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 aim of this study was to compare the vascular reactivity and morphology of iliac artery (IA) in adult spontaneously hypertensive rats (SHR) and hereditary hypertriglyceridemic (hHTG) rats. The isolated rings of iliac artery (IA) from Wistar rats (controls), SHR and hHTG rats were used for measurement of relaxant responses to acetylcholine (ACh) and contractile responses to noradrenaline (NA). Morphological changes of IA were measured using light microscopy. Systolic blood pressure (BP) measured by plethysmographic method was increased in SHR approximately by 88 % and in hHTG rats by 44 % compared to controls. BP increase was accompanied by cardiac hypertrophy. In both SHR and hHTG groups (experimental groups) reduced relaxation to ACh and enhanced maximal contraction and sensitivity to adrenergic stimuli were observed. The sensitivity to NA in SHR was higher also in comparison with hHTG. Geometry
of IA in both experimental groups revealed increased wall thickness and wall cross-sectional area, in SHR even in comparison with hHTG. Inner diameter was decreased in both experimental groups. Thus, independently of etiology, hypertension in both models was connected with impaired endothelial function accompanied by structural alterations of
IA. A degree of BP elevation was associated with arterial wall hypertrophy and increased contractile sensitivity.
High blood pressure, increased level of cholesterol, diabetes, hypertriglyceridemia and obesity are risk factors accompanied metabolic syndrome. The aim of the study was to compare geometry of carotid artery (AC) of 3-week-old (3w) and 52-week-old (52w) hereditary hypertriglyceridemic rats (hHTG) and spontaneously hypertensive rats (SHR) which represent a genetic model of human essential hypertension with age-matched Wistar rats. After sacrificing the rats were perfused with a glutaraldehyde fixative under the pressure 90 mm Hg (3w) and 120 mm Hg (52w) for 10 min via cannula placed into left ventricle. Middle part of AC was excised and processed according to standard electron
microscopy procedure. Geometry of AC was evaluated in light microscopy. SHR vs. Wistar rats: BP of 3w did not differ, in 52w it was increased; cardiac hypertrophy was found in both ages; wall thickness (WT) and cross sectional area (CSA) in 3w did not differ, in 52w both were increased; inner diameter (ID) in 3w and 52w was decreased; WT/ID was increased in both ages. Hereditary HTG vs. Wistar rats: BP was increased in both periods; cardiac hypertrophy was observed in 3w; WT in 3w was decreased, in 52w it was increased; CSA and ID were decreased in both ages; WT/ID was increased only in 52w. Discrepancies between development of BP, cardiac hypertrophy in SHR and hHTG rats were observed. Alterations of BP were not in harmony with alterations in geometry of carotid arteries in both SHR and hHTG rats. We suggest that BP is not the main stimuli evoked hemodynamic and structural alterations of cardiovascular system in ontogenic development of SHR and hHTG rats.
It has been shown that endothelium-derived nitric oxide (NO) plays an important role in regulation of vascular tone in the prenatal and early postnatal period. The aim of this paper was to determine the reactivity and accompanying structural changes in thoracic aorta from 4-week-old spontaneously hypertensive rats (SHR) and rats with hereditary
hypertriglyceridemia (hHTG) in comparison with age-matched normotensive controls. For functional studies thoracic aorta was excised, cut into rings and mounted in organ baths for measurement of isometric contractile force. For morphological studies cardiovascular system of rats was perfused with glutaraldehyde fixative (at 100 mm Hg) via cannula placed in the left ventricle. Morphological changes of thoracic aorta were measured using light microscopy. Systolic blood pressure (SBP) in SHR (98±1 mm Hg) did not significantly differ from that of age-matched control rats (95±4 mm Hg), but was slightly increased in hHTG rats (110±2 mm Hg, P<0.05). Heart weight/body weight ratio was higher in SHR and hHTG rats than in control group indicating the hypertrophy of the heart in both models of hypertension. Endothelium-dependent relaxation of aorta induced by acetylcholine was preserved in all groups and did not differ from that in control normotensive rats. The maximal isometric contraction of thoracic aorta to noradrenaline (NA) was reduced in hypertensive groups and the concentration-response curves to NA were shifted to the right indicating increased sensitivity of smooth muscle to NA. The values of wall thickness and cross sectional area as well as inner diameter of thoracic aorta in SHR and hHTG rats were significantly decreased in comparison to control groups. Endothelial dysfunction seems to be absent in all young rats before development of hypertension. In conclusion, our observations indicate that in early stage of experimental hypertension NO-dependent relaxation is preserved so that putative impairment of this function provides no significant pathogenic contribution to the onset of hypertension in these two experimental models.
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.
Cardiovascular effects of LVV-hemorphin-7, a member of the family of fragments from β-chain of human or bovine hemoglobin, were studied in conscious spontaneously hypertensive (SHR) and Wistar-Kyoto (WKY) rats by radiotelemetry. Intraperitoneal injection of hemorphin in a dose of 100 g/kg significantly decreased blood pressure in SHR, whereas negligible effect was seen in normotensive WKY rats. Blood pressure changes were accompanied by reduction of heart rate. In conclusion, a direct effect of LVV-hemorphin-7 on blood pressure was demonstrated in SHR. These biologically active peptides could be involved in blood pressure regulation especially in hypertensive rats, but the precise mechanism should be elucidated.
We have searched for polymorphism of inducible nitric oxide synthase gene (
Nos2 gene) in the Prague colony of salt-sensitive and salt-resistant Dahl/Rapp rats. Specific primers were used to confirm previously described Nos2 gene polymorphism because this gene was suggested to be a potential candidate gene for genetic hypertension. Phenotyping
(blood pressure, organ weight, plasma lipids) have confirmed the data known from other colonies of Dahl/Rapp rats. However, in our colony we were not able to find any Nos2 gene polymorphism between salt-sensitive and salt-resistant rats, which was previously described in animals from Harlan colony. Moreover, the genetic homogeneity of our salt-sensitive and salt-resistant rats in terms of Nos2 gene was the same as in the original Brookhaven colony of Dahl rats. This is surprising because our colony has been established from breeding pairs kindly provided by Prof. J.P. Rapp more
than 15 years ago. It seems that the polymorphism found in Harlan colony could be the result of previous contamination or genetic drift during the breeding conditions specific for this colony.
The imbalance between nitric oxide (NO) and reactive oxygen species (ROS) production appears to be a common feature of experimental and human hypertension. Previously, different antioxidants and/or scavengers of oxygen free radicals were shown to activate nitric oxide synthase (NO synthase, NOS) and to increase the expression of both endothelial and neuronal NO synthase isoforms leading to blood pressure reduction. On the other hand, various antihypertensive drugs have been documented to possess antioxidant properties, which may contribute to their beneficial effect on blood pressure. This review is focused on the effects of antioxidant treatment in different models of
experimental hypertension with a special attention to the prevention of oxidative damage and the augmentation of NO synthase activity and expression of NOS isoforms.