Effect of emotional stress on the contractility, adrenoreactivity and calcium sensitivity of smooth muscles of the portal vein in spontaneously hypertensive rats

The emotional stress decreased contractility and adrenoreactivity in normotensive rats, while in spontaneously hypertensive rats (SHR) the changes were less pronounced. The changes in adrenoreactivity, as well as increased permeability of smooth muscle cells for calcium and reduced reactivity to exogenous calcium revealed in hypertensive animals contribute to high resistance of portal vein smooth muscles to stress.     

Breathing pattern of spontaneously hypertensive rats

The trachea of rats anaesthetized with sodium pentobarbitone was cannulated and the air flow velocity and the pressure of the oesophagus were measured. In the spontaneously hypertensive rats the breathing frequency was higher, the tidal volume and the effective lung resistance were smaller than that of the normotensive Wistar rats. It seems that the neurohumoral control of respiration in SHR animals differs from that of normotensive rats.     

Comparison of somatosympathetic reflex in normotensive and spontaneously hypertensive rats

In chloralose anaesthetized and paralyzed normotensive (Wistar, Wistar--Kyoto) and spontaneously hypertensive rats (SHR), a somatosympathetic reflex in the cervical sympathetic trunk elicited by a single electrical shock to forelimb afferent fibres in the median nerve was recorded. It has been shown that the elicited response of SHR is similar to the response of normotensive rats. Amplitude of somatosympathetic reflex in SHR is larger than that of somatosympathetic reflex in normotensive animals. It is supposed that somatosympathetic reflex in hypertensive and normotensive rats is formed in the same way. However, reflex excitability of sympathetic nervous system in SHR is greater.     

A comparative study on defense systems for lipid peroxidation by free radicals in spontaneously hypertensive and normotensive rat myocardium.

1. Antiperoxidation ability and lipid peroxidation in myocardium were examined in spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) at 6 and 16 weeks of age. 2. Glutathione peroxidase activity was higher in SHR at 6 weeks of age, but lower at 16 weeks compared to that in WKY. alpha-Tocopherol content was lower in SHR at both 6 and 16 weeks of age than in WKY. 3. In vitro formation of free malondialdehyde was more pronounced in SHR myocardium than in WKY. 4. Coincidence of lower antiperoxidation ability and higher peroxidation of membrane phospholipid indicate myocardial cell vulnerability in SHR hypertrophied myocardium.     

Delayed development of hypertension and increased aortic relaxation in spontaneously hypertensive rats after neonatal sympathectomy

The effect of neonatal sympathectomy on vasodilator responses to acetylcholine (ACh) and cAMP has been studied in aortic rings of spontaneously hypertensive rats (SHR) and normotensive animals. The relaxation of intact SHR aorta in response to ACh and cAMP was 20-35% lower than that of normotensive rats. Sympathectomy in normotensive rats did not affect the level of blood pressure and aorta reactivity to Ach. In SHR, sympathectomy caused a decrease in blood pressure, while relaxation in response to ACh and cAMP increased, as compared to intact SHR, but remained lower than in normotensive rats. The data obtained suggest that the decrease in arterial pressure of sympathectomized SHR is a result not only of the reduction in sympathetic effects but also of the increase in smooth muscle relaxation.     

Lower number of atrial natriuretic peptide receptors in thymocytes and spleen cells of spontaneously hypertensive rats

Spontaneously hypertensive rats (SHR) have a much lower number of atrial natriuretic peptide (ANP) receptors in thymus and spleen from young and adult animals than age-matched normotensive controls. In spite of this low receptor concentration, the ANP-stimulated cyclic GMP response in isolated thymocytes and spleen cells from SHR was similar to that of normotensive control rats. Alterations in ANP receptor concentration in thymus and spleen of SHR may be related to the immune abnormalities described in these animals, and to the pathophysiology of genetic hypertension.     

Secretory dysfunction of vascular endothelium limits the effect of angiotensin converting enzyme inhibitor quinapril on aggregation of erythrocytes in experimental hypertension.

Using automatic erythrocyte aggregometer type MA-1 (Myrenne gmbh, Germany), we investigated the hypothesis that therapeutic effectiveness of quinapril--angiotensin converting enzyme inhibitor (ACEI)--in the treatment of hypertension would correlate with improvement of red blood cell (RBC) aggregability. Experiments were performed on commercially available inbred strain of spontaneously hypertensive male rats (SHR) aged 19-21 weeks. Age-matched normotensive Wistar-Kyoto (WKY) rats genetically related to SHR were used as a control. Aggregability of RBC in hypertensive rats was significantly higher than in control WKY animals. Quinapril (100 microg/kg) administered i.p. for 8 days improved RBC aggregability in normotensive rats but surprisingly not in SHR animals. Beneficial effect of quinapril on RBC aggregation observed in normotensive animals did not occur when this drug was injected in combination with aspirin (1 or 50 mg/kg) or with indomethacin (20 mg/kg) or with L-NAME (10 mg/kg). However, much the same damaging effects on RBC aggregability were observed when aspirin, indomethacin or L-NAME were each administered into normotensive animals without quinapril. In contrast with normotensive rats, aggregability of RBC in SHR was not affected either by quinapril or by indomethacin and by L-NAME, given separately or in combination. The only compound significantly worsening RBC aggregability in SHR was aspirin but this effect was not dose-dependent. Quinapril-induced improvement of RBC aggregability in normotensive rats (but not in SHR) was completely abolished by simultaneous administration of B2 receptor antagonist icatibant and successfully mimicked by 8 days of treatment with bradykinin. In vitro aggregability of RBC isolated from WKY was not affected by previous incubation (30 min at 37 degrees C) with quinapril, indomethacin or L-NAME. Only aspirin (3 mM) significantly increased RBC aggregability as compared to placebo. It is concluded that under physiological conditions quinapril efficiently inhibits RBC aggregability and this effect is modulated by secretion of endothelial mediators, mainly prostacyclin and nitric oxide. In hypertension quinapril, in spite of lowering of arterial blood pressure, is unable to display its beneficial effects on RBC aggregability possibly due to the hypertension-induced/accompanied dysfunction of vascular endothelium. Aspirin revealed unique erythrocyte damaging properties, presumably independent of inhibition of cyclooxygenase but related to a direct membrane protein acetylation.     

Involvement of the Na+-independent Cl-/HCO3- exchange (AE) isoform in the compensation of myocardial Na+/H+ isoform 1 hyperactivity in spontaneously hypertensive rats

Enhanced activity of Na+/H+ isoform 1 (NHE-1) and the Na+-independent Cl-/HCO3- exchange (AE) is a feature of the hypertrophied myocardium in spontaneously hypertensive rats (SHR). The present study explored the possibility that sustained intracellular acidosis due to increased myocardial acid loading through AE causes NHE-1 enhancement. To this aim, SHR were treated for 2 weeks with a rabbit polyclonal antibody against an AE3 isoform that was recently developed and proven to have inhibitory effects on myocardial AE activity. We then compared the AE activity in the left ventricle papillary muscles isolated from untreated SHR with antiAE3-treated SHR; AE activity was measured in terms of the rate of intracellular pH recovery after an intracellular alkali load was introduced. AE activity was diminished by approximately 70% in SHR treated with the antiAE3 antibody, suggesting that the AE3 isoform is a major carrier of acid-equivalent influx in the hypertrophied myocardium. However, the antibody treatment failed to normalize NHE-1 activity that remained elevated in the myocardium of normotensive rats. The data therefore rule out the possibility that NHE-1 hyperactivity in hypertensive myocardium was due to sustained intracellular acidosis induced by increased AE activity that characterizes SHR myocardial tissue.     

Increased sensitivity of the fatty tissue of rats with spontaneous hypertension to the action of ACTH. The role of calcium]

The action of ACTH on the adipose tissue lypolysis was studied in rats with spontaneous and renal hypertension as well as in normotensive rats of the respective control groups. It was demonstrated that sensitivity of the adipose tissue SHR to ACTH was increased as compared to normotensive controls. The data presented indicate that the increased sensitivity is due to the state or content of intracellular calcium. The rats with renal hypertension did not show such an increased sensitivity of the adipose tissue to ACTH.     

Spontaneously hypertensive and Wistar Kyoto rats are genetically disparate.

Spontaneously hypertensive rats (SHR) are one of the most common animal models used to study essential hypertension in humans. Because SHR and normotensive Wistar Kyoto (WKY) rats were both established from the same parental, normotensive Wistar stock, WKY animals have been used almost exclusively as control animals in studies of SHR. Recently, the suitability of WKY rats as normotensive controls for SHR has been challenged. To establish whether or not SHR and WKY rats share the same immunologic backgrounds, we initially performed a series of skin grafting experiments on these animals. In all cases, grafts of SHR donor skin to WKY recipients and of WKY donor skin to SHR recipients resulted in complete rejection within 7 to 10 days. In addition, grafts of WKY donor skin to other WKY recipients resulted in graft rejection. By contrast, skin grafts between SHRs were always accepted. To further characterize the genetic distinctions between SHR and WKY rats, allelic profiles based on a series of immunologic and biochemical markers were established for each strain. These findings clearly establish that SHR and WKY rats differ at the major histocompatibility complex, in specific blood group antigens, and in a panel of isozymic markers. Moreover, whereas SHRs have the same genetic profiles irrespective of source, some colonies of WKY rats are outbred, as judged by their variant allelic profiles.     

Erythropoietin increases cytosolic free calcium concentration and thrombin induced changes in cytosolic free calcium in platelets from spontaneously hypertensive rats

Using fura-2 cytosolic free calcium concentrations were measured in intact washed platelets from 9 spontaneously hypertensive rats (SHR) and from 9 age-matched normotensive Wistar-Kyoto rats (WKY). In resting platelets cytosolic free calcium concentration was significantly higher in SHR than in WKY (171.8 +/- 64.4 nM vs 93.1 +/- 59.0 nM, p less than 0.05). After preincubation with erythropoietin cytosolic free calcium concentration was significantly higher in SHR than in WKY (197.5 +/- 83.2 vs 93.0 +/- 60.1, p less than 0.01). Using platelets from SHR erythropoietin increased mean resting cytosolic free calcium concentration by 14.9% (p less than 0.05) and mean thrombin induced changes of cytosolic free calcium by 58.3% (p less than 0.01). In contrast, erythropoietin caused no significant increase in the resting calcium concentration or in thrombin induced changes of cytosolic free calcium in platelets from WKY. It is concluded that erythropoietin is involved in the pathogenesis of hypertension by elevating cytosolic free calcium concentration.     

Minerals in renal and SHR hypertensive rats

References to individual trace minerals in hypertensive rats have been made; however, data on multiple minerals in SHR hypertensive rats is lacking. The purpose of this study was to investigate five trace minerals in normotensive, chronic renal and SHR hypertensive rats. Blood samples were drawn to measure serum levels of Ca, Fe, K, Mg, and Na. Serum K values were elevated in the chronic renal hypertensive animals. Iron levels were decreased in both the renal and SHR hypertensive animals. No difference was observed in levels of Ca, Mg, and Na between normotensive and chronic renal or SHR hypertensive rats. Further study of multiple trace minerals in experimental hypertension is recorded in order to extend these deviations.     

Does Cd36 gene play a key role in disturbed glucose and fatty acid metabolism in Prague hypertensive hypertriglyceridemic rats?

Close links between hypertension, hypertriglyceridemia, insulin resistance and other symptoms of metabolic syndrome was demonstrated in humans and experimental animals. Quantitative trait loci for defects in glucose and fatty acid metabolism, hypertriglyceridemia and hypertension were mapped in spontaneously hypertensive rats (SHR) on chromosome 4 and defective Cd36 gene was identified in this region. Here we investigated the polymorphism of Cd36 gene in Prague hereditary hypertriglyceridemic (HTG) rats, which represent another model of genetic hypertension and metabolic syndrome. These animals were compared with NIH-derived SHR and two different normotensive control strains (WKY, LEW). In spite of the fact that HTG and SHR rats had similar metabolic disturbances, genotype analysis of PCR products has shown that Cd36 mutation was not present in HTG rats. In conclusion, we have revealed that defective Cd36 is probably a candidate gene for disorded fatty-acid metabolism, glucose intolerance and insulin resistance in NIH-derived SHR, but other genes might play a role in pathogenesis of metabolic syndrome in Prague hereditary hypertriglyceridemic rats. This is in accordance with the absence of defective Cd36 gene in original SHR from Japan.     

Changes in elastin composition in aorta of spontaneously hypertensive rats (SHR)

Tropoelastin and elastin preparations obtained from aortae of spontaneously hypertensive rats (SHR) show an increased proportion of polar amino acids (aspartic acid, glutamic acid, arginine and tyrosine). The content of these amino acids is 1.43-3.04 times higher in SHR rats than in similar elastin or tropoelastin preparations obtained from normotensive animals. On the other hand elastin and tropoelastin preparations obtained from SHR rats show a lower frequency of the Val-Pro sequence; this was found to be 35.93 per 1000 amino acid residues in SHR rats as compared to 51.04 per 1000 amino acids in the preparations obtained from control animals. Since similar differences were found not only in elastin preparations but also in tropoelastin, contamination of these preparations with an acidic protein seems unlikely. In general the results obtained are similar to those seen in animals kept on a long term high fat diet. It appears feasible to suggest that these differences are caused by a changed proportion of two different elastin type.     

Quantitative analysis of ACTH-immunoreactive cells in the anterior pituitary of young spontaneously hypertensive and normotensive rats

Summary ACTH-immunoreactive cells in the anterior pituitary of 4-week-old spontaneously hypertensive rats (SHR) were studied with immunocytochemical and morphometric techniques. The results were compared with data from age-matched normotensive Wistar-Kyoto rats (WKY). No significant differences were found in volume density and average size of ACTH-immunoreactive cells between these two strains. However, SHR showed a significantly larger anterior lobe (2 P < 0.01) than WKY, indicating that the total number of ACTH-immunoreactive cells in the anterior pituitary is greater in SHR than in WKY. These data are in agreement with radioimmunological determinations showing a significantly elevated content (2 P < 0.01) but only a moderately higher concentration (0.05 < 2 P < 0.10) of ACTH in the anterior pituitary of SHR as compared to WKY. The present results suggest an enhanced availability of ACTH in the anterior pituitary of 4-week-old SHR, a fact which could explain the markedly enhanced stress-induced release of ACTH previously found in these animals. This study further supports the hypothesis that, among other factors, an instability of the hypothalamo-pituitary-adrenal axis may contribute to the development of genetically programmed hypertension.     

Circadian rhythm of circulating corticosterone and prolactin levels in spontaneously hypertensive rats

Circulating levels of corticosterone and prolactin were measured by radioimmunoassay at hourly intervals during a 24 h period to establish the diurnal rhythm of these hormones in spontaneously hypertensive rats (SHR). Corticosterone levels exhibited a distinct circadian variation with concentrations reaching a zenith at 2000 h and a nadir at 1200 h in male and female SHR. Corticosterone levels in females were consistently greater than males. Circulating prolactin levels were greater during the light h than dark in the female; the opposite occurred in males. Measurement of pituitary prolactin content tended to be low when serum prolactin levels were high and vice versa. The circadian rhythm of circulating corticosterone and prolactin in the hypertensive SHR was found to be similar to the day-night patterns established for normotensive rats. However, these measurements were made under quiescent conditions. It is suggested that because SHR are hyper-responsive to stress and because corticosterone and prolactin have synchronous effects on stress-induced adrenal steroidogenesis, further investigation of prolactin and corticosterone may reveal a participatory role of these hormones in the pathogenesis of the genetically-programmed hypertension of SHR.     

Effects of angiotensin II type 1 receptor blockade on the oxidative stress in spontaneously hypertensive rat tissues

The aim of this work was to investigate the production of oxidative damage in homogenized kidney, liver and brain of spontaneously hypertensive rats (SHR), as well as the involvement of angiotensin (Ang) II in this process. Groups of 12-week-old SHR and Wistar Kyoto rats (WKY) were given 10 mg/kg/day losartan in the drinking water during 14 days. Other groups of WKY and SHR without treatment were used as controls. The production of thiobarbituric acid reactive substances (TBARS), reduced glutathione (GSH) and the activity of the antioxidant enzymes catalase (CAT), superoxide dismutase (SOD) and glutathione peroxidase (Gpx) were determined. No significant difference in TBARS was observed between untreated SHR or WKY rats; GSH content was lower in the liver but higher in the brain of SHR compared to WKY rats. In tissues from the SHR group, SOD and Gpx activities were reduced, whereas CAT activity was slightly increased in kidney. TBARS levels did not change in WKY rats after losartan administration, but were reduced in SHR liver and brain. Losartan treatment decreased GSH content in WKY kidney, but increased GSH in SHR liver. The activity of the antioxidant enzymes was not modified by losartan in WKY rats; however, their activities increased in tissues from treated SHR. The lower activity of antioxidant enzymes in tissues from hypertensive rats compared to those detected in normotensive controls, indicates oxidative stress production. Ang II seems to play no role in this process in normotensive animals, although AT1 receptor blockade in SHR enhances the enzymatic activity indicating that Ang II is implicated in oxidative stress generation in the hypertensive animals.     

Spontaneous and orienting-exploratory motor activity in rats with hereditary arterial hypertension

In rats of spontaneously hypertensive line (SHR) in comparison with normotensive animals of WKY line an increased activity was revealed in new surroundings in conditions of open illuminated space, and reduced activity in limited darkened space with weakened extinction of activity. Male SHR rats had a higher daily motor activity and SHR females--a lower level of defecation. The revealed behavioural changes testify to an enhancement of investigatory motivation and weakening of "fear" in SHR rats as well as to increased excitatory and decreased inhibitory processes in these animals. Behavioural characteristics of SHR rats reflect an increased reactivity of their nervous system which may be connected with the mechanisms of the increase of arterial pressure.     

Heart rate reflex responses during gestation in normotensive and spontaneously hypertensive rats following angiotensin II and vasopressin

Gestation in the human and in rats is accompanied by a decrease in blood pressure and a reduction of the pressor response to vasoconstrictor agents. In humans, the decreased vascular reactivity to angiotensin II (AII) may occur simultaneously with a state of increased baroreceptor sensitivity. We have consequently evaluated the heart rate response to elevation of blood pressure following administration of either AII or arginine8-vasopressin (AVP) in conscious unrestrained, nonpregnant, or term-pregnant normotensive rats (Sprague-Dawley, SDR; Wistar-Kyoto, WKR) and in spontaneously hypertensive rats (SHR). The decrease in heart rate in response to increase in blood pressure by AII in nonpregnant animals was similar in SDR and SHR, but much greater in WKR. The heart rate response to increase in blood pressure by AVP was similar in all three strains of cycling rats. Gestation (20th day) did not change the heart rate response to increase in blood pressure by AII in normotensive animals, but increased slightly the reflex responses in SHR, as shown by a significant increase of the slope of the relationship of the decrement in heart rate versus the increment of blood pressure. The heart rate response to increase in blood pressure by AVP was greater during gestation in normotensive SDR and WKR, but not in SHR. These results show that the heart rate responses to an increase in blood pressure by vasoconstrictor peptides is dependent on the strain of animals used and suggest that the baroreceptor reflexes play a minor role in the blunted effect of vasconstrictor agens at the end of gestation in normotensive and spontaneously hypertensive rats.     

Specificity of the hemodynamic indices’ shift in SHR line rats at different age

Specificities of the changes in the systemic hemodynamics indices in the spontaneously hypertensive line SHR rats have been studied in comparison with the normotensive line WKY rats. It was demonstrated that an increase in blood pressure observed in the young hypertensive male rats, which have completed puberty (8 weeks old), is associated with the development of the hyperkinetic type arterial hypertension, which is characterized by increased cardiac minute output. It has been shown that SHR line male rats reveal the establishment of stable arterial hypertension due to a significant increase in the total peripheral resistance with the simultaneous recovery of the cardiac minute output by the 25th week of life. SHR line rats at the age of 15 weeks may be regarded as being in the period of transition from the hyperkinetic type arterial hypertension to stable arterial hypertension.