Chronic metabolic acidosis (CMA) can be a consequence of persistent hypertension but could potentially play a role in invoking hypertension. Currently, there is a scarcity of studies examining the outcome of induced chronic acidosis on blood pressure regulation. This study investigates CMA as a cause of hypertension. Chronic acidosis was induced in Sprague Dawley rats (100–150 g) by providing a weak acid solution of 0.28 M ammonium chloride (NH4Cl) in tap water for 8 weeks. To determine whether the rats were acidotic, blood pH was measured, while blood pressure (BP) was monitored by tail-cuff plethysmography weekly. Rats were divided into five groups: control, CMA, CMA ± spironolactone, captopril, and tempol. Serum sodium and potassium; renal interstitial fluid (for Angiotensin II concentration); and kidney proximal tubules (for Na+/K+ ATPase- α1 concentration) were analyzed. Reactive oxygen species (ROS) were detected in renal cortical homogenates using electron paramagnetic resonance (EPR). In the CMA rats, a sustained elevation in mean arterial pressure (MAP) associated with a significant decrease in blood pH was observed compared to that of control over the 8 weeks. A significant decrease in MAP was observed in acidotic rats treated with captopril/tempol, whereas spironolactone treatment caused no decrease in MAP as compared to that of the CMA group. The interstitial angiotensin II was increased in the CMA group but decreased in the CMA with captopril and tempol groups. In addition, the urinary sodium was decreased, and the serum sodium levels increased significantly in the CMA groups as compared to that of control. However, the acidotic groups with captopril and tempol showed reduced levels of serum sodium and an elevation in urinary sodium as compared to that of the CMA group. In addition, there was a significant increase in plasma renin and no change in plasma aldosterone in the CMA group with no significant differences in plasma renin or aldosterone observed during spironolactone, captopril, or tempol treatments. The increased expression of Na+/K+ ATPase-α1 in the CMA group suggests that active transport of Na+ to the blood could be causative of the observed hypertension. Furthermore, the EPR analysis confirmed an elevation in superoxide (O2-) radical levels in the CMA group, but the tempol/captopril treated acidotic groups showed less (O2-) compared to that of either the CMA group or control. Taken together, our data suggest that induction of CMA could potentially be causative of hypertension, while the mechanisms underlying the increased BP could be through the activation of intrarenal Ang II and induction of oxidative stress.

Disturbances in acid-base balance leading to the development of hypertension are currently gaining increased attention among researchers. Perturb acid-base balance characterized by metabolic acidosis has been demonstrated in hypertensive animals and humans. Research suggests that acid-base changes are not only the consequences of elevated blood pressure but can precede the development of hypertension. However, no exact mechanism has been identified to link acid-base imbalance with alterations in blood pressure. The kidney proximal tubule is the major site for maintaining normal bicarbonate concentrations which is an important component of acid-base balance. Acid-base transporter proteins in the renal proximal tubule such asNa HCO − cotransporters, Na + /H + exchangers, and anion-exchangers play important roles in controlling acid secretion, ammonia production and bicarbonate reabsorption for maintaining acid-base balance. It is well known that sodium retention in the renal tubules leads to increase in blood volume and consequently increases in blood pressure. Therefore, it is the purpose of this review to discuss the role of sodium-coupled acid-base transporters in regulating proximal tubular sodium retention and controlling blood pressure homeostasis. We will also focus on the capacity of local mediators; angiotensin II, cortisol, prostaglandin and aldosterone, to regulate acid-base and blood pressure homeostasis.

Hypoglycemia is a detrimental complication of rigorous management of type 1 diabetes mellitus. Moderate hypoglycemia (MH) preconditioning of male rats partially affords protection from loss of vulnerable brain neurons to severe hypoglycemia (SH). Current research investigated whether MH preconditioning exerts sex-dimorphic effects on hippocampal CA1 neuron bio-energetic and anti-oxidant responses to SH. SH up-regulated CA1 glucose or monocarboxylate transporter proteins in corresponding hypoglycemia-naïve male versus female rats; precedent MH amplified glucose transporter expression in SH irrespective of sex. Sex-differentiating SH effects on glycolytic and tricarboxylic pathway markers correlated with elevated tissue ATP content and diminished CA1 5'-AMP-activated protein kinase (AMPK) activation in females. MH preconditioned-suppression of mitochondrial energy pathway enzyme profiles and tissue ATP in SH rats coincided with amplified CA1 AMPK activity in both sexes. Anti-oxidative stress enzyme protein responses to SH were primarily sex-contingent; preconditioning amplified most of these profiles, yet exacerbated expression of lipid and protein oxidation markers in SH male and female rats, respectively. Results show that MH preconditioning abolishes female CA1 neuron neuroprotection of positive energy balance through SH, resulting in augmented CA1 AMPK activity and oxidative injury and diminished tissue ATP in hypoglycemia-conditioned versusnaïve rats in each sex. It is unclear if SH elicits differential rates of CA1 neuronal destruction in the two sexes, or how MH may impact sex-specific cell loss. Further research is needed to determine if molecular mechanism(s) that maintain female CA1 neuron metabolic stability in the

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Activation of renal angiotensin II works synergistically with renal superoxides to promote an increase in blood pressure during chronic acidotic conditions has been previously delineated. Uncontrolled high blood pressure instigates renal pathophysiological function and eventual end organ damage is evident. This study aims to investigate the renal consequences of increased blood pressure provoked during chronic metabolic acidosis (CMA). It was a challenging prospect, as both hypertension and chronic metabolic acidosis are two different pathological conditions and can exist independent of each other. Renal functions in rats grouped in 3 groups; i) Control (nonacidotic and normotensive), ii) CMA (acidotic and hypertensive), iii) CMA+captopril+tempol (acidotic and normotensive) were critically assessed by measuring Glomerular Filtration Rate (GFR), Fractional excretion of sodium (FENa), urine flow rate, weight of the kidneys and albuminuria. Picro‐sirius staining of the cortical sections was performed to examine the collagen content as an index of fibrosis. The results demonstrated significant attenuation of GFR in the CMA group compared to the control group. However, GFR in captopril+tempol treated acidotic rats is significantly increased compared to the CMA groups, which suggested that the reduced GFR in CMA group is because the rats are hypertensive. Conversely, the FENa was significantly increased in the CMA group compared to the control but the captopril+tempol treated group showed a significant decrease in FENa compared to the CMA group, this implied that hypertension but not acidosis is the cause of increased FENa which increases blood flow to the kidney potentially leading to the pressure natriuresis and could potentially lead to kidney damage. The urinary albumin excretion was also significantly elevated in acidotic rats as compared to control but the captopril+tempol treated group showed a significant reduction in albuminuria, which revealed the acidosis‐induced hypertension is contributing for impaired renal infiltration and augmenting the albuminuria. The morphological analysis of renal changes using Picro‐sirius staining revealed significant structural damage in the glomeruli of chronically acidotic rats. However, when these rats were treated with captopril and tempol combined, the glomeruli were intact and a reduction in fibrosis was observed. Overall, our results suggested the renal consequences of acidosis induced hypertension can lead to eventual end organ damage which is independent to the function of acidosis. Hence, intrarenal Ang II and superoxide release in the kidney could be a potential target to reduce the blood pressure, albuminuria, and protection of renal function and delayed the onset of end‐stage renal disease associated with acidosis evoked hypertension.

The newly reported model of experimental hypertension delineates the scope of chronic metabolic acidosis as a cause of hypertension. The observed mechanism to promote hypertension during the acidotic conditions are regulated by intrarenal angiotensin II (Ang II) and oxidative stress functioning synergistically. The present study investigates the role of Rho Kinase (ROCK1) in mediating intrarenal activation of Ang II and the renal cell oxidative state during the observed acidosis elicited hypertension. Chronic metabolic acidosis (CMA) was induced in male Sprague Dawley rats (100-150 g) by providing a weak acid solution of 0.28 M ammonium chloride (NH4CL) in tap water for 8 weeks. To confirm the rats were acidotic, blood pH was measured, while blood pressure was monitored weekly using tail-cuff. Rats were divided into five groups: Control (vehicle treated), CMA (acidotic), CMA+spironolactone (to evaluate aldosterone effect), CMA+captopril (to evaluate Ang II effect), and CMA+tempol (to evaluate free radical effect). Microdialysis probes were implanted to the rat’s renal compartments in each group to collect the interstitial fluid. ELISA was performed to quantifying the ROCK1 in all the dialysate samples. In the CMA rats, sustained elevation in the mean arterial pressure (MAP), associated with the significant decrease in blood pH was observed compared to the Control group over the 8 weeks. A significant decrease in MAP was observed in CMA rats treated with captopril and tempol, whereas spironolactone treatment caused no decrease in MAP as compared to the CMA group. The interstitial ROCK1 was significantly increased in the CMA group vs control but decreased significantly in the CMA+captopril vs CMA and CMA+tempol vs CMA groups respectively. This suggested the intrarenal ROCK1 is regulating the Ang II and ROS generation in the renal compartment. Overall, this supports our hypothesis that ROCK pathway and its interaction with intrarenal Ang II and oxidative stress plays a pivotal role in the pathogenesis of acidosis promoted hypertension. VCOM Departmental funding This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.