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A study on three models of hypertension : genetic, mineralocorticoid, and ethanol-induced Chan, Thomas C. K.


The Okamoto-Aoki strain of spontaneously hypertensive rats (SHR) is probably the most studied animal model of hypertension. Previous experience from our laboratory indicated that the vascular smooth muscle of the SHR is hyper-reactive to pressor agents in vitro, and that the sensitivity to calcium is also altered in these tissues. Since there is evidence for sodium ion and sodium pump abnormalities in erythrocytes of hypertensive patients and animals, the decision was made to use the erythrocyte membrane as a model for studying calcium-membrane interactions in the SHR. The Ca⁺⁺/Mg⁺⁺ ATPase activities (both high and low affinity) in the erythrocyte membrane from SHR were measured and found to be significantly elevated when compared to those of normotensive controls (WKY). Other erythrocyte membrane enzymes are not different between the two groups. Passive calcium influx into intact erythrocytes at 4°C was examined using ⁴⁵Ca as tracer and a significant increase in the passive permeability to calcium across the SHRs erythrocyte membrane was found when compared to the WKYs. Other abnormalities in the SHR erythrocyte include a reduction in osmotic fragility and increased levels of membrane cholesterol, phosphatidyl choline and sphingomyelin with marginal decreases in phosphatidyl ethanolamine and phosphatidyl serine. These findings indicate that structural and compositional alterations are present in the SHR erythrocyte membrane and these may be related to the increased passive permeability to calcium and the possibly compensatory increase in Ca⁺⁺/Mg⁺⁺ ATPase activity described earlier. Studies on the erythrocyte membranes of DOCA/salt hypertensive (DOCA) rats revealed no major differences in the activities of the membrane enzymes between the DOCA and nephrectomized controls (NC) animals. Furthermore, no difference was observed in passive calcium permeability between the erythrocytes from both groups of animals. Contrary to what was found in the SHR, osmotic fragility of the DOCA erythrocytes is slightly higher than that of NC's at all NaCl concentrations studied. No gross differences in membrane cholesterol and phospholipid profile were detected between the erythrocyte membranes from the two groups of animals'. These findings can be viewed as supportive evidence for the hypothesis that the membrane abnormalities observed in the SHR erythrocyte are probably genetically determined and not a consequence of elevated arterial pressure. In the third model of hypertension studied, rats were given increasing amounts of ethanol in their drinking water over period of 12 weeks, and a mild but significant (approx. 20%) elevation of systolic pressure was .observable beginning at week 4 and persisting through week 12. Urine ion analysis revealed that the ethanol-treated animals have reduced 24 hour urinary output and significant sodium retention. These findings prompted us to study the plasma volume in the animals using ¹⁴C-methyl-Y-globulins as an indicator. The plasma volume of the ethanol-treated animals averaged 20% higher than that of the control animals. Plasma catecholamine analysis revealed a significant increase in the levels of circulating noradrenaline in the ethanol-treated animals, but no differences in adrenaline and dopamine levels could be found when compared to controls. In vitro vascular smooth muscle responsiveness and erythrocyte membrane properties are not different between the two groups of animals. These results suggest that the mild blood pressure elevation in the ethanol-treated animals may be associated with both plasma volume expansion and elevated levels of circulating noradrenaline, and is probably not the result of. increased vascular responsiveness. Membrane alterations observed in SHR were not present in the erythrocytes of the ethanol-treated animals. To further investigate the confounding factors responsible for the blood pressure elevation in ethanol-treated animals, both controls and alcoholic animals were subjected to heat stress beginning at the 4th week of ethanol treatment, and a stratified distribution in the mean blood pressure is observed at week 12. The control unstressed (CU) animals have the lowest pressures, the control stressed ' (CS) animals have significantly higher pressures than CU groups, the alcoholic unstressed (AU) animals have the second highest pressure values, with the alcoholic 'Stressed (AS) having the highest mean blood pressure of all. Plasma volume is not different among the two control (CU, CS) and the two alcoholic (AU, AS) groups. The plasma noradrenaline levels correlated very well with the extent of blood pressure elevation and followed the same stratified distribution with CU animals having the lowest and AS animals having the highest levels. These results suggest that ethanol and stress may interact to produce hypertension, and that elevated plasma noradrenaline levels may play a role in the blood pressure elevation induced by stress.

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