Neonatal Spontaneously Hypertensive Rats Research Articles

Altering Early Life Gut Microbiota Has Long-Term Effect on Immune System and Hypertension in Spontaneously Hypertensive Rats.

Hypertension is regulated by immunological components. Spontaneously hypertensive rats (SHR) display a large population of proinflammatory CD161 + immune cells. We investigated the effect of early post-natal gut microbiota on the development of the immune system and resulting hypertension in the SHR. We first examined the microbial populations in the fecal samples of SHR and normotensive control WKY using 16S rDNA sequencing. We found that in the newborn SHR (1-week old) the gut microbiota was qualitatively and quantitatively different from the newborns of normotensive WKY. The representation of the predominant bacterial phylum Proteobacteria was significantly less in 1-week old SHR pups than in WKY (94.5% Proteobacteria in WKY vs. 65.2% in SHR neonates). Even within the phylum Proteobacteria, the colonizing genera in WKY and SHR differed dramatically. Whereas WKY microbiota was predominantly comprised of Escherichia-Shigella, SHR microbiota was represented by other taxa of Enterobacteriaceae and Pasteurellaceae. In contrast, the representation of phylum Firmicutes in the neonatal SHR gut was greater than WKY. Cross-fostering newborn SHR pups by lactating WKY dams caused a dramatic shift in 1-week old cross-fostered SHR gut microbiota. The two major bacterial taxa of phylum Proteobacteria, Enterobacteriaceae and Pasteurellaceae as well as Lactobacillus intestinalis, Proteus, Romboustia and Rothia were depleted after cross-fostering and were replaced by the predominant genera of WKY (Escherichia-Shigella). A proinflammatory IL-17F producing CD161 + immune cell population in the spleen and aorta of cross-fostered SHR was also reduced (30.7% in self-fostered SHR vs. 12.6% in cross-fostered SHR at 30 weeks of age) as was the systolic blood pressure in adult cross-fostered SHR at 10 weeks of age. Thus, altered composition of gut microbiota of SHR toward WKY at early neonatal age had a long-lasting effect on immune system by reducing proinflammatory immune cells and lowering systolic blood pressure.

Early Postnatal Gut Microbiota Determines SHR Hypertension

Hypertension is regulated by immunological components. We have shown that spontaneously hypertensive rats (SHR) display a genetic abnormality in a large population of proinflammatory CD161+ immune cells. Although early postnatal gut microbiota is important for development of the immune system, this relationship has not been studied in hypertension. Cross‐fostering SHR pups by normotensive Wistar‐Kyoto (WKY) dams lowers the blood pressure in adulthood when cross‐fostering is initiated at a very young age. In this study, we tested whether early alteration in postnatal gut microbiota affect s the immune system and blood pressure of SHR. We first examined the microbial populations in the fecal samples of SHR and normotensive control WKY using 16s rDNA sequencing. We found that the newborn SHR (1‐week old) have abnormal gut microbiota that is qualitatively and quantitatively different from the newborns of normotensive WKY. The representation of the predominant bacterial phylum Proteobacteria was significantly less in 1‐week old SHR pups than in WKY (94% Proteobacteria in WKY vs. 65% in SHR neonates). Even within the phylum Proteobacteria, the colonizing genera in WKY and SHR differed dramatically. Whereas WKY microbiota was predominantly comprised of Escherichia‐Shigella (92.5%), SHR microbiota was represented by Klebsiella (34.7%) and Haemophilus (27.8%). In contrast, the representation of phylum Fermicutes in the neonatal SHR gut was greater than WKY (5% Fermicutes in WKY vs. 31% in SHR). We cross‐fostered newborn SHR pups by lactating WKY dams and measured the resulting changes in the gut microbiota, immune system and blood pressure. Cross‐fostering caused a dramatic shift in 1‐week old cross‐fostered SHR gut microbiota. The two major bacterial genera of phylum Proteobacteria, Klebsiella and Haemophilus, present in self‐fostered SHR pups, were depleted after cross‐fostering, and were replaced by the predominant genera of WKY (Escherichia‐Shigella). A proinflammatory CD161+ immune cell population in the spleen of cross‐fostered SHR was also reduced (30.7% in self‐fostered SHR vs. 12.6% in cross‐fostered SHR at 30 weeks of age) as was the systolic blood pressure in adult cross‐fostered SHR (SHR 204 mmHg vs. cross‐fostered SHR 177 mmHg, p= 0.02, n= 4 each group). Thus, cross‐fostering of SHR pups by WKY dams shifted the composition of their gut microbiota toward WKY within one week. Additionally, reduction in proinflammatory immune cells and lowering of systolic blood pressure were observed in cross‐fostered SHR. In summary, SHR have a congenital defect in their immune system that results in greater proinflammatory response associated with hypertension. Gut microbiota of the SHR is remarkably different from that of normotensive WKY, and likely contributes to SHR blood pressure by modulating early development of the immune system.Support or Funding InformationNational Institutes of Health Program Project Grant to FMA (HL 14388) VA Merit Review Award to MWC (1 I01BX001414), American Heart Association Innovative Research Grant to MVS (16IRG27260323).

Influence of Early Postnatal Gut Microbiota on Immune System in SHR Hypertension

Hypertension exhibits a prominent immunological component. We have recently shown that spontaneously hypertensive rats (SHR) have a genetic abnormality whereby they are born with a large population of proinflammatory CD161+ immune cells. Although early postnatal maternal environment is important for development of hypertension, its impact on the immune system is not known. Cross‐fostering SHR pups by normotensive Wistar‐Kyoto (WKY) dams lowers the blood pressure in adulthood only if the cross‐fostering is initiated at a very young age. In this study, we used SHR as a genetic model of hypertension to test whether early postnatal gut microbiota affect the immune system and blood pressure of SHR. Since cross‐fostering permanently changes the gut microbiota of the fostered offspring, we first examined the microbial populations in the fecal samples of SHR and normotensive control WKY using 16s rDNA sequencing. We found that the newborn SHR (1‐week old) have abnormal gut microbiota that is qualitatively and quantitatively different from the newborns of normotensive WKY. The representation of predominant bacterial phylum Proteobacteria was less in 1‐week old SHR pups (94% Proteobacteria in WKY vs. 65% in SHR neonates). Even within the phylum Proteobacteria, the colonizing genera in WKY and SHR differed dramatically. In contrast, the representation of phylum Fermicutes in the neonatal SHR gut was greater than WKY (5% Fermicutes in WKY vs. 31% in SHR). We also observed a dramatic shift in 1‐week old SHR gut microbiota when we cross‐fostered WKY and SHR pups beginning at 1‐day of age. Two major bacterial genera of phylum Proteobacteria present in self‐fostered SHR pups, but absent in WKY, were depleted after cross‐fostering, and were replaced by other bacteria predominant in WKY gut. Investigation of immune cells in the spleen of cross‐fostered SHR using cell surface markers and flow cytometry showed that there was a clear reduction in CD161+ cells (30.7% in self‐fostered SHR vs. 12.6% in cross‐fostered SHR at 30 weeks of age), a marker associated with inflammation. Thus, cross‐fostering of SHR pups by WKY dams shifted the composition of their gut microbiota toward WKY within one week. Additionally, preliminary results suggest lower systolic blood pressure (tail cuff pressure) in cross‐fostered SHR. In summary, SHR are born with a defect in their immune system that results in greater proinflammatory response associated with hypertension. Moreover, the gut microbiota of the SHR is remarkably different from that of normotensive WKY, and cross‐fostering of SHR by WKY dams favorably changes the gut microbiome and immune regulation.Support or Funding InformationNational Institutes of Health Program Project Grant to FMA (HL 14388) VA Merit Review Award to MWC (1 I01 BX001414), American Heart Association Innovative Research Grant to MVS (16IRG27260323).This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Persistent α1-adrenergic receptor function in the nucleus locus coeruleus causes hyperexcitability in AD/HD model rats

Spontaneously hypertensive rats (SHR) are widely used as a model of attention deficit hyperactivity disorder (ADHD) as their ADHD-like behaviors are restored by methylphenidate. However, a postnatal neural development in SHR is unknown. We performed whole cell patch clamp recordings from locus coeruleus (LC) neurons in neonatal [postnatal day (P) 3-5], juvenile (P21-28), and adult (P 49-56) SHR and age-matched Wistar rats to evaluate α1- and α2-adrenergic receptor (ARs) activities at each developmental period. LC neurons in neonatal Wistar rats and SHR showed no difference in resting membrane potential and spontaneous firing rate, while juvenile and adult SHR LC neurons showed depolarized resting membrane potential and faster spontaneous firing rate than in Wistar rats. Blockade of α1-AR activity by prazosin hyperpolarized the membrane and abolished spontaneous firings in all developmental periods in SHR LC neurons, but not in juvenile and adult Wistar rats. α1-AR stimulation by phenylephrine evoked an inward current in juvenile LC neurons in SHR, but not in juvenile Wistar rats. This phenylephrine-induced inward current was abolished by nonselective cation channel blockers. By contrast, α2-AR stimulation-induced outward currents in the presence of an α1-AR antagonist were equivalent in SHR and Wistar LC neurons. These data suggest that Wistar LC neurons lose α1-AR function during development, whereas α1-ARs remain functional in SHR LC neurons. Thus persistent intrinsic activity of α1-ARs may be a neural mechanism contributing to developmental disorders in juvenile SHRs.

Increased intrinsic excitability of muscle vasoconstrictor sympathetic preganglionic neurones in neonatal spontaneously hypertensive rats

Young, spontaneously hypertensive (SH) rats show an increased level of sympathetic activity that predates the development of hypertension (Simms et al 2009 J Physiol).We have examined the properties of muscle vasoconstrictor sympathetic preganglionic neurones (MVC‐SPN) in neonatal SH and Wistar rats. Whole‐cell recordings were obtained from SPN (Wistar n=169, SH n=76; aged p9–14) in T3–4 segment of the working heart‐brainstem preparation.SPN of SH rats showed a higher firing frequency (1.7 vs 3.0Hz) and smaller AHP amplitude. When analysed by functional subgroup it was apparent that these difference were secondary to changes in the excitability of MVC‐SPN. These showed significantly higher firing frequencies (2.2 vs 3.5Hz) with increased respiratory modulation. Additionally, the SH MVC‐SPN had shorter, smaller AHPs, lower input resistances and a weaker transient rectification (IA).Voltage clamp analysis of spontaneous excitatory synaptic events in MVC‐SPN showed similar frequencies and amplitudes of EPSCs. There was a modest preponderance of large EPSCs in SH rats (>30pA, <0.3Hz) which alone did not account for the increased spike discharge.In summary, the MVC SPN of neonatal SH rats are intrinsically more excitable. These changes occur prior to, and may play a causal role in, the development of hypertension.

Enhanced survival of vascular smooth muscle cells accounts for heightened elastin deposition in arteries of neonatal spontaneously hypertensive rats

Abnormal stiffening and narrowing of arteries are characteristic features of spontaneously hypertensive rats (SHR). In this strain, we have previously demonstrated an increased elastin content and abnormal organization of lamellae in conduit and resistance arteries from neonatal rats that preceded the impending inward remodelling, increased vascular stiffness and development of hypertension. The aim of this study was to assess the mechanism responsible for such excessive and aberrant elastin deposition in SHR vessels during perinatal development. We compared elastin, collagen and fibronectin production (inmunocytochemistry and quantitative assay of metabolically labelled insoluble elastin), DNA content as well as cell proliferation (proliferative cellular nuclear antigen, bromodeoxyuridine incorporation) and death rates (propidium iodide exclusion test, terminal transferase nick and labeling (TUNEL) assay) in cultures of vascular smooth muscle cells (VSMC) derived from neonatal SHR and Wistar-Kyoto (WKY) control rats. Cultures of VSMC derived from neonatal SHR exhibited hypertrophy, produced more elastin, collagen and fibronectin and contained more DNA than equally plated WKY counterparts. Further analysis revealed that the higher net DNA content in SHR-derived cultures was due to increased diploidy, but not to a heightened cell multiplication. The SHR-derived VSMC also exhibited lower rates of cell death and apoptosis, which were associated with increased levels of the anti-apoptotic protein, survivin. We therefore conclude that the peculiar heightened survival of matrix-producing VSMC in neonatal SHR is responsible for accumulation of hard-wearing elastin and other extracellular matrix elements in the growing arteries, thereby contributing to the subsequent development of systemic hypertension.

Heightened aberrant deposition of hard-wearing elastin in conduit arteries of prehypertensive SHR is associated with increased stiffness and inward remodeling

Elastin is a major component of conduit arteries and a key determinant of vascular viscoelastic properties. Aberrant organization of elastic lamellae has been reported in resistance vessels from spontaneously hypertensive rats (SHR) before the development of hypertension. Hence, we have characterized the content and organization of elastic lamellae in conduit vessels of neonatal SHR in detail, comparing the carotid arteries from 1-wk-old SHR with those from Wistar-Kyoto (WKY) and Sprague Dawley (SD) rats. The general structure and mechanics were studied by pressure myography, and the internal elastic lamina organization was determined by confocal microscopy. Cyanide bromide-insoluble elastin scaffolds were also prepared from 1-mo-old SHR and WKY aortas to assess their weight, amino acid composition, three-dimensional lamellar organization, and mechanical characteristics. Carotid arteries from 1-wk-old SHR exhibited narrower lumen and greater intrinsic stiffness than those from their WKY and SD counterparts. These aberrations were associated with heightened elastin content and with a striking reduction in the size of the fenestrae present in the elastic lamellae. The elastin scaffolds isolated from SHR aortas also exhibited increased relative weight and stiffness, as well as the presence of peculiar trabeculae inside the fenestra that reduced their size. We suggest that the excessive and aberrant elastin deposited in SHR vessels during perinatal development alters their mechanical properties. Such abnormalities are likely to compromise vessel expansion during a critical period of growth and, at later stages, they could compromise hemodynamic function and participate in the development of systemic hypertension.

Influence of neonatal sympathectomy on proximal renal resistance artery function in spontaneously hypertensive rats.

Renal transplantation experiments have shown that the kidney contributes to chronic sympathectomy-induced arterial pressure reduction in spontaneously hypertensive rats (SHR). The underlying mechanisms are currently unclear but may include alterations in the function of small renal arteries. Neonatal SHR were sympathectomized by intraperitoneal guanethidine injections and removal of adrenal medullary tissue. Controls were sham- or hydralazine-treated. At 12 weeks of age, distal interlobar artery segments were investigated using small-vessel wire myography. Vessels from sympathectomized animals showed increased sensitivity to noradrenaline (NE). Vasopressin- and endothelin-1-induced vasoconstriction was similar in all groups (as reflected by the pD(2), i.e. -logEC(50), where EC(50) is the molar concentration of agonist eliciting a half-maximal response). Maximum vasopressin-induced tension was similar in all groups while endothelin-1-induced maximum tension was significantly higher in sympathectomized than in sham-treated SHR. The sensitivity of NE-induced vasoconstriction to extracellular Ca(2+) did not differ between groups while sensitivity to L-type Ca(2+) channel activation was significantly higher in both sympathectomized and hydralazine-treated animals than in sham-treated animals. Endothelium-dependent and independent vasodilation were similar in all groups. Sequential blockade of NO-synthase and cyclooxygenase had similar effects in all groups. In conclusion, neonatal sympathectomy does not induce any changes in the function of isolated proximal renal resistance arteries from SHR that could explain the blood pressure lowering effect of a kidney graft from sympathectomized SHR.

Effect of cross-fostering on neonatal sodium balance and adult blood pressure in the spontaneously hypertensive rat.

1. The aim of the present study was to compare electrolyte handling in naturally reared neonatal spontaneously hypertensive rats (SHR) with those reared by a Wistar-Kyoto (WKY) rat foster mother (denoted SHRX), as cross-fostering SHR pups to a WKY rat dam lowers adult blood pressure in the SHR. 2. The electrolyte content of WKY rat and SHR dams' milk was determined and electrolyte intake and urinary excretion rates were calculated in both naturally reared and cross-fostered WKY rat and SHR pups. 3. The milk sodium concentration fell in both strains (WKY rat: 31.8 +/- 2.0 to 15.2 +/- 1.2 mmol/L; SHR 31.9 +/- 2.5 to 18.2 +/- 1.6 mmol/L; P < 0.001), as did potassium (P < 0.001), over lactation, but there were no differences between strains. Calcium and magnesium concentrations increased (P < 0.001), although SHR dam's milk contained less calcium (P < 0.001) than that of WKY rat dams during the third week of lactation. 4. Spontaneously hypertensive rat pups ingested less milk (P < 0.05) than WKY rat pups; therefore, their cumulative sodium intake over postnatal days 4-15 was significantly lower than that of WKY rat pups (WKY rat vs SHR: 84.4 +/- 3.6 vs 59.7 +/- 2.6 mumol/g bodyweight, respectively; P < 0.05) and fostered SHRX pups (77.7 +/- 7.0 mumol/g bodyweight; P < 0.05). Potassium and magnesium intakes were comparable between SHR, WKY rat and SHRX pups, but SHR pups ingested significantly less calcium than either WKY rat pups (136.1 +/- 6.4 vs 200.1 +/- 9.5 mumol/g bodyweight, respectively; P < 0.05) or SHRX pups (200.0 +/- 18.0 mumol/g bodyweight; P < 0.05). 5. These data show that the neonatal SHR experiences a period of sodium deficiency during the developmental stage when cross-fostering is effective in lowering blood pressure. This is consistent with the reported up-regulation of the renin-angiotensin system observed in SHR at this time and may have a long-term influence on blood pressure.

Decreased developmental cell death in sympathetic and spinal sensory nervous systems of the Kyoto spontaneously hypertensive rat.

To investigate the hypotheses that Kyoto spontaneously hypertensive rats (SHR) possess more sympathetic neurons than do normotensive Wistar-Kyoto (WKY) animals due to reduced perinatal cell death and that this is due to increased availability of the sympathetic survival neurotrophin, nerve growth factor. Total cell counts of neuron numbers were performed in neonatal and adult SHR and WKY rat superior cervical ganglia and correlated with counts of apoptotic cells. The values for sympathetic neuron numbers were compared with those for a spinal sensory ganglion. Immunocytochemistry was used to obtain more information about the phenotypes of neurons counted. Adult SHR sympathetic ganglia contained about 25% more sympathetic neurons than did those of WKY animals. Similar elevation of numbers was found both for neurons containing and for those devoid of neuropeptide Y. In neonatal animals, in contrast, there was no strain difference in sympathetic cell numbers but the number of apoptotic cells was reduced in SHR. Spinal sensory neuron numbers in adult SHR were elevated to a similar extent as were sympathetic neurons, but biochemical and morphometric data suggested that this change does not involve cells that are sensitive to nerve growth factor. Although our results support the view that there is reduced developmental cell death both in sympathetic and in sensory systems, they also suggest that this is unlikely to be due to a simple excess of nerve growth factor during development.

Neuronal angiotensin-converting enzyme (ACE) gene expression is increased by converting enzyme inhibitors (CEI)

Exposure to angiotensin-converting enzyme (ACE) inhibitors has been associated with increased ACE activity in vivo and in vitro. In the current study, we examined the effects of ACE inhibitors on ACE gene expression and activity in brain and primary neuronal cultures prepared from brains of neonatal spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) controls. ACE mRNA levels were increased in brain and neuronal cultures following ACE inhibitor exposure. A concomitant increase in ACE activity was evident in brain, but ACE activity was decreased in neuronal cultures following ACE inhibitor exposure. Since ACE has been localized to several cell types in the brain, including endothelial cells and glia, as well as neurons, the differences in ACE activity between whole brain and neuronal cultures following exposure to ACE inhibitors may be related to differential regulation of the ACE gene in these cell types. These findings and the observation that ACE mRNA levels are >20-fold higher in cultured neurons from neonatal SHR than in those from WKY support the conclusions that the activity of the brain renin angiotensin system is enhanced in SHR and that blockade of this system by chronic ACE inhibitor treatment contributes to the sustained antihypertensive effect of ACE inhibitors in this model.

Hypertensive Diabetic Rats: Different Effects of Streptozotocin Treatment on Blood Pressure in Adult SHR and in Neonatal SHR

The effect of streptozotocin (STZ) treatment on blood pressure in adult spontaneously hypertensive rats (SHR) was compared with that in neonatal SHR. Three-month-old SHR were intravenously given 10, 30 or 50 mg/kg of STZ. When STZ was given in adult SHR, weight loss, overt hyperglycemia and the reduction of blood pressure occurred dose dependently. Two-day-old pups from SHR were subcutaneously injected with 100 mg/kg of STZ. Neonatal STZ treatment did not attenuate the development of hypertension in SHR. Since neonatally STZ-treated SHR develop mild diabetic symptom with hypertension and develop mild diabetic glomerulosclerosis, they are a good model for studying vascular complications or other disorder relating to the synergism between hypertension and diabetes mellitus.

Hippocampal levels of dynorphin A (1?8) in neonatal and 16-week-old spontaneously hypertensive rats: Comparisons with DOCA-salt hypertension

In this study the possible role of hippocampal dynorphin in the development of hypertension in spontaneously hypertensive rats (SHR) was investigated by determining dynorphin A (1-8) (DN A (1-8] levels in hippocampus in 16 week old SRH, Wistar Kyoto (WKY) controls and SHR treated with antihypertensive drugs as well as DOCA-salt hypertensive Sprague Dawley (SD) rats, using radioimmunoassay (RIA). We found that DN A (1-8) was decreased significantly in both dorsal (-68%) and ventral (-58%) hippocampus in SHR compared with WKY rats. Treatment with hydralazine and guanethidine (25 mg/kg/24 hr of each drug in drinking water) for 8 weeks to prevent the development of hypertension in young SHR had no effect on this low hippocampal dynorphin level. We failed to find significant changes in hippocampal DN A (1-8) level in DOCA-salt hypertensive rats. The low level of hippocampal dynorphin existed before the development of hypertension in 6 day neonatal SHR (-73%). Hippocampal Met-enkephalin was unchanged in all experimental groups except for a slight decrease in neonatal SHR. The results establish a genetic difference in the hippocampal dynorphin system of SHR compared with WKY, the significance of which, for the development of hypertension, remains to be investigated.

Dietary calcium alters blood pressure in neonatal spontaneously hypertensive rats.

Dietary alterations in young genetically hypertensive rats have been shown to have a substantial impact on subsequent blood pressure (BP) development. In the present study, spontaneously hypertensive rat (SHR) pups fostered at birth to high calcium (2%) SHR dams developed significantly lower mean arterial pressures by 28 days of age than pups fostered to low calcium (0.1%) dams (93.7 v 107.7 mm Hg, P less than .01). To determine whether BP differences were due to milk ingestion or to late lactational solid diet consumption, a second experiment was performed. Pups were fostered at birth to medium calcium (1.0%) dams and weaned at 21 days to one of three calcium diets. Blood pressures were determined at 28 days after birth. Pups weaned to the high diet at 21 days had lower pressures at 28 days than pups weaned to the low diet (94.2 v 108.3, P less than .01), suggesting that the pressure variations in the first experiment were due primarily to solid food consumption by the pups late in the suckling period. This rapid BP alteration suggests that neonatal SHR have an enhanced susceptibility to the pressure effects of dietary calcium.

Altered Responsiveness to Autonomic Transmitters of Hearts from Neonatal Spontaneously Hypertensive Rats

Responsiveness to autonomic neurotransmitters of isolated hearts from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) were compared in 1-day-old and 4-week-old neonates and adults. Chronotropic responses to norepinephrine (NE) and acetylcholine (Ach) were examined using right atrial preparations. There was no difference in the basal beating rate between SHR and WKY at all ages tested. The maximum beating rate produced by NE was higher in SHR only at 1 day after birth; there was no difference in the 4-week-old neonate and the adult. The sensitivity (pD2 values) to Ach was lower in SHR at both 1 day and 4 weeks after birth, but not in the adult. Inotropic responses to NE were examined using right ventricular preparations. The sensitivity was slightly higher in SHR at 1 day after birth, but no difference was observed in the 4-week-old neonate and the adult. These results suggested that the neonatal SHR heart has an increased function due to altered responsiveness to autonomic neurotransmitters, which may play a role in the initiation of hypertension.

Restoration of T cell depression and suppression of blood pressure in spontaneously hypertensive rats (SHR) by thymus grafts or thymus extracts.

Spontaneously hypertensive rats (SHR) that develop hypertension and arterial lesions resembling human periarteritis nodosa were found to possess a selective depression of T cell functions with an appearance of natural thymocytotoxic autoantibody (NTA). The relationship between T cell depression and hypertension in these animals was investigated. The immune responsiveness of T cell-depressed SHR was completely recovered by histocompatible thymus grafts and was partially restored by histoincompatible allogeneic or xenogeneic thymus grafts or by injection of thymus extracts. Transplantation of compatible thymus tissues into neonatal SHR produced long-lasting recovery of immune functions. When complete immunologic restoration was achieved, significant suppression of high blood pressure was obtained. The SHR that showed high blood pressure were always accompanied with high NTA titers and arterial lesions. Thymus grafts or thymus extracts significantly decreased the titers of NTA. The development and dissemination of arterial lesions, which may cause increased blood flow resistance, were completely prevented by compatible thymus grafts into neonatal SHR. These results suggest that thymus grafts and thymus extracts may suppress the development of hypertension by preventing or curing the periarteritis nodosa in SHR.