Search

Loria A, Reverte V, Salazar F, Saez F, Llinas MT, Salazar FJ. Changes in renal hemodynamics and excretory function induced by a reduction of ANG II effects during renal development. Am J Physiol Regul Integr Comp Physiol 293' R695-R700, 2007. First published May 9, 2007; doi:10.1152/ajpregu.00191.2007.--The aim was to evaluate whether blockade of ANG II effects during renal development modifies the renal response to an increment of plasma amino acid concentration. It was also examined in anesthetized rats whether the reduction of the renal ability to eliminate an acute volume expansion (VE), elicited by blockade of ANG II during renal development, is sex and/or age dependent. Newborn Sprague-Dawley rats were treated with vehicle or an A[T.sub.1]-receptor antagonist (ARA) during postnatal nephrogenesis. Amino acid infusion induced increments (P < 0.05) of glomerular filtration rate (31 [+ or -] 6%) and renal plasma flow (26 [+ or -] 5%) in male but not in female vehicle-treated rats. Natriuretic and diuretic responses to amino acid infusion were similar in male and female vehicle-treated rats. These renal hemodynamics and excretory responses to amino acid infusion were abolished in ARA-treated rats. Renal responses to VE were evaluated at 3-4 and 9-10 mo of age in vehicle and ARA-treated rats. VE-induced natriuresis and diuresis were reduced by more than 38% (P < 0.05) in 3- to 4-mo-old male and female ARA-treated rats. An age-dependent reduction (P < 0.05) in the renal ability to eliminate VE was found in male but not in female rats treated with ARA. Our results demonstrate that the renal effects induced by an increment in amino acids are abolished when ANG II effects have been reduced during nephrogenesis. In addition, this reduction of ANG II effects elicits an impairment of the renal ability to eliminate an acute VE in males and females, which is aggravated by age only in male rats. amino acid; filtration rate; nephrogenesis; renal vasodilatation; volume expansion

Loria A, Reverte V, Salazar F, Saez F, Llinas MT, Salazar FJ. Sex and age differences of renal function in rats with reduced ANG II activity during the nephrogenic period. Am J Physiol Renal Physiol 293: F506-F510, 2007. First published April 18, 2007; doi: 10.1152/ajprenal.00066.2007.--This study was designed to test the hypothesis that blockade of angiotensin II effects during renal development accelerates the aging-related changes in renal hemodynamics and proteinuria, and that these changes are sex dependent. It has also been examined whether the deterioration of urinary concentrating ability elicited by angiotensin II blockade is sex and/or aging dependent. Newborn Sprague-Dawley rats were treated with vehicle or an AT~ angiotensin II receptor antagonist (ARA) during the first 14 postnatal days. Blood pressure, glomerular filtration rate, proteinuria, and urinary concentrating ability in response to dehydration were examined in conscious rats at 3 and 11 mo of age. ARA treatment elicited a similar increment in blood pressure in males and females that was greater (P < 0.05) at 11 than at 3 mo of age. Glomerular filtration rate only decreased (P < 0.05) in 11-mo-old male ARA-treated rats (0.59 [+ or -] 0.07 vs. 0.80 [+ or -] 0.07 ml x [min.sup.-1] x [g.sup.-1] in control group). At 3 mo of age, proteinuria increased in male (107%) but not in female ARA-treated rats. However, at 11 mo of age, proteinuria increased in both sexes, but the increment was greater (P < 0.05) in male (244%) than in female (138%) ARA-treated rats. Renal ability to concentrate urine in response to prolonged water dehydration was only reduced in ARA-treated males. The reduction of urinary concentrating ability was accentuated by aging. Therefore, we conclude that blockade of angiotensin II effects during renal development elicits an important deterioration of cortical and medullary function that is sex and aging dependent. dehydration; nephrogenesis; proteinuria; renal function; urine osmolality

We have reported that the renal hemodynamic effects of norepinephrine (NE) are modulated by cyclooxygenase-2 (COX-2)-derived metabolites. Our main objective was to examine whether there is an interaction between nitric oxide (NO) and COX-2 in modulating the renal hemodynamic effects of NE. NE was infused at three doses to anesthetized dogs pretreated with vehicle (n = 8), a selective COX-2 inhibitor (nimesulide) (n = 6), an NO synthesis inhibitor [[N.sup.G]-nitro-L-arginine methyl ester; L-NAME] (n = 8), or with nimesulide and L-NAME (n = 5). During NE infusion, PG[E.sub.2] excretion increased (125%) in the control group and did not change in the L-NAME-treated dogs. The simultaneous inhibition of NO and COX-2 potentiated to a greater extent the NE-induced renal vasoconstriction than inhibition of either NO or COX-2. The NE-induced renal vasoconstriction during NO and COX-2 inhibition was reduced (P < 0.05) by infusing an A[T.sub.1] receptor antagonist (n = 6). These results suggest that there is an interaction between NO and COX-2 in protecting the renal vasculature from the NE effects and that angiotensin II partly mediates the NE-induced renal vasoconstriction when NO synthesis and COX-2 activity are reduced. renal adrenergic system; cyclooxygenases; A[T.sub.1] receptors antagonist; kidney

Changes in NOS activity and protein expression during acute and prolonged ANG II administration. Am J Physiol Regulatory Integrative Comp Physiol 282: R31-R37, 2002.--The aim of this study was to assess the effects of acute or prolonged increases of ANG II on nitric oxide synthase (NOS) activities and protein expression in mesenteric resistance vessels, left ventricle, renal cortex, and renal medulla. The response of NOS activities to ANG II is compared with that induced by phenylephrine. ANG II or phenylephrine were infused over either 3 h or 3 days to conscious rats. NOS activity was examined by measuring the rate of conversion of L-[[sup.14]C] arginine to L-[[sup.14]C] citrulline. Protein levels of endothelial (e) and neuronal (n) NOS were determined by Western blot analysis. Arterial pressure (AP) increased (P < 0.05) during acute and prolonged ANG II infusion. [Ca.sup.2+]-dependent NOS activity values (pmol of citrulline * [min.sup.-] * g wet [wt.sup.-1]) for control rats were 21 [+ or -] 9 in mesenteric arteries, 13 [+ or -] 7 in left ventricle, 14 [+ or -] 8 in renal cortex, and 411 [+ or -] 70 in renal medulla. Acute ANG II infusion increased (P < 0.05) [Ca.sup.2+]-dependent NOS activity in renal cortex and renal medulla (81 [+ or -] 18 and 611 [+ or -] 48, respectively), but no differences were found in mesenteric arteries and left ventricle with respect to control rats. In contrast to the renal changes in NOS activity, acute ANG II infusion did not modify eNOS or nNOS expression in any of the tissues examined. Prolonged ANG II infusion increased (P < 0.05) [Ca.sup.2+]-dependent NOS activity in mesenteric arteries (70 [+ or -] 17), renal cortex (104 [+ or -] 31), and left ventricle (49 [+ or -] 8) and did not elicit changes in renal medulla. After a prolonged ANG II infusion, eNOS and nNOS levels increased in all tissues examined with the exception of eNOS in the mesenteric arteries and nNOS in the left ventricle, which were not altered. Acute and prolonged phenylephrine infusion elevated AP to a similar extent as ANG II but only elicited significant increments of [Ca.sup.2+]-dependent NOS activity in renal cortex. These data indicate that acute and prolonged elevations in ANG II upregulate [Ca.sup.2+]-dependent NOS activity and protein expression in different tissues related to the control of blood pressure. However, these ANG II effects are heterogeneous with respect to the tissue implicated, the time course of the stimulation, and the NOS isoform involved. Phenylephrine only induces a significant elevation of [Ca.sup.2+]-dependent NOS activity in renal cortex. heart; mesenteric arteries; nitric oxide synthase; phenylephrine renal cortex; renal medulla

The renal response to an extracellular volume expansion (ECVE) is intervened by the interaction among nitric oxide (NO) and angiotensin II (ANG II). During an ECVE the vasoconstrictor and antinatriuretic influences of ANG II are coordinated by endogenous NO. The rise in the reabsorption of sodium generated by the restriction of NO synthesis is mediated by the levels of endogenous ANG II.

A study conducted on anesthetized dogs shows that prostaglandins synthesis (PG) inhibition does not affect the extracellular volume expansion (ECVE)-induced renal response of increases in sodium excretion and fractional excretion of lithium. Renal hemodynamics are unaffected by nitric oxide (NO) synthesis reduction, but the NO synthesis reduction does cause a reduction in increments in sodium excretion and fractional excretion induced by ECVE. Therefore, PG and NO synthesis interact to mediate renal response.

A study of the effects on renal excretion and hemodynamics confirms that nitric oxide regulates the renal vasoconstrictor effects of angiotensin II (ANG II). NO synthesis inhibition within the kidney through intrarenal L-NAME administration improves the renal hemodynamic effects of ANG II and reduces the glomerular filtration rate. NO synthesis blockade improves the effect of ANG II on sodium excretion in a dose-dependent-manner, due to the significant decrease in glomerular filtration rate and filtered sodium load.

Experimental examination of the renal hyperemic responses of dogs to a meat meal, to determine the function of nitric oxide in the response, reveals that NO mediates the responses, and in its absence, the meat meal-induced increases in glomerular filtration rate (GFR) and renal plasma flow (RPF) disappear. Pretreatment of the dogs with intrarenal NG-nitro-L-arginine methyl ester (L-NAME) infusions results in the inhibition of GFR and RPF enhancement, while coinfusion of L-NAME and L-arginine does not have inhibitory effects. The effects of NO suggest that increases in the NO levels help enhance meat meal-induced hyperfiltration and renal vasodilation.

Renal prostaglandins (PGs) do not have a significant function in regulating the renal interstitial hydrostatic pressure (RIHP)-caused increase in natriuresis of proximal sodium reabsorption during extracellular volume expansion (ECVE). The antinatriuretic influence of angiotensin II (ANG II) are not potentiated II (ANG II) restriction of PG production during ECVE. The renal vasoconstrictor influence of ANGII in spontaneously hypersenstive rats is a likely result of reduction in renal PG synthesis.

Llinas, Maria T., Francisca Rodriguez, Carol Moreno, and F. Javier Salazar. Role of cyclooxygenase-2derived metabolites and nitric oxide in regulating renal function. Am J Physiol Regulatory Integrative Comp Physiol 279: R1641-R1646, 2000.--The aim of this study was to examine the relative contribution of both cyclooxygenase (COX) isoforms in producing the prostaglandins (PG) involved in the regulation of renal function, when nitric oxide (NO) synthesis is reduced. In anesthetized dogs with reduction of NO synthesis, the renal effects of a nonisozyme-specific COX inhibitor (meclofenamate) were compared with those elicited by a selective COX-2 inhibitor (nimesulide) before and during an extracellular volume expansion (ECVE). Intrarenal [N.sup.G]-nitro-L-arginine methyl ester ([sub.L]-NAME) infusion (1 [micro] g [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1]; n = 6) did not elicit renal hemodynamic changes and reduced (P [is less than] 0.01) the renal excretory response to ECVE. Intravenous nimesulide (5 [micro] g [multiplied by] [kg.sup.-1] [multiplied by] min-1; n = 6) did not modify renal hemodynamic and reduced (P < 0.05) sodium excretion before ECVE. Simultaneous L-NAME and nimesulide infusion (n = 7) elicited an increment (37%) in renal vascular resistance (RVR; P [is less than] 0.05) before ECVE and no hemodynamic changes during ECVE. The reduced excretory response elicited by L-NAME and nimesulide was similar to that found during L-NAME infusion. Finally, simultaneous L-NAME and meclofenamate infusion (10 [micro] g [multiplied by] [kg.sup.-1] [multiplied by] [min.sup.-1]; n = 7) induced an increase in RVR (91%, P [is less than] 0.05), a decrease in glomerular filtration rate (35%, P [is less than] 0.05), and a reduction of the renal excretory response to ECVE that was greater (P [is less than] 0.05) than that elicited by L-NAME alone. The results obtained support the notion that PG involved in regulating renal hemodynamic and excretory function when NO synthesis is reduced are mainly dependent on COX-1 activity. sodium excretion; renal hemodynamic

Role of COX-2-derived metabolites in regulation of the renal hemodynamic response to norepinephrine. Am J Physiol Renal Physiol 281: F975-F982, 2001.--The objective of this study was to examine the role of cylcooxygenase (COX)-2-derived prostaglandins (PG) in modulating the renal hemodynamic effects of norepinephrine (NE) during low or normal sodium intake. The relative contribution of each COX isoform in producing the PG that attenuate the renal NE effects during normal sodium intake was also evaluated. The renal response to three doses of NE (50,100, and 250 ng * [kg.sup.-1] * [min.sup.-1]) was evaluated in anesthetized dogs pretreated with vehicle, a selective COX-2 inhibitor (nimesulide), or a nonselective COX inhibitor (meclofenamate). Intrarenal infusion of the two lower doses of NE in vehicle-pretreated dogs with normal sodium intake (n = 8) elicited an increase in renal vascular resistance (RVR; 21 and 34%) without inducing changes in glomerular filtration rate (GFR). The highest dose of NE in this group induced a further increment in RVR (113%) and a decrease in GFR (33%). Pretreatment with nimesulide in dogs with normal sodium intake (n = 7) did not modify the NE-induced increments in RVR but enhanced the decreases in GFR induced by the three NE doses (12, 26, and 64%). The renal hemodynamic response to NE in meclofenamate-pretreated dogs with normal sodium intake (n = 7) was similar to that found in dogs pretreated with nimesulide. Infusion of the lowest dose of NE to vehicle-pretreated dogs with low sodium intake (n = 6) did not modify GFR and elicited an increase in RVR (42%). Infusion of the second and third doses of NE led to a decrease in GFR (35 and 91%) and a rise in RVR (82 and 587%). Infusion of the first two doses of NE in nimesulide-pretreated dogs with low sodium intake (n = 5) induced a fall in GFR (64 and 92%) and an increase in RVR (174 and 2,293%) that were greater (P < 0.05) than those induced by NE in vehicle-pretreated dogs. The elevation in the urinary excretion rates of PG[E.sub.2] and 6-keto-PG[F.sub.1[alpha]] elicited by NE was prevented in the nimesulide-pretreated dogs. Our results show that COX-2 inhibition potentiates the renal hemodynamic effects of NE and propose that the PG involved in modulating them are mainly derived from COX-2 activity. renal function; glomerular filtration rate; renal vascular resistance; prostaglandins; cyclooxygenase-2

Numerous studies have evaluated blood pressure (BP) and renal changes in several models of developmental programming of hypertension. The present study examined to what extent BP, renal hemodynamic, and renal structure are affected at an old age in male and female animals with altered renal development. It also evaluated whether renal damage is associated with changes in cyclooxygenase (COX)-2 and neuronal nitric oxide synthase (NOS1) expression and immunoreactivity. Experiments were carried out in rats at 10-11 and 16-17 mo of age treated with vehicle or an ANG II type 1 receptor antagonist during the nephrogenic period (ARAnp). A progressive increment in BP and a deterioration of renal hemodynamics were found in both sexes of ARAnp-treated rats, with these changes being greater (P < 0.05) in male rats. The decrease in glomerular filtration rate at the oldest age was greater (P < 0.05) in male (74%) than female (32%) ARAnp-treated rats. Sex-dependent deterioration of renal structure was demonstrated in optical and electron microscopic experiments. COX-2 and NOS1 immunoreactivity were enhanced in the macula densa of male but not female ARAnp-treated rats. The present study reports novel findings suggesting that stimuli that induce a decrease of ANG II effects during renal development lead to a progressive increment in BP and renal damage at an old age in both sexes, but these BP and renal changes are greater in males than in females. The renal damage is associated with an increase of COX-2 and NOS1 in the macula densa of males but not females with altered renal development. [ABSTRACT FROM AUTHOR]

This study was performed to test the hypothesis that ANG II contributes to the hypertension and renal functional alterations induced by a decrease of COX2 activity during the nephrogenic period. It was also examined whether renal functional reserve and renal response to volume overload and high sodium intake are reduced in 3-4- and 9-11-mo-old male and female rats treated with vehicle or a COX2 inhibitor during nephrogenic period (COX2np). Our data show that this COX2 inhibition induces an ANG II-dependent hypertension that is similar in male and female rats. Renal functional reserve is reduced in COX2nptreated rats since their renal response to an increase in plasma amino acids levels is abolished, and their renal ability to eliminate a sodium load is impaired (P < 0.05). This reduction in renal excretory ability is similar in both sexes during aging but does not induce the development of a sodium-sensitive hypertension. However, the prolonged high-sodium intake at 9-11 mo of age leads to a greater proteinuria in male than in female (114 ± 12 g/min vs. 72 ± 8g/min; P < 0.05) COX2np-treated rats. Renal hemodynamic sensitivity to acute increments in ANG II is unaltered in both sexes and at both ages in COX2np-treated rats. In summary, these results indicate that the reduction of COX2 activity during nephrogenic period programs for the development of an ANG II-dependent hypertension, reduces renal functional reserve to a similar extent in both sexes, and increases proteinuria in males but not in females when there is a prolonged increment in sodium intake. [ABSTRACT FROM AUTHOR]

Renal effects induced by prolonged mPGES1 inhibition. Am J Physiol Renal Physiol 306: F68-F74, 2014. First published November 6, 2013; doi:10.1152/ajprenal.00492.2013.-The importance of membrane-bound PGE synthase 1 (mPGES1) in the regulation of renal function has been examined in mPGES1-deficient mice or by evaluating changes in its expression. However, it is unknown whether prolonged mPGES1 inhibition induces significant changes of renal function when Na+ intake is normal or low. This study examined the renal effects elicited by a selective mPGES1 inhibitor (PF-458) during 7 days in conscious chronically instrumented dogs with normal Na+ intake (NSI) or low Na+ intake (LSI). Results obtained in both in vitro and in vivo studies have strongly suggested that PF-458 is a selective mPGES1 inhibitor. The administration of 2.4 mg.kg-1.day-1 PF-458 to dogs with LSI did not induce significant changes in renal blood flow (RBF) and glomerular filtration rate (GFR). A larger dose of PF-458 (9.6 mg.kg-1.day-1) reduced RBF (P < 0.05) but not GFR in dogs with LSI and did not induce changes of renal hemodynamic in dogs with NSI. Both doses of PF-458 elicited a decrease (P < 0.05) in PGE2 and an increase (P < 0.05) in 6-keto-PGF1α. The dministration of PF-458 did not induce significant changes in renal excretory function, plasma renin activity, and plasma aldosterone and thromboxane B2 concentrations in dogs with LSI or NSI. The results obtained suggest that mPGES1 is involved in the regulation of RBF when Na+ intake is low and that the renal effects elicited by mPGES1 inhibition are modulated by a compensatory increment in PGI2. These results may have some therapeutical implications since it has been shown that prolonged mPGES1 inhibition has lower renal effects than those elicited by nonsteroidal anti-inflammatory drugs or selective cyclooxygenase-2 inhibitors. [ABSTRACT FROM AUTHOR]

Numerous studies have demonstrated that angiotensin II (ANG II) is involved in hypertension and renal changes occurring as a consequence of an adverse event during renal development. However, it was unknown whether this involvement is sex and age dependent. This study examines whether the increments in arterial pressure (AP) and in the renal sensitivity to ANG II are sex and age dependent in rats with altered renal development. It also evaluates whether the ANG II effects are accompanied by increments in AT1 receptors and oxidative stress. Experiments were performed in 3- to 4- and 10- to 11-mo-old rats treated with vehicle or an AT1 receptor antagonist (ARAnp) during the nephrogenic period. ARAnp-treated rats were hypertensive, but an age-dependent rise in AP was only found in males. Three days of treatment with candesartan (7 mg.kg-1.day-1) led to a fall of AP that was greater (P < 0.05) in male than in female 10- to 11-mo-old ARAnp-treated rats. Oxidated proteins were elevated (P < 0.05), and the decrease in AP elicited by candesartan was reduced (P < 0.05) when these rats are also treated with tempol (18 mg.kg-1.day-1). Hypertension was not maintained by an elevation of AT1 receptors in kidneys and mesenteric arteries. The acute renal hemodynamic response to ANG II (30 ng.kg-1.min-1) was similarly enhanced (P < 0.05) in both sexes of ARAnp-treated rats at 3-4 but not at 10-11 mo of age. Our results suggest that an adverse event during the nephrogenic period induces an ANG II-dependent increment in AP that is aggravated only in males during aging and that oxidative stress but not an increase in AT1 receptor contributes to the rise in AP. This study also shows that the renal hemodynamic sensitivity to ANG II is transitorily enhanced in both sexes of rats with altered renal development. [ABSTRACT FROM AUTHOR]

Cyclooxygenase 2 (COX2) is involved in regulating renal hemodynamics after renal ablation. It is also known that high protein intake (HPI) leads to a deterioration of renal function when there is preexisting renal disease and that there are important gender differences in the regulation of renal function. This study tested the hypothesis that the role of COX2 in regulating renal function and the renal hemodynamic effects elicited by HPI are enhanced when nephrogenesis is altered during renal development. It was also expected that the role of COX2 and the effects elicited by HPI are age and sex dependent. Newborn Sprague-Dawley rats were treated with an AT1 ANG II receptor antagonist during the nephrogenic period (ARAnp). Experiments were performed at 3-4 and 10-11 mo of age. Arterial pressure was elevated (P < 0.05) at both ages and in both sexes of ARAnp-treated rats. Renal COX2 expression was only elevated (P < 0.05) at 10-11 mo of age in both sexes of ARAnp-treated rats. COX2 inhibition induced greater renal vasoconstriction in male and female hypertensive than in normotensive rats at both ages. HPI did not induce glomerular filtration rate (GFR) in the youngest hypertensive rats and in the oldest female hypertensive rats. However, the GFR decreased during HPI (0.63 ± 0.07 to 0.19 ± 0.05 ml/min) in the oldest male hypertensive rats. The HPI-induced increment in proteinuria was greater (P < 0.05) in male (99 ± 22 mg/day) than in female (30 ± 8 mg/day) hypertensive rats. These results show that COX2 plays an important role in the regulation of renal function when renal development is altered and that prolonged HPI can lead to a renal insufficiency in males but not in females with reduced nephron endowment. [ABSTRACT FROM AUTHOR]

Presents a study of the effect of prostaglandins (PG) and nitric oxide (NO) during extracelluar volume expansion (ECVE). Mediation of hemodynamic and excretory responses to increase in extracellular volume by NO and PG; Proximal sodium reabsorption.

Tests the hypothesis that nitric oxide is involved in the renal hyperemic responses to a meat meal in dogs. Vasodilation and hyperfiltration after ingesion of a meat meal; Effects of a meat meal on renal hemodynamics; Intrarenal infusion of NG-nitro-L-arginine methyl ester to inhibit nitric oxide synthesis within the kidney.

Prolonged high-fat diet (HFD) accelerates the cardiovascular, renal, and metabolic dysfunction in hypertensive rats with altered renal development (ARDev). Soluble guanylate cyclase (sGC) stimulation or sodium-glucose cotransporter 2 (SGLT2) inhibition may improve cardiovascular, renal, and metabolic function in settings of hypertension and obesity. This study examined whether 6 wk treatment with an SGLT2 inhibitor (empagliflozin, 7 mg/kg/day) enhances the cardiovascular, renal, and metabolic effects of a sGC stimulator (praliciguat, 10 mg/kg/day) in hypertensive rats with ARDev and prolonged exposure to HFD. Arterial pressure (AP), renal vascular resistance (RVR), fat abdominal volume (FAV), insulin resistance, leptin and triglycerides levels, and intrarenal infiltration of inflammatory cells were higher, but cardiac output and creatinine clearance were lower in hypertensive rats ( n = 15) than in normotensive rats ( n = 7). Praliciguat administration ( n = 10) to hypertensive rats reduced ( P < 0.05) AP, FAV, plasma concentrations of leptin and triglycerides, and increased ( P < 0.05) cardiac output and creatinine clearance. Empagliflozin administration ( n = 8) only increased ( P < 0.05) glucosuria and creatinine clearance and decreased ( P < 0.05) plasma leptin and triglycerides concentrations in hypertensive rats. Simultaneous administration of praliciguat and empagliflozin ( n = 10) accelerated the decrease in AP, improved glucose tolerance, reduced ( P < 0.05) incremental body weight gain, and decreased ( P < 0.05) insulin resistance index, RVR, and the infiltration of T-CD3 lymphocytes in renal cortex and renal medulla. In summary, the combined administration of praliciguat and empagliflozin leads to a greater improvement of the cardiovascular, renal, and metabolic dysfunction secondary to prolonged exposure to HFD in hypertensive rats with ARDev than the treatment with either praliciguat or empagliflozin alone. NEW & NOTEWORTHY This is the first study, to our knowledge, showing that SGLT2 inhibition potentiates the beneficial cardiovascular, renal, and metabolic effects elicited by sGC stimulation in hypertensive rats with prolonged high-fat diet. The effects of the simultaneous administration of praliciguat and empagliflozin are greater than those elicited by either one alone. The effects of the simultaneous treatment may be related to a greater reduction in the inflammatory status.