Abstract 507: Dual AT1 Receptor/Neprilysin (NEP) Inhibition (ARNI) vs. AT1 Receptor Blockade in TGR(mRen2)27 Rats: The More NEP Inhibition The Better?

Hypertension ◽  
2014 ◽  
Vol 64 (suppl_1) ◽  
Author(s):  
Lodi C Roksnoer ◽  
Joep H van Esch ◽  
Richard van Veghel ◽  
Ingrid M Garrelds ◽  
Usha M Bhaggoe ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Vascular Reactivity ◽  
Weight Ratio ◽  
At1 Receptor ◽  
Mesenteric Arteries ◽  
Heart Weight ◽  
Sodium Reabsorption ◽  
High Dose ◽  
Arterial Blood ◽  
Nep Inhibition

Objective: Neprilysin inhibitors (NEPi) prevent the breakdown of natriuretic peptides, promoting vasodilation and natriuresis. However, they also increase angiotensin and endothelin-1 (ET1). This study compared the combination of an AT1 receptor antagonist (irbesartan, IRB) ± a low or a high dose of the NEPi thiorphan in renin-overexpressing, hypertensive TGR(mREN2)27 rats. Methods: TGR(mREN2)27 rats were treated for three weeks with vehicle, IRB (15 mg/kg.day) or IRB + thiorphan (0.1 or 1.0 mg/kg.day; TH0.1 and TH1.0). Hemodynamics were evaluated by telemetry, and vascular reactivity was determined in isolated mesenteric arteries (Mulvany myograph). Results: Baseline mean arterial blood pressure (MAP) was 168±3 mmHg. All treatments lowered MAP by ≈50 mmHg around day 4. After 7 days, MAP started to increase during treatment with IRB or IRB+TH1.0 (to 141±10 mmHg and 133±10 mmHg, respectively, on day 21), while MAP in rats treated with IRB+TH0.1 remained low at 104±5 mmHg on day 21. Heart weight/body weight ratio, cardiac ANP expression and myocyte size decreased only in the IRB+TH0.1 group. Plasma ET1 was increased only by TH1.0 versus IRB alone, and this increase was accompanied by an increase in renal sodium-hydrogen exchanger 3 (NHE3) protein expression: ET1-induced constriction was reduced by IRB+TH0.1 only. Vascular ET B R expression levels and studies with the ET1 type B receptor (ET B R) antagonist BQ788 revealed that this reduction was most likely due to ET B R upregulation. Conclusion: TH0.1 enhanced the blood pressure-lowering effects of irbesartan and diminished cardiac hypertrophy. Higher doses of thiorphan resulted in significant ET1 rises and renal NHE3 upregulation, thereby increasing blood pressure and sodium reabsorption. The simultaneously occurring upregulation of vasodilatory ET B R was insufficient to overcome this effect. Clearly therefore, too much NEPi on top of AT1 receptor antagonism might be harmful.

CYP4A1 antisense oligonucleotide reduces mesenteric vascular reactivity and blood pressure in SHR

2001 ◽  
Vol 280 (1) ◽  
pp. R255-R261 ◽  
Author(s):  
Mong-Heng Wang ◽  
Fan Zhang ◽  
Jackleen Marji ◽  
Barbara A. Zand ◽  
Alberto Nasjletti ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Arachidonic Acid ◽  
Antisense Oligonucleotide ◽  
Vascular Reactivity ◽  
Spontaneously Hypertensive Rat ◽  
Mesenteric Arteries ◽  
Arachidonic Acid Metabolite ◽  
Spontaneously Hypertensive ◽  
Arterial Blood ◽  
Renal Tubular

The cytochrome P-450 4A (CYP4A)-derived arachidonic acid metabolite 20-hydroxyeicosatetraenoic acid (20-HETE) affects renal tubular and vascular functions and has been implicated in the control of arterial pressure. We examined the effect of antisense oligonucleotide (ODN) to CYP4A1, the low K m arachidonic acid ω-hydroxylating isoform, on vascular 20-HETE synthesis, vascular reactivity, and blood pressure in the spontaneously hypertensive rat (SHR). Administration of CYP4A1 antisense ODN decreased mean arterial blood pressure from 137 ± 3 to 121 ± 4 mmHg ( P < 0.05) after 5 days of treatment, whereas treatment with scrambled antisense ODN had no effect. Treatment with CYP4A1 antisense ODN reduced the level of CYP4A-immunoreactive proteins along with 20-HETE synthesis in mesenteric arterial vessels. Mesenteric arteries from rats treated with antisense ODN exhibited decreased sensitivity to the constrictor action of phenylephrine (EC50 0.69 ± 0.17 vs. 1.77 ± 0.40 μM). Likewise, mesenteric arterioles from antisense ODN-treated rats revealed attenuation of myogenic constrictor responses to increases of transmural pressure. The decreased vascular reactivity and myogenic responses were reversible with the addition of 20-HETE. These data suggest that CYP4A1-derived 20-HETE facilitates myogenic constrictor responses in the mesenteric microcirculation and contributes to pressor mechanisms in SHR.

Blood pressure-independent renoprotection in diabetic rats treated with AT1 receptor–neprilysin inhibition compared with AT1 receptor blockade alone

2016 ◽  
Vol 130 (14) ◽  
pp. 1209-1220 ◽  
Author(s):  
Lodi C.W. Roksnoer ◽  
Richard van Veghel ◽  
Marian C. Clahsen- van Groningen ◽  
René de Vries ◽  
Ingrid M. Garrelds ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Vascular Reactivity ◽  
Diabetic Rats ◽  
At1 Receptor ◽  
Heart Weight ◽  
Receptor Blockade ◽  
Beneficial Effects ◽  
Neprilysin Inhibition ◽  
Pressure Independent

ARNI [dual AT1 (angiotensin II type 1) receptor–neprilysin inhibition] exerts beneficial effects on blood pressure and kidney function in heart failure, compared with ARB (AT1 receptor blockade) alone. We hypothesized that ARNI improves cardiac and kidney parameters in diabetic TGR(mREN2)27 rats, an angiotensin II-dependent hypertension model. Rats were made diabetic with streptozotocin for 5 or 12 weeks. In the final 3 weeks, rats were treated with vehicle, irbesartan (ARB) or irbesartan+thiorphan (ARNI). Blood pressure, measured by telemetry in the 5-week group, was lowered identically by ARB and ARNI. The heart weight/tibia length ratio in 12-week diabetic animals was lower after ARNI compared with after ARB. Proteinuria and albuminuria were observed from 8 weeks of diabetes onwards. ARNI reduced proteinuria more strongly than ARB, and a similar trend was seen for albuminuria. Kidneys of ARNI-treated animals showed less severe segmental glomerulosclerosis than those of ARB-treated animals. After 12 weeks, no differences between ARNI- and ARB-treated animals were found regarding diuresis, natriuresis, plasma endothelin-1, vascular reactivity (acetylcholine response) or kidney sodium transporters. Only ARNI-treated rats displayed endothelin type B receptor-mediated vasodilation. In conclusion, ARNI reduces proteinuria, glomerulosclerosis and heart weight in diabetic TGR(mREN2)27 rats more strongly than does ARB, and this occurs independently of blood pressure.

Abstract 13798: Ablation of the Hypertension Candidate Gene ATP2B1 Results in Increased Blood Pressure and Cardiac Hypertrophic Remodeling

Circulation ◽  
2014 ◽  
Vol 130 (suppl_2) ◽  
Author(s):  
Sally K Hammad ◽  
Min Zi ◽  
Sukhpal Prehar ◽  
Robert Little ◽  
Ludwig Neyses ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiac Hypertrophy ◽  
Diastolic Pressure ◽  
Association Studies ◽  
Weight Ratio ◽  
Blood Pressure Regulation ◽  
Heart Weight ◽  
Genome Wide Association Studies ◽  
Pressure Regulation ◽  
The Impact

Introduction: Hypertension is a major risk factor for cardiac hypertrophy and heart failure. Genome wide association studies have recently identified single nucleotide polymorphisms in ATP2B1 , the gene encoding the calcium extrusion pump, plasma membrane calcium ATPase (PMCA1), as having a strong association with hypertension risk. Hypothesis: PMCA1 plays an important role in regulation of blood pressure and protection against hypertension and cardiac hypertrophy. Aims: We aim to examine whether there is a functional link between PMCA1 and blood pressure regulation, and the development of hypertension. And to determine the impact this link may have on cardiac structure and function. Methods and Results: To study the role of PMCA1 we generated a global PMCA1 heterozygous knockout mouse (PMCA1 Ht ). PMCA1 Ht mice had 46% to 52% reduction in PMCA1 protein expression compared to the WT, in aorta, heart, kidney and brain. To study the mice under hypertensive stress conditions, 3 month old PMCA1 Ht and wild type (WT) mice were infused via minipump with angiotensin II (1mg/Kg/daily) or water as a control. Upon angiotensin treatment, PMCA1 Ht mice showed a significantly greater increase in systolic (62.24±3.05 mmHg) and diastolic pressure (52.68±4.67 mmHg), in comparison to the WT (33.37±2.91 mmHg and 23.94±4.56 mmHg, respectively), P<0.001, n=12. Moreover, PMCA1 Ht mice showed a significantly greater hypertrophic response as indicated by a greater heart weight to tibia length ratio, cardiomyocyte cell size (410±18.7 μm 2 ), compared to WT mice (340.4±9.8 μm 2 ), and increased expression of B-type natriuretic peptide (BNP), 2.36 ± 0.25 fold change, n =5-6, P< 0.01. Echocardiography showed no significant changes between PMCA1 Ht and WT mice, in heart rate, and in cardiac function, as indicated by fractional shortening and ejection fraction. In addition, PMCA1 Ht mice showed no sign of lung congestion as indicated by lung weight to body weight ratio. Conclusion: ATP2B1 deletion leads to increased blood pressure and cardiac hypertrophy. This provides functional evidence that PMCA1 is involved in blood pressure regulation and protects against the development of hypertension and cardiac hypertrophy.

Exercise training and its effects with renal hypertensive rats

1985 ◽  
Vol 59 (5) ◽  
pp. 1410-1415 ◽  
Author(s):  
K. D. Marcus ◽  
C. M. Tipton
Keyword(s):  
Blood Pressure ◽  
Exercise Training ◽  
Capillary Density ◽  
Heart Weight ◽  
Sprague Dawley ◽  
Vo2 Max ◽  
Arterial Blood ◽  
Sprague Dawley Rats ◽  
Resting Blood Pressure ◽  
Renal Hypertensive Rats

The influence of endurance training on functional capacity [maximal O2 consumption (VO2 max)], caudal arterial blood pressure, and myocardial capillary density were investigated in normotensive rats and rats made hypertensive using the two-kidney one-clip approach (Goldblatt's hypertension). Male Sprague-Dawley rats were assigned to sham (N: 120–140 mmHg), moderately hypertensive (MH = 0.30-mm clips, 150–170 mmHg), or severely hypertensive (SH = 0.25-mm clips, 190–230 mmHg) groups. Rats designated to be runners (T) were exercised on a motor-driven treadmill equal to 50–70% of their VO2 max values for 8–12 wk. Compared with their nontrained (NT) controls, training was associated with significantly higher VO2 max values (12–15%) and muscle cytochrome-c oxidase activities (33–78%). Resting systolic blood pressure was not significantly changed in the N-and MH-T subgroups; however, it was 20–30 mmHg higher in the SH-T subgroup. Mean absolute heart weight for only the N-T group was significantly heavier than their NT controls. However, the mean predicted heart weights (heart wt = 0.639 X body wt of N-NT + 0.001 g) of the two SH groups were significantly higher than expected. The SH-T group had a lower (11%) subepicardial capillary density mean than its NT control and significantly fewer capillaries in the subendocardial region than the other five subgroups. It was concluded that moderate exercise training appeared to be detrimental to rats with severe hypertension because it increased resting blood pressure and decreased myocardial capillary density, even though it improved their functioning capacity.

Abstract 670: Immediate And Sustained Blood Pressure Lowering by CRF-receptor Stimulation: A Novel Approach To Antihypertensive Therapy?

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Thomas Dieterle ◽  
Silvia Meili-Butz ◽  
Katrin Buehler ◽  
Christian Morandi ◽  
Dietlinde John ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Body Weight ◽  
Arterial Hypertension ◽  
Weight Ratio ◽  
Chronic Administration ◽  
Cardiovascular Responses ◽  
High Salt ◽  
Heart Weight ◽  
Receptor Stimulation ◽  
Novel Approach

Background: Recently, novel corticotropin-releasing factor (CRF)-related peptides, named urocortin I (UcnI), UcnII, and UcnIII were described. Available data suggest that the Ucns are part of a peripheral CRF system modulating cardiovascular function and mediating cardiovascular responses to stress. Blood pressure (BP) lowering effects have been described after administration of UcnI. However, no data are available on effects of UcnII on BP in an animal model of systemic arterial hypertension. Methods: Experiments were performed in Dahl salt-sensitive (DSS) and salt-resistant rats (DSR, control). Animals were fed a diet containing 4% NaCl (high salt) to induce arterial hypertension in DSS rats. At the end of week 2 of high salt diet, both DSS and DSR rats were randomly assigned to i.p. injections of either UcnII (2.5 μg/kg body weight) or vehicle b.i.d. for five weeks. Animals underwent repetitive tail cuff BP measurements at baseline (prior to first injection), at 5 and 15 minutes after the first injection and at week 1, 2, and 5 of b.i.d. treatment. At week 5 animals were sacrificed to determine heart weight /body weight ratio. Results: Systolic BP (SBP, mmHg) and heart rate (HR, min −1 ) are given in the following table as mean ± SD (n=10 per group). Conclusions: In hypertensive DSS rats, acute CRF-receptor stimulation by UcnII immediately lowered BP to the range observed in DSR rats. Compared to vehicle-treated DSS rats, sustained BP reduction was observed with further chronic administration of UcnII. No severe reflex tachycardia was observed after administration of UcnII. Thus, CRF-receptor stimulation might represent a novel approach to the treatment of arterial hypertension.

Antihyperlipidemic and Antiobesity potential of Aquilaria agallocha & Borago officinalis in Fixed Dose Combination; A Contingent Probe with Atorvastatin & Orlistat

2021 ◽  
Vol 17 ◽  
Author(s):  
Rohima Oraon ◽  
Tarique Mahmood ◽  
Arshiya Shamim ◽  
Farogh Ahsan ◽  
Mohammad Shariq ◽  
...  
Keyword(s):  
Weight Ratio ◽  
Good Control ◽  
Fixed Dose Combination ◽  
Atherogenic Index ◽  
Heart Weight ◽  
Fixed Dose ◽  
Control Group ◽  
High Dose ◽  
Borago Officinalis ◽  
Dose Combination

: Hyperlipidemia and Obesity have been an alarmingly rising health disorders for the past few decades worldwide. They eventually pave way for cardiovascular and other metabolic health risks that are manifested with elevated blood lipid levels. Atherosclerosis, Coronary artery disease and Cerebrovascular diseases, are some major complications of hyperlipidemia. The current clinically available drugs like, Statins & HMG-Co-A inhibitors have a good control on hyperlipidemia but present many insalubrious effects like myopathy & hepatotoxicity that questions their risk-benefit ratio. The current study was designed to develop a fixed-dose combination (FDC) of extracts of Aquilaria agallocha and Borago officinalis, to delve into therapeutic resources that have synergistic benefits and could overpower the adverse effects of modern therapy. These plants are well reported for cardioprotective, immunomodulatory and hepatoprotective potentials. The FDC developed with these plants was examined for its antihyperlipidemic and antiobesity potential in HFD fed animal model (Vijaya et al) for Hyperlipidemia. The extracts from leaves of Borago officinalis and Aquilaria agallocha were administered perorally for 28 days in a fixed dose combination (FDC) in HFD fed rats. The physical and the biochemical parameters; viz, the gross examination of liver, heart, heart weight/body weight ratio, atherogenic index, various hepatic & cardiac biomarker enzymes and serum lipid markers were scrutinized. The result of the study suggested that both the low and high dose of the FDC of Aquilaria agallocha & Borago officinalis has significant Anti-Hyperlipidemic and Anti-Obesity potential against High-fat diet-induced Hyperlipidemia and Obesity when compared to disease control group (at p<0.01 & p<0.001) and their effects were at par with clinically established drugs Atorvastatin & Orlistat.

Pressure natriuresis during saline expansion in newborn and adult dogs

1984 ◽  
Vol 246 (6) ◽  
pp. F828-F834 ◽  
Author(s):  
L. I. Kleinman ◽  
R. O. Banks
Keyword(s):  
Blood Pressure ◽  
Arterial Blood Pressure ◽  
Perfusion Pressure ◽  
Renal Perfusion ◽  
Sodium Reabsorption ◽  
Renal Perfusion Pressure ◽  
Arterial Blood ◽  
Bilateral Carotid ◽  
Glomerular Filtrate ◽  
Pressure Natriuresis

Pressure natriuresis was studied in anesthetized saline-expanded adult (n = 10) and neonatal (n = 23) dogs. One group (protocol B) received ethacrynic acid and amiloride to block distal nephron function. Studies in the other group (protocol A) were done without diuretics. Renal arterial blood pressure was raised by bilateral carotid artery occlusion. Renal perfusion pressure was then lowered in steps by partially occluding the aorta proximal to the renal arteries. In protocol B carotid occlusion was associated with an increase in both absolute and fractional sodium excretion by adult and newborn dogs. Moreover, there was significant negative correlation (P less than 0.01) between absolute change in renal arterial pressure and change in tubular reabsorption of sodium per milliliter glomerular filtrate for both age groups. For each mmHg increase in blood pressure there was greater inhibition of sodium reabsorption in the puppy (0.55 mueq/ml glomerular filtrate) than in the adult (0.18 mueq/ml, P less than 0.05). In protocol A puppies, the inhibition of sodium reabsorption due to increases in renal perfusion pressure was less than that occurring in protocol B, indicating that some of the sodium escaping proximal nephron reabsorption was reabsorbed distally. Results of these studies indicate that during saline expansion pressure natriuresis is primarily a proximal tubular event, and the sensitivity of the proximal tubule to changes in renal arterial blood pressure is greater in the newborn than the adult kidney.

Effects of age, gender, and blood pressure on myogenic responses of mesenteric arteries from C57BL/6 mice

2002 ◽  
Vol 282 (1) ◽  
pp. H380-H388 ◽  
Author(s):  
Robert Gros ◽  
Ryan Van Wert ◽  
Xiaomang You ◽  
Eric Thorin ◽  
Mansoor Husain
Keyword(s):  
Blood Pressure ◽  
Perfusion Pressure ◽  
Inverse Correlation ◽  
Mesenteric Arteries ◽  
Physiological Parameter ◽  
Experimental Hypertension ◽  
Set Point ◽  
Arterial Blood ◽  
Old Mice

The myogenic response (MR) may represent an important physiological parameter underlying arterial blood pressure (BP). We studied the effects of age, gender, and BP on the MR of mesenteric arteries from 8- to 52-wk-old mice. Increasing age and BP are associated with an increase in the perfusion pressure at which tone develops (myogenic set point). An inverse correlation exists between age and extent (magnitude) of the MR in male ( r 2 = 0.93, P = 0.0087) and female mice ( r 2 = 0.90, P = 0.013) as well as between BP and extent of the MR in male ( r 2 = 0.96, P = 0.0036) and female ( r 2 = 0.90, P = 0.014) mice. In contrast, the strength of the MR (slope of active diameter-pressure relationship) and phenylephrine-mediated constriction did not differ among these groups. Although gender had no effect on MR at any perfusion pressure or age, only male mice showed significant salt-induced hypertension and an associated increase in the set point and reduction in the extent of the MR. The set point and extent of the MR is linked to the in vivo pressure during development and experimental hypertension.

P4481NI956/QGC006, a potent orally active, brain-penetrating aminopeptidase A inhibitor prodrug for treating hypertension

2019 ◽  
Vol 40 (Supplement_1) ◽  
Author(s):  
M Keck ◽  
H De Almeida ◽  
D Compere ◽  
N Inguimbert ◽  
A Flahault ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Oral Administration ◽  
Sulfonic Acid ◽  
Plasma Sodium ◽  
High Dose ◽  
Hypertensive Rats ◽  
Arterial Blood ◽  
Angiotensin Iii ◽  
Aminopeptidase A ◽  
Orally Active

Abstract Background Brain renin-angiotensin system hyperactivity has been implicated in the development and maintenance of hypertension. We previously showed that aminopeptidase A (APA) generates in the brain, angiotensin III, which exerts a tonic stimulatory control over blood pressure in hypertensive rats. Thus, the central injection of the specific and selective APA inhibitor, EC33 ((3S)-3-amino-4-sulfanyl-butane-1-sulfonic acid), by blocking the formation of brain angiotensin III, normalizes blood pressure in experimental models of hypertension. Therefore, brain APA appears as a potential new therapeutic target for the treatment of hypertension. We then developed RB150/firibastat, a prodrug of EC33, able of inhibiting brain APA activity and decreasing blood pressure in hypertensive rats after oral administration. Purpose However, considering the high dose of orally active RB150/firibastat required to decrease BP in spontaneously hypertensive rats (SHR) (150 mg/kg) and deoxycorticosterone acetate-salt (DOCA-salt) (50 mg/kg) rats, the aim of our work was to develop new more potent APA inhibitor prodrugs with greater bioavailability for inhibiting brain APA activity. Methods We used a salt- and volume-dependent model of hypertension, the DOCA-salt rat. For in vivo assessments of brain APA activity, brains were collected 4 hours after the oral administration. A catheter was inserted into the right femoral artery to monitor mean arterial blood pressure in alert rats. We evaluated plasma arginine-vasopressin (AVP) levels by radioimmunoassay. Rats were individually housed in metabolic cages for urine and electrolyte output measurements. Results We report here the development of a new APA inhibitor prodrug, NI956/QGC006, obtained by the disulfide bridge-mediated dimerization of NI929 ((3S,4S)-3-amino-4-mercapto-6-phenyl-hexane-1-sulfonic acid). NI929 is 10 more efficient than EC33 at inhibiting recombinant mouse APA activity in vitro. Following oral administration at a dose of 4 mg/kg in conscious DOCA-salt rats, NI956/QGC006 normalized brain APA activity and induced a marked decrease in blood pressure of −44±13 mmHg four hours after treatment (p<0.001), sustained over ten hours (−21±12 mmHg, p<0.05). Moreover, NI956/QGC006 decreased plasma AVP levels, and increased diuresis and natriuresis, that may decrease blood pressure by reducing the size of the fluid compartment. Finally, NI956/QGC006 did not affect plasma sodium and potassium concentrations. Conclusions This study shows that NI956/QGC006 is a “best-in-class” central-acting APA inhibitor prodrug, belonging to the same drug class as RB150/firibastat, supporting the strategy of brain APA inhibition for hypertension treatment. Acknowledgement/Funding ANR (Agence Nationale de la Recherche) grant to Catherine Llorens-Cortes (LabCom CARDIOBAPAI) and Quantum Genomics financial support.

Sign in / Sign up

Export Citation Format

Share Document