Short communicationAngiotensin II-induced vasodilatation in cerebral arteries is mediated by endothelium-derived hyperpolarising factor
Introduction
Angiotensin II controls vascular tone by activating angiotensin type 1 (AT1) and type 2 (AT2) receptors (Chiu et al., 1989). Angiotensin AT1 receptors are believed to be mainly located on smooth muscle cells and to induce vasoconstriction (Touyz and Schiffrin, 2000), while angiotensin AT2 receptors mediate endothelium-dependent vasodilatation (Carey et al., 2000). In the peripheral circulation, blood vessel tone is primarily controlled by vasoconstrictors. Conversely, the intracranial vascular tone is predominantly influenced by vasodilatory mediators (Toda and Okamura, 1998).
Endothelium-dependent dilatation has mainly been characterised by the use of strong vasodilators such as acetylcholine, bradykinin and substance P. Nitric oxide and prostaglandins are well-characterised vasodilatory mediators, while the existence of endothelium-derived hyperpolarising factor (EDHF) in cerebral blood vessels was unknown until 1995 (Petersson et al., 1995). It is now believed that EDHF is one of the most important regulators of cerebrovascular tone (Kitazono et al., 1995, Petersson et al., 1997, Schildmeyer and Bryan, 2002).
Angiotensin II-induced vasodilatation has been shown to be mediated by nitric oxide and prostaglandins (Henrion et al., 2001). Involvement of EDHF was observed in a recent study on the peripheral rat vasculature (Soares de Moura et al., 2004). The dilatory mechanisms of angiotensin II have not yet been fully explored in the cerebral circulation and the role of EDHF remains to be elucidated. The present study was designed to examine the angiotensin II-induced vasodilatation in cerebral arteries, especially regarding EDHF. By applying the drugs luminally in a pressurised arteriograph, the dilatory angiotensin II receptors on the endothelium could be examined without the interference of vasocontractile angiotensin II receptors on smooth muscle cells.
Section snippets
In vitro pharmacology
Middle cerebral artery segments (1–2 mm in length) from male Sprague–Dawley rats (250–300 g) were mounted in a pressurised arteriograph (Living System, Burlington, VT, USA) containing a bicarbonate-based physiological salt solution (37 °C). Micropipettes were inserted into both ends of the segment and secured in place with nylon ties. The transmural pressure was maintained at 85 mm Hg and the luminal perfusion rate was 100 μl/min. The blood vessel was monitored using a microscope coupled to an
Results
The mean baseline diameter of the middle cerebral arteries examined was 195 ± 13 μm after initial pressurisation, and 136 ± 6 μm after development of spontaneous tone. Luminally applied ATP (10 μM) produced relaxation to 156 ± 9 μm, indicating a functional endothelium. The precontraction induced by abluminal application of 1 μM 5-HT amounted to 122 ± 4 μm.
Abluminal application of angiotensin II induced vasoconstriction (Emax = 15 ± 1% of the initial diameter, pEC50 = 8.0 ± 0.1). Luminal application of
Discussion
EDHF is an endothelium-dependent dilatory mediator that has been suggested to play a major role in the regulation of blood flow in the cerebral circulation (Petersson et al., 1995, Petersson et al., 1997, Schildmeyer and Bryan, 2002). The present study was designed to investigate the angiotensin II dilatory effects in cerebral arteries in detail, especially with regard to EDHF, since this pathway has not yet been fully elucidated in the cerebrovasculature.
Angiotensin II is a strong
Acknowledgements
This study was supported by the Åke-Wieberg Foundation, the Magn. Bergvall Foundation, the Swedish Medical Association, the Royal Physiographic Society in Lund, the Swedish Medical Research Council, the Crafoord Foundation, the Swedish Heart–Lung Foundation, the Swedish Government Grant for Clinical Research and the Swedish Hypertension Society.
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