Sex-specific influence of angiotensin type 2 receptor stimulation on renal function:a novel therapeutic target for hypertension

The renin-angiotensin system is a powerful regulator of arterial pressure and body fluid volume. Increasing evidence suggests that the angiotensin type 2 receptor (AT 2 R), which mediates the vasodilatory and natriuretic actions of angiotensin peptides, is enhanced in females and may, therefore, represent an innovative therapeutic target. We investigated the therapeutic potential of direct AT 2 R stimulation on renal function in 11- to 12-week–old anesthetized male and female Sprague-Dawley rats. Renal blood flow was examined in response to a graded infusion of the highly selective, nonpeptide AT 2 R agonist, compound 21 (100, 200, and 300 ng/kg per minute), in the presence and absence of AT 2 R blockade (PD123319; 1 mg/kg per hour). Direct AT 2 R stimulation significantly increased renal blood flow in both males and females, without influencing arterial pressure. This was dose dependent in females only and occurred to a greater extent in females at the highest dose of compound 21 administered (males: 13.1±2.4% versus females: 23.0±3.2% change in renal blood flow at 300 ng/kg per minute versus baseline; P &lt;0.01). In addition, AT 2 R stimulation significantly increased sodium and water excretion to a similar extent in males and females ( P Group =0.05 and 0.005). However, there was no significant change in glomerular filtration rate in either sex, suggesting that altered tubular function may be responsible for AT 2 R-induced natriuresis rather than hemodynamic effects. Taken together, this study provides evidence that direct AT 2 R stimulation produces vasodilatory and natriuretic effects in the male and female kidney. The AT 2 R may, therefore, represent a valuable therapeutic target for the treatment of renal and cardiovascular diseases in both men and women. </jats:p

Angiotensin Type 2 Receptor Stimulation Increases Renal Function in Female, but Not Male, Spontaneously Hypertensive Rats

Accumulating evidence suggests that the protective pathways of the renin–angiotensin system are enhanced in women, including the angiotensin type 2 receptor (AT 2 R), which mediates vasodilatory and natriuretic effects. To provide insight into the sex-specific ability of pharmacological AT 2 R stimulation to modulate renal function in hypertension, we examined the influence of the AT 2 R agonist, compound 21 (100–300 ng/kg per minute), on renal function in 18- to 19-week-old anesthetized male and female spontaneously hypertensive rats. AT 2 R stimulation significantly increased renal blood flow in female hypertensive rats ( P Treatment &lt;0.001), without influencing arterial pressure. For example, at 300 ng/kg per minute of compound 21, renal blood flow increased by 14.3±1.8% from baseline. Furthermore, at 300 ng/kg per minute of compound 21, a significant increase in urinary sodium excretion was observed in female hypertensive rats (+180±59% from baseline; P &lt;0.05 versus vehicle-treated rats). This was seen in the absence of any major change in glomerular filtration rate, indicating that the natriuretic effects of AT 2 R stimulation were likely the result of altered renal tubular function. Conversely, we did not observe any significant effect of AT 2 R stimulation on renal hemodynamic or excretory function in male hypertensive rats. Finally, gene expression studies confirmed greater renal AT 2 R expression in female than in male hypertensive rats. Taken together, acute AT 2 R stimulation enhanced renal vasodilatation and sodium excretion without concomitant alterations in glomerular filtration rate in female hypertensive rats. Chronic studies of AT 2 R agonist therapy on renal function and arterial pressure in hypertensive states are now required to establish the suitability of AT 2 R as a therapeutic target for cardiovascular disease, particularly in women. </jats:p

A narrative review of the potential pharmacological influence and safety of ibuprofen on coronavirus disease 19 (COVID-19), ACE2, and the immune system: a dichotomy of expectation and reality

The coronavirus disease 19 (COVID-19) pandemic is currently the most acute healthcare challenge in the world. Despite growing knowledge of the nature of Severe Acute Respiratory Syndrome coronavirus-2 (SARS-CoV-2), treatment options are still poorly defined. The safety of non-steroidal anti-inflammatory drugs (NSAIDs), specifically ibuprofen, has been openly questioned without any supporting evidence or clarity over dose, duration, or temporality of administration. This has been further conflicted by the initiation of studies to assess the efficacy of ibuprofen in improving outcomes in severe COVID-19 patients. To clarify the scientific reality, a literature search was conducted alongside considerations of the pharmacological properties of ibuprofen in order to construct this narrative review. The literature suggests that double-blind, placebo-controlled study results must be reported and carefully analysed for safety and efficacy in patients with COVID-19 before any recommendations can be made regarding the use of ibuprofen in such patients. Limited studies have suggested: (i) no direct interactions between ibuprofen and SARS-CoV-2 and (ii) there is no evidence to suggest ibuprofen affects the regulation of angiotensin-converting-enzyme 2 (ACE2), the receptor for COVID-19, in human studies. Furthermore, in vitro studies suggest ibuprofen may facilitate cleavage of ACE2 from the membrane, preventing membrane-dependent viral entry into the cell, the clinical significance of which is uncertain. Additionally, in vitro evidence suggests that inhibition of the transcription factor nuclear factor-κB (NF-kB) by ibuprofen may have a role in reducing excess inflammation or cytokine release in COVID-19 patients. Finally, there is no evidence that ibuprofen will aggravate or increase the chance of infection of COVID-19

Transcutaneous assessment of glomerular filtration rate in unanesthetized rats using a small animal imager:Impact on arterial pressure, heart rate, and activity

Transcutaneous assessment of fluorescein isothiocyanate (FITC)‐sinistrin clearance using a small animal imager has recently been validated as an accurate method for the measurement of glomerular filtration rate (GFR) in freely moving rats. This technique involves a brief, light period of anesthesia during which the imager is adhered to the rat and FITC‐sinistrin is administered. The rat is then moved to an experimental chamber where it is housed unrestrained for a 2‐h data collection period. This study assessed the impact of the experimental protocol on mean arterial pressure (MAP), heart rate, and locomotor activity in adult Sprague Dawley rats using radiotelemetry given that anesthesia and stress are known to affect arterial pressure and kidney function. These data were compared with time‐equivalent measurements made in the same rats at rest. MAP was low following anesthesia, but increased within 15 min and remained stable thereafter. Heart rate was not affected by the GFR protocol. Locomotor activity increased following anesthesia before decreasing to relatively low levels during the final 75‐min, the approximate period from which GFR is calculated. Moreover, MAP, heart rate, and locomotor activity during the final 75‐min of the data collection period were not different to that observed during an equivalent time period at baseline. Taken together, our findings suggest that this recently developed minimally invasive procedure for the measurement of GFR in unanesthetized rats does not negatively impact arterial pressure, heart rate, or locomotor activity. Thus, it is likely to be a valuable implement for acquiring serial measurements of GFR in unanesthetized rats

Pressor responsiveness to angiotensin II in female mice is enhanced with age:Role of the angiotensin type 2 receptor

BACKGROUND: The pressor response to angiotensin II (AngII) is attenuated in adult females as compared to males via an angiotensin type 2 receptor (AT(2)R)-dependent pathway. We hypothesized that adult female mice are protected against AngII-induced hypertension via an enhanced AT(2)R-mediated pathway and that in reproductively senescent females this pathway is no longer operative. METHODS: Mean arterial pressure was measured via telemetry in 4-month-old (adult) and 16-month-old (aged) and aged ovariectomized (aged-OVX) wild-type and AT(2)R knockout (AT(2)R-KO) female mice during baseline and 14-day infusion of vehicle (saline) or AngII (600 ng/kg/min s.c.). Real-time reverse transcription polymerase chain reaction (RT-PCR) was used to determine renal gene expression of angiotensin receptors and angiotensin-converting enzyme 2 in response to 14-day treatment with vehicle or AngII. RESULTS: Basal mean arterial pressure was similar between the groups. The pressor response to AngII was augmented in adult AT(2)R-KO compared to adult wild-type mice (29 ± 3 mmHg versus 10 ± 4 mmHg, respectively, on day 14 as compared to basal mean arterial pressure, P = 0.002). In wild-type mice, pressor responsiveness to AngII was augmented with age, such that the pressor response to AngII was similar between aged AT(2)R-KO and wild-type female mice (31 ± 4 mmHg versus 34 ± 3 mmHg, respectively, on day 14, P = 0.9). There were no significant differences in pressor responsiveness to AngII between aged and aged-OVX mice. Vehicle-treated aged wild-type mice had a lower renal AT(2)R/AT(1)R balance as compared to adult counterparts. In response to AngII, the renal AT(2)R/AT(1)R balance in aged wild-type females was greater than that observed in vehicle-treated aged wild-type females and adult wild-type females, yet the protective effects of AT(2)R activation were not restored. CONCLUSIONS: The protective role of the AT(2)R depressor pathway is lost with age in female mice. Therefore, targeting deficits in AT(2)R expression and/or signaling may represent a novel anti-hypertensive approach in aged females

Blunted sodium excretion in response to a saline load in 5 year old female sheep following fetal uninephrectomy

Previously, we have shown that fetal uninephrectomy (uni-x) causes hypertension in female sheep by 2 years of age. Whilst the hypertension was not exacerbated by 5 years of age, these uni-x sheep had greater reductions in renal blood flow (RBF). To further explore these early indications of a decline in renal function, we investigated the renal response to a saline load (25 ml/kg/40 min) in 5-year old female uni-x and sham sheep. Basal mean arterial pressure was similar to 15 mmHg greater (P-Grou