Angiotensin-(3–4) normalizes the elevated arterial blood pressure and abnormal Na+/energy handling associated with chronic undernutrition by counteracting the effects mediated by type 1 angiotensin II receptors

Abstract

We investigated the mechanisms by which chronic administration of a multideficient diet after weaning alters bodily Na+ handling, and culminates in high systolic blood pressure (SBP) at a juvenile age. From 28 to 92 days of age, weaned male Wistar rats were given a diet with low content and poor-quality protein, and low lipid, without vitamin supplementation, which mimics the diets consumed in impoverished regions worldwide. We measured food, energy and Na+ ingestion, together with urinary Na+ excretion, Na+ density (Na+ intake/energy intake), plasma Na+ concentration, SBP, and renal proximal tubule Na+-transporting ATPases. Undernourished rats aged 92 days had only one-third of the control body mass, lower plasma albumin, higher SBP, higher energy intake, and higher positive Na+ balance accompanied by decreased plasma Na+ concentration. Losartan or Ang-(3–4) normalized SBP, and the combination of the 2 substances induced an accentuated negative Na+ balance as a result of strong inhibition of Na+ ingestion. Na+ density in undernourished rats was higher than in control, irrespective of the treatment, and they had downregulated (Na++K+)ATPase and upregulated Na+-ATPase in proximal tubule cells, which returned to control levels after Losartan or Ang-(3–4). We conclude that Na+ density, not only Na+ ingestion, plays a central role in the pathophysiology of elevated SBP in chronically undernourished rats. The observations that Losartan and Ang-(3–4) normalized SBP together with negative Na+ balance give support to the proposal that Ang II⇒AT1R and Ang II⇒AT2R axes have opposite roles within the renin-angiotensin-aldosterone system of undernourished juvenile rats.

Undernutrition Modifies the Antihypertensive and Metabolic Responses of Rostafuroxin in Male Rats: Outcomes on Bodily Na⁺ Handling and Renal Na⁺-transporting ATPases

“…Figure 7 shows the opposite influence of the nutritional status and rostafuroxin administration on the two Na + -transporting ATPases present in the basolateral membranes of proximal tubule cells [16]. The activity of the main pump, the ouabain-sensitive (Na + +K + )ATPase (Figure 7A), decreased by 30% in RBD rats in comparison to CTRL, as previously described [17], with rostafuroxin promoting a further decrease in both groups. In the case of the ouabain-resistant, furosemide-sensitive Na + -ATPase (Figure 7B), undernutrition provoked a 50% increment in its activity, equalized at the same higher levels in CTRL+Rosta and RBD+Rosta after further upregulation in the animals given the drug.…”

“…In a recent study [17] and here (Figure 7A,B) we demonstrated that chronic undernutrition provoked by the continued administration of RBD to male rats downregulates the ouabain-sensitive (Na + +K + )ATPase and upregulates the ouabain-resistant Na + -ATPase, the two Na+-transporting ATPases that are responsible for the proximal renal reabsorption of more than 70% of the Na + filtered in the glomeruli [46,47]. Even though the hydrolytic activity of (Na + +K + )ATPase in membrane preparations does not quantitatively reflect the transport stoichiometry in intact cells, it is possible to propose that less bulk Na + is reabsorbed in these tubules in undernourished rats because the lower transport demand in lower-sized animals.…”

“…One widely used model of a multideficient diet for rats is that formulated based on the alimentary habits of people from several developing countries [10][11][12][13] the so-called Regional Basic Diet (RBD) [14] (Table 1) (for a recent review, see [15]). This pro-hypertensive diet [15][16][17] has brown beans, manioc flour, jerked meat, and sweet potatoes as the main ingredients. [17].…”

“…This pro-hypertensive diet [15][16][17] has brown beans, manioc flour, jerked meat, and sweet potatoes as the main ingredients. [17]. 2 CTRL diet.…”

Different antihypertensive and metabolic responses to rostafuroxin in undernourished and normonourished male rats: Outcomes on bodily Na+ handling

“…In the case of RBD undernourished rats, the cortical renal tubulointerstitium has more than four times the number of angiotensin II‐positive cells found in CTRL rats (Silva, Muzi‐Filho, et al, 2014), evidence of an increased tissular RAAS activity. Moreover, rostafuroxin‐sensitive hypertension they develop (Figure 8) is also completely normalized by the administration of losartan (Pereira‐Acácio et al, 2022), an antagonist of type 1 angiotensin II receptors (Timmermans et al, 1995), suggesting an interaction between rostafuroxin and RAAS. In terms of actions in vessels (such as the thoracic aorta and mesenteric arteries), rostafuroxin appears to have opposite effects and the same final targets as RAAS.…”