Enhanced calcium-sensitivity of erythrocytes in hypertension--calcium-induced changes of erythrocyte osmotic fragility in essential hypertension

To investigate the Ca-sensitivity of the erythrocyte membrane in hypertension, the changes of the osmotic fragility of erythrocytes by Ca-loading and the effects of Ca-channel blockers or calmodulin-antagonist were observed in patients with essential hypertension. Erythrocytes were obtained from untreated patients with essential hypertension and age-matched normotensive subjects. Treatment of erythrocytes with Ca-ionophore A23187 and Ca in bathing medium caused the reduction of the osmotic fragility of erythrocytes dose-dependently on Ca-concentration. The degree in alteration of the osmotic fragility of erythrocytes was greater in essential hypertension than that in normotensive controls. In addition, Ca-induced changes of erythrocyte osmotic fragility was inversely correlated with the plasma renin activity in essential hypertension. In the presence of Ca-antagonists (verapamil, diltiazem) or calmodulin-antagonist (trifluoperazine), the reduction of the osmotic fragility of erythrocytes by Ca-loading was inhibited, and the differences of the osmotic fragility of erythrocytes between the hypertensives and the normotensive controls were abolished by these drugs. These results suggest that the greater changes of the osmotic fragility of the erythrocytes by Ca-loading in essential hypertension might be due to the abnormality of Ca-handling of the cell membranes causing an increase in the intracellular Ca concentration, contributing at least partially to the pathogenesis of hypertension.     

Metformin attenuates salt-induced hypertension in spontaneously hypertensive rats.

Metformin, an antihyperglycemic agent used for treatment of type 2 diabetes mellitus, lowers blood pressure in humans and experimental animals. We recently demonstrated that short-term administration of metformin may lower blood pressure by reducing sympathetic neural outflow. The present studies were initiated to determine whether long-term administration of metformin blunts salt-induced hypertension, a condition characterized by elevated sympathetic activity. Male spontaneously hypertensive rats, in which radiotelemeters had been implanted for continuous monitoring of heart rate and blood pressure, were randomly assigned to groups that received vehicle (drinking water) or metformin (500 mg/kg per day) and ate a normal 0.3% NaCl diet and to groups that received vehicle or metformin and ate a high 8.0% NaCl diet for a period of 4 weeks. Although metformin did not affect blood pressure in the animals that ate the normal-salt diet (vehicle, 130+/-3 mm Hg; metformin, 133+/-5 mm Hg; mean+/-SEM), drug treatment blunted the rise in pressure caused by a high-salt diet (vehicle, 153+/-4 mm Hg; metformin, 140+/-5 mm Hg; P<0.001). In agreement, during direct pressure recordings in anesthetized rats, the animals that ate the high-salt diet had higher pressures (136+/-13 mm Hg) than those in the control (98+/-5 mm Hg, P<0.01), metformin (100+/-7 mm Hg, P<0.01), and metformin/high-salt groups (92+/-3 mm Hg, P<0.01). Finally, metformin lowered heart rate in rats that ate the normal- and high-salt diets (310+/-3 and 305+/-4 bpm) compared with rats that ate normal- and high-salt diets given vehicle (332+/-3 and 324+/-2 bpm, P<0.01). These data indicate that the chronic depressor actions of metformin are enhanced in animals with hypertension exacerbated by a high-salt diet.     

Genetic association of hypertension and vascular changes in stroke-prone spontaneously hypertensive rats

Isolated tail arteries from stroke-prone spontaneously hypertensive rats (SHRSP) exhibit oscillatory contractile activity in response to norepinephrine, whereas those from normotensive Wistar-Kyoto rats (WKY) do not. To determine whether the norepinephrine-induced oscillations are related to high blood pressure or to separable genetic differences between strains, the response to norepinephrine was studied in adult SHRSP, WKY, and progeny of genetic crosses of SHRSP and WKY (F1, F2, F1 X SHRSP, F1 X WKY). Helical tail artery strips were mounted in a tissue bath for isometric force recording. Rats were classified as responders if oscillatory activity in the presence of 1.8 X 10(-7) M norepinephrine exceeded 250 mg/10 min (milligrams of force amplitude during a 10-minute interval). The blood pressures (mm Hg +/- SEM; tail cuff method) and percentage of rats exhibiting norepinephrine-induced oscillations were as follows: WKY: 109 +/- 3, 0%; F1: 129 +/- 4, 0%; F2: 150 +/- 4, 38%; F1 X WKY: 137 +/- 3, 9%; F1 X SHRSP: 188 +/- 7, 71%; SHRSP: 207 +/- 7, 100%. The distribution of the frequency of animals with oscillatory activity among the progenies was consistent with the hypothesis that a single gene locus determines the observed difference in oscillatory activity between the WKY and SHRSP strains. The allele from the SHRSP that determines the activity phenotype is recessive to the allele contributed by the normotensive WKY strain. In the segregating F2 progeny, the blood pressure of the responders was higher than that of the nonresponders (161 +/- 6 vs 144 +/- 4 mm Hg; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Increased inositol trisphosphate in erythrocytes of spontaneously hypertensive rats

Phosphoinositide (PI) turnover, a major control mechanism of cellular function, was studied in erythrocytes of spontaneously hypertensive rats (SHR). After 32p (inorganic phosphate) incorporation in intact cells, release of inositol trisphosphate (IP3) and inositol bisphosphate (IP2) from membrane fractions was measured in SHR with or without prior Ca2+ stimulation. The present study revealed an increase of Ca2(+)-stimulated IP3 release in SHR, suggesting high polyphosphoinositide phosphodiesterase activity in this model of hypertension.     

Portal hypertension ameliorates arterial hypertension in spontaneously hypertensive rats

Systemic hemodynamic effects of portal hypertension in arterial hypertension and their relationship to serum bile acid levels were investigated using spontaneously hypertensive rats 2 and 15 weeks after partial portal vein ligation (SHR-PVL) or sham operation (SHR-SH) and normotensive controls. Mean arterial pressure in SHR-PVL at 2 weeks was decreased to normal due to a decrease in peripheral resistance. Mean arterial pressure and peripheral resistance in SHR-PVL at 15 weeks did not differ from SHR-SH. Resolution of this arterial hypotensive effect and systemic hyperdynamic circulation was associated with decreased portal-systemic shunting. Bile acid levels were increased in both SHR-PVL groups. These results suggest that an endogenous circulating vasodilator(s) associated with portal hypertension ameliorates the systemic vasoconstriction in SHR. Bile acids, while not direct mediators of these hemodynamic events, may be prototypic of this vasodilator. This arterial hypertensive model may aid further investigation of the mechanisms contributing to the hyperdynamic state in portal hypertension.     

Sodium transport kinetics in erythrocytes from spontaneously hypertensive rats

Rat erythrocytes with five different amounts of Na+ content have been prepared by using a new, nondetrimental Na+-loading method (net NaHPO4-influx through the anion carrier). This method allowed the determination of 1) maximal translocation rates and apparent dissociation constants for internal Na+ of the Na+-K+ pump, outward Na+-K+ cotransport, and Na+-Li+ countertransport and 2) rate constants of Na+ leak in erythrocytes from spontaneously hypertensive rats of the Okamoto strain and Wistar-Kyoto normotensive controls aged 2 to 26 weeks. Two major abnormalities were found in erythrocytes from spontaneously hypertensive rats: 1) a decreased cotransport affinity for internal Na+, which was constantly observed from 2 to 26 weeks of age (mean intracellular Na+ content for half-maximal stimulation of outward Na+-K+ cotransport = 33.1 +/- 7.0 [SD] mmol/L cells in spontaneously hypertensive rats vs 16.7 +/- 4.7 mmol/L cells in Wistar-Kyoto rats; p less than 0.001), and 2) a decreased maximal pump rate in adult (15- to 26-week-old) spontaneously hypertensive as compared with that for age-matched Wistar-Kyoto rats (9-37 vs 34-70 mmol/L cells/hr). Therefore, the low cotransport affinity for internal Na+ appears to be a stable, possibly genetic defect of spontaneously hypertensive rats. Conversely, the decreased maximal pump rate may be a secondary event, possibly reflecting the appearance of endogenous pump inhibitors in the plasma of adult spontaneously hypertensive rats.     

Alterations in catecholamine release in the central nervous system of spontaneously hypertensive rats.

The aim of the present study was to investigate alterations in catecholamine release in the central nervous system of spontaneously hypertensive rats. Slices of hypothalamus, medulla oblongata and striatum were prepared from spontaneously hypertensive rats (SHR: 9-10 weeks old) and age-matched Wistar Kyoto rats (WKY). The slices were incubated with (3H)norepinephrine (NE) or (3H)dopamine (DA), superfused with Krebs-solution in vitro, and the release of the catecholamines was compared between the two strains. The basal release of hypothalamic (3H)NE did not differ between SHR and WKY slices. However, stimulation (1 Hz)-evoked (3H)NE release was significantly greater in SHR than in WKY (percent fractional release of total tissue NE: WKY 0.494 +/- 0.019%, n = 6, SHR 0.730 +/- 0.053%, n = 6, p less than 0.05). The stimulation-evoked (3H)NE release from the medulla oblongata did not differ significantly between SHR and WKY slices. Finally stimulation-evoked release of striatal (3H)DA was significantly depressed in SHR (percent fractional release of total tissue DA: WKY 2.048 +/- 0.24%, n = 6, SHR 1.460 +/- 0.068%, n = 6, p less than 0.05). These results indicate that the release of hypothalamic NE and striatal DA are altered in SHR. It is suggested that enhanced hypothalamic noradrenergic activity and reduced striatal dopaminergic activity can increase sympathetic outflow to the periphery, which may play a role in the pathogenesis of this form of hypertension.     

Increased ability of erythrocytes to aggregate in spontaneously hypertensive rats

The development of hypertension is accompanied by changes in the rheological properties of blood, particularly by increased red blood cell (RBC) aggregation leading to further pathological complications. However, it is not clear whether these changes in aggregation are caused only by increased concentrations of plasma adhesion proteins or if alterations in RBC membranes are also involved. The aim of the present study was to determine if RBC aggregability is altered during hypertension and if these changes correlate with alterations in RBC membrane protein concentrations. Aggregability changes were evaluated by comparing fibrinogen (Fb)-induced aggregation of RBCs from spontaneously hypertensive rats (SHR) with RBCs from age matched normotensive Wistar Kyoto (WKY) rats. ANOVA showed a significant increase in dose-dependent Fb-induced aggregation of RBCs in the SHR group. Analysis of Coomassie-stained gels of RBC membrane proteins using SDS-PAGE showed a significant increase in the amount of a protein at 110 kD in the SHR group. These results show that increased RBC aggregability is accompanied by alterations in RBC membrane protein composition during hypertension development.     

DOCA-salt induced malignant hypertension in spontaneously hypertensive rats

DOCA-salt hypertension was produced in 10 male 10-week-old normotensive Wistar-Kyoto (WKY) rats receiving deoxycorticosterone acetate (DOCA; 100 mg/kg, subcutaneous pellet) and 1% NaCl drinking water and was compared with data from 10 age- and sex-matched WKY receiving normal tap water (C). These data were also compared with spontaneously hypertensive (SHR) rats similarly treated. After 10 weeks on these programmes, systemic and regional haemodynamics were determined in conscious rats using microsphere techniques. DOCA-salt treatment increased mean arterial pressure (MAP), total peripheral resistance index (TPRI), cardiac and renal weights in both WKY and SHR. In contrast to SHR (C), the SHR (DOCA) demonstrated more severe MAP elevation (204 +/- 4 versus 185 +/- mmHg; P less than 0.01), more severe systemic and regional (especially renal) vasoconstriction, and malignant vasculitis associated with azotaemia and hyperuricaemia. The hyperuricaemia was related inversely to renal blood flow (r = -0.74; P less than 0.01) and directly to renal vasoconstriction (r = 0.65; P less than 0.05) in SHR (DOCA). These data suggest that in both WKY and SHR, DOCA and salt produced marked cardiovascular changes and SHR rats developed malignant hypertension.     

Ultrastructural changes in hypertrophied myocardium of spontaneously hypertensive rats.

In seven arbitrarily selected groups of 3-, 5-, 9-, 11-, 15-, and 21-week and one-year-old spontaneously hypertensive rats (SHR) (F25-26), qualitative as well as quantitative light and electron microscope studies were conducted on the myocardium in the left ventricular papillary muscle and lateral wall. Age-and body-weight-matched groups of normotensive Wistar-Kyoto rats were employed as controls. In the strain of SHR used in this study blood pressure was significantly higher than in the controls in the 7th week of age, reached sustained levels (approximately 180 mmHg) in the 15th week of age and remained higher thereafter. The heart weight/body weight ratio gradually increased in SHR after the 15th week of age. In 3-week-old SHR, there was no significant difference in fine structure of the myocardium in comparison with control animals. The cardiocytes were small in size and rapidly growing. Myofibrillogenesis seemed to occur in association with juvenile forms of intercalated discs, subsarcolemmal dense mats, occasional Z band expansions and unorganized filamentous structures in the periphery of preexisting myofibrils. In 5- and 9-week-old SHR, the muscle fiber diameters in the papillary muscle were significantly larger than those in control animals of the same age. Subcellular structures of many cardiocytes were, however, apparently equal in both papillary muscle and lateral wall of the left ventricle in SHR and control animals. In 11-week-old SHR, the cardiocytes were moderately hypertrophied in both papillary muscle and lateral wall. The myofibrils were significantly increased in mass in association with altered intercalated discs, extended subsarcolemmal dense mats and unorganized filamentous structures in the periphery of preexisting myofibrils. Focal interstitial fibroses occurred in in the myocardium, and tunnel capillaries appeared in some hypertrophied cardiocytes. In 15-week-old SHR, the cardiocytes had markedly hypertrophied in accordance with the establishment of sustained hypertension. The intracellular volume ratios of myofibrils and T system had increased significantly whereas the mitochondrial volume had markedly decreased resulting in a significant increase in the myofibril/mitochondria volume ratio. There were marked changes in the intercalated discs associated with numerous immature sarcomers, and frequent abnormal Z band expansions. Interstitial fibroses had markedly increased in number and extent. In 21-week-old SHR, in addition to findings similar to those in 15-week-old SHR, heterogeneous changes of the contractile material, mitochondria and sarcoplasmic matrix were more prominent, suggesting heterogeneous malfunctions in later stages of cardiac hypertrophy. In one-year-old SHR, subcellular changes in many cardiocytes qualitatively resembled those in 21-week-old SHR. Interstitial fibroses and tunnel capillaries were also increased in extent and number...     

Partitioning of erythrocytes from spontaneously hypertensive and Wistar-Kyoto rats

The charge-associated and non-charge-associated (probably lipid-related) surface properties of erythrocytes from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY), from which SHR were originally derived, were studied by cell partitioning in dextran-polyethylene glycol aqueous phase systems. A major difference was found in the surface charge-associated and lipid-related properties of red blood cells from SHR and WKY: the cells from WKY had the higher partition ratio in both charge-sensitive and non-charge-sensitive phases. No difference in partitioning could be found between any two SHR nor between any two WKY. The SHR and WKY erythrocytes showed the same difference when compared with one another even when rats had the same blood pressure. When red blood cells from SHR with different blood pressure were compared, there still was no difference in their surface properties. These results suggest that the differences in both charge-associated and lipid-related surface properties of erythrocytes from SHR and WKY are strain-specific (i.e., genetic) but that there is no correlation, reflected by partitioning, between red blood cell surface properties and the degree of the rats' hypertension.     

Potassium depletion ameliorates hypertension in spontaneously hypertensive rats

The hemodynamic effect of moderate K+ depletion in hypertension is unknown. Since severe K+ depletion reduces systemic vascular resistance in normotensive rats, we determined the effect of K+ depletion on the natural history of hypertension in spontaneously hypertensive rats (SHR). Wistar-Kyoto rats (WKY) and SHR were fed a K+-replete, a moderately K+-depleted, or a severely K+-depleted diet. After 6 weeks, systemic vascular resistance was reduced by 25% in WKY on the severely K+-depleted diet while mean arterial pressure and systemic vascular resistance were comparable in WKY on the other two diets. In SHR on the severely K+-depleted diet for 6 weeks, muscle K+ was reduced by 23% and growth rate by 65%. In SHR on the moderately K+-depleted diet, growth rate was reduced by 23% after 3 weeks. By 6 weeks, however, muscle K+ was reduced by 5 to 6% and growth rate was comparable to that in SHR receiving the K+-replete diet. The administration of either K+-depleted diet prevented the development of hypertension (systolic blood pressure: severely depleted, 116 +/- 4; moderately depleted, 122 +/- 3; K+-replete, 155 +/- 5 mm Hg; p less than 0.001 compared with both K+-depleted groups) and reversed established hypertension (systolic blood pressure: severely depleted, 116 +/- 4; moderately depleted, 128 +/- 3; K+-replete, 171 +/- 5 mm Hg; p less than 0.001 compared with both K+-depleted groups). The protective effect of K+ depletion was mediated by a 40% reduction in systemic vascular resistance. These results suggest that K+ depletion has a potent antihypertensive effect in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)     

Arterial structural changes with verapamil in spontaneously hypertensive rats.

Reducing pulse pressure might be more powerful than reducing mean arterial pressure to obtain regression of vascular hypertrophy. However, this hypothesis has never been investigated in the conduit arteries of intact hypertensive animals. A group of 4-week-old spontaneously hypertensive rats (SHR) was treated with the calcium-entry blocker verapamil (50 mg/kg) for 16 weeks and compared with untreated SHR and control Wistar Kyoto (WKY) normotensive rats of the same age. At the end of the experiment, intraarterial thoracic aorta blood pressure was measured both in the conscious and anesthetized animals. Carotid artery diameter and stiffness (echo-tracking techniques) and aortic histomorphometry were determined in parallel. With verapamil, pulse pressure, but not mean arterial pressure, was significantly decreased but did not reach the normotensive values. Carotid internal diameter, medial thickness, and collagen content were significantly reduced by comparison with SHR and did not differ from the values of the WKY group. A significant positive and independent correlation was observed between pulse pressure and medial thickness in the overall population. The study shows that, in SHR chronically treated with verapamil, structural changes may be completely prevented without any change in mean arterial pressure. The parallel change in pulse pressure might suggest that mechanosensitive elements within the vascular wall may be selectively sensitive to the dynamic aspects of physical forces and are able to convert frequency and amplitude information into cellular responses that lead to vascular remodeling.     

Calcium ATPase in erythrocytes of spontaneously hypertensive rats of the Milan strain

Calcium (Ca)-dependent ATPase activity was determined in erythrocyte membrane ghosts from normal and spontaneously hypertensive rats of the Milan strain in order to detect changes in enzyme activity which had previously been shown in the spontaneously hypertensive rat strain. Activity was similar in control and hypertensive rats in the absence of calmodulin. In contrast, activity in the presence of saturating amounts of calmodulin was significantly lower in the hypertensive rats. At the Vmax (free Ca2+ concentration 10 mumol/l) the decrease was about 30% (70.1 +/- 8.94 versus 49.1 +/- 4.75 nmol of ATP split/mg of ghost proteins per min; P less than 0.05). The affinity of the ATP-dependent Ca2+ pump for Ca2+ (Km about 1 mumol/l) was not altered in the hypertensive rats. It is possible that deficient Ca ATPase activity sustains an increase of intracellular free Ca in cells of hypertensive rats concomitant with the intracellular sodium (Na) decrease typical of this strain.     

Alterations in the plasma membrane properties of the myocardium of spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats were used to investigate the adaptive biochemical changes in the myocardium in response to chronic afterload. Ouabain-inhibited Na+,K+-adenosine triphosphatase (ATPase) activity was decreased by 40% in myocardium of SHR compared with that from WKY, which may lead to increased intracellular Ca2+ through Na+-Ca2+ exchange. Similarly, alpha 1-adrenergic receptor density, estimated by [3H]prazosin binding, was decreased by 42% in myocardial membranes of SHR, while the affinity for the agonist and the antagonist was not altered. In contrast, the number of Ca2+ channels estimated by [3H]nitrendipine binding was increased by 45% in myocardial membranes of SHR, while the affinity was comparable between SHR and WKY. These differences between WKY and SHR in the membrane properties were not due to differential contamination of plasma membranes because the activities of other putative plasma membrane marker enzymes were comparable between WKY and SHR. There were no differences between WKY and SHR in the myosin ATPase activity estimated using myofibrils, actomyosin, and myosin. These results suggest that specific alterations have occurred in the plasma membrane properties of myocardium of SHR that result in altered intracellular Ca2+ metabolism. These alterations may have an important bearing on excitation-contraction coupling in myocardium of SHR.     

Intracerebroventricular metformin attenuates salt-induced hypertension in spontaneously hypertensive rats

The aim of this study was to examine the effects of long-term continuous intracerebroventricular (icv) infusion of metformin on blood pressure (BP) in spontaneously hypertensive rats (SHR). To accelerate the development of hypertension, SHR were fed a 8% NaCl diet during the 3-week study period. Metformin was given in the following doses: 0 (isotonic saline; n = 7), 25 (n = 8), 50 (n = 6), 100 (n = 6), and 200 μg/day icv (n = 5). Mean arterial pressure (MAP) and heart rate (HR) were measured by radiotelemetry, and as a measure of the contribution of sympathetic nerve activity to BP, the decrease in MAP in response to ganglionic blockade with hexamethonium, 30 mg/kg iv, was determined once weekly. In vehicle treated rats, MAP increased by 27 ± 4 mm Hg, whereas in rats treated with a low dose of metformin (25 μg/day), MAP increased only by 7 ± 3 mm Hg (P < .01). The hypotensive response to hexamethonium was attenuated by all doses of metformin suggesting that chronic icv metformin decreased central sympathetic outflow. The highest doses of metformin (100 and 200 μg/day) also prevented development of hypertension, but these doses were highly neurotoxic as demonstrated by histologic evaluation post mortem. Fast-Fourier transformation of MAP revealed increased variability within the 0.15 to 0.6 Hz frequency range in rats treated with neurotoxic doses of metformin, suggesting impaired sympathetic control of BP in these animals. In conclusion, long-term icv infusion with apparently nontoxic doses of metformin attenuates hypertension and decreases the hypotensive responses to ganglionic blockade in SHR, suggesting a centrally elicited sympathoinhibitory action.     

Alterations of calcium channels in vascular smooth muscle cells from spontaneously hypertensive rats.

We examined the possible alterations in calcium handling through the calcium channels of spontaneously hypertensive rats (SHR) using 45Ca2+ uptake measurements in cultured aortic cells. Primary cultures of vascular smooth muscle cells (VSMC) were obtained by enzymatic dissociation of the thoracic aortas from 8-week-old SHR and age-matched Wistar-Kyoto rats (WKY). The functions of voltage sensitive calcium channels (VSCC) and receptor operated calcium channels (ROCC) were estimated from the activated 45Ca2+ uptake in VSMC with high K+ depolarization and arginine vasopressin (AVP), respectively. Compared to basal conditions, depolarization with 55 mM KCl increased 45Ca2+ uptake at 20 min by 94 +/- 17 (SE) % in SHR and 38 +/- 6% in WKY. The activated 45Ca2+ uptake was significantly greater in SHR than in WKY (p < 0.01). There was no significant difference in 45Ca2+ uptake at 20 min in the presence of 5 x 10(-8)M AVP between SHR and WKY. These results suggest that calcium uptake, at least through VSCC, is increased in VSMC of SHR. This enhanced activity may be implicated in the hypertensive mechanisms in this model of hypertension.     

Cerebrospinal fluid sodium and enhanced hypertension in salt-loaded spontaneously hypertensive rats.

OBJECTIVE AND DESIGN: The present study was designed to determine whether increases in sodium concentration in the cerebrospinal fluid (CSF) play a role in the augmented hypertension induced by long-term salt loading in spontaneously hypertensive rats (SHR), and whether the enhanced arginine vasopressin (AVP) activity and/or the sympathetic nervous system contribute to the increased hypertension. METHODS: Measurement of CSF sodium concentration and systolic blood pressure of SHR during salt loading, with or without uninephrectomy, for 7 weeks. Assessment of the hypotensive response to AVP antagonist and hexamethonium, and the plasma levels of AVP and catecholamines. RESULTS: Salt-loading for 7 weeks led to gradual increase in hypertension in SHR. CSF sodium in the SHR was increased by a combination of uninephrectomy and saline-drinking after 7 weeks, but not 3 weeks. The difference in mean arterial pressure (MAP) among the three groups of SHR disappeared after the combined blockade of AVP and sympathetic nervous function. CSF sodium correlated with both resting MAP and the fall in MAP induced by the combined administration of AVP antagonist and hexamethonium. Plasma levels of AVP were significantly elevated in the salt-loaded uninephrectomized SHR. Plasma catecholamines did not change significantly as a result of treatment. CONCLUSIONS: We tentatively conclude that chronic salt loading may lead to an increase in CSF sodium, in association with an enhancement of sympathetic nerve activity and, to some extent, of AVP release. These events may explain the augmented development of hypertension in SHR.