The aim of this study was to evaluate the mutual relationship among perivascular adipose tissue (PVAT) and endogenous and exogenous H2S in vasoactive responses of isolated arteries from adult normotensive (Wistar) rats and hypertriglyceridemic (HTG) rats, which are a nonobese model of metabolic syndrome. In HTG rats, mild hypertension was associated with glucose intolerance, dyslipidemia, increased amount of retroperitoneal fat, increased arterial contractility, and endothelial dysfunction associated with arterial wall injury, which was accompanied by decreased nitric oxide (NO)-synthase activity, increased expression of H2S producing enzyme, and an altered oxidative state. In HTG, endogenous H2S participated in the inhibition of endothelium-dependent vasorelaxation regardless of PVAT presence; on the other hand, aortas with preserved PVAT revealed a stronger anticontractile effect mediated at least partially by H2S. Although we observed a higher vasorelaxation induced by exogenous H2S donor in HTG rats than in Wistar rats, intact PVAT subtilized this effect. We demonstrate that, in HTG rats, endogenous H2S could manifest a dual effect depending on the type of triggered signaling pathway. H2S within the arterial wall contributes to endothelial dysfunction. On the other hand, PVAT of HTG is endowed with compensatory vasoactive mechanisms, which include stronger anti-contractile action of H2S. Nevertheless, the possible negative impact of PVAT during hypertriglyceridemia on the activity of exogenous H2S donors needs to be taken into consideration.
- MeSH
- aorta thoracica patofyziologie MeSH
- cévní endotel patofyziologie MeSH
- cystathionin-gama-lyasa metabolismus MeSH
- hypertriglyceridemie metabolismus MeSH
- metabolický syndrom metabolismus patofyziologie MeSH
- modely nemocí na zvířatech MeSH
- noradrenalin farmakologie MeSH
- oxidace-redukce MeSH
- potkani Wistar MeSH
- signální transdukce * MeSH
- superoxiddismutasa metabolismus MeSH
- superoxidy metabolismus MeSH
- synthasa oxidu dusnatého, typ III metabolismus MeSH
- tuková tkáň metabolismus MeSH
- vazodilatace fyziologie MeSH
- vazokonstrikce účinky léků MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
BACKGROUND: The brain stem contains important nuclei that control cardiovascular function via the sympathetic nervous system (SNS), which is strongly influenced by nitric oxide. Its biological activity is also largely determined by oxygen free radicals. Despite many experimental studies, the role of AT1R-NAD(P)H oxidase-superoxide pathway in NO-deficiency is not yet sufficiently clarified. We determined changes in free radical signaling and antioxidant and detoxification response in the brain stem of young and adult Wistar rats during chronic administration of exogenous NO inhibitors. METHODS: Young (4 weeks) and adult (10 weeks) Wistar rats were treated with 7-nitroindazole (7-NI group, 10 mg/kg/day), a specific nNOS inhibitor, with NG-nitro-L-arginine-methyl ester (L-NAME group, 50 mg/kg/day), a nonspecific NOS inhibitor, and with drinking water (Control group) during 6 weeks. Systolic blood pressure was measured by non-invasive plethysmography. Expression of genes (AT1R, AT2R, p22phox, SOD and NOS isoforms, HO-1, MDR1a, housekeeper GAPDH) was identified by real-time PCR. NOS activity was detected by conversion of [3H]-L-arginine to [3H]-L-citrulline and SOD activity was measured using UV VIS spectroscopy. RESULTS: We observed a blood pressure elevation and decrease in NOS activity only after L-NAME application in both age groups. Gene expression of nNOS (youngs) and eNOS (adults) in the brain stem decreased after both inhibitors. The radical signaling pathway triggered by AT1R and p22phox was elevated in L-NAME adults, but not in young rats. Moreover, L-NAME-induced NOS inhibition increased antioxidant response, as indicated by the observed elevation of mRNA SOD3, HO-1, AT2R and MDR1a in adult rats. 7-NI did not have a significant effect on AT1R-NADPH oxidase-superoxide pathway, yet it affected antioxidant response of mRNA expression of SOD1 and stimulated total activity of SOD in young rats and mRNA expression of AT2R in adult rats. CONCLUSION: Our results show that chronic NOS inhibition by two different NOS inhibitors has age-dependent effect on radical signaling and antioxidant/detoxificant response in Wistar rats. While 7-NI had neuroprotective effect in the brain stem of young Wistar rats, L-NAME- induced NOS inhibition evoked activation of AT1R-NAD(P)H oxidase pathway in adult Wistar rats. Triggering of the radical pathway was followed by activation of protective compensation mechanism at the gene expression level.
- MeSH
- antioxidancia metabolismus MeSH
- indazoly farmakologie MeSH
- inhibitory enzymů farmakologie MeSH
- krysa rodu rattus MeSH
- metabolická inaktivace * MeSH
- mozkový kmen účinky léků metabolismus MeSH
- NG-nitroargininmethylester farmakologie MeSH
- oxid dusnatý nedostatek MeSH
- potkani Wistar MeSH
- synthasa oxidu dusnatého antagonisté a inhibitory MeSH
- věkové faktory MeSH
- volné radikály metabolismus MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
Cardiovascular studies have confirmed that hydrogen sulphide (H(2)S) is involved in various signaling pathways in both physiological and pathological conditions, including hypertension. In contrast to nitric oxide (NO), which has a clear vasorelaxant action, H(2)S has both vasorelaxing and vasoconstricting effects on the cardiovascular system. H(2)S is an important antihypertensive agent, and the reduced production of H(2)S and the alterations in its functions are involved in the initiation of spontaneous hypertension. Moreover, cross-talk between H(2)S and NO has been reported. NO-H(2)S interactions include reactions between the molecules themselves, and each has been shown to regulate the endogenous production of the other. In addition, NO and H(2)S can interact to form a nitrosothiol/s complex, which has original properties and represents a novel nitroso-sulphide signaling pathway. Furthermore, recent results have shown that the interaction between H(2)S and NO could be involved in the endothelium-regulated compensatory mechanisms that are observed in juvenile spontaneously hypertensive rats. The present review is devoted to role of H(2)S in vascular tone regulation. We primarily focus on the mechanisms of H(2)S-NO interactions and on the role of H(2)S in blood pressure regulation in normotensive and spontaneously hypertensive rats.
- MeSH
- buněčný převod mechanických signálů MeSH
- gasotransmitery metabolismus MeSH
- hypertenze patofyziologie MeSH
- krevní tlak * MeSH
- krysa rodu rattus MeSH
- oxid dusnatý metabolismus MeSH
- potkani inbrední SHR MeSH
- sulfan metabolismus MeSH
- svaly hladké cévní patofyziologie MeSH
- vazodilatace MeSH
- vazokonstrikce MeSH
- vazomotorický systém patofyziologie MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- přehledy MeSH
We evaluated the effects of N(G)-nitro-L-arginine methylester (L-NAME) (50 mg/kg/day) and 7-nitroindazole (7NI) (10 mg/kg/day) administered from 10th-16th week of age either individually or together on cardiovascular system of Wistar rats and SHR. Systolic blood pressure (sBP) was measured weekly by the plethysmographic method. For morphological studies, the animals (n=10) were perfused with a fixative (120 mm Hg), and thoracic aorta and carotid and coronary arteries were processed for electron microscopy. For functional investigation (n=10), aortic rings were used in an organ bath. In Wistar rats, L-NAME evoked an increase of sBP; hypertrophy of the heart and arterial walls; an increase in cross-sectional areas (CSA) of endothelial cells (EC), muscle cells (SMC), extracellular matrix (ECM), and a decrease in acetylcholine-induced endothelial-dependent relaxation (EDR). 7NI evoked sBP-independent hypotrophy of the heart and arterial walls, a decrease in CSA of EC and SMC without affecting the CSA of ECM, and a mild decrease in acetylcholine-induced EDR. 7NI and L-NAME administered together evoked lower effect on BP and trophicity of the heart and all arteries, and a similar decrease in acetylcholine-induced EDR compared to L-NAME alone. In SHR, 7NI did not evoke any effect on the studied parameters.
- MeSH
- aorta thoracica účinky léků enzymologie patofyziologie ultrastruktura MeSH
- arteriae carotides účinky léků enzymologie patofyziologie ultrastruktura MeSH
- hypertenze farmakoterapie enzymologie patologie patofyziologie MeSH
- indazoly farmakologie MeSH
- inhibitory enzymů farmakologie MeSH
- kardiomegalie enzymologie patologie patofyziologie prevence a kontrola MeSH
- koronární cévy účinky léků enzymologie patofyziologie ultrastruktura MeSH
- krevní tlak účinky léků MeSH
- modely nemocí na zvířatech MeSH
- NG-nitroargininmethylester farmakologie MeSH
- potkani inbrední SHR MeSH
- potkani Wistar MeSH
- remodelace cév účinky léků MeSH
- remodelace komor účinky léků MeSH
- srdeční komory účinky léků enzymologie patologie patofyziologie MeSH
- synthasa oxidu dusnatého antagonisté a inhibitory metabolismus MeSH
- vazodilatace účinky léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- srovnávací studie MeSH
- MeSH
- cévní endotel fyziologie MeSH
- krevní tlak fyziologie MeSH
- lidé MeSH
- oxid dusnatý * biosyntéza fyziologie MeSH
- oxidační stres fyziologie MeSH
- signální transdukce fyziologie MeSH
- synthasa oxidu dusnatého, typ I antagonisté a inhibitory fyziologie MeSH
- synthasa oxidu dusnatého, typ III antagonisté a inhibitory fyziologie MeSH
- synthasa oxidu dusnatého * antagonisté a inhibitory fyziologie MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- zvířata MeSH
- Publikační typ
- práce podpořená grantem MeSH
- přehledy MeSH
Since the identification of the alternative angiotensin converting enzyme (ACE)2/Ang-(1-7)/Mas receptor axis, renin-angiotensin system (RAS) is a new complex target for a pharmacological intervention. We investigated the expression of RAS components in the heart and kidney during the development of hypertension and its perinatal treatment with losartan in young spontaneously hypertensive rats (SHR). Expressions of RAS genes were studied by the RT-PCR in the left ventricle and kidney of rats: normotensive Wistar, untreated SHR, SHR treated with losartan since perinatal period until week 9 of age (20 mg/kg/day) and SHR treated with losartan only until week 4 of age and discontinued until week 9. In the hypertrophied left ventricle of SHR, cardiac expressions of Ace and Mas were decreased while those of AT1 receptor (Agtr1a) and Ace2 were unchanged. Continuous losartan administration reduced LV weight (0.43 ± 0.02; P < 0.05 versus SHR) but did not influence altered cardiac RAS expression. Increased blood pressure in SHR (149 ± 2 in SHR versus 109 ± 2 mmHg in Wistar; P < 0.05) was associated with a lower renal expressions of renin, Agtr1a and Mas and with an increase in ACE2. Continuous losartan administration lowered blood pressure to control levels (105 ± 3 mmHg; P < 0.05 versus SHR), however, only renal renin and ACE2 were significantly up-regulated (for both P < 0.05 versus SHR). Conclusively, prevention of hypertension and LV hypertrophy development by losartan was unrelated to cardiac or renal expression of Mas. Increased renal Ace2, and its further increase by losartan suggests the influence of locally generated Ang-(1-7) in organ response to the developing hypertension in SHRs.
- MeSH
- angiotensin konvertující enzym metabolismus MeSH
- hypertenze komplikace farmakoterapie genetika prevence a kontrola MeSH
- hypertrofie levé komory srdeční komplikace farmakoterapie genetika prevence a kontrola MeSH
- ledviny účinky léků enzymologie MeSH
- losartan aplikace a dávkování farmakologie terapeutické užití MeSH
- messenger RNA genetika metabolismus MeSH
- myokard enzymologie MeSH
- novorozená zvířata MeSH
- oxid dusnatý metabolismus MeSH
- potkani inbrední SHR MeSH
- protoonkogenní proteiny metabolismus MeSH
- receptory spřažené s G-proteiny metabolismus MeSH
- regulace genové exprese účinky léků MeSH
- renin-angiotensin systém účinky léků genetika MeSH
- signální transdukce účinky léků MeSH
- srdeční komory účinky léků metabolismus patologie MeSH
- zvířata MeSH
- Check Tag
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
We investigated the effect of pertussis toxin (PTX) on hypotensive response induced by acetylcholine (ACh) and bradykinin (BK) and on noradrenaline (NA)-induced pressor response in spontaneously hypertensive rats (SHR). Fifteen-week-old Wistar rats and age-matched SHR were used. Half of SHR received PTX (10 microg/kg/i.v.) and the experiments were performed 48 h later. After the anesthesia the right carotid artery was cannulated in order to record blood pressure (BP). The hypotensive response to ACh was enhanced in SHR compared to Wistar rats. After pretreatment of SHR with PTX the hypotensive response to ACh was reduced compared to untreated SHR and it was also diminished in comparison to Wistar rats. Similarly, the hypotensive response to BK was also decreased after PTX pretreatment. The pressor response to NA was increased in SHR compared to Wistar rats. NA-induced pressor response was considerably decreased after PTX pretreatment compared to untreated SHR. In conclusion, the enhancement of hypotensive and pressor responses in SHR was abolished after PTX pretreatment. Our results suggested that the activation of PTX-sensitive inhibitory G(i) proteins is involved in the regulation of integrated vasoactive responses in SHR and PTX pretreatment could be effectively used for modification of BP regulation in this type of experimental hypertension.
- MeSH
- acetylcholin MeSH
- analýza párové shody MeSH
- bradykinin MeSH
- fyziologická adaptace účinky léků MeSH
- hemodynamika fyziologie účinky léků MeSH
- hypotenze chemicky indukované patofyziologie MeSH
- inhibitory enzymů MeSH
- krevní tlak genetika účinky záření MeSH
- krysa rodu rattus MeSH
- noradrenalin metabolismus MeSH
- pertusový toxin farmakologie MeSH
- potkani inbrední SHR MeSH
- potkani Wistar MeSH
- proteiny vázající GTP - alfa-podjednotky Gi-Go metabolismus účinky léků MeSH
- signální transdukce fyziologie účinky léků MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- MeSH
- experimenty na zvířatech MeSH
- financování organizované MeSH
- hypertenze MeSH
- kůra ledviny účinky léků MeSH
- losartan diagnostické užití MeSH
- polymerázová řetězová reakce metody využití MeSH
- potkani inbrední WKY MeSH
- renin-angiotensin systém účinky léků MeSH
- zvířata MeSH
- Check Tag
- zvířata MeSH
- Publikační typ
- abstrakty MeSH
