitro and in vivo, as well as their anti-oxidative potential in in vitro ferric reducing antioxidant power (FRAP) and 2,2-diphenyl-1-picryl-hydrazyl-hydrate free radical (DPPH) assays. Our results clearly show that PSB-KD-107 dilates blood vessels. This effect is related to its activation of GPR18 as it can be blocked by the GPR18 antagonist PSB-CB-92. Moreover, our finding confirms the presence of GPR18 in blood vessels. The mechanism of the vasorelaxant activity of PSB-KD-107 is mainly related to endothelial nitric oxide generation; however, we cannot exclude additional nitric oxide-independent mechanisms or a direct influence on K+ channels. PSB-KD-107 may affect blood pressure and heart function after a single administration; however, this effect was no longer observed after repeated administrations once daily for eight days. PSB-KD-107 does not affect platelet aggregation—an important feature considering the safety of its administration. PSB-KD-107 also shows a significant anti-oxidant effect and further studies of its antioxidant activity in vivo are justified.

Angiotensins and rheumatoid arthritis

2019 ◽  
Vol 56 (6) ◽  
pp. 753-759
Author(s):  
N. M. Savushkina ◽  
E. A. Galushko ◽  
N. V. Demidova ◽  
A. V. Gordeev
Keyword(s):  
Rheumatoid Arthritis ◽  
Enzyme Inhibitors ◽  
Renin Angiotensin System ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
The Body ◽  
Converting Enzyme Inhibitors ◽  
In Vivo Experiments ◽  
Endothelial Growth Factor

At present, the role of the renin-angiotensin system (RAS) in regulating the cardiovascular system and maintaining water and electrolyte homeostasis has been well studied. However, over the past decades, new components of the RAS have been identified, suggesting a wider range of its potential effects on the body. It is of fundamentally importance for rheumatologists to affect inflammation, including rheumatoid inflammation, through blockade of angiotensin (AT) II formation via the effects of AT 1–7 and angiotensin-converting enzyme inhibitors, as well as through suppression of angiogenesis, primarily by reducing the production of endothelial growth factor. The organ-protective and antiinflammatory potential of drugs that reduce the production of AT, which has been proven in in vitro and in vivo experiments, allows us to consider them as first-line angiotropic agents in patients with rheumatoid arthritis, especially in the presence of concomitant hypertension and/or nephropathy.

scholarly journals Angiotensin-Converting Enzyme Inhibitors Reduce Uterine Fibroid Incidence in Hypertensive Women

2020 ◽  
Author(s):  
Nicole M Fischer ◽  
Tim O Nieuwenhuis ◽  
Bhuchitra Singh ◽  
Gayane Yenokyan ◽  
James H Segars
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Enzyme Inhibitor ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
The United States ◽  
Population Based ◽  
Research Database ◽  
Converting Enzyme ◽  
Converting Enzyme Inhibitors

Absctract Context In vitro and in vivo evidence has supported the role of angiotensin II blockade in reducing leiomyoma cell proliferation and growth. However, no population-based study to date has investigated this potential association. Objective This work aims to determine whether prior angiotensin-converting enzyme inhibitor (ACEi) use is associated with a reduced odds of leiomyoma development. Design A nested case-control study was conducted. Setting The population was assembled from the Truven Health MarketScan Research Database, which includes private health insurance claims from January 1, 2012 to December 31, 2017. Patients or Other Participants We included (n = 353 917) women age 18 to 65 with hypertension. Cases (n = 13 108) with a leiomyoma diagnosis were matched to controls (n = 340 808) with no such diagnosis at a 1:26 ratio by age and region of origin within the United States. Intervention Prior ACEi use was determined from outpatient drug claims. Main Outcome Measure Leiomyoma development was indicated by a first-time diagnosis code. Results Women on an ACEi experienced a 31.8% reduced odds of developing clinically recognized leiomyoma compared to nonusers (odds ratio [OR] 0.68; 95% CI, 0.65-0.72). This association was significant for each age group: 30 to 39 years (OR 0.86; 95% CI, 0.74-0.99), 40 to 49 years (OR 0.71; 95% CI, 0.66-0.76), 50 to 59 years (OR 0.63; 95% CI, 0.58-0.69), and 60 to 65 years (OR 0.58; 95% CI, 0.50-0.69). Of the ACEis, lisinopril (OR 0.67; 95% CI, 0.64-0.71), quinapril (OR 0.62; 95% CI, 0.41-0.92), and ramipril (OR 0.35; 95% CI, 0.23-0.50) demonstrated a significant association with reduced leiomyoma incidence. Conclusions ACEi use was associated with a reduced odds of developing clinically recognized leiomyoma in adult hypertensive women.

Abstract P423: Chronic Doxycycline Administration Inhibits Angiotensin Converting Enzyme Activity and Exerts Antioxidants Effects in Renovascular Hypertensive Rats

Hypertension ◽  
2017 ◽  
Vol 70 (suppl_1) ◽  
Author(s):  
Elen Rizzi Sanchez ◽  
Giselle F Bonacio ◽  
Danielle A Guimaraes ◽  
Gustavo Oliveira Paula ◽  
Jefferson Henrich Amaral ◽  
...  
Keyword(s):  
Angiotensin Converting Enzyme ◽  
Cardiovascular Effects ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Converting Enzyme ◽  
Hypertensive Rats ◽  
Angiotensin I ◽  
Converting Enzyme Inhibitors ◽  
Ace Activity

Doxycycline (Dox), an established matrix metalloproteinase (MMP) inhibitor, and angiotensin-converting enzyme inhibitors (ACEi) present beneficial cardiovascular effects which could be consequence of their antioxidants properties. Furthermore, some evidences have shown other biochemical similarities between Dox and ACEi suggesting that Dox could also inhibit ACE and ACEi directly interact with MMPs and inhibit these proteases. Supporting this idea, Dox is able to chelate divalent metals, such as calcium and zinc, which are essential for the ACE activity. In this regard, we hypothesized that Dox inhibits ACE activity in hypertensive rats which leads to a reduction in ROS production and decrease hypertension. Sham-operated or 2K1C hypertensive rats were treated with Dox (30 mg/Kg/day) or water for 4 weeks. Systolic blood pressure (SBP) was monitored weekly. Dox treatment reduced SBP in 2K1C rats from 200±12 mmHg to 158±8 mmHg (P<0.05). In addition, Dox treatment attenuated reactive oxygen species (ROS) levels in hypertensive animals measured by lucigenin chemiluminescense (in RLU/mg of aorta: from 711±1.0 to 377±93; P<0.05). ACE activity in aorta was increased in untreated 2K1C rats (22±0.8 nmols/min/g) when compared with the Sham group (12±1.0 nmols/min/g; P<0.05) and Dox treatment was able to reduce ACE activity in 2K1C rats (15±2.0 nmols/min/g; P<0.05). To evaluate whether Dox inhibits ACE activity in vitro , aortic tissues from 2K1C rats were incubated with Dox or Captopril (a known ACEi ). Dox in vitro did not affect ACE activity while captopril inhibited 80% of its activity. To verify whether Dox could inhibit ACE activity in vivo , an acute assay was performed with different doses of angiotensin I (in μg/Kg: 0.03, 0.3 and 3), after the single administration of Dox or saline (i.p.). Angiotensin I infusion increased mean arterial pressure dose-dependently and Dox pretreatment did not attenuated these increases significantly (P>0.05) as Captopril.Taken together, these results show that chronic treatment with Dox inhibits ACE activity in aorta of 2K1C rats, which contribute to ROS reduction and SBP attenuation. However, the mechanism by which Dox inhibits ACE activity needs further investigation.

Early gestation dexamethasone alters baroreflex and vascular responses in newborn lambs before hypertension

2006 ◽  
Vol 291 (2) ◽  
pp. R481-R488 ◽  
Author(s):  
Jeffrey L. Segar ◽  
Robert D. Roghair ◽  
Emily M. Segar ◽  
Melissa C. Bailey ◽  
Thomas D. Scholz ◽  
...  
Keyword(s):  
Nitric Oxide ◽  
Blood Pressure ◽  
Vascular Reactivity ◽  
Systemic Hypertension ◽  
Arterial Baroreflex ◽  
Vascular Responses ◽  
Early Gestation ◽  
Arterial Blood

Exposure of the early gestation ovine fetus to exogenous glucocorticoids induces alterations in postnatal cardiovascular physiology, including hypertension. To determine whether autonomic function and systemic vascular reactivity are altered by in utero programming before the development of systemic hypertension, we examined arterial baroreflex function and in vivo hemodynamic and in vitro vascular responses to vasoactive agents in 10- to 14-day-old newborn lambs exposed to early gestation glucocorticoids. Dexamethasone (Dex, 0.28 mg·kg−1·day−1) or saline was administered to pregnant ewes by intravenous infusion over 48 h beginning at 27 days gestation (term 145 days), and lambs were allowed to deliver ( n = 6 in each group). Resting mean arterial blood pressure (MABP; 77 ± 1 vs. 74 ± 3 mmHg) and heart rate (HR; 249 ± 9 vs. 226 ± 21 beats/min) were similar in Dex-exposed and control animals, respectively. The arterial baroreflex curve, relating changes in HR to MABP, was significantly shifted toward higher pressure in the Dex-exposed lambs although no change in the sensitivity (gain) of the response was seen. In vivo changes in blood pressure in response to bolus doses of ANG II (20, 50, and 100 ng/kg) and phenylephrine (2, 5, and 10 μg/kg) were similar in the two groups. However, Dex lambs displayed greater decreases in MABP in response to ganglionic blockade with tetraethylammonium bromide (10 mg/kg; −30 ± 3 vs. −20 ± 3 mmHg, P < 0.05) and greater increases in MABP after nitric oxide synthase blockade with NG-nitro-l-arginine (25 mg/kg; 23 ± 3 vs. 13 ± 2 mmHg, P < 0.05) compared with control lambs. By in vitro wire myography, mesenteric and femoral artery microvessel contractile responses to KCl were similar, whereas responses to endothelin (in mesenteric) and norepinephrine (in femoral) were significantly attenuated in Dex lambs compared with controls. Femoral vasodilatory responses to forskolin and sodium nitroprusside were similar in the two groups ( n = 4). These findings suggest that resetting of the baroreflex, accompanied by increased sympathetic activity and altered nitric oxide-mediated compensatory vasodilatory function, may be important contributors to programming of hypertension.

An ACE inhibitor reduces bactericidal activity of human neutrophils in vitro and impairs mouse neutrophil activity in vivo

2021 ◽  
Vol 13 (604) ◽  
pp. eabj2138
Author(s):  
Duo-Yao Cao ◽  
Jorge F. Giani ◽  
Luciana C. Veiras ◽  
Ellen A. Bernstein ◽  
Derick Okwan-Duodu ◽  
...  
Keyword(s):  
Bactericidal Activity ◽  
Angiotensin Converting Enzyme Inhibitors ◽  
Leukotriene B4 ◽  
Human Neutrophils ◽  
Converting Enzyme Inhibitors ◽  
Bacterial Killing ◽  
Increased Risk ◽  
The Impact

Angiotensin-converting enzyme inhibitors (ACEIs) are used by millions of patients to treat hypertension, diabetic kidney disease, and heart failure. However, these patients are often at increased risk of infection. To evaluate the impact of ACEIs on immune responses to infection, we compared the effect of an ACEI versus an angiotensin receptor blocker (ARB) on neutrophil antibacterial activity. ACEI exposure reduced the ability of murine neutrophils to kill methicillin-resistant Staphylococcus aureus (MRSA), Pseudomonas aeruginosa, and Klebsiella pneumoniae in vitro. In vivo, ACEI-treated mice infected with MRSA had increased bacteremia and tissue bacteria counts compared to mice treated with an ARB or with no drug. Similarly, ACEIs, but not ARBs, increased the incidence of MRSA-induced infective endocarditis in mice with aortic valve injury. Neutrophils from ACE knockout (KO) mice or mice treated with an ACEI produced less leukotriene B4 (LTB4) upon stimulation with MRSA or lipopolysaccharide, whereas neutrophils overexpressing ACE produced more LTB4 compared to wild-type neutrophils. As a result of reduced LTB4 production, ACE KO neutrophils showed decreased survival signaling and increased apoptosis. In contrast, neutrophils overexpressing ACE had an enhanced survival phenotype. Last, in a cohort of human volunteers receiving the ACEI ramipril for 1 week, ACEI administration reduced neutrophil superoxide and reactive oxygen species production and neutrophils isolated from volunteers during ramipril treatment had reduced bactericidal activity. Together, these data demonstrate that ACEI treatment, but not ARB treatment, can reduce the bacterial killing ability of neutrophils.

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