Milan Normotensive Rats Research Articles

Na+-H+ exchange and other ion-transport systems in erythrocytes of essential hypertensives and spontaneously hypertensive rats: a comparative analysis

The activity of ion-transport systems and Ca2+-induced erythrocyte haemolysis were compared between patients with essential hypertension and two strains of spontaneously hypertensive rats. Previous data on the increased rate of Na+-Li+ countertransport in erythrocytes of essential hypertensives were confirmed in this study. However, identification of Na+-Li+ countertransport in rat erythrocytes remained a complicated person because of the high rate of sodium-independent efflux of Li+. The rate of Na+-H+ exchange increased by 50-80% both in spontaneously hypertensive Wistar-Kyoto rats (SHR) and in patients with essential hypertension. No difference between Milan hypertensive strain rats (MHS) and Milan normotensive strain rats (MNS) was found. The rate of Na+,K+ cotransport increased in SHR and MHS erythrocytes compared with rats of the control strains [normotensive Wistar-Kyoto rats (WKY) and MNS; 30-50 and 90-110%, respectively]. No difference in this parameter was found between patients with essential hypertension and healthy subjects. Erythrocytes of patients with essential hypertension and of SHR were characterized by a higher sensitivity of their K+ channels to the increased concentration of intracellular Ca2+. This parameter did not change in MHS erythrocytes. Ca2+-induced haemolysis increased four- to fivefold in MHS erythrocytes compared with MNS and did not change in erythrocytes of SHR and patients with essential hypertension. The conclusion from these data is that the SHR strain is a more adequate model of human essential hypertension than the MHS.

Na,K-ATPase Activity in Renal Tubule Cells From Milan Hypertensive Rats

Several abnormalities of cation transport have been described in the Milan hypertensive rats (MHS). In this study we examined Na,K-ATPase activity in proximal convoluted tubules (PCT) cells and medullary thick ascending limb of Henle cells (TAL) from MHS and from the Milan normotensive rats (MNS). Na,K-ATPase activity was determined as 32P-ATP hydrolysis in single tubule segments. Na,K-ATPase activity (pmol Pi/mm t/h) was significantly higher in MHS than MNS both in PCT (903 +/- 227 n = 8 v 506 +/- 285 n = 12) and TAL (4324 +/- 800 n = 5 v 3063 +/- 625 n = 5). Na,K-ATPase dependent respiration was determined in PCT cell from MNS and MHS. Under basal condition Na,K-ATPase dependent respiration (mumol O2/mg protein/h) was higher in MHS than in MNS (24.2 +/- 1.8 n = 5 v 16.1 +/- 0.4 n = 5). When the cells were Na loaded by amphotericin Na,K-ATPase dependent respiration increased significantly more in MHS than MNS (38.4 +/- 1.6 v 26.8 +/- 2.2 n = 4). Thus, Na,K-ATPase activity is higher in renal tubule cells both at normal intracellular Na and after the cells have been Na loaded. The results indicate that regulation of Na homeostasis in renal tubule cell is different in MHS and MNS.

Renal Abnormalities in Experimental Models of Hypertension

Renal regulation of extracellular fluid volumes via the tubuloglomerular feedback control (TGF) has been studied in rat experiments. Important modulation of the TGF mechanism was achieved from arterial blood pressure level and extracellular fluid volume via renal interstitial pressure changes. This volume-regulating mechanism has been studied in spontaneously hypertensive rats of the Milan strain (MHS) and compared with Milan normotensive rats (MNS). During development of hypertension, the TGF mechanism was highly sensitive and activated to reduce glomerular filtration rate and retain electrolytes and water. When blood pressure was increased in the adult MHS animals the TGF mechanism was normalized. It could be speculated that the cause of the increased TGF mechanism was dependent on an increased Na-K-2 Cl cotransport into the macula densa cells. In SHR rats compared to Wistar-Kyoto rats, the TGF sensitivity was also increased but, in contrast, the TGF mechanism was not activated in these animals to retain fluid. Some other mechanism for the development of hypertension in these rats has to be proposed.

Renal Abnormalities in Experimental Models of Hypertension

Summary: Renal regulation of extracellular fluid volumes via the tubuloglomerular feedback control (TGIF) has been studied in rat experiments. Important modulation of the mechanism was achieved from arterial blood pressure level and extracellular fluid volume via renal interstitial pressure changes. This volume-regulating mechanism has been studied in spontaneously hypertensive rats of the Milan strain (MHS) and compared with Milan normotensive rats (MNS). During development of hypertension, the TMG mechanism was highly sensitive and activated to reduce glomerular filtration rate and retain electrolytes and water. When blood pressure was increased in the adult MHS animals the TGF mechanism was normalized. It could he speculated that the cause of the increased TGF mechanism was dependent on an increased Na-K-2 CI cotransport into the macula densa cells. In SHR rats compared to Wistar-Kyoto at, the TGF sensitivity was also increased but, in contrast. the TGF mechanism was not activated in these animals to retain fluid. Some other mechanism for the development of hypertension in these rats has to be proposed.

Relationship between erythrocyte volume and sodium transport in the Milan hypertensive rat and age-dependent changes.

The relationship between differences in red blood cell (RBC) volume and ion transport across the erythrocyte cell membrane were investigated in the Milan Hypertensive (MHS) and Milan Normotensive (MNS) rat strains, under different experimental conditions and during ageing. The results obtained indicate that: the difference in Na+/K+ cotransport between MHS and MNS disappear when the RBC volume of the two strains becomes equal under hypotonic swelling; MHS RBCs are osmotically more fragile than those of MNS, probably because of a different membrane structure rather than a different amount of membrane surface, and the smaller volume and the lower Na+ content of MHS RBCs are maintained throughout the life span, while Na+/K+ pump activity and Na+/K+ cotransport undergo age-dependent changes, related to the development of hypertension. All these findings suggest that a primary abnormality of the cell membrane structure of MHS, probably located in the cytoskeleton, is responsible for the cell functional alterations that we previously demonstrated to be genetically associated with MHS hypertension.