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- Title
The influence of endogenously generated reactive oxygen species on the inotropic and chronotropic effects of adrenoceptor and ET-receptor stimulation.
- Authors
Sand, Carsten; Peters, Stephan L. M.; Pfaffendorf, Martin; Van Zwieten, Pieter A.
- Abstract
Reactive oxygen species (ROS) play a role in cardiovascular diseases such as heart failure and hypertension. Furthermore, increasing evidence has accumulated suggesting that ROS can also be formed subsequent to the stimulation of various receptors, thus functioning as second messengers. The objective of the present study was to elucidate the role of intracellular-generated ROS in the inotropic and chronotropic effects of the α1- and β-adrenoceptor and the ET-receptor stimulation in isolated rat atria. In addition, we investigated whether the MAPKerk pathway is involved in the ROS-provoked rise of contractile force. For this purpose hydrogen peroxide was applied, which is known to serve several endogenous functions as a second messenger. Moreover, hydrogen peroxide readily crosses cell membranes, which thus allows to mimic the intracellular formation. Preincubation of atria with EUK 8 (400 μM), a cell permeable superoxide dismutase- and catalase-mimetic, reduced the positive inotropic effect upon α1-adrenoceptor and ET-receptor stimulation. The responsiveness to β-adrenoceptor stimulation remained unaffected by this pretreatment. The chronotropic effects were not altered by preincubation with EUK 8. In contrast to the MAPKp38 inhibitor SB203580 (2 and 10 μM), the two MKKmek inhibitors PD98059 (30 and 100 μM) and U0126 (10 μM) significantly attenuated the positive inotropic response to hydrogen peroxide in isolated rat left atria. In addition, inhibition of the Na+/H+ exchange (NHE) by cariporide (1 μM) counteracted ROS-provoked increase of contractile force. From the present study we conclude that the inotropic responses to α1-adrenoceptor and ET-receptor stimulation are, at least partially, caused by intracellular-formed ROS, that subsequently may activate the MAPKerk pathway and the NHE.
- Subjects
REACTIVE oxygen species; CARDIOVASCULAR diseases; HEART failure; HYPERTENSION; CELL receptors; HYDROGEN peroxide
- Publication
Naunyn-Schmiedeberg's Archives of Pharmacology, 2003, Vol 367, Issue 6, p635
- ISSN
0028-1298
- Publication type
Article
- DOI
10.1007/s00210-003-0745-0