A study of brain and serum brain-derived neurotrophic factor protein in Wistar and Wistar-Kyoto rat strains after electroconvulsive stimulus.

BACKGROUND: Serum brain-derived neurotrophic factor (BDNF) protein has been related to depression and less consistently to its treatments in human studies. However, animal studies have failed to demonstrate a clear link between BDNF protein in serum and brain tissue. METHODS: Serum and brain tissue levels of BDNF protein were measured with ELISA in the Wistar-Kyoto (WKY) and Wistar strains at 1 and 7 days after 5 daily electroconvulsive stimulus sessions or sham treatments. RESULTS: The WKY strain showed lower baseline serum BDNF protein relative to Wistar controls. After 5 electroconvulsive stimuli, BDNF protein density was significantly increased in hippocampus and cortical regions, but not in the cerebellum or in serum. A clear correlation between brain and serum BDNF was not observed in either strain or treatment group. DISCUSSION: Despite lower baseline serum BDNF protein in the WKY strain, a lack of change in serum BDNF after electroconvulsive stimulus and a lack of correlation between brain and serum BDNF protein calls into question the relevance of serum BDNF as a measure of depression and treatment response.

Baseline serum cardiac troponin I concentrations in Sprague-Dawley, spontaneous hypertensive, Wistar, Wistar-Kyoto, and Fisher rats as determined with an ultrasensitive immunoassay.

Cardiac troponins have proved to be reliable blood biomarkers for identifying a variety of myocardial alterations in humans and animals. Recently, an ultrasensitive cTnI assay (Erenna IA) has been used to demonstrate increases in baseline cTnI resulting from drug-induced myocardial injury in rats, dogs, and monkeys, as well as to document baseline cTnI ranges in Sprague-Dawley (SD) rats. The present study was initiated to use the Erenna cTnI assay to further document baseline cTnI concentrations in normal control animals from multiple strains, including SD, Spontaneous Hypertensive (SHR), Wistar, Wistar-Kyoto (WKY), and Fisher strains. Baseline cTnI concentrations were quantified in all rats tested, and males had higher mean cTnI concentrations than females of the same strain. SHR males had the highest mean cTnI concentrations and the largest cTnI variability. Interestingly, cTnI concentrations increased in castrated SHR compared with unaltered male SHR, whereas cTnI concentrations decreased in ovariectomized SHR compared with unaltered female SHR. These results show significant differences in cTnI concentrations between strains, sexes, and noncardiac surgical alterations in control animals, and identify these as potential contributing factors to cTnI baseline variability that should be taken into account when using ultrasensitive cTnI as a biomarker to assess preclinical cardiotoxicity.

Similarities of essential and spontaneous hypertension. Volume and number of blood cells.

Spontaneously hypertensive rats have long been used as an animal counterpart of human essential hypertension. The validation of this strain as a model rests mainly on the "clinical" similarity of the two syndromes, but it has scarcely been founded on numerical comparison of measurable parameters. We investigated three hematological indexes previously recognized to be altered in spontaneously hypertensive rats: the single-cell volume of erythrocytes, the single-cell volume of platelets, and the erythrocyte number. Erythrocyte volume was lower by 7%, platelet volume was higher by 12%, and erythrocyte count was higher by 22% in spontaneously hypertensive rats in comparison with Wistar-Kyoto controls. More unexpectedly, it was found that erythrocyte volume is lower by 2%, platelet volume is higher by 3%, and erythrocyte number is higher by 6% in essential hypertensive subjects when compared with normotensive healthy subjects. These results, combined with previously reported blood cell alterations in subjects and rats, reinforce the evidence of a biological similarity between essential and spontaneous hypertension.

Activation of the humoral antihypertensive system of the kidney increases diuresis.

Isolated kidneys taken from normotensive Wistar-Kyoto rats were cross-perfused extracorporeally by normotensive strain-matched donor rats. The extracorporeal perfusion circuit was arranged so that the perfusion pressure to the normotensive recipient kidney could be varied from 90 to 200 mm Hg without any change in total flow through this circuit. This setup avoided hemodynamic or mechanical interferences with reflexogenic circulatory control in the normotensive donor rat when the recipient kidney was manipulated. Diuresis and natriuresis were measured in the normotensive donor rat and the normotensive recipient kidney. A few minutes after normotensive recipient kidney perfusion pressure had been raised, mean arterial pressure (MAP) and heart rate started to decline rapidly in the normotensive donor rat, and circulatory collapse ensued within 15 to 100 minutes. During the control period at 90 mm Hg normotensive recipient kidney perfusion pressure, urinary flow, MAP and heart rate were stable in the normotensive donor rat and the normotensive recipient kidney. When perfusion pressure was raised to 200 mm Hg in the recipient kidney, the urinary flow in the donor rat increased 62% on average in the first 10 minutes over values recorded before the pressure rise (p less than 0.05) while MAP simultaneously fell by 16% and HR remained unchanged. During the subsequent period, the urinary flow of the donor rat declined together with MAP and heart rate. In the extracorporeally high-pressure perfused recipient kidneys, an eightfold to ninefold increase in diuresis and natriuresis occurred during the first 45 minutes.(ABSTRACT TRUNCATED AT 250 WORDS)

Immunoreactive plasma concentrations of an endogenous antiopiate are higher in spontaneously hypertensive rats than in Wistar-Kyoto rats.

Tyrosine-MIF-1 (Tyr-Pro-Leu-Gly-NH2) is present in rat brain in varying concentrations throughout the day and can act as an opiate antagonist. Since altered sensitivity to pain is known to occur in hypertension, plasma and brain concentrations of Tyr-MIF-1--like immunoreactivity were measured in spontaneously hypertensive rats (SHR) and compared every 4 hours for 24 hours with the concentrations in control Wistar-Kyoto rats (WKY). The Tyr-MIF-1--like immunoreactivity in plasma was significantly higher in SHR than in the WKY at each interval; the mean difference was 62% (p less than 0.001). High-performance liquid chromatography demonstrated that peak immunoreactivity eluted in the same position as the synthetic tetrapeptide. Brain concentrations of the peptide were not reliably different between SHR and WKY. The diurnal rhythm was particularly evident in SHR: the highest concentrations of peptide in both brain and plasma occurred at 2000 hours. These results suggest the presence of another difference between SHR and WKY.

Evidence for a difference in vitamin D metabolism between spontaneously hypertensive and Wistar-Kyoto rats.

It has been contended that the metabolism of vitamin D in spontaneously hypertensive rats (SHR) is different from that in Wistar-Kyoto rats (WKY). To investigate this possibility, the plasma concentration of 1,25-dihydroxycholecalciferol (1,25[OH]2D) and several known determinants of its production rate were measured in SHR and WKY given normal and restricted amounts of dietary phosphorus. In 12-week-old male SHR given a normal amount of dietary phosphorus, the mean plasma concentration of 1,25(OH)2D (72 +/- 5 pg/ml) was significantly lower than that in age-matched WKY (129 +/- 6 pg/ml; p less than 0.001). The lower plasma concentration of 1,25(OH)2D in the SHR could not be attributed to higher circulating levels of inorganic phosphorus or ionized calcium, lower plasma concentrations of 25-hydroxycholecalciferol, or acidosis. However, in the SHR, urinary excretion of cyclic adenosine 3',5'-monophosphate (12.5 +/- 0.4 nmol/mg creatinine) was significantly lower than that in WKY (15.2 +/- 0.3 nmol/mg creatinine; p less than 0.001). In both SHR and WKY, restriction of dietary phosphorus for 1 week induced an increase in the plasma concentration of 1,25(OH)2D without affecting blood pressure. The current findings indicate that in 12-week-old male SHR, 1,25(OH)2D metabolism is different from that in age-matched WKY. The activity of 25-hydroxyvitamin D-1 alpha-hydroxylase, however, appears to be at least partially responsive to short-term restriction of dietary phosphorus. In SHR, the activity of 25-hydroxyvitamin D-1 alpha-hydroxylase may be lower than that in WKY, perhaps due in part to some impairment in the renal metabolism of, or responsiveness to, cyclic adenosine 3',5'-monophosphate.

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.

Ouabainlike Na+,K+-ATPase inhibitor in the plasma of normotensive and hypertensive humans and rats.

Acute volume expansion, increased sodium intake, and restraint on sodium excretion endow the plasma with an increased capacity to inhibit sodium transport. Cytochemical techniques can detect the presence of Na+K+-adenosine triphosphatase (ATPase) inhibitor in the plasma of normal humans and rats, the concentration of which is controlled by salt intake. The substance responsible appears to originate in the hypothalamus, where the concentration is also controlled by salt intake. The plasma concentration of the cytochemically detectable Na+,K+-ATPase inhibitor is substantially raised in the plasma of patients with essential hypertension, spontaneously hypertensive rats (SHR) and of Milan hypertensive rats. The concentration of activity in the hypothalamus of SHR is also considerably raised. These findings demonstrate that these forms of hypertension are associated with a rise in the concentration of a cytochemically detectable circulating Na+,K+-ATPase inhibitor that under normal circumstances is controlled by salt intake.

Platelet lipoxygenase in spontaneously hypertensive rats.

We have previously reported that the nonselective lipoxygenase inhibitor phenidone is a potent hypotensive agent in the spontaneously hypertensive rat (SHR). In the present study, we examined the relationship between production of platelet 12-hydroxyeicosatetraenoic acid (12-HETE) and intra-arterial blood pressure in SHR and Wistar-Kyoto rats (WKY) using both a cross-sectional analysis and an acute pharmacological intervention. Basal generation rate of 12-HETE by platelets collected from the SHR was approximately 3.7-fold higher than in the WKY (0.86 +/- 0.24 versus 0.23 +/- 0.05 nmol/mL per 10 minutes, respectively; P < .01). Systolic arterial pressure was positively related to platelet 12-HETE formation rate when the entire rat population was considered (r = .70, P < .001). The specific 12-lipoxygenase inhibitor cinnamyl-3,4-dihydroxycyanocinnamate induced lowering of both arterial blood pressure and platelet 12-lipoxygenase activity in SHR. At 15 mg/kg, cinnamyl-3,4-dihydroxycyanocinnamate elicited a marked hypotensive effect in SHR but not in WKY. This reduction in arterial pressure was accompanied by an approximate 70% inhibition in platelet 12-HETE production rate. The return of high blood pressure to basal levels was associated with a significant rise in the production of platelet 12-HETE toward control values (baseline, 0.97 +/- 0.33 nmol/mL per 10 minutes; nadir of blood pressure, 0.19 +/- 0.03; resumption of basal pressure, 0.42 +/- 0.14). In contrast, captopril (15 mg/kg) induced a quantitatively similar decrease in blood pressure but had no effect on platelet 12-HETE generation rate. Thus, hypertension in SHR is linked to increased production rate of platelet 12-HETE. Acute blood pressure reduction attained during lipoxygenase inhibition but not by angiotensin converting enzyme inhibition leads to a concomitant reduction in the production of platelet 12-HETE. We speculate that since rat arterial tissue produces 12-HETE, increased 12-lipoxygenase activity in SHR may contribute to the maintenance of elevated arterial pressure in this strain.

Calcium transport and vitamin D in three breeds of spontaneously hypertensive rats.

Conflicting results have been published by different laboratories comparing the rate of intestinal calcium transport and concentration of circulating 1,25-dihydroxyvitamin D (1,25-[OH]2D) in the spontaneously hypertensive rat (SHR) and control Wistar-Kyoto rat (WKY): They have been reported to be greater, the same, or lower in the SHR than in the WKY. We tested the possibility that the conflicting results might be breeder-related by measuring 1) the rate of intestinal mucosal calcium transport, 2) the concentration of circulating 25-hydroxyvitamin D (25-OH-D) and 1,25-(OH)2D, and 3) the concentration of intestinal mucosal receptor for 1,25-(OH)2D in the two strains of animals from three different breeders. Sodium and water transport were also measured because of their relevance to hypertension. Blood pressure was always higher and calcium, as well as mean sodium and water transport, was always lower in the SHR than in the WKY. The concentration of 1,25-(OH)2D was the same, higher, or lower in the SHR than in the WKY and was age- and breeder-dependent. Mean mucosal 1,25-(OH)2D receptor concentration was higher in the SHR and was variable, depending on breeder. We conclude that 1) the rate of calcium transport is lower in the SHR than in the WKY and independent of breeder and concentration of 1,25-(OH)2D in serum, 2) the variability in 1,25-(OH)2D concentration among investigators may be breeder-dependent, and 3) the higher receptor concentration in the intestinal mucosa of the SHR could be a compensatory response to the decreased rate of calcium transport. These differences in calcium and sodium transport may be an expression in the enterocyte of factors etiological for hypertension.

Defective protein phosphorylation associated with hypofunctions in stroke-prone spontaneously hypertensive rat platelets.

The mechanism of platelet dysfunctions in stroke-prone spontaneously hypertensive rats (SHRSP) was investigated. Platelet aggregation was inversely correlated with blood pressure or heart weight/body weight ratios in various strains of spontaneously hypertensive rats (SHR), indicating genetic defects. Thrombin-induced 47 kDa protein phosphorylation was markedly reduced in platelets of SHRSP compared with that in Wistar-Kyoto (WKY) rat platelets, accompanying reduced aggregation and secretion, but in 20 kDa protein phosphorylation was unchanged. Ca2+ ionophore A23187-induced responses were also significantly decreased in SHRSP, and the degrees of the changes were greater than those by thrombin. However, 12-O-tetradecanoylphorbol 13-acetate-induced responses in SHRSP were similar to those in WKY rats, suggesting that protein kinase C activity and its substrate were normally present in SHRSP platelets. Phosphatidylinositol content in platelets of SHRSP was 20% less than that in WKY rat platelets, but the contents of other phospholipids, including phosphatidylinositol-4-monophosphate and phosphatidylinositol-4,5-bisphosphates, were unaltered. Thrombin-induced formation of diacylglycerols and phosphatidic acid did not differ from each other at the low concentrations. In the absence of Ca2+, thrombin-induced responses occurred to a similar degree in both platelets, whereas the enhancements by Ca2+ were much greater in WKY rats than in SHRSP. These results suggested that defective Ca2+ functions in receptor-mediated activation of protein kinase C and postkinase-mediated events appear to be an underlying mechanism for the hypofunctions in SHRSP platelets.

Vascular conversion of angiotensin I in stroke-prone spontaneously hypertensive and Wistar-Kyoto rats.

OBJECTIVE: Linkage studies have shown that the gene locus for angiotensin converting enzyme (ACE) is associated with the expression of hypertension in stroke-prone spontaneously hypertensive rats (SHRSP). We tested the hypothesis that the conversion of angiotensin I (Ang I) to angiotensin II (Ang II) in blood vessels is elevated in SHRSP. DESIGN: We measured the conversion rate of Ang I to Ang II during one pass through an isolated resistance vessel bed. We used the same substrains of SHRSP and Wistar-Kyoto control rats (WKY) that had been employed in the earlier linkage studies. METHODS: Isolated hindquarters from young and adult (10- to 12- and 36- to 38-week-old) rats were perfused with an artificial medium and then infused with Ang I at 0.5 and 2 pmol/ml. Ang I and II were measured with high-performance liquid chromatography and radioimmunoassay in hindquarter effluent and in blank control channels. Conversion and extraction rates were calculated from angiotensin levels in hindquarter and blank perfusion channels, respectively. RESULTS: The conversion rates of Ang I to Ang II did not differ between SHRSP and WKY in young or in adult rats. Captopril completely abolished the formation of Ang II in all groups of rats. During infusion at the higher dose of Ang I, the extraction of Ang I was significantly decreased in SHRSP compared with WKY. CONCLUSIONS: Our results are consistent with the notion that the metabolism of angiotensin is decreased in spontaneously hypertensive rats. However, we found no support for the hypothesis that vascular ACE is responsible for high blood pressure in SHRSP. These findings suggest that other genes close to the ACE locus or the hyperexpression of the enzyme in other areas may contribute to hypertension in these rats.

Effects of chronic alcohol consumption and alcohol withdrawal on blood pressure in stroke-prone spontaneously hypertensive rats.

The development of blood pressure was monitored by the tail-cuff method in normotensive (WKY) and stroke-prone spontaneously hypertensive rats (SHRSP) receiving ethanol (alcohol) in drinking water from weaning (approximately 1 month of age). Alcohol administration over a 3-month period attenuated the development of hypertension in SHRSP and also caused a small reduction of the initial blood pressure rise in WKY. This was accompanied by a reduction of fluid intake and an increase of circulating antidiuretic hormone (arginine vasopressin; AVP). Circulatory volume remained constant. Direct measurement of arterial blood pressure in conscious rats before and after autonomic blockade confirmed the antihypertensive effect of alcohol in SHRSP and indicated that it is at least partly dependent on altered activity of neural mechanisms. Sudden withdrawal of alcohol caused an immediate increase of fluid intake followed by a rise of blood pressure lasting several days in both WKY and SHRSP. This withdrawal hypertension could not be attributed to changes in plasma catecholamines or AVP.

Increased plasma level of endothelin-1 in the Okamoto spontaneously hypertensive rat.

The objectives of this study were to determine plasma levels of endothelin (ET) in a genetic model of hypertension and in control rats during control conditions and in response to short-term volume expansion with saline. Okamoto spontaneously hypertensive rats (SHR) and control Wistar-Kyoto (WKY) rats were used in this study. One group of each strain served as control animals, and another group of each strain underwent volume expansion with saline (5% of body weight infused during a period of 30 minutes). The levels of ET-1 and ET-3 were measured in plasma by using a double-antibody radioimmunoassay. In the control groups of SHR and WKY rats, plasma ET-1 levels were 72.5 +/- 14.9 pg/ml (N = 8) and 40.2 +/- 7.5 pg/ml (N = 12), respectively (P < 0.05). In the volume-expanded SHR group (N = 8), the plasma ET-1 level was 45.5 +/- 11.1 pg/ml (approximately 37% less than that of the control SHR group), whereas it was 40.6 +/- 10.2 pg/ml in the volume-expanded group of WKY rats (N = 10) (almost identical to that of the control WKY group). Plasma levels of ET-3 were similar in control and in volume-expanded groups of SHR and WKY rats. These data show that basal levels of plasma ET-1 are significantly higher in the SHR than in the WKY rat.(ABSTRACT TRUNCATED AT 250 WORDS)

Reduced calcium binding capacity is an intrinsic abnormality of red blood cell membrane in spontaneously hypertensive rats.

Reduced calcium (Ca) binding capacity is a widespread and primary abnormality in SHR. It was reported that in red blood cell (RBC) membranes it is detectable only in membrane preparations containing sealed inside-out vesicles, the formation of which implies the partial removal of cytoskeletal proteins from the RBC membrane. The present study compares the Ca binding capacity of RBC membrane preparations with normal (+CS) and reduced (-CS) cytoskeleton content in SHR and normotensive WKY control rats. In addition to Ca binding capacity and protein content, the cholesterol content and the acetylcholinesterase (ACE) activity were measured as having a quantitative measure of integral membrane components in the different membrane preparations. In both strains the cholesterol/protein ratio, the ACE activity per mg of membrane protein, and the Ca binding capacity were all significantly higher in -CS compared to +CS membrane preparations (P less than .001). A statistically significant difference in Ca binding capacity between SHR and WKY was observed only using -CS membranes preparation. The results support the concept of a reduced membrane Ca binding capacity in rat genetic hypertension: this abnormality is detectable only in membrane preparations with reduced cytoskeletal content.

Congenital changes of platelet functions in stroke-prone SHR: aggregability of gel-filtered platelets, PRP and whole blood, and effects of hypotensive treatment.

Platelet aggregation in whole blood, platelet rich plasma, and gel-filtered platelets were markedly attenuated in SHRSP compared with those in age-matched normotensive WKY. The result was consistent with the previous report of washed platelets. Despite prevention of high blood pressure, a long duration of hypotensive treatment only slightly improved aggregability of washed platelets but did not restore it to the range of age-matched WKY platelets. Blood pressure, heart ratios and thrombin-induced washed platelet aggregation were examined in SHRSP, WKY, and the cross (F1: WKY x SHRSP). The higher blood pressure and heart ratios the lower platelet aggregability was observed in the three strains, and there was no overlapping distribution of these values. F1 progeny exhibited intermediate values in blood pressure, heart ratio and platelet aggregability between the parental values. These results suggested that hypofunctions of SHRSP platelet were not secondary changes due to high blood pressure, but primary changes which are genetically linked to high blood pressure.

Endogenous digoxin-like material in normotensive and hypertensive strains of rats.

We measured the concentration of endogenous digoxin-like materials (EDLM) in the serum of spontaneously hypertensive rats (SHR) and three normotensive rat strains at four stages during growth using a sensitive RIA. In the SHR, there was a significant peak in the EDLM level between 0.057-0.087 ngE/mL at 6 to 8 weeks of age, shortly after the onset of hypertension. The EDLM concentration returned to normal levels by 20 weeks of age. Sprague-Dawley and Wistar-Kyoto rats had EDLM levels below 0.050 ngE/mL at all time points studied. In contrast, Fischer 344 rats displayed persistently elevated serum EDLM concentrations that exceeded 0.124 ngE/mL from 3 to 20 weeks of life. We conclude that (1) there are significant interstrain differences in serum EDLM levels in rats; and (2) the SHR has a unique peak in serum EDLM levels at 6 to 8 weeks of age, indicating a possible role for the substance in the inception of hypertension.

Effect of serum from spontaneously hypertensive rats on 86Rb washout in cultured vascular smooth muscle cells.

In addition to the known genetic abnormalities affecting the membrane permeability of vascular smooth muscle cells (VSMC) of spontaneously hypertensive rats (SHR), serum humoral factors may also play some role in the alteration of permeability of VSMC and possibly contribute to the pathogenesis of hypertension in SHR. To test this hypothesis, the passive K permeability described as the washout rate constant (Ke) was measured based on 86Rb washout from cultured VMC in response to serum from SHR, Wistar-Kyoto rats (WKY), and Wistar rats (W). Serum from the three rat strains produced a substantial increase in the Ke of 86Rb washout from 9.6 +/- 1.7 for the control (C) of 17.3 +/- 2.0 for SHR. 15.3 +/- 0.9 for WKY, and 16.0 +/- 2.4 for W (x 10(-3)/min) (p less than 0.001 comparing C with SHR, W and p less than 0.01 comparing C with WKY respectively). However, comparison of the Ke of 86Rb washout among the three rats strains revealed no significant differences. It is concluded that serum increased passive K permeability of VSMC in culture. However, the data do not support the suggestion that some unknown humoral factors in the serum from SHR are involved in the abnormal alterations of membrane permeability to cations and thus contributing to the pathogenesis of hypertension in the SHR.

[Ectacytometry of the erythrocytes in rats of the SHR, WKY and Wistar strains]. / Ektatsitometriia éritrotsitov krys linii SHR, WKY i Vistar.

Deformation properties of erythrocytes have been studied using osmotic gradient ectacytometric procedure in rats with spontaneous hereditary hypertension (SHR), normal tension rats from Wistar-Kyoto strain and albino rats from Wistar strain. It was shown that high intrinsic viscosity and, to a less extent, changes in their form account for the increased rigidity of the erythrocytes from SHR rats. No significant changes in visco-elastic properties of the membrane were found. The degree of hydration of haemoglobin significantly increases in the order SHR-WKY-Wistar.

Inverse changes in erythroid cell volume and number regulate the hematocrit in newborn genetically hypertensive rats.

Erythrocytosis and microcytosis have been described in strains of genetically hypertensive rats and in essentially hypertensive humans. Published discussion of these phenomena has centered around their relationship to observed alterations in ionic transport and the pathogenesis of hypertension. In presenting data for another strain of spontaneously hypertensive rats in which these findings are exhibited, we note that erythroid cell size decreases concurrently with the increase in cell numbers so that the hematocrit and the mean corpuscular hemoglobin concentration remain constant. Data from the literature support the hypothesis that erythroid cell size is inversely proportional to cell count in a large number of species. Erythrocytosis, as it develops in the neonatal rat, is a consequence of the marked immaturity of this species at birth. Erythrocytosis in the spontaneously hypertensive rat is not due to a difference in the affinity of its hemoglobin for oxygen or to significant tissue anorexia. Microcytosis in the spontaneously hypertensive rat is the consequence of a continuation of the linear volume decrease with age of its erythroid cells seen in the normotensive animals and may be accounted for by the production of smaller cells with concomitant regulation of individual cell volume.