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The effect of high-fructose intake on the vasopressor response to angiotensin II and adrenergic agonists in Sprague-Dawley rats

Abdulla MH, Sattar MA, Abdullah NA, Johns EJ

Pak J Pharm Sci, 2013 Jul;26(4):727-32.
PMID: 23811449

Effect of losartan was assessed on systemic haemodynamic responses to angiotensin II (Ang II) and adrenergic agonists in the model of high-fructose-fed rat. Twenty-four Sprague-Dawley (SD) rats were fed for 8 weeks either 20% fructose solution (FFR) or tap water (C) ad libitum. FFR or C group received losartan (10mg/kg/day p.o.) for 1 week at the end of feeding period (FFR-L and L) respectively, then the vasopressor responses to Ang II, noradrenaline (NA), phenylephrine (PE) and methoxamine (ME) were determined. The responses (%) to NA, PE, ME and Ang II in FFR were lower (P<0.05) than C (FFR vs. C; 22±2 vs. 32±2, 30±3 vs. 40±3, 9±1 vs. 13±1, 10±1 vs. 17±1) respectively. L group had blunted (P<0.05) responses to NA, PE, ME and Ang II compared to C (L vs. C; 26±2 vs. 32±2, 30±3 vs. 40±3, 7±0.7 vs. 13±1, 5±0.4 vs. 17±1) respectively. FFR-L group had aggravated (P<0.05) response to NA and ME, but blunted response to Ang II compared to FFR (FFR-L vs. FFR; 39±3 vs. 22±2, 11±1 vs. 9±1, 3±0.4 vs. 10±1) respectively. Fructose intake for 8 weeks results in smaller vasopressor response to adrenergic agonists and Ang II. Data also demonstrated an important role played by Ang II in the control of systemic haemodynamics in FFR and point to its interaction with adrenergic neurotransmission.

Matched MeSH terms: Losartan/pharmacology
Fasting increases circulating angiotensin levels and brain Agtr1a expression in male rats

Paes-Leme B, Monteiro LDRN, Gholami K, Hoe SZ, Ferguson AV, Murphy D, et al.

J Neuroendocrinol, 2023 Nov;35(11):e13334.
PMID: 37667574 DOI: 10.1111/jne.13334

In addition to being recognised for involvement in cardiovascular control and hydromineral balance, the renin-angiotensin system (RAS) has also been associated with the neuroendocrine control of energy balance. One of the main brain sites for angiotensin II (ANG II)/type 1 receptor (AT1 R) signalling is the subfornical organ (SFO), a circumventricular organ related to the control of autonomic functions, motivated behaviours and energy metabolism. Thus, we hypothesised that circulating ANG II may act on the SFO AT1 R receptors to integrate metabolic and hydromineral balance. We evaluated whether food deprivation can modulate systemic RAS activity and Agrt1a brain expression, and if ANG II/AT1 R signalling influences the hypothalamic expression of mRNAs encoding neuropeptides and food and water ingestion in fed and fasted Wistar rats. We found a significant increase in both ANG I and ANG II plasma levels after 24 and 48 h of fasting. Expression of Agrt1a mRNA in the SFO and paraventricular nucleus (PVN) also increased after food deprivation for 48 h. Treatment of fasted rats with low doses of losartan in drinking water attenuated the decrease in glycemia and meal-associated water intake without changing the expression in PVN or arcuate nucleus of mRNAs encoding selected neuropeptides related to energy homeostasis control. These findings point to a possible role of peripheral ANG II/SFO-AT1 R signalling in the control of refeeding-induced thirst. On the other hand, intracerebroventricular losartan treatment decreased food and water intake over dark time in fed but not in fasted rats.

Matched MeSH terms: Losartan/pharmacology
The effect of losartan and carvedilol on renal haemodynamics and altered metabolism in fructose-fed Sprague-Dawley rats

Abdulla MH, Sattar MA, Abdullah NA, Johns EJ

J Physiol Biochem, 2012 Sep;68(3):353-63.
PMID: 22281695 DOI: 10.1007/s13105-012-0147-1

The aim of this study is to assess the effects of losartan and carvedilol on metabolic parameters and renal haemodynamic responses to angiotensin II (Ang II) and adrenergic agonists in the model of fructose-fed rat. Thirty-six Sprague-Dawley rats were fed for 8 weeks either 20% fructose solution (F) or tap water (C) ad libitum. F or C group received either losartan or carvedilol (10 mg/kg p.o.) daily for the last 3 weeks of the study (FL and L) and (FCV and CV), respectively, then in acute studies the renal vasoconstrictor actions of Ang II, noradrenaline (NA), phenylephrine (PE) and methoxamine (ME) were determined. Data, mean±SEM were analysed using ANOVA with significance at P <0.05. Losartan and carvedilol decreased the area under the glucose tolerance curve of the fructose-fed group. The responses (%) to NA, PE, ME and Ang II in F were lower (P <0.05) than C (F vs. C, 17±2 vs. 38±3; 24±2 vs. 48±2; 12±2 vs. 34±2; 17±2 vs. 26±2), respectively. L had higher (P <0.05) responses to NA and PE while CV had blunted (P <0.05) responses to NA, PE and Ang II compared to C (L, CV vs. C, 47±3, 9±2 vs. 38±3; 61±3, 29±3 vs. 48±2; 16±3, 4±3 vs. 26±2), respectively. FL but not FCV group had enhanced (P <0.05) responses to NA, PE and ME compared to F (FL vs. F, 33±3 vs. 17±2; 45±3 vs. 24±2; 26±3 vs. 12±2), respectively. Losartan and carvedilol had an important ameliorating effect on fructose-induced insulin resistance. Losartan treatment could be an effective tool to restore normal vascular reactivity in the renal circulation of the fructose-fed rat.

Matched MeSH terms: Losartan/pharmacology*
Assessment of Losartan 50 mg on Survival of Post-Dialysis Euvolemic Hypertensive Patients: Findings from HELD Trial

Aftab RA, Khan AH, Adnan AS, Sulaiman SAS, Khan TM

Blood Purif., 2019;48(3):233-242.
PMID: 31387098 DOI: 10.1159/000500997

AIMS AND OBJECTIVE: To estimate the effect of losartan 50 mg on survival of post-dialysis euvolemic hypertensive patients.
METHODOLOGY: A single center, prospective, single-blind randomized trial was conducted to estimate the survival of post-dialysis euvolemic hypertensive patients when treated with lorsartan 50 mg every other day. Post-dialysis euvolemic assessment was done by a body composition monitor. Covariate Adaptive Randomization was used for allocation of participants to the standard or intervention arm, and the follow-up duration was twelve months. The primary end point was achieving targeted blood pressure (BP) of <140/90 mm Hg and maintaining for 4 weeks, whereas secondary end point was all cause of mortality. Pre-, intra-, and post-dialysis session BP measurements were recorded, and survival trends were analyzed using Kaplan-Meier analysis.
RESULTS: Of the total 229 patients, 96 (41.9%) were identified as post-dialysis euvolemic hypertensive. Final samples of 88 (40.1%) patients were randomized into standard (n = 44) and intervention arms (n = 44), and 36 (81.8%) patients in each arm completed a follow-up of 12 months. A total of eight patients passed away during the 12-month follow-up period (6 deaths among standard arm and 2 in intervention arm). However, the probability of survival between both arms was not significant (p = 0.13). Cox regression analysis revealed that chances of survival were higher among the patients in the intervention (OR 3.17) arm than the standard arm (OR 0.31); however, the survival was found not statistically significant.
CONCLUSION: There was no statistical significant difference in 1 year survival of post-dialysis euvolemic hypertensive patients when treated with losartan 50 mg.

Matched MeSH terms: Losartan/pharmacology
Blood pressure lowering effect of Ficus deltoidea var kunstleri in spontaneously hypertensive rats: possible involvement of renin-angiotensin-aldosterone system, endothelial function and anti-oxidant system

Azis NA, Agarwal R, Ismail NM, Ismail NH, Kamal MSA, Radjeni Z, et al.

Mol Biol Rep, 2019 Jun;46(3):2841-2849.
PMID: 30977084 DOI: 10.1007/s11033-019-04730-w

This study investigated the effects of a standardised ethanol and water extract of Ficus deltoidea var. Kunstleri (FDK) on blood pressure, renin-angiotensin-aldosterone system (RAAS), endothelial function and antioxidant system in spontaneously hypertensive rats (SHR). Seven groups of male SHR were administered orally in volumes of 0.5 mL of either FDK at doses of 500, 800, 1000 and 1300 mg kg- 1, or captopril at 50 mg kg- 1 or losartan at 10 mg kg- 1 body weight once daily for 4 weeks or 0.5 mL distilled water. Body weight, systolic blood pressures (SBP) and heart rate (HR) were measured every week. 24-hour urine samples were collected at weeks 0 and 4 for electrolyte analysis. At week 4, sera from rats in the control and 1000 mg kg- 1 of FDK treated groups were analyzed for electrolytes and components of RAAS, endothelial function and anti-oxidant capacity. SBP at week 4 was significantly lower in all treatment groups, including captopril and losartan, when compared to that of the controls. Compared to the controls, ACE activity and concentrations of angiotensin I, angiotensin II and aldosterone were lower whereas concentrations of angiotensinogen and angiotensin converting enzyme 2 were higher in FDK treated rats. Concentration of eNOS and total anti-oxidant capacity were higher in FDK treated rats. Urine calcium excretion was higher in FDK treated rats. In conclusion, it appears that ethanol and water extract of FDK decreases blood pressure in SHR, which might involve mechanisms that include RAAS, anti-oxidant and endothelial system.

Matched MeSH terms: Losartan/pharmacology
Fulltext Safety and Efficacy of Losartan 50 mg in Reducing Blood Pressure among Patients with Post-Dialysis Euvolemic Hypertension: A Randomized Control Trial

Aftab RA, Khan AH, Adnan AS, Sulaiman SAS, Khan TM

Sci Rep, 2017 12 18;7(1):17741.
PMID: 29255272 DOI: 10.1038/s41598-017-17437-4

The aim of current study was to assess the effectiveness of losartan 50 mg in reducing blood pressure among post-dialysis euvolemic hypertensive patients, observing their survival trends and adverse events during the course of study. A multicentre, prospective, randomised, single-blind trial was conducted to assess the effect of losartan 50 mg every other day (EOD), once a morning (OM) among post-dialysis euvolemic hypertensive patients. Post-dialysis euvolemic assessment was done by a body composition monitor (BCM). Covariate Adaptive Randomization was used for allocation of participants to the standard or intervention arm. Of the total 229 patients, 96 (41.9%) were identified as post-dialysis euvolemic hypertensive. Final samples of 88 (40.1%) patients were randomized into standard and intervention arms. After follow-up of 12 months' pre-dialysis systolic (p Losartan 50 mg achieve an overall significant decline in blood pressure among post-dialysis euvolemic hypertensive patients.

Matched MeSH terms: Losartan/pharmacology*
The effect of losartan and carvedilol on vasopressor responses to adrenergic agonists and angiotensin II in the systemic circulation of Sprague Dawley rats

Abdulla MH, Sattar MA, Abdullah NA, Khan MA, Anand Swarup KR, Johns EJ

Auton Autacoid Pharmacol, 2011 Jan-Apr;31(1-2):13-20.
PMID: 21166975 DOI: 10.1111/j.1474-8673.2010.00461.x

1 Interaction between renin-angiotensin (RAS) and sympathetic nervous systems (SNS) was investigated by examining the effect of cumulative blockade of angiotensin II (Ang II) and adrenergic receptors in normal Sprague Dawley rats. 2 Rats were treated with losartan (10 mg/kg), carvedilol (5 mg/kg), or losartan plus carvedilol (10+5 mg/kg) orally for 7 days. On day 8, the animals were anaesthetized with pentobarbitone and prepared for systemic haemodynamic study. Dose-response relationships for the elevation of mean arterial pressure or change in heart rate (HR) in response to intravenous injections of noradrenaline (NA), phenylephrine (PE), methoxamine (ME) and Ang II were determined. 3 Losartan or the combination of losartan with carvedilol blunted vasopressor responses to ME and Ang II. Dose-response relationships for agonist action on HR were significantly inhibited by all treatments except for the combination of losartan and carvedilol on the decrease in HR induced by PE. Carvedilol decreased vasopressor responses to NA, PE and Ang II, and HR responses to NA, ME and Ang II. Combination treatment produced similar effects to losartan on the vasopressor and HR responses but had a greater effect on vasopressor responses to ME and Ang II, and on HR responses to NA and Ang II than carvedilol alone. 4 It is concluded that peripheral vasoconstriction induced by Ang II is partly mediated by adrenergic action and that the vasopressor responses to adrenergic agonists depend on an intact RAS. These observations suggest an interactive relationship between RAS and SNS in determining systemic haemodynamic responses in 'normal' rats.

Matched MeSH terms: Losartan/pharmacology*
Chronic treatment with losartan and carvedilol differentially modulates renal vascular responses to sympathomimetics compared to treatment with individual agents in normal Wistar Kyoto and spontaneously hypertensive rats

Abdulla MH, Sattar MA, Abdullah NA, Khan MA, Abdallah HH, Johns EJ

Eur J Pharmacol, 2009 Jun 10;612(1-3):69-74.
PMID: 19356722 DOI: 10.1016/j.ejphar.2009.03.064

This study set out to investigate the impact of chronic cumulative blockade of angiotensin II and adrenoceptors in WKY and SHR and to explore how the renovascular responses to adrenergic and angiotensin II receptor agonists may be interdependent. Rats were treated with either losartan, carvedilol or losartan+carvedilol for 7 days and on day eight, animals were pentobarbitone anaesthetized and prepared for renal haemodynamic study. Dose-response relationships were determined in terms of reduction/elevation in the magnitude of renal blood flow in response to intrarenal arterial injection of dopamine, phenylephrine and isoprenaline. Renal vascular responses were blunted in WKY and SHR treated with either losartan or carvedilol as compared to their untreated counterparts (P<0.05). In the combined treated rats, the vascular responses to isoprenaline and phenylephrine were restored to levels observed in the untreated rats, but the renal vasoconstrictor responses to dopamine decreased (P<0.05) in both WKY and SHR. There was a reduction of (P<0.05) in the magnitude of the isoprenaline induced renal vasodilation in all SHR as compared to WKY groups. The data obtained showed that the renal vascular action of dopamine, phenylephrine and isoprenaline depended on an intact renin-angiotensin system (RAS) in WKY and SHR. Treatment with losartan or carvedilol blunted the renal vasoconstrictor/vasodilator responses to sympathomimetics which was attenuated with the combined treatment. These observations using chronic blockade of adrenergic and angiotensin receptors demonstrated that there was a long standing interdependency between the RAS and sympathetic nervous system (SNS) in determining the responsiveness of the renal vasculature of normal and hypertensive rats.

Matched MeSH terms: Losartan/pharmacology*
Influence of sympathetic and AT-receptor blockade on angiotensin II and adrenergic agonist-induced renal vasoconstrictions in spontaneously hypertensive rats

Abdulla MH, Sattar MA, Khan MA, Abdullah NA, Johns EJ

Acta Physiol (Oxf), 2009 Mar;195(3):397-404.
PMID: 19183357 DOI: 10.1111/j.1748-1716.2008.01895.x

This study investigated the influence of angiotensin II (Ang II) receptor and adrenergic blockade on the renal vasoconstrictions caused by Ang II and adrenergic agonists in spontaneously hypertensive rats (SHR).

Matched MeSH terms: Losartan/pharmacology
Inhibition of Ang II and renal sympathetic nerve influence dopamine-and isoprenaline-induced renal haemodynamic changes in normal Wistar-Kyoto and spontaneously hypertensive rats

Abdulla MH, Sattar MA, Abdullah NA, Hazim AI, Anand Swarup KR, Rathore HA, et al.

Auton Autacoid Pharmacol, 2008 Oct;28(4):95-101.
PMID: 18778332 DOI: 10.1111/j.1474-8673.2008.00422.x

1. This study was undertaken to elucidate the effects of inhibiting the renin-angiotensin system (RAS) with losartan, and acute unilateral renal denervation on renal haemodynamic responses to intrarenal administration of vasoconstrictor doses of dopamine and vasodilator doses of isoprenaline in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). 2. Acute unilateral renal denervation of the left kidney in rats was confirmed by a drop in the renal vasoconstrictor response to renal nerve stimulation (P < 0.05) along with diuresis and natriuresis. Rats were pretreated with losartan for 7 days and thereafter animals fasted overnight were anaesthetized (sodium pentobarbitone, 60 mg/kg i.p.) and acute renal haemodynamic responses studied. 3. Dose-response curves were constructed for dopamine and isoprenaline that induced falls or increases in renal blood flow, respectively. It was observed that renal vascular responses were greater in the denervated as compared with rats with intact renal nerves (all P < 0.05). Dopamine-induced renal vasoconstrictor responses were markedly lower in losartan-treated denervated WKY and SHR compared with their untreated counterparts (all P < 0.05). It was also observed that in losartan-treated and denervated WKY rats the vasodilatory responses to isoprenaline were markedly lower compared with untreated rats (all P < 0.05). However, in SHR, under the same conditions, there was no difference in the renal response to isoprenaline whether or not rats were treated with losartan (P > 0.05). 4. The data obtained showed that the renal vasoconstrictor effect of dopamine depends on intact renal nerves and RAS in WKY and SHR. Isoprenaline responses were likewise sensitive to renal denervation and RAS inhibition in WKY rats but not SHRs. Our observations reveal a possible relationship between renal AT(1) receptors and alpha(1)-adrenoceptors in WKY and SHR. There is also evidence to suggest an interaction between renal beta-adrenoceptors and AT(1) receptors in WKY rats.

Matched MeSH terms: Losartan/pharmacology
Effect of acute unilateral renal denervation on renal hemodynamics in spontaneously hypertensive rats

Abdulla MH, Sattar MA, Salman IM, Abdullah NA, Ameer OZ, Khan MA, et al.

Auton Autacoid Pharmacol, 2008 Apr-Jul;28(2-3):87-94.
PMID: 18598290 DOI: 10.1111/j.1474-8673.2008.00421.x

1 This study was undertaken to characterize the renal responses to acute unilateral renal denervation in anaesthetized spontaneously hypertensive rats (SHR) by examining the effect of acute unilateral renal denervation on the renal hemodynamic responses to a set of vasoactive agents and renal nerve stimulation. 2 Twenty-four male SHR rats underwent acute unilateral renal denervation and the denervation was confirmed by significant drop (P < 0.05) in renal vasoconstrictor response to renal nerve stimulation along with marked diuresis and natriuresis following denervation. After 7 days treatment with losartan, the overnight fasted rats were anaesthetized (sodium pentobarbitone, 60 mg kg(-1) i.p.) and renal vasoconstrictor experiments were performed. The changes in the renal vasoconstrictor responses were determined in terms of reductions in renal blood flow caused by renal nerve stimulation or intrarenal administration of noradrenaline, phenylephrine, methoxamine and angiotensin II. 3 The data showed that there was significantly (all P < 0.05) increased renal vascular responsiveness to the vasoactive agents in denervated rats compared to those with intact renal nerves. In losartan-treated denervated SHR rats, there were significant (all P < 0.05) reductions in the renal vasoconstrictor responses to neural stimuli and vasoactive agents as compared with that of untreated denervated SHR rats. 4 The data obtained in denervated rats suggested an enhanced sensitivity of the alpha(1)-adrenoceptors to adrenergic agonists and possible increase of AT(1) receptors functionality in the renal vasculature of these rats. These data also suggested a possible interaction between sympathetic nervous system and renin-angiotensin system in terms of a crosstalk relationship between renal AT(1) and alpha(1)-adrenoceptor subtypes.

Matched MeSH terms: Losartan/pharmacology

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