Spontaneously Hypertensive Group Research Articles

Breathing irregularities in spontaneously hypertensive neonate rats

An excessive sympathetic drive is commonly observed in hypertensive patients and critically contributes to increasing arterial pressure levels. The quality of postnatal life can impact sympathetic control in adulthood. Spontaneously hypertensive (SH) rats, an experimental model of neurogenic hypertension, exhibit breathing irregularities in adult life. In this study, we investigated whether SH rats display breathing abnormalities after birth, which could be a risk factor for developing sympathetic overactivity. Using head-out plethysmography, we found that the neonate (P0-2, male and female) SH rats (n=9) exhibited lower minute ventilation than age-matched normotensive rats (NT, n=14; 816±177 vs 1261±189 ml/min/kg, P<0.05) under resting conditions, mainly due to reductions in respiratory frequency (93±15 vs 132±13 cpm, P<0.05). The reduced baseline ventilation in the SH group was accompanied by a greater prevalence of periods of apneas and respiratory irregularities (P<0.05). Under hypoxia conditions (10% O2, 10 min), SH and NT rats (n=9/each) mounted similar transient increases in minute ventilation during the initial period of exposure due to increments in tidal volume. In contrast, the respiratory frequency in the SH rats decreased progressively below baseline levels during hypoxia exposure (42% reduction, P<0.05), while it remained similar to pre-hypoxia values in the control group. In rhythmic in vitro preparations from neonate SH rats (n=2), we identified ectopic bursts in the hypoglossal activity and prolonged inspiratory-related bursts in the preBötzinger complex compared to preparations from NT rats (n=2). Our findings indicate that breathing irregularities in SH rats are present from birth and could be linked to dysfunctions in the inspiratory rhythm-generating network. Financial support: FAPESP, CNPq. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Cardiac, biochemical and histopathological analysis reveals impaired heart function in hypertensive rats with apical periodontitis.

To investigate the association between experimentally induced apical periodontitis (AP) and heart function in hypertensive rats. Forty-eight normotensive Wistar albino and spontaneously hypertensive (SHR) rats were divided into four equal groups: control (C), normotensive with AP (AP), SHR and SHR with AP (SHR+AP). AP was induced on the first right mandibular molars by exposing the pulp chambers to the oral environment for four weeks and confirmed radiographically. Thereafter, the animals were sacrificed by cervical dislocation, whilst hearts were isolated and perfused according to the Langendorff technique gradually increasing coronary perfusion pressures 40-120cmH2 O. The hemimandibles were analysed radiographically (mm2 and pixels) to verify the presence of AP. Biomarkers of cardiac oxidative stress (OS) were determined in coronary venous effluent and cardiac tissue homogenate. Cardiac tissue was analysed histopathologically for signs of heart damage (oedema, fibrosis and necrosis). All data were analysed by Kruskal-Wallis and one-way anova tests (p<.05). The levels of the maximum left ventricular pressure development rate of the SHR+AP group were significantly increased compared to the AP and C groups, and of the SHR group compared with the C group (p<.05). The levels of the minimum left ventricular pressure development rate of the SHR+AP group were significantly decreased compared to the AP, SHR and C groups, and of the SHR group compared to the C group (p<.05). The radiographic AP area was significantly larger in the SHR+AP group than in the AP group (p<.01). The levels of superoxide anion were significantly higher in the SHR+AP group than in the AP, SHR and C groups (p<.05). The activities of superoxide dismutase in cardiac tissue homogenate were significantly lower in the SHR+AP and AP groups compared with the SHR and C groups (p<.05). In rats, AP was associated with impaired cardiodynamics, disturbed cardiac OS, antioxidant defence and cardiac pathologic changes in hypertensive conditions. Hypertension was associated with an increase in the AP radiographic area. Further studies should confirm whether root canal treatment can have a cardioprotective effect and reduce cardiac OS in hypertensive conditions.

WHAT IS THE MAJOR FACTOR ON THE KIDNEY INJURY INDUCED BY HYPERTENSION OR HYPERHOMOCYSTEINEMIA

Objective: As we all know kidney injury could be induced by hypertension or hyperhomocysteinemia (HHcy). What is the major factor? HHcy plays a synergistic role with hypertension in vascular injury; however, the relationship between HHcy and hypertension in renal injury remains unclear. Here, we sought to evaluate the relationship between HHcy and hypertension in the context of renal injury and to elucidate the mechanism of action underlying this relationship. Design and method: Wistar Kyoto (WKY) and spontaneously hypertensive (SHR) rats were randomized into WKY, WKY+HHcy, SHR, and SHR+HHcy groups. Blood pressure, plasma homocysteine, creatinine, serum malondialdehyde (MDA), serum superoxide dismutase (SOD), and urinary albumin creatinine ratio (UACR) were measured. mRNA and protein expression levels of NOX2, NOX4, and nephrin in the kidneys were also examined. Results: The WKY+HHcy group exhibited lower serum SOD levels, relative to the WKY group, along with higher levels of both serum MDA and UACR. Similar effects were observed in the SHR+HHcy group, relative to the SHR group. Moreover, compared with the levels in the WKY+HHcy group, mean SOD levels in the SHR+HHcy group were lower, while mean MDA and UACR levels were higher. Higher mRNA and protein expression levels of NOX2 and NOX4, along with lower mRNA and protein expression levels of nephrin, were observed in the kidneys of WKY+HHcy and SHR+HHcy rats, relative to SHR and WKY controls, respectively. Furthermore, the mRNA and protein levels of NOX2 and NOX4 were higher and the mRNA and protein levels of nephrin were lower in the SHR+HHcy group than in the WKY+HHcy group. In addition, compared with WKY+HHcy group, the UACR level of SHR group was higher. Conclusions: HHcy appears to synergistically increase hypertensive renal damage by enhancing oxidative stress. However, hypertension remains a major risk factor for renal impairment compared to HHcy.

Comparative transcriptomic analysis revealed novel potential therapeutic targets of traditional Chinese medicine (Pinggan-Qianyang decoction) on vascular remodeling in spontaneously hypertensive rats

BackgroundBoth experimental and clinical studies have revealed satisfactory effects with the traditional Chinese formula Pinggan Qianyang decoction (PGQYD) for improving vascular remodeling caused by essential hypertension. The present study explored various therapeutic targets of PGQYD using mRNA transcriptomics.MethodsIn this study, rats were randomly divided into three groups: Wistar-Kyoto (WKY; normal control), spontaneously hypertensive (SHR), and PGQYD-treated rat groups. After 12 weeks of PGQYD treatment, behavioral tests were employed and the morphology of thoracic aortas were examined with hematoxylin–eosin (HE) and Masson staining and electron microscopy. The mRNA expression profiles were identified with RNA-Seq and quantitative real-time PCR to validate changes in gene expression observed with microarray analysis. The gene ontology and pathway enrichment analyses were carried out to predict gene function and gene co-expressions. Pathway networks were constructed to identify the hub biomarkers, which were further validated by western blotting and immunofluorescence analysis.ResultsAfter PGQYD treatment, the behavioral tests and histological and morphological findings of vascular remodeling were obviously meliorated compared with the SHR group. In the rat thoracic aorta tissues, 626 mRNAs with an exact match were identified. A total of 129 of mRNAs (fold change > 1.3 and P-value < 0.05) were significantly changed in the SHR group compared to the WKY group. Among them, 16 mRNAs were markedly regulated by PGQYD treatment and validated with quantitative real-time PCR. Additionally, target prediction and bioinformatics analyses revealed that these mRNAs could play therapeutic roles through biological processes for regulating cell metabolic processes (such as glycation biology), biological adhesions, rhythmic processes, and cell autophagy. The cellular signaling pathways involved in autophagy may be AGE–RAGE/PI3K/Akt/mTOR signaling pathway.ConclusionThe present study provides novel insights for future investigations to explore the mechanisms by which PGQYD may effectively inhibit vascular remodeling by activating the AGE–RAGE/PI3K/Akt/mTOR signal pathway in cell autophagy biology.

The pathophysiology of acute gastric ulcer development in normotensive and hypertensive rats: A comparative study

Although gastric ulcers and hypertension are diseases that affect a large part of the population, the association of these comorbidities is still poorly studied. Therefore, the present study investigated the response of normotensive (NTR) and spontaneously hypertensive (SHR) rats to gastric ulcers induced by indomethacin or ethanol. For that, adult male and female NTR and SHR received indomethacin (100 mg/kg, p.o) or ethanol P.A (5 ml/kg, p.o) to induce gastric ulcer, after the pre-treatment with prostaglandin E2 (PGE2) and carbenoxolone (CBX), respectively. The results revealed that, when compared to NTR, the SHR, both male and female, showed lower lesion area indexes when exposed to indomethacin. On the other hand, ethanol caused an area of lesion approximately 60% larger in the male and female SHR in comparison with the NTR. Significantly, the pre-treatment with PGE2 or CBX prevented the gastric ulcer damage promoted by indomethacin or ethanol, respectively. The histological analyses of the gastric mucosa from ethanol-induced ulcer revealed severe disruption of gastric architecture and bleeding points, that have been exacerbated in the SHR group. The gastric tissue from the SHR group also showed high levels of nitrite, a marker of nitric oxide production, which was accompanied by an increase in lipid hydroperoxide levels, an important biomarker of oxidative damage, in comparison with NTR. Taking together, the results of the present study showed important differences in the development of gastric ulcer between NTR and SHR. Further studies are needed for an in-depth analysis of the pathophysiological mechanisms involved in these responses.

Effects of Aerobic Physical Training on Thermoregulatory Adjustments During Physical Exercise in Spontaneously Hypertensive Rats

This study aimed to investigate the effects of physical training on thermoregulatory adjustments during running exercise and its effects on brain neuronal nitric oxide synthase (n‐NOS) expression. Male spontaneously hypertensive (SHR) and normotensive Wistar rats (NWR) at 8‐weeks age old were divided into four groups: untrained NWR (NWR‐U), trained NWR (NWR‐T), untrained SHR (SHR‐U) and trained SHR (SHR‐T). Experimental procedures were approved by the CEUA‐UFMG (#21/2015). Aerobic exercise training was performed on a treadmill running for 8 weeks. On the day of the experiments, the rats were subjected to a constant‐speed (60% of Vmáx) protocol until fatigue at 25°C. Tail skin temperature (Ts) and abdominal temperature (Ta) were measured every minute throughout the exercise trials. The preoptic area (POA) and paraventricular nuclei (PVN) of hypothalamus was collected to quantification of n‐NOS(ser852) by western blot. During exercise, the SHR‐U group showed greater increase in Ta compared to with NWR‐U group from the 16th min until the 23th min (min 23: 1.62 ± 0.15 °C vs. 1.21 ± 0.12 °C, p&lt;0.05) and lower Ts from the 1th until the 16th min of exercise (min 16: 0.09 ± 0.95 °C vs. 1.39 ± 0.41 °C, p&lt;0.05). Physical training in SHRs group did not change Ta response during exercise (fatigue: SHR‐T: 1.54 ± 0.29 °C vs. SHR‐U: 1.70 ± 0.18 °C, p&lt;0.05) but caused a greater increase in Ts in SHR‐T group (min 12: −0.54 ± 0.93 °C vs. −2.64 ± 0.80 °C, p&lt;0.05). Physical training in NWR group did not change Ta response during exercise (fatigue: NWR‐T: 1.62 ± 0.26 °C vs. NWR‐U: 1.71 ± 0.26 °C, p&lt;0.05) but caused a greater increase in Ts in NWR‐T group (fatigue: 3.65 ± 0.38 °C vs. 1.60 ± 0.47 °C, p&lt;0.05). The p‐nNOS expression in APO was lower in SHR‐U group when compared to the NWR‐U (0.06 ± 0.01 u.a. vs. 0.09 ± 0.01 u.a., p&lt;0.05). Physical training increased the p‐nNOS expression in the APO in the SHR group (0.10 ± 0.01 u.a. vs. 0.06 ± 0.01 u.a., p&lt;0.05). The p‐nNOS expression in PVN was similar between SHR‐U and NWR‐U groups (SHR‐U: 1.10 ± 0.19 u.a vs. NWR NT: 0.94 ± 0.13 u.a., p&gt;0.05). Physical training increased p‐NOS expression in the APO in both SHR group (1.58 ± 0.17 u.a. vs. 1.10 ± 0.19 u.a., p&lt;0.05) and NWR group (1.56 ± 0.25 u.a vs. 0.94 ± 0.13 u.a., p&lt;0.05). We conclude that physical training increases the efficiency of thermoregulatory control during exercise in hypertensive animals, which can be explained, at least in part, to an increase in the activity of neuronal nitric oxide synthase in trained animals.Support or Funding InformationFapemig, Capes, and CNPq.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

BRD4 expression in patients with essential hypertension and its effect on blood pressure in spontaneously hypertensive rats

The objective of this study was to investigate BRD4 expression in patients with essential hypertension (EH) and its effects on the blood pressure in spontaneously hypertensive (SHR) rats. BRD4 expression was detected by quantitative real-time polymerase chain reaction and western blot in 163 patients with EH and its relation to systolic blood pressure and diastolic blood pressure were analyzed accordingly. In vivo, rats were divided into WKY (Wistar-Kyoto rats), SHR (spontaneously hypertensive rats), SHR + JQ1 (BRD4 inhibitor), and SHR + Vehicle control. Rats' blood pressure was measured by the tail-cuff method. The protein expressions related to inflammation and oxidative stress of rats were determined. BRD4 was higher in patients with EH than healthy controls, which was positively correlated to systolic blood pressure and diastolic blood pressure of enrolled subjects including patients with EH and healthy controls. Rats in the SHR group showed reduced food-intake, decreased body weight, and gradually increased blood pressure compared with WKY group. Besides, SHR rats were upregulated in plasma levels of Ang II, ET-1, MDA, IL-6, and TNF-α, and substantially downregulated in NO, NOS, and SOD levels. Moreover, eNOS activity in aortic tissues of SHR rats declined obviously, whereas the content of nitrite and O2−, the activity of NADPH oxidase and NADH oxidase, and the expression of p-NF-κB p65 went up statistically, which could be partially reversed by JQ1. BRD4 was highly expressed in patients with EH, and inhibiting BRD4 could reduce oxidative stress and inflammatory response, alleviate endothelial cell damage, ameliorate aortic injury, and lower blood pressure, supporting the hypothesis that BRD4 inhibition could be a potential target for the clinical treatment of patients with EH.

Neuroprotective effects of exogenous melatonin on spontaneously hypertensive rats with focal cerebral ischemia

Hypertension is involved in the exacerbation of stroke; thus, in the present study, we investigated the neuroprotective effects of melatonin against focal cerebral ischemia in spontaneously hypertensive (SHR). We examined whether hypertension influences focal cerebral ischemia. Following middle cerebral artery occlusion‐reperfusion (MCAo), melatonin was injected subcutaneously each day at 7:00 and 19:00 for four weeks. The brains of the rats were then isolated and sectioned at 2‐mm intervals from the frontal to the occipital pole to yield six coronal slices. The slices were then immersed for 30 min in 2% TTC at 37°C. Gene expression was then analyzed, and the infarct volume was quantified using Image‐J analysis software. The infarct volume in the SHR group was significantly increased compared to the normal vehicle group (p&lt;.01). Exposure to melatonin decreased the infarct volume compared to vehicle exposure. NOS expression was decreased in the melatonin‐treated group after MCAo; however, BDNF gene expression in the melatonin‐treated group was increased, as compared to that in the vehicle group. These results suggest that melatonin can prevent neurological injury in cases of hypertension‐assisted focal cerebral ischemia.

Antihypertensive Effects ofGynura procumbensExtract in Spontaneously Hypertensive Rats

Aqueous extracts of Gynura procumbens (Lour.) Merr. were orally administered to spontaneously hypertensive (SHR) rats for 4 weeks, and antihypertensive effects were determined. Oral administration of 500 mg/kg of G. procumbens (Lour.) Merr. extract (GPE) resulted in significantly lower blood pressure in SHR rats compared with SHR rats not given GPE (P < .05). Furthermore, GPE-administered rats had significantly lower serum lactate dehydrogenase, creatine phosphate kinase, and increased nitric oxide (NO), a known vasodilator, compared with the non-GPE-administered SHR group (P < .05). These results suggest that oral administration of aqueous GPE may be useful for prevention and treatment of hypertension through increasing NO production in blood vessels.

Hypertension and Exercise Training Differentially Affect Oxytocin and Oxytocin Receptor Expression in the Brain

We have previously shown that exercise training activates nucleus tractus solitarii (NTS) oxytocinergic projections, resulting in blunted exercise tachycardia. The objective of this study was to determine the effects of hypertension and training on oxytocin (OT) and OT receptor expression in the hypothalamic paraventricular nucleus (PVN) and projection areas (dorsal brain stem [DBS]). Male, normotensive, Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats were trained (55% maximal exercise capacity, 3 months) or kept sedentary, and pressure was measured weekly. DBS sections were processed for immunohistochemistry (polyclonal guinea pig anti-OT) or in situ hybridization for OT and OT receptor (35S-oligonucleotide probes). Other groups of rats had brains removed and frozen to isolate the DBS and PVN; samples were processed for OT and OT receptor cDNA reverse transcription-polymerase chain reaction amplification with beta-actin as the housekeeping gene. Training was equally effective in improving running distance in both groups, with pressure reduction only in SHR (-10%, P<0.05). In trained WKY, baseline bradycardia (P<0.05) occurred simultaneously with increased NTS OT immunostaining and mRNA expression (+3.5-fold), without any change in OT receptor mRNA expression. PVN OT mRNA and DBS OT receptor mRNA expressions were significantly lower in SHR versus WKY (-39% and -56%, respectively). Training did not alter DBS OT receptor density in the SHR group but increased OT mRNA in both PVN and DBS areas (+78% and +45%, respectively). Our results show a marked hypertension-induced reduction in OT receptor mRNA expression, not altered by training. In contrast, training increased OT mRNA expression in sedentary and hypertensive rats, which may facilitate training-induced cardiac performance.

Calpain is activated in experimental uremia: Is calpain a mediator of uremia-induced myocardial injury?

The cysteine proteases calpain and caspase-3 are known mediators of cell death. The aim of this study was to assess their contribution to the tissue damage found in experimental uremia. Calpain and caspase-3 activities were measured in the hearts of rats that were sham-operated (control), sham-operated and spontaneously hypertensive (SHR), and those rendered uremic by 5/6 nephrectomy (uremic). In an in vitro study, heart myoblasts (Girardi) were incubated with human serum from healthy subjects (control serum conditioned media, CSCM) or uremic patients (uremic serum conditioned media, USCM), in the presence and absence of calpain and caspase-3 inhibitors. After 48 hours the activity of calpain and caspase-3 was measured, and cell injury determined by DNA fragmentation (ELISA) and lactate dehydrogenase (LDH) release. An in situ assay was designed to study how USCM affects calpain activity over time. In the in vivo study, mean calpain activities were almost identical in the control and SHR groups, but calpain and caspase-3 activities were much elevated in the uremic group (P < 0.01 and 0.001 respectively vs. control). The SHR group had significantly higher mean arterial blood pressure (P < 0.001 vs. control, 0.01 vs. uremic). In the in vitro study calpain activity and DNA fragmentation were markedly higher in USCM treated cells compared to CSCM (both P<0.05). Both were reduced in USCM cells containing calpain inhibitors (E64d, calpastatin, or PD 150606). LDH release was raised also in USCM treated cultures (P < 0.05), which only the E64d treatment could significantly reduce (P < 0.02). Caspase-3 activities were similar in USCM and CSCM groups. The in situ assay showed significant increases in calpain activity in USCM treated cells compared to CSCM after just 3.5 hours (P<0.01). In vivo results suggest that the increases in calpain and caspase-3 activity in uremic rat hearts were primarily due to uremia and not to hypertension. In vitro data demonstrate that uremia-induced cell injury can be attenuated by calpain inhibition. Therefore, it is likely that calpain is a mediator of uremia-induced myocardial injury.

Diminished cardiac contractile response to tetrahydropapaveroline in hypertension: role of β-adrenoceptors and intracellular Ca 2+

Tetrahydropapaveroline (THP), a condensation product of ethanol-derived acetaldehyde, potentiates cardiac function through a β-adrenergic mechanism. It is well established that β-adrenergic activity is markedly depressed in hypertension. However, little is known about the myocardial action of THP in hypertension. In this study, the effect of THP was examined using left ventricular papillary muscles and ventricular myocytes from 10-week-old normotensive (WKY) and spontaneously hypertensive (SHR) rats. The mechanical parameters evaluated include: peak tension developed (PTD), peak twitch amplitude (PTA), time-to-PTD/PTA (TPT/TPS), time-to-90% relaxation/relengthening (RT 90/TR 90), and the maximal velocities of contraction/shortening and relaxation/relengthening (±VT/±d L/d t). Intracellular Ca 2+ transients were measured as fura-2 fluorescence intensity changes (ΔFFI). THP (0.01–100 μM) produced a concentration-dependent increase in myocardial contraction on muscles and myocytes from both groups of animals. However, preparations from the SHR group were generally less responsive to THP than their normotensive counterparts. The increase in contractility by THP was associated with increases in ΔFFI and ±VT, and shortening of TPT/TPS and RT 90/TR 90. The role of β-adrenoceptor(s) in the mechanism of action of THP was explored using specific β-receptor subtype antagonists CGP 207.12A (β 1) and ICI 118,551 (β 2). In preparations from both WKY and SHR hearts, the THP-induced increase in cardiac contractility was either attenuated or blocked by CGP 207.12A and ICI 118,551. These results indicate that THP exhibits a positive action on myocardial contraction that is mediated, in part, through both β 1 and β 2 adrenergic receptors. This cardiac inotropic response, however, is markedly diminished in hypertension, which is due possibly to alterations in β-adrenergic signal transduction.

4-Hydroxynonenal, a novel indicator of lipid peroxidation for reperfusion injury of the myocardium

4-Hydroxynonenal (HNE) has been proposed as an important marker of radical-induced lipid peroxidation (LPO) during postischemic reperfusion injury of the myocardium. Therefore, the liberation of HNE into the effluent of isolated perfused rat hearts was investigated. For the first time, the formation of the aldehyde is demonstrated in myocardium. During control perfusion, 1.28 +/- 0.33 pmol HNE.min-1.mg protein-1 were formed by the hearts of 18-mo-old Wistar-Kyoto (WKY) rats and 2.74 +/- 1.12 pmol.min-1.mg protein-1 by those of 18-mo-old spontaneously hypertensive (SHR) rats, respectively. In the WKY group, HNE release increased to 3.35 +/- 1.13 pmol.min-1.mg protein-1 2 min after the onset of reperfusion following 30 min of total and global ischemia compared with the preischemic control period (P < 0.05). In the SHR group, HNE liberation was higher during reperfusion (8.66 +/- 1.33 pmol.min-1.mg protein-1, maximum at 2 min reperfusion) compared with both the respective preischemic control and the respective reperfusion interval of the WKY group (P < 0.05 each). The SHR rats showed signs of congestive cardiac failure of a decompensated hypertrophy in comparison to the normotensive WKY rats. Moreover, the SHR rat hearts exhibited a lower release of adenine nucleotide degradation products (adenine, inosine, hypoxanthine plus uric acid: 48.1 +/- 10.2 nmol.30 min-1.mg protein-1; P < 0.05) and a diminished functional recovery (left ventricular developed pressure, 32 +/- 16 mmHg; P < 0.05) during 30 min of reperfusion compared with the WKY group (77.9 +/- 14.4 nmol.30 min-1.mg protein-1; 90 +/- 21 mmHg).(ABSTRACT TRUNCATED AT 250 WORDS)

Potassium supplementation attenuates experimental hypertensive renal injury.

The long-term roles of dietary sodium and potassium on the renal end-organ damage of hypertension were investigated in Wistar-Kyoto (WKY) and in spontaneously hypertensive (SHR) rats. Eight rats from each strain were maintained since 1 month of age on one of four dietary combinations of either low (0.4%) or high (6.0%) NaCl and low (0.51%) or high (7.6%) KCl providing sodium/potassium molar ratios of 1:1, 1:15, 15:1, and 15:15, respectively. Urinary sodium/potassium excretion ratios confirmed the proportion of salts consumed. Systolic blood pressures (SBP) were similar at 5 months of age and at the completion of the study at 9.5 months; SBP was significantly higher in SHR than in WKY rats and was not attenuated by dietary potassium supplementation of a magnitude that raised plasma potassium concentrations. Albumin excretion rate (AER) was also higher in SHR than in WKY rats (P less than 0.0001). In SHR, AER rose further with high sodium intake (P less than 0.035) but, contrary to SBP, was ameliorated by an equimolar addition of potassium (P less than 0.01). Morphologic lesions were generally absent in WKY rats and were more common in SHR as a group (P less than 0.001). In all four SHR groups, the graded histopathologic injury correlated well with measured AER but a major improvement in hypertensive renal lesions occurred largely in the KCl-supplemented, salt-loaded SHR group. These results show a disassociation between the effects of dietary monovalent cations on the level of SBP and their effect on renal injury. Sodium aggravates renal injury and potassium protects against this renal effect of sodium independent of SBP effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of Cicletanine on Reperfusion-Induced Arrhythmias and Ion Shifts in Isolated Rat Hearts

Isolated hearts from normotensive (NT) and spontaneously hypertensive (SH) rats, subjected to normothermic global ischemia, were used to study whether cicletanine (a new antihypertensive drug) treatment exerts an antiarrhythmic effect against reperfusion-induced arrhythmias. The effect of the drug on myocardial ion contents (Na+, K+, Ca2+, and Mg2+) during ischemia and reperfusion was also determined. Using the optimal doses of cicletanine (30 and 100 mg/kg orally for 14 days), the incidence of reperfusion-induced ventricular fibrillation (VF) and ventricular tachycardia (VT) was reduced from their control values of 91 and 100% (after 30 min of ischemia) to 41 (p less than 0.05), 50 (p less than 0.05) and 41 (p less than 0.05), 58% in the NT group, while the corresponding value in the SH group for VF and VT were 17 (p less than 0.001), 33 (p less than 0.01) and 17 (p less than 0.001), 25% (p less than 0.001), respectively. The results obtained indicate that the cardioprotective effect of cicletanine was greater in the SH group than in the NT group. Cicletanine significantly reduced the ischemia- and reperfusion-induced myocardial Na+ and Ca2+ gains and inhibited the loss of myocardial K+ and Mg2+ in both NT and SH groups. The antiarrhythmic effect of cicletanine appears to be correlated with the preservation of myocardial Na+, K+, Ca2+, and Mg2+ contents via an ion transport modulation.

GABAergic responses in ventrolateral medulla in spontaneously hypertensive rats

Gamma-Aminobutyric acid (GABA) and the GABA antagonist bicuculline methiodide were used to investigate the role of GABAergic transmission in the rostral and caudal ventrolateral medulla in 12- to 13-wk-old spontaneously hypertensive (SH) (n = 7) and normotensive, control Wistar-Kyoto (WKY) (n = 7) rats. Animals were anesthetized with urethan (1.25 g/kg sc), paralyzed with gallamine triethiodide (10 mg/kg iv), and artificially ventilated. Femoral arterial and venous catheters were inserted for the measurement of mean arterial pressure (MAP) and heart rate responses and for intravenous infusions. The ventral surface of the brain stem then was exposed. The responsiveness of the rostral ventrolateral medulla to GABA was compared in SH and WKY rats using unilateral microinjections (30 nl) of GABA at 1, 10, and 100 mM concentrations, which produced significantly (P less than 0.05) larger decreases of MAP in SH rats compared with WKY at the 10 and 100 mM concentrations (-37.3 +/- 2.8 mmHg for SH vs. -27.3 +/- 2.7 mmHg for WKY at 100 mM). Tonic GABAergic inhibition was gauged using bilateral microinjections (30 nl) of bicuculline (2 and 4 mM) into the rostral ventrolateral medulla, which caused significantly larger increases in MAP in the WKY group (+84.8 +/- 8.5 mmHg at 4 mM) compared with the SH group (+14.9 +/- 5.8 mmHg at 4 mM). In contrast, the ability to drive sympathetic outflow by microinjection of L-glutamate in the rostral ventrolateral medulla was not significantly different between WKY and SH rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular effects of l-glutamate and tetrodotoxin microinjected into the rostral and caudal ventrolateral medulla in normotensive and spontaneously hypertensive rats

The purpose of this study was to compare the responsiveness of the rostral and caudal ventrolateral medulla in spontaneously hypertensive (SH) and normotensive Wistar-Kyoto (WKY) rats to microinjection of l-glutamate, and to estimate tonic output of these areas by microinjecting the neurotoxin tetrodotoxin. Rats were anesthetized with 1.25 g/kg urethane s.c., implanted with arterial (femoral) and venous (femoral) catheters, artificially ventilated and paralyzed with gallamine triethiodide (10 mg/kg). Using a ventral approach to the brainstem, the mean arterial pressure and heart rate responses to microinjection (30 nl) of l-glutamate (1, 10 and 100 mM) and tetrodotoxin (10 μM) into the rostral and caudal ventrolateral medulla were compared in SH ( n = 7) and WKY ( n = 7) groups. Microinjection of l-glutamate into the rostral ventrolateral medulla produced equivalent increases in mean arterial pressure (maximum+33 ± 3and+36 ± 6 mm Hg, SH and WKY groups respectively) and minimal changes in heart rate. Similar administration of l-glutamate into the caudal ventrolateral medulla caused decreases in mean arterial pressure and heart rate; changes in mean arterial pressure were significantly greater in the SH group than in the WKY group (−52.3 ± 2.9 mm Hg for SH,−22.6 ± 2.6 mm Hg for WKY). Bilateral microinjection of tetrodotoxin into the caudal ventrolateral medulla produced significantly larger increases of mean arterial pressure in WKY rats (+8 ± 4vs+46 ± 8 mm Hg for SH vs WKY). These data indicate that SH rats may have a lower tonic activity of neurons in the caudal ventrolateral medulla, resulting in a lower restraining influence on sympathetic outflow in the SH rat. (Supported by: HL 36552 and KY-THRI 5-42078).

Body fluids and plasma atrial peptide after its chronic infusion in hypertensive rats.

To determine the role of body fluid volume in the chronic hypotensive effect of atrial natriuretic factor (ANF), spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats were infused with the peptide (Arg 101-Tyr 126) at a rate of 100 ng/h/rat for 5 days. Blood pressure (BP) was decreased from 176 +/- 4 to 133 +/- 3 mmHg in the SHR group 4 days after ANF infusion was initiated, whereas no changes were observed in ANF-infused WKY animals. Starting 5 days after the infusion began, body fluid measurements revealed no differences in plasma, blood and extracellular fluid volumes or in interstitial spaces. BP and plasma ANF concentrations were determined in another set of experiments before, during and after chronic ANF infusion. BP declined from 169 +/- 3 to 133 +/- 5 mmHg in SHR 5 days after the infusion commenced, but returned to basal values by day 10 or 11. Plasma ANF was significantly higher in SHR than in WKY rats throughout the observation period. However, there were no discernible changes in this parameter in ANF-infused SHR compared to non-infused SHR. A 3-fold rise in plasma ANF was noted in infused WKY rats at day 3 only. It is concluded that the chronic hypotensive effect of ANF in hypertensive animals is not related to changes in either body fluid volume or distribution. Moreover, the finding that chronic ANF infusion reduces BP in SHR without altering its plasma levels suggests a rapid ANF turnover.

Increased dietary calcium lowers blood pressure in the spontaneously hypertensive rat

The effect of increased dietary calcium on the development of hypertension in spontaneously hypertensive (SH) rats was investigated by feeding lab chow fortified with calcium carbonate (2.5% calcium, hCa) beginning at 4 wk of age. A control SH group was fed regular lab chow (1.2% calcium, rCa). Two groups of age-matched Wistar-Kyoto (WKY) rats were treated in parallel. Systolic blood pressure (BP) was measured weekly until the age of 18 wk using a tail cuff method. The hCa diet significantly attenuated the time course of hypertension in SH rats even though both SH groups eventually developed hypertension. The hCa also lowered BP in WKYs, but to a lesser extent. Urine output (24-hr volumes) was not affected by hCa, but in both SH and WKY groups fed the hCa diet, the excretion of Na +, K + and Ca ++ was markedly elevated at 11, 15, and 19 wk of age. Urine osmolality was also elevated. Plasma Na +, Ca ++ and osmolality were not significantly altered by the diet in either SH or WKY rats; plasma potassium was significantly lower in the SH group fed the hCa diet than in the group given rCa. The hCa diet did not significantly affect the body or heart, kidney, adrenal, or thymus weights. The results suggest that hCa diet may attenuate genetic hypertension by inducing an osmotic diuresis.

Heart rate responses of spontaneously hypertensive rats during aversive classical conditioning

Heart rate (HR) responses of restrained spontaneously hypertensive (SHR) and normotensive (WKY) female rats were compared during aversive classical conditioning. Baseline HR of the SHR group was temporarily higher than that of the WKY group. For both groups, the directions of the HR-orienting response to the novel CS prior to conditioning as well as the HR-conditioned response during conditioning were decelerative. Although the magnitude of the orienting response was larger in the SHR group than in the WKY group, the conditioned responses of the two groups were nearly the same. It was suggested that the orienting response in both groups was due to inhibition of sympathetic activity in conjunction with increased vagal outflow. It was further suggested that the enhanced orienting response in the SHR group could be accounted for by the greater β-adrenergic tone in the resting HR of the SHR which, with inhibition of sympathetic tone, resulted in a relatively larger fall in HR.