a1_Fifty years ago, Lewis K. Dahl has presented a new model of salt hypertension – salt-sensitive and salt-resistant Dahl rats. Twenty years later, John P. Rapp has published the first and so far the only comprehensive review on this rat model covering numerous aspects of pathophysiology and genetics of salt hypertension. When we summarized 25 years of our own research on Dahl/Rapp rats, we have realized the need to outline principal abnormalities of this model, to show their interactions at different levels of the organism and to highlight the ontogenetic aspects of salt hypertension development. Our attention was focused on some cellular aspects (cell membrane function, ion transport, cell calcium handling), intra- and extrarenal factors affecting renal function and/or renal injury, local and systemic effects of reninangiotensin-aldosterone system, endothelial and smooth muscle changes responsible for abnormal vascular contraction or relaxation, altered balance between various vasoconstrictor and vasodilator systems in blood pressure maintenance as well as on the central nervous and peripheral mechanisms involved in the regulation of circulatory homeostasis. We also searched for the age-dependent impact of environmental and pharmacological interventions, which modify the development of high blood pressure and/or organ damage, if they influence the saltsensitive organism in particular critical periods of development (developmental windows). Thus, severe self-sustaining salt hypertension in young Dahl rats is characterized by pronounced dysbalance between augmented sympathetic hyperactivity and relative nitric oxide deficiency, attenuated baroreflex as well as by a major increase of residual blood pressure indicating profound remodeling of resistance vessels. Salt hypertension development in young but not in adult Dahl rats can be attenuated by preventive increase of potassium or calcium intake., a2_On the contrary, moderate salt hypertension in adult Dahl rats is attenuated by superoxide scavenging or endothelin-A receptor blockade which do not affect salt hypertension development in young animals., J. Zicha, ... [et al.]., and Obsahuje seznam literatury
Tissue renin-angiotensin systems are known to behave differently from the circulating renin-angiotensin system (RAS). It has already been proposed that not only the circulating RAS, but also RAS localized in the cardiac tissue plays an important role in the heart failure. The objective of this study was to compare the gene expression of individual components of the renin-angiotensin system in hearts of normotensive and hypertensive rats. Two genetically hypertensive rat strains - spontaneously hypertensive rats (SHR) and hereditary hypertriglyceridemic rats (HTG) - were compared with Wistar-Kyoto (WKY) and Lewis (LEW) normotensive controls. In addition, developmental changes in gene expression of individual components of cardiac RAS were studied in 20-day-old fetuses, 2-day-old newborns and 3-month-old HTG and LEW rats. In our study, the angiotensinogen gene expression did not differ either among adult normotensive and hypertensive strains, or during development. In contrast, the renin gene expression was significantly increased in hearts of hypertensive compared to normotensive rats. Moreover, a 5-fold increase of renin mRNA was observed in hearts of HTG rats between day 2 and the third month of age. There was also an age-dependent increase of ACE gene expression in both HTG and LEW rats which was substantially delayed in HTG hearts. In conclusion, the results of our study suggest that overexpression of the cardiac renin gene in hypertensive strains could participate in the structural and functional changes of the heart during the development of hypertension., D. Jurkovičová, Z. Dobešová, J. Kuneš, O. Križanová., and Obsahuje bibliografii
A total genome scan and pharmacogenetic study were designed to search for genetic determinants of blood pressure (BP) as well as heart and kidney weights. Genome scanning was carried out in 266 F2 intercrosses from Prague hypertensive hypertriglyceridemic rats for phenotypes of organ weights, baseline BP, BP after blockade of the renin-angiotensin system (RAS) by losartan, of the sympathetic nervous system (SNS) by pentolinium, and of the nitric oxide (NO) synthase by NG-nitro-L-arginine methyl ester. Pharmacogenetic analysis showed that, in males, BP was controlled by two loci on chromosomes 1 and 5 (Chr1, Chr5) through the SNS, and these loci showed a positive contribution for relative kidney weight (KW/BW). On the other hand, baseline BP in females was controlled by two loci on Chr3 and Chr7. The effect of these loci was not mediated by the RAS, SNS or NO system. These loci did not show any effect for KW/BW. Negatively-linked loci for KW/BW and relative heart weight (HW/BW) were identified on Chr2 in both genders. Another negatively-linked locus for KW/BW, located on Chr8 in males, affected BP through the SNS. This locus on Chr8 overlapped with a previously-reported modifier locus for polycystic kidney disease (PKD). In conclusion, this pharmacogenetic study determined two loci for BP and relative organ mass implicating sympathetic overactivity. Concordance of the identified locus for KW/BW and BP through the SNS on Chr8 with the PKD locus revealed the importance of this region for renal complications in various diseases., T. Ueno, J. Tremblay, J. Kuneš, J. Zicha, Z. Dobešová, Z. Pausová, A. Y. Deng, Y. Sun, H. J. Jacob, P. Hamet., and Obsahuje bibliografii
Blood pressure (BP) level results from the balance of vasoconstrictors (mainly sympathetic nervous system) and vasodilators (predominantly nitric oxide and endothelium-derived hyperpolarizing factor). Most of the forms of experimental hypertension are associated with sympathetic hyperactivity and endothelial dysfunction. It is evident that nitric oxide and norepinephrine are antagonists in the control of calcium influx through L-type voltage-dependent calcium channels (L-VDCC). Their effects on L-VDCC are mediated by cGMP and cAMP, respectively. Nevertheless, it remains to determine whether these cyclic nucleotides have direct effects on L-VDCC or they act through a modulation of calcium-activated K+ and Cl- channels which influence membrane potential. Rats with genetic or salt hypertension are characterized by a relative (but not absolute) NO deficiency compared to the absolute enhancement of sympathetic vasoconstriction. This dysbalance of vasoconstrictor and vasodilator systems in hypertensive animals is reflected by greater calcium influx through L-VDCC susceptible to the inhibition by nifedipine. However, when the modulatory influence of cyclic nucleotides is largely attenuated by simultaneous ganglionic blockade and NO synthase inhibition, BP of spontaneously hypertensive rats remains still elevated compared to normotensive rats due to augmented nifedipine-sensitive BP component. It remains to determine why calcium influx through L-VDCC of hypertensive rats is augmented even in the absence of modulatory influence of major vasoactive systems (sympathetic nervous system, nitric oxide)., M. Pintérová ... [et al.]., and Obsahuje seznam literatury
High blood pressure (BP) of L-NAME hypertensive rats is maintained not only by the absence of nitric oxide (NO)-dependent vasodilatation but also by the enhancement of both sympathetic and angiotensin II-dependent vasoconstriction. The aim of the present study was to evaluate the role of inhibitory G (Gi) proteins, which are involv ed in tonic sympathetic vasoconstriction, in the pathogenesis of NO-deficient hypertension. We therefore studied BP response to chronic L-NAME administration (60 mg/kg/day for 4 weeks) in rats in which the in vivo inactivation of Gi proteins was induced by injection of pertussis toxin (PTX, 10 μg/kg i.v.). The impairment of sympathetic vasoconstriction due to PTX-induced Gi protein inactivation prevents the full development of NO-deficient hypertension because BP of PTX-treated rats subjected to chronic L-NAME administration did not reach hypertensive values. Nevertheless, chronic NO synthase inhibition per se is capable to increase moderately BP even in PTX-treated rats. Our data suggest that the sympathetic vasoconstriction is essential for the development of established NO-deficient hypertension., J. Zicha ... [et al.]., and Obsahuje seznam literatury
Spontaneously hypertensive rats (SHR) are characterized by enhanced nifedipine-sensitive component of sympathetic vasoconstriction. Our study tried to elucidate the mechanisms responsible for long-term reduction of blood pressure (BP) in SHR subjected to early transient captopril treatment. Adult untreated SHR aged 30-34 weeks were compared with animals subjected to chronic captopril treatment for 6 weeks either in youth (between 4 and 10 weeks of age) or in adulthood (between 24 and 30 weeks of age). Antihypertensive effects of captopril were more pronounced in young than adult SHR. This was due to greater attenuation of sympathetic and nifedipine-sensitive BP components and prevention of residual BP rise in young captopril-treated SHR in which the reductions of nifedipine-sensitive BP component and residual BP persisted for 20 weeks after captopril withdrawal. The magnitude of nifedipine-sensitive component of sympathetic vasoconstriction is decisive for BP maintenance not only in untreated SHR but also in SHR during active captopril treatment by or after its withdrawal., J. Zicha, Z. Dobešová,J. Kuneš., and Obsahuje bibliografii a bibliografické odkazy
High blood pressure (BP) of spontaneously hypertensive rats (SHR) is maintained by enhanced activity of sympathetic nervous system (SNS), whereas that of Ren-2 transgenic rats (Ren-2 TGR) by increased activity of renin-angiotensin system (RAS). However, both types of hypertension are effectively attenuated by chronic blockade of L-type voltage-dependent calcium channel (L-VDCC). The aim of our study was to evaluate whether the magnitude of BP response elicited by acute nifedipine administration is proportional to the alterations of particular vasoactive systems (SNS, RAS, NO) known to modulate L-VDCC activity. We therefore studied thes e relationships not only in SHR, in which mean arterial pressure was modified in a wide range of 100-210 mm Hg by chronic antihypertensive treatment (captopril or hydralazine) or its withdrawal, but also in rats with augmented RAS activity such as homozygous Ren-2 TGR, pertussis toxin- treated SHR or L-NAME-treated SHR. In all studied groups the magnitude of BP response to nifedipine was proportional to actual BP level and it closely correlated with BP changes induced by acute combined blockade of RAS and SNS. BP response to nifedipine is also closely related to the degree of relative NO deficiency. This was true for both SNS- and RAS-dependent forms of genetic hypertension, suggesting common mechanisms responsible for enhanced L-VDCC opening and/or their upregulation in hypertensive animals. In conclusions, BP response to nifedipine is proportional to the vasoconstrictor activity exerted by both SNS and RAS, indicating a key importance of these two pressor systems for actual L-VDCC opening necessary for BP maintenance., J. Zicha ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy
The objective of the current study was to search for genetic determinants associated with antihypertensive effects of angiotensin-converting enzyme (ACE) inhibitor captopril. Linkage and correlation analyses of captopril-induced effects on blood pressure (BP) with renal transc riptome were performed in the BXH/HXB recombinant inbred (RI) strains derived from spontaneously hypertensive rat (SHR) and Brown Norway (BN-Lx) progenitors. Variability of blood pressure lowering effects of captopril among RI strains was continuous suggesting a polygenic mode of inheritance. Linkage analysis of captopril- induced BP effects revealed a significant quantitative trait locus (QTL) on chromosome 15. This QTL colocalized with cis regulated expression QTL (eQTL) for the Ednrb (endothelin receptor type B) gene in the kidney (SHR allele was associated with increased renal expression) and renal expression of Ednrb correlated with captopril-induced BP effects. These results suggest that blood pressure lowering effects of ACE inhibitor captopril may be modulated by the variants at the Ednrb locus., J. Zicha ... [et al.]., and Obsahuje bibliografii a bibliografické odkazy