Article

Angiotensin II-induced hypertension is associated with a selective inhibition of endothelium-derived hyperpolarizing factor-mediated responses in the rat mesenteric artery.

Département de Pharmacologie et Physicochimie, Unité Mixte de Recherche 7175 Centre National de Recherche Scientifique/Université Louis Pasteur (Strasbourg I), Faculté de Pharmacie 74, Illkirch, France.
Journal of Pharmacology and Experimental Therapeutics (Impact Factor: 3.89). 12/2008; 328(2):478-86. DOI: 10.1124/jpet.108.145326
Source: PubMed

ABSTRACT Hypertension has been shown to be associated with impaired endothelium-derived hyperpolarizing factor (EDHF)-mediated arterial relaxation and hyperpolarization. Treatments of hypertensive rats with inhibitors of the renin-angiotensin system have been shown to restore both EDHF-mediated responses and the expression of connexins involved in the intercellular transfer of the hyperpolarization in mesenteric arteries. The present study was designed to determine whether chronic treatment of rats with angiotensin II impairs EDHF-mediated responses and the expression of connexins in the mesenteric arterial wall. Male Wistar rats were treated with angiotensin II (0.4 mg/kg/day) for 21 days using osmotic minipumps. Arterial pressure was measured by tail-cuff plethysmography. Contractile responses and membrane potential were measured in isolated mesenteric arteries. The expression of the three connexins (Cxs), Cx37, Cx40, and Cx43, was quantified in segments of mesenteric arteries by immunohistochemistry and quantitative real-time reverse transcriptase-polymerase chain reaction. Angiotensin II administration increased the mean systolic blood pressure. EDHF-mediated relaxation and hyperpolarization to acetylcholine and red wine polyphenols were significantly impaired in mesenteric arteries from angiotensin II-treated rats in comparison with control animals, whereas nitric oxide-mediated relaxation was unaltered. The expression of connexins Cx37, Cx40, and Cx43 was significantly decreased in the mesenteric artery from angiotensin II-treated rats. These findings indicate that angiotensin II-induced hypertension is associated with a selective impairment of EDHF-mediated relaxation and hyperpolarization in the rat mesenteric artery. The inhibition of EDHF-mediated responses is due, at least in part, to a decreased expression of connexins Cx37, Cx40, and Cx43 in the arterial wall.

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Kahdella maidon fermentaatioprosessissa maidon kaseiinista muodostuvalla tripeptidillä, isoleusiini-proliini-proliinilla (Ile-Pro-Pro) ja valiini-proliini-proliinilla (Val-Pro-Pro) on aiemmissa tutkimuksissa havaittu olevan verenpainetta alentavaa vaikutusta, mutta tieto taustalla olevista mekanismeista sekä tripeptidien verisuonivaikutuksista on vähäistä. Väitöstutkimuksessa käytettiin pääosin perinnöllisen verenpainetaudin sekä tyypin 2 diabeteksen kokeellisia tutkimusmalleja. Näitä malleja hyödyntäen osoitettiin, että tripeptidien tai niitä sisältävien fermentoitujen maitotuotteiden päivittäinen, pitkäaikainen saanti osittain esti verenpaineen kohoamista. Kolesterolia alentavat kasvisterolit eivät lisänneet tripeptidien suotuisia verenpainevaikutuksia. Tutkimuksen mukaan tripeptidien valmistusmenetelmällä ei ole merkitystä tehon kannalta. Pienellä kliinisellä aineistolla havaittiin, että jo yksi annos tripeptidejä ja kasvisteroleja sisältävää fermentoitua maitotuotetta laski verenpainetta koehenkilöillä, joilla verenpaine oli lievästi koholla. Tämä suotuisa vaikutus kesti koko kahdeksan tunnin seuranta-ajan. Verisuonten toimintakokeet osoittivat, että Ile-Pro-Pro ja Val-Pro-Pro sekä niitä sisältävät fermentoidut maitotuotteet paransivat verisuonten laajenemiskykyä sekä lyhyt- että pitkäaikaisissa kokeellisissa tutkimuksissa. Vaikutuksen osoitettiin välittyvän verisuonen sisimmän kerroksen, endoteelin kautta. Kliinisessä kokeessa ei havaittu merkitsevää vaikutusta koehenkilöiden verisuonten toimintaan pulssiaaltoanalyysiä (PWA) käyttäen. Väitöskirjatyön biokemialliset analyysit osoittivat, että tripeptidit Ile-Pro-Pro ja Val-Pro-Pro vaikuttavat verenpaineen säätelyssä keskeiseen reniini-angiotensiinijärjestelmään. 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