Metabolic syndrome (MetS) is a cluster of risk factors that increase the likelihood of developing cardiovascular, metabolic and other diseases. The pharmacological management of MetS often involves polypharmacy, making it essential to understand how drug-metabolising enzymes, transporters, transcription factors and other proteins involved are affected under different metabolic conditions. This study investigated the relative mRNA expression of key hepatic and intestinal genes involved in drug metabolism, including Cyp1a2, Cyp3a23, Cyp2d1, Cyp2c11, Cyp2c6, Cyp2e1, Cyp7a1, Cyp2b1, Cyp2a1, Abcg5, Abcg8, Abcb1, Nr1i3, Nr1i2, Ahr, Gsta1 and Comt, in four nonobese rat models of MetS: hereditary hypertriglyceridaemic (HHTg), spontaneously hypertensive rat (SHR), SHR expressing transgenic human C-reactive protein (SHR-CRP), and bilaterally ovariectomised Wistar (W-OVX), compared to Wistar controls. Gene expression was quantified by RT-PCR with data normalised using the ΔΔCt method. Between the models studied, measurements showed significant differences in the liver. The upregulation of Cyp2c6 and Cyp3a23 was observed only in SHR; upregulated Cyp2d1 was found in SHR as well as in HHTg rats. The downregulated Cyp1a2 was measured in a condition of hypertriglyceridemia, postmenopause or hypertension. These findings highlight model-specific alterations in gene expression that may affect drug metabolism and interactions. The HHTg may be, in particular, a suitable model for preclinical studies focusing on intestinal drug-drug interactions in MetS-related conditions.

• Keywords
• drug metabolism, metabolic syndrome, rat model,
• MeSH
• Liver metabolism   enzymology   MeSH
• Rats MeSH
• Humans MeSH
• Membrane Transport Proteins * genetics   metabolism   MeSH
• RNA, Messenger * metabolism   genetics   MeSH
• Metabolic Syndrome * genetics   metabolism   MeSH
• Disease Models, Animal MeSH
• Rats, Inbred SHR MeSH
• Rats, Wistar MeSH
• Receptors, Cytoplasmic and Nuclear * genetics   metabolism   MeSH
• Cytochrome P-450 Enzyme System * genetics   metabolism   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Membrane Transport Proteins * MeSH
• RNA, Messenger * MeSH
• Receptors, Cytoplasmic and Nuclear * MeSH
• Cytochrome P-450 Enzyme System * MeSH

The study of ontogenetic aspects of water and electrolyte metabolism performed in the Institute of Physiology (Czechoslovak Academy of Sciences) led to the research on the increased susceptibility of immature rats to salt-dependent forms of hypertension since 1966. Hemodynamic studies in developing rats paved the way to the evaluation of hemodynamic mechanisms during the development of genetic hypertension in SHR. A particular attention was focused on altered renal function and kidney damage in both salt and genetic hypertension with a special respect to renin-angiotensin system. Renal damage associated with hypertension progression was in the center of interest of several research groups in Prague. The alterations in ion transport, cell calcium handling and membrane structure as well as their relationship to abnormal lipid metabolism were studied in a close cooperation with laboratories in Munich, Glasgow, Montreal and Paris. The role of NO and oxidative stress in various forms of hypertension was a subject of a joint research with our Slovak colleagues focused mainly on NO-deficient hypertension elicited by chronic L-NAME administration. Finally, we adopted a method enabling us to evaluate the balance of vasoconstrictor and vasodilator mechanisms in BP maintenance. Using this method we demonstrated sympathetic hyperactivity and relative NO deficiency in rats with either salt-dependent or genetic hypertension. At the end of the first decennium of this century we were ready to modify our traditional approach towards modern trends in the research of experimental hypertension. Keywords: Salt-dependent hypertension o Genetic hypertension o Body fluids o Hemodynamics o Ion transport o Cell membrane structure and function o Renal function o Renin-angiotensin systems.

• MeSH
• History, 20th Century MeSH
• History, 21st Century MeSH
• Hypertension * metabolism   physiopathology   MeSH
• Blood Pressure MeSH
• Rats MeSH
• Humans MeSH
• Disease Models, Animal MeSH
• Renin-Angiotensin System MeSH
• Animals MeSH
• Check Tag
• History, 20th Century MeSH
• History, 21st Century MeSH
• Rats MeSH
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Historical Article MeSH

Long-lasting disturbances in lipid and glucose metabolism present in metabolic syndrome (MetS) lead to serious cardiovascular diseases. The study was aimed to evaluate the effect of natural antioxidant vitamin E (VitE, 100 mg/kg/day, p.o.) on basal biochemical and physiological parameters characterizing MetS and on the changed function of the heart. Furthermore, the possible potentiation of VitE effect by synthetic pyridoindole antioxidant SMe1EC2 (SMe, 15 mg/kg/day, p.o.) was also tested. MetS was induced in hereditary hypertriglyceridemic rats (HTG) by the 5 weeks administration of high-fat fructose diet (HFFD: 1 % cholesterol, 7.5 % pork lard, 10 % fructose). The heart function was tested using Langendorff preparation under constant pressure. The functional parameters of isolated heart, dysrhythmias and evoked fibrillations were evaluated in conditions of ischemia-reperfusion. The HFFD increased body weight gain and serum levels of total cholesterol, low-density lipoproteins and blood glucose. The HFFD significantly increased heart flow and force of contraction, compared to standard diet (SD). During the reperfusion, the HFFD caused the increase of the ventricular premature beats number at the expense of decreasing the duration of serious dysrhythmias (ventricular tachycardias and fibrillations). The addition of VitE, SMe or their combination to the HFFD decreased body weight gain, depressed blood pressure, improved particular biochemical parameters. The combination of VitE and SMe suppressed the occurrence of serious dysrhythmias. Our data indicate that the HFFD-related disturbances led to alterations within pathophysiology in HTG rats. The results showed that a combination of antioxidants might have the potential to amend disorders accompanying MetS.

• MeSH
• Antioxidants pharmacology   MeSH
• Diet, High-Fat MeSH
• Fructose MeSH
• Weight Gain MeSH
• Blood Glucose metabolism   MeSH
• Rats MeSH
• Metabolic Syndrome * complications   drug therapy   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Antioxidants MeSH
• Fructose MeSH
• Blood Glucose MeSH

Prague hypertriglyceridemic (HTG) rats represent a suitable model of metabolic syndrome. We have established the set of F(2) hybrids derived from HTG and Lewis progenitors to investigate the relationship between respective polymorphism(s) of Igf2 gene and blood pressure (BP) or other cardiovascular phenotypes. HTG rats had elevated systolic BP and plasma triglycerides but lower plasma cholesterol compared to Lewis rats of both genders. In males, there was higher mean arterial pressure, diastolic BP and relative heart weight in HTG than in Lewis rats. The results obtained in the total population of F(2) hybrids indicated strong segregation of Igf2 genotype with plasma triglycerides. There was no segregation of Igf2 genotype with any BP component except BP changes occurring after the blockade of either renin-angiotensin system (RAS) or NO synthase. When F(2) population was analyzed according to gender, male F(2) progeny homozygous for HTG Igf2 allele had significantly higher plasma triglycerides and greater BP changes after NO synthase blockade than those homozygous for Lewis allele. On the contrary, male F(2) progeny homozygous for HTG Igf2 allele had significantly lower plasma cholesterol and smaller BP changes after RAS blockade. PCR analysis of Igf2 gene by using of microsatelite D1Mgh22 has shown polymorphism between HTG and Lewis rats. Sequence analysis of cDNA revealed insertion of 14 nucleotides in HTG gene. In conclusion, polymorphism in Igf2 gene may be responsible for differences in lipid metabolism between HTG and Lewis rats. It remains to determine how these abnormalities could be involved in BP regulation by particular vasoactive systems.

• MeSH
• Genetic Linkage MeSH
• Genotype MeSH
• Hypertriglyceridemia blood   genetics   pathology   physiopathology   MeSH
• Rats, Inbred Strains MeSH
• Insulin-Like Growth Factor II genetics   MeSH
• Blood Pressure physiology   MeSH
• Crosses, Genetic MeSH
• Rats MeSH
• Kidney anatomy & histology   MeSH
• Lipids blood   MeSH
• Microsatellite Repeats MeSH
• DNA Mutational Analysis MeSH
• Rats, Inbred Lew MeSH
• Heart anatomy & histology   MeSH
• Body Weight genetics   MeSH
• Organ Size genetics   MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Female MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Comparative Study MeSH
• Names of Substances
• Insulin-Like Growth Factor II MeSH
• Lipids MeSH