The age-dependent changes in baroreflex control of heart rate were studied in inbred Dahl rats. At the age of 8 weeks the baroreflex slope was significantly greater in salt-resistant (R/Jr) than in salt-sensitive (S/Jr) rats fed a low- salt diet. The reverse was true in 16-week-old animals. High salt intake (8 % NaCI diet for 4 weeks) suppressed baroreflex efficiency in both age groups of S/Jr animals whereas no effects occurred in R/Jr rats. Baroreflex slope was, however, significantly lower in young S/Jr rats with a severe form of salt hypertension than in adult salt-loaded S/Jr rats in which only a moderate blood pressure elevation was observed.
This review summarizes our findings concerning the altered balance of vasoactive systems (namely sympathetic nervous system and nitric oxide) in various forms of experimental hypertension – genetic hypertension (SHR, HTG rats), salt hypertension (Dahl rats) and NO-deficient hypertension (L-NAME-treated rats). An attempt is made to define relative NO deficiency (compared to the existing level of sympathetic vasoconstriction), to describe its possible causes and to evaluate particular indicators of its extent. A special attention is paid to reactive oxygen species, their interaction with NO metabolism, cell Ca2+ handling and blood pressure regulation. Our current effort is focused on the investigation of abnormal regulation of cytosolic Ca2+ levels in smooth muscle and endothelium of hypertensive animals. Such a research should cl
arify the mechanisms by which genetic and/or environmental factors could chronically modify blood pressure level.
High plasma triglyceride (TG) level is a major independent risk factor of coronary heart disease. A newly identified Apolipoprotein A5 (Apoa5) gene has been shown to play an important role in determining plasma TG concentrations in humans and mice. Prague hereditary hypertriglyceridemic (HTG) rats are a useful model of human hypertriglyceridemia and other symptoms of metabolic syndrome. Thus, the variation of Apoa5 gene and its expression were studied in this strain under normal conditions and after chronic fructose loading. Lewis and Wistar rats served as normotriglyceridemic controls. Plasma TG were significantly higher in HTG rats in comparison with both control strains. Sequence analysis of the rat Apoa5 gene revealed the existence of two introns. However, screening of the coding regions and intron-exon boundaries of Apoa5 gene did not indicate any mutation of this gene in HTG rats in comparison with Lewis and Wistar ones. Under the basal conditions the expression of Apoa5 was lower in all age groups of HTG rats compared to Wistar animals. Furthermore, during chronic fructose loading there were no significant changes of Apoa5 expression in HTG rats, although plasma TG levels rose 3-4 times within first two days of fructose loading and were increased during the whole period of fructose treatment. In conclusion, Apoa5 does not seem to be a genetic determinant of hypertriglyceridemia in HTG rats. The absence of significant changes in Apoa5 gene expression during chronic fructose-induced TG elevation excludes its major role in mechanisms compensating severe hypertriglyceridemia.
The influence of chronic angiotensin ATi receptor blockade by specific antibody on the development of genetic hypertension was studied in young spontaneously hypertensive rats (SHR). The immunization of 4-week-old SHR with a small part of the angiotensin ATi receptor molecule attenuated the development of hypertension in these animals. After five subcutaneous injections of the antigen both systolic and diastolic blood pressures were significantly lower (p<0.005) in immunized SHR compared to sham- immunized SHR. No effect on blood pressure was seen in immunized Wistar-Kyoto control rats. We conclude that renin-angiotensin system might be partially involved in the development of hypertension in young spontaneously hypertensive rats because it can be attenuated by a specific antibody raised against a part of the angiotensin ATi receptor.
The relationship between possible alterations in the volume or distribution of extracellular fluid and the development of salt hypertension was studied in inbred salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) Dahl rats. Blood pressure, cardiac and renal hypertrophy as well as body fluid volumes were determined in young and adult SS/Jr and SR/Jr rats of both sexes that were subjected to low, normal or high salt intake for various periods of time. Salt hypertension in young salt-sensitive rats fed a 4 % NaCl diet was not accompanied by any substantial intravascular or interstitial expansion as compared to salt-resistant rats that remained normotensive. There was no sex difference in the response of blood pressure or body fluids to high salt intake. Major expansion of plasma and blood volume, which was elicited by 8 % NaCl diet feeding from prepuberty, was not accompanied by a further blood pressure rise (compared to salt hypertensive SS/Jr rats fed 4 % NaCl diet). In conclusions, salt hypertension can occur in Dahl salt-sensitive rats without major salt and water retention. The degree of intravascular expansion is not directly related to blood pressure levels in salt-loaded Dahl rats. A high salt intake seems to exert its hypertensive effects in Dahl rats preferentially by influencing the balance of vasoconstrictor and vasodilator systems rather than by increasing the haemodynamically active intravascular volume.
Our studies in hypertensive Ren-2 transgenic rats (TGR) demonstrated that chronic administration of atrasentan (ETA receptor antagonist) decreased blood pressure by reduced Ca2+ influx through L-type voltage-dependent calcium channels (L-VDCC) and attenuated angiotensin II-dependent vasoconstriction. We were interested whether bosentan (nonselective ETA/ETB receptor antagonist) would have similar effects. Young 4-week-old (preventive study) and adult 8-weekold (therapeutic study) heterozygous TGR and their normotensive Hannover Sprague-Dawley (HanSD) controls were fed normal-salt (NS, 0.6 % NaCl) or high-salt (HS, 2 % NaCl) diet for 8 weeks. An additional group of TGR fed HS was treated with bosentan (100 mg/kg/day). Bosentan had no effect on BP of TGR fed highsalt diet in both the preventive and therapeutic studies. There was no difference in the contribution of angiotensin II-dependent and sympathetic vasoconstriction in bosentan-treated TGR compared to untreated TGR under the condition of high-salt intake. However, bosentan significantly reduced NO-dependent vasodilation and nifedipine-sensitive BP component in TGR on HS diet. A highly important correlation of nifedipine-induced BP change and the BP after L-NAME administration was demonstrated. Although bosentan did not result in any blood pressure lowering effects, it substantially influenced NO-dependent vasodilation and calcium influx through L-VDCC in the heterozygous TGR fed HS diet. A significant correlation of nifedipine-induced BP change and the BP after L-NAME administration suggests an important role of nitric oxide in the closure of L-type voltage dependent calcium channels.
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.
Our study addresses selected parameters of rat erythrocyte ion transport (Na+-K+ pump, Na+-K+-2Cl- cotransport, and passive cation fluxes) after acute or chronic hypoxia exposure. We did not find any significant change of ion transport after acute hypoxia. However, chronic hypoxia could modify ion transport because the affinity of Na+-K+ pump for intracellular Na+seems to be decreased.
Hypertriglyceridemia and hypertension seem to be very important cardiovascular risk factors. The Prague hereditary hypertriglyceridemic (hHTG) rat was developed as a model of human hypertriglyceridemia. It was demonstrated that these rats are not obese, they are hypertensive and insulin resistant and they have some disturbances in glucose
metabolism. Several QTLs were identified for blood pressure, its particular components (dependent on major vasoactive systems) and plasma triglycerides throughout the genome of hHTG rats by using of F2 hybrids strategy. It is evident that hHTG rats are a suitable model for the study of metabolic disturbances in relation to blood pressure as well as for the
search of genetic determinants of these abnormalities. Numerous abnormalities of blood pressure regulation as well as alterations in the structure and function of cardiovascular apparatus (heart, conduit and resistance arteries) were found in hHTG rats. A special attention was paid to possible changes in the efficiency of various vasoactive systems such as
nitric oxide, renin-angiotensin-aldosterone system and sympathetic nervous system, which seem to contribute substantially to cardiovascular and/or metabolic abnormalities observed in Prague hereditary hypertriglyceridemic rats.
A set of 131 F2 hybrids, obtained from a cross between normotensive Lewis and hypertensive hypertriglyceridaemic (HTG) rats, was studied in order to assess the relationship between blood pressure, plasma triglycerides and plasma uric acid. In progenitors, the plasma levels of triglycerides and uric acid were twice as high in HTG rats than in the Lewis rats. It was observed In the F2 cohort that high mean arterial pressure (MAP) was unrelated to body weight and relative heart or kidney weights. On the other hand, there were significant correlations between MAP and plasma triglycerides (r=0.420, n=131, p<0.0001) and between MAP and plasma uric acid (r=0.325, p<0.001). Plasma triglycerides of F2 hybrids were below the midparental values, suggesting a stronger influence of normotensive Lewis alleles. In conclusion, hypertension in hypertriglyceridaemic rats strongly cosegregated with plasma triglycerides and plasma uric acid. Our results indicated a linkage between high blood pressure and several metabolic alterations characteristic for the X syndrome.