Psychotherapy in suicidal youth

Thrombotic potential and hemodynamic changes were assessed in the cerebral microcirculation in normal rats (WKY), non-stroke-prone spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP) at the age of 4, 16 and 32 weeks. Whole blood platelet aggregation revealed that the platelet aggregability in vitro was significantly depressed in SHRSP compared to WKY at 16 and 32 weeks using 2 microg/ml collagen but was similar or higher than WKY at 32 weeks using 20 or 40 microg/ml collagen. Platelet-rich thrombi were induced using a helium-neon (He-Ne) laser technique in vivo. The numbers of laser pulses required to induce an occlusive thrombus in arterioles were similar in the three strains at the age of 4 weeks. In contrast, the numbers of laser pulses needed to induce vascular occlusion in SHR (5.5 +/- 0.7; n = 4) and SHRSP (4.9 +/- 0.3; n = 4) were lower than in WKY (7.4 +/- 0.3; n = 5) at the age of 16 weeks. Similar differences were observed at 32 weeks (SHR 5.8 +/- 0.2; n = 6; SHRSP 4.3 +/- 0.1; n = 4; WKY 7.0 +/- 0.2; n = 7). Red blood cell velocities were measured in pial arterioles using a fiber-optic laser Doppler anemometer microscope. Red cell velocities and wall shear rates in SHR and SHRSP were significantly lower than those in WKY (p < 0.05) at the age of 16 weeks and were markedly lower in SHRSP than in either WKY or SHR at the age of 32 weeks. The plasma concentration of nitrite/nitrate determined by the Griess reaction was significantly reduced in SHRSP at 32 weeks compared with 4-week-old rats. These changes could contribute to the enhanced tendency to cerebrovascular stroke in SHRSP.     

Monitoring norepinephrine levels by microdialysis in the white adipose tissue of spontaneously hypertensive rats

1. To investigate whether microdialysis is suitable to monitor catecholamine in white adipose tissue of conscious rat and to assess eventual differences in norepinephrine (NE) interstitial levels, two groups of 12 male spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats, 14-16 weeks old, were compared. 2. A flexible microdialysis probe was implanted subcutaneously in the parascapular region, and perfused with Ringer solution (flow rate: 2.0 mu L/min). After a 20 min equilibration period, NE levels were monitored over a 120 min period; then, tyramine hydrochloride (0.1 nmol/min) was perfused for 80 min. Dialysates from each 20 min collection period were analysed by HPLC with electrochemical detection for NE. 3. Basal levels of NE (adjusted for the recovery) were higher in SHR compared to WKY (1210.0 +/- 140.5 pg/mL dialysate vs 573.3 +/- 75.8 pg/mL dialysate; P < 0.001, ANOVA). In both strains tyramine perfusion increased NE concentration in dialysates; the net (i.e. baseline subtracted) NE output was lower (76.3 pg/h, s.e.m. 22.3) in SHR compared with that shown by WKY rats (201.0 pg/h, s.e.m 18.4, P < 0.01). 4. The increased basal levels of NE observed in SHR are associated with a blunted response to tyramine challenge. Since tyramine is known to cause NE release from the cytosol but not from vesicle stores, such a blunted response is consistent with an increased turnover rate of NE or with an accelerated uptake in pre-synaptic vesicles which, together with the higher basal levels, would suggest increased noradrenergic activity.     

The correlation of blood pressure, age and endothelin-1 binding sites in aortic smooth muscle cells of rats

Spontaneously hypertensive (SHR), Wistar-Kyoto (WKY), and Sprague-Dawley (SD) rats at the ages of 4, 8, 12, 16 and 24 weeks were used to examine the effects of age on the density of endothelin-1 (ET-1) binding sites in aortic smooth muscle cells and systolic blood pressure (SBP). The SBP of the 3 different rat strains was measured, and the maximum binding value (Bmax) and dissociation constant (Kd) of ET-1 binding sites in smooth muscle cells of the thoracic aorta were determined. The results showed that the SBP and Bmax values of SHR, WKY and SD rats increased with age; the SBP and Bmax value at each corresponding age were significantly higher in SHR than in WKY and SD rats, however, there was no significant difference between WKY and SD rats. The relationship of age vs SBP, age vs Bmax, and Bmax vs SBP showed significantly positive correlation in all 3 rat strains. The regression line in the Bmax of endothelin binding sites against SBP in the 3 different rat strains presented a similar slope. These results indicate that SBP, which increased with age, could be related to an increased density of ET-1 binding sites on vascular smooth muscle cells in these 3 different rat strains.     

Antihypertensive effect of a newly synthesized endothelin antagonist, BQ-123, in a genetic hypertensive model

A newly synthesized ET(A)-selective antagonist, BQ-123, was examined with respect to its anti-endothelin(ET) action in vitro and in vivo and its effect on blood pressure in Wistar Kyoto rats (WKY), spontaneously hypertensive rats (SHR) and stroke-prone spontaneously hypertensive rats (SHRSP). In isolated porcine coronary arteries, BQ-123 (0.07 microM to 6.0 microM) shifted the concentration-response curve for ET-1 to the right without affecting the maximal response of ET-1, its pA2 value being 7.35. Intravenous infusion of BQ-123 at a rate of 1.2 and 30 mg/kg/hr produced a significant decrease in blood pressure in 20- to 29-week-old SHRSP, but did not alter blood pressure in 13- to 16-week-old WKY or in 18- to 19-week-old and 40-week-old SHR. The hypotensive effect of BQ-123 depended on the pretreatment blood pressure level. These results suggest that ET-1 is involved in part in the maintenance of high blood pressure in malignant hypertension, as exemplified by SHRSP.     

Increase of the background human exposure to mercury through fish consumption due to gold mining at the Tapajós River region, Pará State, Amazon

Plasma and lipoprotein lipid composition and endogenous hepatic antioxidant status were investigated in hypertensive, 14-week-old spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats fed a standard commercial rat chow. Total plasma calcium and magnesium concentrations were similar between both rat strains; however, systolic blood pressure in SHR was greater than in WKY at 13 weeks of age (197 +/- 12 vs. 132 +/- 14 mmHg; p < or = 0.05), confirming hypertension in SHR. Total plasma cholesterol and triacylglycerol concentrations were lower (p < or = 0.05) in SHR compared with WKY. A lower (p < 0.05) HDL cholesterol level in SHR plasma resulted in a higher LDL to HDL cholesterol ratio compared with WKY counterparts. No significant differences in the relative proportion of HDL apolipoprotein A-I fraction were observed between SHR and WKY. Both SHR VLDL and HDL triacylglycerol fractions were lower (p < 0.05) in SHR than WKY. Analysis of liver antioxidant enzyme activities showed no differences in rat liver superoxide dismutase (SOD), but lower (p < 0.05) liver glutathione peroxidase (GSH-Px) activity in SHR. However, liver glutathione (GSH) levels were similar in SHR and WKY counterparts. A possible compensatory effect to the oxidative status of SHR was suggested by the significant (p < 0.05) increase in both liver catalase (CAT) and glutathione reductase (GSSG-Red) activities. Despite these results, in vitro oxidative challenge studies with H2O2 demonstrated a greater susceptibility of liver to GSH depletion in the SHR, although no parallel change in thiobarbituric acid reactive substances (TBARS) production was observed. The comparatively lower plasma cholesterol observed in hypertensive SHR paralleled specific differences in liver catalase and glutathione redox antioxidant enzyme activities.     

Heart and red blood cell antioxidant status and plasma lipid levels in the spontaneously hypertensive and normotensive Wistar-Kyoto rat

Heart and red blood cell endogenous antioxidant status and plasma lipids were investigated in hypertensive, 14-week-old spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats fed a standard commercial rat chow. Specific heart and red blood cell antioxidant enzyme activities, as well as the susceptibility of tissues to H2O2-induced glutathione (GSH) depletion and lipid peroxidation, were measured. Systolic blood pressure in SHR was greater than in WKY rats at 13 weeks of age (197 +/- 12 vs. 132 +/- 14 mmHg (1 mmHg = 133.3 Pa); p < or = 0.05), confirming the presence of hypertension in SHR. Red blood cell catalase (CAT) and superoxide dismutase (SOD) activities were greater (p < or = 0.05) in SHR than WKY rats. Red blood cell CAT activity was positively correlated (r = +0.634; p = 0.026) with SOD, which in turn was correlated (r = +0.709; p = 0.049) with systolic blood pressure. Heart SOD activity was higher (p < or = 0.05) in SHR, while glutathione reductase (GSSG-Red) activity was lower (p < or = 0.05) than in WKY rats. This reduced ability to recycle GSH in the heart coincided with greater (p < or = 0.05) levels of H2O2-induced lipid oxidation products in SHR. Plasma total cholesterol and triacylglycerol levels were lower (p < or = 0.05) in SHR than WKY rats, with no visible signs of atherosclerosis in either SHR or WKY rats. In summary, hypertension in SHR was associated with alterations in antioxidant enzyme profiles of red blood cells and heart, with the latter showing an increased susceptibility to in vitro lipid oxidation. Although hypertension is a recognized factor in the development of human atherosclerosis, spontaneously hypertensive rats did not exhibit signs of aortic plaque, reflecting the resistance of this species to the development of atherosclerosis.     

Plasma and blood vessel endothelin-1 concentrations in hypertensive uremic rats treated with erythropoietin

The present study was designed to evaluate whether changes in plasma and blood vessel endothelin-1 (ET-1) concentrations may play a role in the enhanced blood pressure response to recombinant human erythropoietin (r-HuEPO) replacement therapy in uremia. Renal failure was induced by 5/6 nephrectomy (Nx). Uremic rats received either r-HuEPO (100 u s.c. three times a week) or the vehicle for 5 weeks. They were compared to control rats receiving the vehicle. Systolic blood pressure (tail cuff method), hematocrit, serum creatinine, plasma and tissue ET-1 were measured at the end of the protocol. Immunoreactive ET-1 (ir-ET-1) was determined by radioimmunoassay of acid-extracts from the plasma, thoracic aorta and mesenteric arterial bed. Creatinine increased about three fold in Nx animals. Blood pressure in control rats was 120+/-3 mmHg compared to 161 +/-6 mmHg in the Nx + vehicle group (p <0.01) and 199+/-9 mmHg in the Nx + r-HuEPO group (p <0.01 vs Nx + vehicle). Hematocrit in control rats was 41.3+/-0.4% vs 32.6+/-1.8% in the Nx + vehicle group (p <0.01) and 47.6+/-1.5% in the Nx + r-HuEPO group (p <0.01). Plasma ir-ET-1 levels were similar in the Nx + vehicle and Nx + r-HuEPO groups (7.9+/-1.0 and 7.8+/-0.8 pg/ml). In contrast, thoracic aorta ir-ET-1 content was significantly higher in the Nx + r-HuEPO group than in the Nx + vehicle group (20.3+/-2.9 vs 13.4+/-1.9 pg, p <0.05). Similar results were obtained in the mesenteric arterial bed. There were significant correlations between blood pressure and ir-ET-1 content in the thoracic aorta (r= 0.45, p<0.05) and in the mesenteric arterial bed (r= 0.41, p<0.05). Vascular ET-1 content but not plasma levels are increased in uremic rats treated with r-HuEPO suggesting an increase in blood vessel ET-1 production which may play a role in the pathogenesis of r-HuEPO-induced hypertension.     

Transradial approach for coronary procedures: initial experience and results

To characterize the myogenic response during the development of hypertension, we evaluated the myogenic response of small arteries isolated from the cremaster muscle of spontaneously hypertensive rats (SHR) aged 4-5 and 7-8 weeks, as compared with age-matched Wistar-Kyoto rats (WKY), using an in vitro system. The myogenic response of SHR aged 7-8 weeks (but not those aged 4-5 weeks) significantly exceeded that of WKY. Measurement of intracellular levels of free calcium ([Ca2+]i) in small arteries of the 7-8-week-old SHR and WKY loaded with a calcium-sensitive dye showed that the increase in [Ca2+]i in SHR was significantly greater than that in WKY during the myogenic response. The inhibitory effects of nitrendipine on the increased myogenic response and [Ca2+]i were greater in SHR. Thus, the myogenic response was enhanced in SHR and may be explained in part by an increase in Ca2+ entry through the voltage-dependent calcium channel (VDCC). The myogenic response and Ca2+ entry through the VDCC may be increased in association with the elevation of blood pressure.     

Susceptibility to neonatal streptozotocin-induced diabetes in spontaneously hypertensive rats

We studied the difference in the susceptibility to neonatal streptozotocin (STZ) diabetes between spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY). Two-day-old female SHR and WKY were injected intraperitoneally with 75.0 mg/kg of STZ or vehicle for control. Hyperglycemia developed in both strains at 4 days of age, but SHR were more hyperglycemic. Overt hyperglycemia developed in SHR with aging after a partial recovery from initial hyperglycemia at 10 days of age, whereas WKY did not develop significant hyperglycemia except shortly after STZ treatment. Percentage of insulin-positive B cells in total islet cells and pancreatic immunoreactive insulin (IRI) content were measured at 4 days, 10 days, 4 weeks, and 12 weeks of age. B cells per islet and pancreatic IRI content were significantly reduced in STZ-treated groups as compared with control in both SHR and WKY at 4 days of age, but later they increased significantly with aging in both strains. However, the reduction in pancreatic IRI content relative to control was significantly greater in SHR than in WKY from 4 days (-94.5 +/- 3.5%, -84.1 +/- 4.8%; p < 0.01) to 12 weeks (-97.1 +/- 2.1%, -28.0 +/- 2.5%; p < 0.05), and the reduction in B cells per islet was also greater in SHR at 4 weeks of age. These results indicated that the initial destruction of pancreatic B cells induced by STZ was greater, and the following regeneration was less in SHR than in WKY. The association of the susceptibility to neonatal STZ diabetes with the development of genetic hypertension in SHR remained to be elucidated.     

Guanine nucleotide-binding inhibitory protein-mediated inhibition of adenylyl cyclase is enhanced in spontaneously hypertensive rat preglomerular arteriolar smooth muscle cells

The purpose of our study was to determine whether Gi-mediated control over adenylyl cyclase in preglomerular arteriolar smooth muscle cells (PGASMC) is enhanced in the spontaneously hypertensive rat (SHR). PGASMC were cultured from preglomerular microvessels isolated from adult SHR (14-15 wk of age) and age-matched WKY rats. Confluent monolayers of cells in third passage were used for the experiments. cAMP released into the media (30 min) as well as cellular levels of cAMP were measured in the presence of a phosphodiesterase inhibitor, 1-isobutyl-3-methyl-xanthine (IBMX; 100 microM) and expressed as pmol/mg protein. Total (released + cellular) cAMP was significantly lower in SHR (14.19 +/- 2.30 pmol/mg protein) as compared with WKY (28.3 +/- 3.04 pmol/mg protein). Correspondingly, the released (4.6 +/- 0.4 pmol/mg protein) as well as cellular (9.78 +/- 2.18 pmol/mg protein) cAMP levels were also significantly lower in SHR when compared with WKY (8.85 +/- 1.26 and 18.86 +/- 2.0 pmol/mg protein, respectively). The steady-state levels of none of the Gi alpha subunits, namely Gi alpha 1, Gi alpha 2 and Gi alpha 3, were higher in the SHR PGASMC. Pertussis toxin treatment (PTX; 100 ng/ml; 24 hr) caused complete ADP-ribosylation of Gi alpha subunits in both WKY and SHR PGASMC. The same treatment of PTX also produced a significant increase in total cAMP in SHR, but not in WKY, such that the total cAMP levels after PTX treatment were not significantly different between the two strains. Interestingly, PTX significantly increased the released (20.26 +/- 0.90 pmol/mg protein) but not the cellular (13.63 +/- 1.63 pmol/mg protein) cAMP in SHR. Forskolin (1 microM) induced similar increases in total cAMP and isoproterenol (1 microM) caused greater increases in total cAMP in SHR cells compared with WKY cells. These data strongly suggest that in SHR PGASMC total adenylyl cyclase activity is not altered. Furthermore, steady-state expressions of Gi alpha-1, Gi alpha-2 and Gi alpha-3 are not increased whereas Gi-mediated inhibition of adenylyl cyclase is augmented in SHR PGASMC.     

Current progress in the development of a totally implantable Gyro centrifugal artificial heart

We studied the contractile responses to endothelin-1 (ET-1) of aortic strips from female transgenic rats, TGR(mRen2)27, heterozygous for the Ren-2 mouse gene, during the phases of developing (blood pressure in rats aged 5 weeks; 156 +/- 8 mmHg), steady (blood pressure in rats aged 11 weeks: 206 +/- 27 mmHg), and reversed (blood pressure in rats aged 35 weeks: 151 +/- 17 mmHg) hypertension. These responses were compared with those of aortae from sex- and age-matched, genetically homogeneous, normotensive Sprague-Dawley (SD) rats. Aortic strips from both transgenic and SD rats were deprived of endothelium before isometrically recording developed tension to cumulatively added ET-1. Aortic strips from 5- and 11-week-old female transgenic TGR(mRen2)27 (hfTG) rats responded to ET-1 with higher Emax values and lower EC50 values than those of age-matched SD rats. Conversely, aortic strips from 35-week-old hfTG rats exhibited lower Emax and higher EC50 values than aortic strips from SD rats. Within the hfTG rats, aortic strips from 11-week-old rats showed increased Emax and decreased EC50 of ET-1 as compared with either 5- or 35-week-old hfTG rats. These data are in keeping with the hypothesis that ET-1 contributes to the hypertension of hfTG rats and suggest that an altered vascular responsiveness to the peptide may be implicated in the changes of their systolic blood pressure occurring with ageing in this animal model.     

Tissue-specific regulation of angiotensinogen gene expression in spontaneously hypertensive rats

Angiotensinogen is expressed in many tissues besides the liver. Recent studies have suggested that abnormalities in the regulation of angiotensinogen gene expression may be involved in the development of hypertension. However, little information is available concerning the functional significance of tissue angiotensinogen. In this study, we measured plasma angiotensinogen concentration by radioimmunoassay and examined the expression of tissue angiotensinogen by Northern blot analysis in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Although plasma angiotensinogen concentration in SHR was comparable to that in WKY at 6 weeks of age, it was increased significantly at 14 weeks of age in SHR and became higher than that in WKY. The levels of hepatic angiotensinogen mRNA were similar in SHR and WKY, and the levels of aortic, adrenal, and renal angiotensinogen mRNAs were lower in SHR than in WKY at both 6 and 14 weeks of age. Brain angiotensinogen expression in SHR was higher than in WKY at 6 weeks of age and was comparable to that in WKY at 14 weeks of age. On the other hand, cardiac and fat angiotensinogen mRNA levels were significantly increased at 14 weeks of age in SHR. These results demonstrate that the expression of tissue angiotensinogen is regulated differently in SHR and WKY and indicate that the development of hypertension is accompanied at least temporally with increases in plasma angiotensinogen concentration as well as cardiac and adipogenic angiotensinogen mRNA in SHR.     

Reduced pulmonary clearance of endothelin-1 contributes to the increase of circulating levels in heart failure secondary to myocardial infarction

BACKGROUND: The pulmonary vascular bed is a major site for endothelin-1 (ET-1) clearance. A reduced clearance could contribute to the increase in circulating ET-1 levels found in heart failure (HF). We therefore evaluated the effect of HF on pulmonary ET-1 clearance and on plasma ET-1 concentrations. METHODS AND RESULTS: Rats with myocardial infarction (n=24) were compared with sham-operated rats (n=22). The lungs were isolated and perfused at a constant flow rate of 10 mL/min. Pulmonary ET-1 clearance was measured by the single-bolus indicator-dilution technique with 125I-labeled ET-1. Infarct rats developed HF with mild pulmonary hypertension. ET-1 extraction was reduced by HF from 63+/-1.5% to 41+/-4.5% (mean+/-SEM, P<0.001). Mixed venous (MV) and aortic ET-1 levels doubled with HF. There was a plasma ET-1 gradient across the lungs of sham rats (MV-aortic levels, 0.21+/-0.12 pg/mL) but not in lungs of HF rats (0.01+/-0.17 pg/mL). Plasma ET-1 levels correlated closely and inversely with ET-1 extraction (P<0.001). CONCLUSIONS: HF is associated with reduced pulmonary ET-1 clearance that contributes to the increase in circulating levels.     

Alterations in heart and kidney membrane phospholipids in hypertension as observed by 31P nuclear magnetic resonance

Abnormalities of phospholipids in hypertension have previously been described in human erythrocyte, platelet, and plasma lipoproteins. Since the heart and kidney are adversely affected by hypertension, we investigated possible alterations in their membrane phospholipids, which could play a role in the derangement of intracellular ion balance widely observed in hypertension. The phospholipid compositions of heart and kidney from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats were determined by using 31P nuclear magnetic resonance (NMR) spectroscopy. Absolute contents of all phospholipids in hypertensive hearts and kidneys were significantly higher than in normotensive hearts and kidneys. Expressed as a fraction of total phospholipid, cardiolipin (CL) and phosphatidylethanolamine plasmalogen (PEp) were significantly increased in SHR hearts compared to WKY hearts (CL and PEp were 7.95+/-0.22% and 13.16+/-0.35% in SHR vs. 7.01+/-0.20% and 11.19+/-0.42% in WKY rats, P< or =0.05), but phosphatidylethanolamine (PE) and phosphatidylcholine (PC) were significantly decreased in SHR (PE and PC were 22.46+/-0.37% and 44.81+/-0.43% in SHR vs. 24.02+/-0.44% and 46.01+/-0.50% in WKY rats, P< or =0.05). In the phospholipids extracted from rat kidneys, the percentage of PE was significantly higher for SHR than for WKY rats (20.37+/-0.60% vs. 18.43+/-0.37%, P< or =0.05), while PEp and phosphatidylserine (PS) were significantly lower for SHR (PEp and PS were 10.22+/-0.36% and 8.42+/-0.28% in SHRs vs. 11.29+/-0.36% and 9.71+/-0.40% in WKY rats, P< or =0.05). The above alterations in phospholipid composition might contribute to the higher oxygen consumption in the hypertensive heart and abnormal intracellular ion concentrations and ion transport in the heart and the kidney in hypertension.     

In vivo hypothalamic release and synthesis of catecholamines in spontaneously hypertensive rats

Juvenile spontaneously hypertensive rats (SHR) have higher plasma levels of catechols and markedly larger catechol responses to yohimbine than do normotensive Wistar-Kyoto rats, indicating increased sympathoadrenal outflow and increased alpha 2-adrenergic receptor-mediated restraint of peripheral catecholamine release during hypertension development in SHR. Yohimbine-induced catecholamine release and metabolism in the posterolateral hypothalamus of the brain were assessed in juvenile (6 to 7 weeks) and adult (15 to 16 weeks) SHR and Wistar-Kyoto rats. In vivo microdialysis was used to obtain samples for measurements of norepinephrine, dihydroxyphenylglycol, methoxyhydroxyphenylglycol, and dihydroxyphenylacetic acid in conscious animals before and after yohimbine injection (1 mg/kg IV) beginning 24 hours after probe implantation. Catecholamine synthesis was examined from elevations of 3,4-dihydroxyphenylalanine levels after probe perfusion with NSD-1015, an inhibitor of L-aromatic acid decarboxylase. In adults, SHR had higher dialysate norepinephrine (277 +/- 38 versus 181 +/- 35 pg/mL), dihydroxyphenylglycol (3260 +/- 509 versus 2231 +/- 201 pg/mL), methoxyhydroxyphenylglycol (2659 +/- 369 versus 1890 +/- 144 pg/mL), and dihydroxyphenylacetic acid (46,312 +/- 5512 versus 13,187 +/- 1963 pg/mL) levels and markedly larger increases in 3,4-dihydroxyphenylalanine levels after NSD-1015 than Wistar-Kyoto rats. In juveniles, SHR had larger proportionate increments in microdialysate norepinephrine levels after yohimbine than Wistar-Kyoto rats (85% versus 25%). Although juvenile SHR and Wistar-Kyoto rats had similar NSD-1015-elicited increments in 3,4-dihydroxyphenylalanine levels, systemic yohimbine enhanced the NSD-1015-elicited 3,4-dihydroxyphenylalanine elevations in juvenile SHR but not in Wistar-Kyoto rats. These findings suggest augmented norepinephrine release and catecholamine synthesis in the posterolateral hypothalamus of adult SHR and augmented alpha 2-adrenergic receptor restraint of both norepinephrine release and catecholamine synthesis in juvenile 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.     

Dietary calcium decreases blood pressure without decreasing renal vascular resistance or altering the response to NO blockade

Many vasoactive elements are involved in the elevation of blood pressure in spontaneously hypertensive rats (SHR). Elevated dietary calcium has been observed to reduce blood pressure in SHR. This study investigates interactions among dietary calcium, renal vascular resistance (RVR), elevation of blood pressure and effects of norepinephrine and nitric oxide synthesis. We completed a series of experiments on two groups each (fed low, 0.1% and high, 2.0% dietary calcium, respectively) of 9-week-old Wistar Kyoto (WKY), 9-week-old and 6-week-old SHR. Although 9-week-old SHR had elevated baseline blood pressure compared to 9-week-old WKY and also compared to 6 week-old SHR, there was no corresponding elevation in baseline RVR. All SHR fed high calcium diets had lower blood pressure compared to low calcium diets, and there was no corresponding reduction in RVR. WKY controls' blood pressure and RVR were unaffected by dietary calcium levels. In all hypertensive rats the blood pressure and renal vascular resistance were elevated by N(G)-nitro-L-arginine methylester (L-NAME), but the dietary differences were sustained. Blood pressure of WKY was unaffected by the low dose of L-NAME. The increase in RVR to L-NAME was greater in SHR than in controls. The renal vascular response to norepinephrine was related to diet in older SHR, but smaller and unrelated to diet in younger SHR. Following L-NAME, WKY had greater responses to norepinephrine than 9-week-old SHR. We conclude that noradrenergic vasoconstriction is enhanced in the adult SHR, especially in the absence of high calcium diet. Alterations in NO synthesis may effect the norepinephrine response.     

Increase in affinity and loss of 5-hydroxytryptamine2A-receptor reserve for 5-hydroxytryptamine on the aorta of spontaneously hypertensive rats

1. The aim of this study was to determine whether the KA value and fractional occupancy-response relationship for 5-hydroxytryptamine (5-HT) at 5-HT2A-receptors were altered in a rat model of genetic hypertension. Thus, the effects of phenoxybenzamine, an irreversible blocker at 5-HT2A-receptors, on the responses of the aorta from spontaneously hypertensive rats (SHRs) and normotensive rats to 5-HT have been examined. The two strains of normotensive rats used were Wistar Kyoto (WKY) rats and Wistar rats bred in Auckland (WA rats). 2. The sensitivity to 5-HT was increased in aortae from hypertensive rats. The pD2 values for 5-HT during the first challenge were 5.54 +/- 0.08 (14), 5.43 +/- 0.05 (12) and 6.08 +/- 0.04 (12) on the aorta of WKY rats, WA rats, and SHRs, respectively. 3. The affinity for 5-HT was increased in hypertension. Phenoxybenzamine at 2 x 10(-8)M for 30 min caused nonparallel rightward shifts of 5-HT response curves and the KA values were 16.8 x 10(-6)M, 45.6 x 10(-6)M and 4.4 x 10(-6)M on the WKY rat, WA rat, and SHR aorta, respectively. 4. There was a loss of receptor reserve for 5-HT in aortae from hypertensive rats. On the WKY and WA rat aortae, 5-HT caused 50 and 95% maximal responses by occupying 10-20 and 45-60%, whereas on the SHR aorta 5-HT produced 50 and 95% maximal responses by occupying 20-30 and 75-85% of the available 5-HT2A receptors, respectively. 5. The sensitivity to phenylephrine was not altered in hypertension. The mean pD2 values for phenylephrine were 7.14 +/- 0.05 (22) and 7.11 +/- 0.06 (22) on the WKY rat and SHR aorta, respectively. 6. These results show that there is a selective increase in sensitivity to 5-HT on the aorta in a rat model of genetic hypertension. There is also an increase in affinity for 5-HT at the 5-HT2A-receptors and a loss of 5-HT2A-receptor reserve for 5-HT responses on the aorta of SHRs.     

Full expression of the exaggerated salt appetite of the spontaneously hypertensive rat requires a prenatal factor

1. The spontaneously hypertensive rat (SHR) exhibits a lower bodyweight in utero and an exaggerated salt appetite post partum. To determine whether salt appetite is affected by the perinatal environment, we measured the salt appetite of embryo-cross-transferred SHR and Wistar Kyoto (WKY) rats at maturity. 2. One-cell embryos were collected from the oviducts of donor rats and transferred into the oviducts of recipients through the infundibulum. The salt appetite of the resultant female offspring for 0.10 and 0.15 mol/L saline was measured at 20-30 weeks of age. 3. Salt intake of SHR gestated in WKY rats was significantly lower than that of SHR gestated in SHR, while that of WKY rats gestated in SHR was higher than that of WKY rats gestated in WKY rats. 4. Therefore, some maternal factor plays a role in the development of the exaggerated salt appetite of the SHR. This factor is also able to affect the later salt appetite of WKY rat offspring born to SHR surrogates.