C Pharmacology & Toxicology 2003, 92, 160–162. Copyright C Printed in Denmark . All rights reserved ISSN 0901-9928 Annotations & Reflections Hypertension Due to Blockade of Adenosine Receptors* Serafim Guimara ˜es, Manuela Morato, Teresa Sousa and Anto ´nio Albino-Teixeira Institute of Pharmacology and Therapeutics, Faculty of Medicine, University of Porto, Alameda Hernani Monteiro 4200-319, Porto, Portugal Abstract: Chronic treatment of rats with 90 mg/kg/day DPSPX (1,3-dipropyl-8-sulphophenylxanthine) during seven days leads to a hypertensive state which is characterized by marked morphological changes of the blood vessel walls as well as by important functional alterations. While the angiotensin-converting enzyme (ACE) inhibitor captopril and the antagon- ist of angiotensin II AT 1 receptors losartan prevent the development of both hypertension and morphological changes, the selective b 1 -adrenoceptor antagonist atenolol could prevent only the increase in blood pressure. It is concluded that at least two factors are involved in the development of the hypertensive state. It is well established that long-term treatment of male adult Wistar rats with 1,3-dipropyl-8-sulphophenylxanthine (DPSPX), a non-selective antagonist of adenosine receptors causes a hypertensive state which lasts for at least one month after the administration of the drug had been stopped (Albino-Teixeira et al. 1991; Guimara ˜es & Albino- Teixeira 1996) (for methodological details see Albino-Teixei- ra 1990). From the second day of treatment on, the blood pressure increases regularly, reaching a maximum value of about 40 mmHg for the systolic and 35 mmHg for the diastolic press- ure at about the 6th day. This increase in blood pressure is accompanied by important morphological changes of the blood vessel walls and by functional alterations as well. Morphological data There are very impressive morphological changes in DPSPX-treated rats . Small arteries and arterioles (of about 60 mm diameter) show marked structural alterations. In the renal and tail arteries there is an increase in the thickness of the media and in individual smooth muscle cell width, as well as an increase in the mean diameter of the myocardial cell nuclei. The increase in size and number of subendothel- ial cells create buttoms which protrude into the lumen and very often occlude the vessel (Albino-Teixeira et al. 1991). When 30 mg/kg/day DPSPX is administered, three to four weeks after the end of DPSPX administration, the hyper- tensive state disappears but the hyperplastic alterations, e.g. * Presented at the Ove A. Nedergaard Symposium, 2002. Author for correspondence: Serafim Guimara ˜es, Department of Pharmacology and Therapeutics, Faculty of Medicine, 4200 Porto, Portugal (fax π351 22 5502402, e-mail sguimara/med.up.pt). buttoms of smooth muscle in the intimal layers remain. When 90 mg/kg/day is administered, which is the concen- tration more commonly used, the hypertensive state lasts for at least 2–3 months and the morphological changes re- main unchanged. Functional data b-Adrenoceptor-mediated positive influence on noradrenaline release evoked by electrical stimulation. The non-selective b-adrenoceptor agonist isoprenaline which causes a concentration-dependent facilitation of nor- adrenaline overflow elicited by electrical stimulation (Guim- ara ˜es et al. 1978) is much more effective in arteries from DPSPX-treated than in arteries from control rats; while 27.8 nM isoprenaline were required in control animals to increase the overflow of noradrenaline by 30%, the same increase was obtained in DPSPX-treated rats with 7.0 nM isoprenaline (Guimara ˜es et al. 1995). Furthermore, the maximal increase of noradrenaline overflow was higher in DPSPX-treated than in control rats (by 48.6% and 32.6%, respectively). a 2 -Adrenoceptor-mediated negative influence on noradren- aline release evoked by electrical stimulation. Prejunctional a 2 -adrenoceptors of the rat tail artery of DPSPX-treated animals also became supersensitive to the selective a 2 -adrenoceptor agonist UK-14,304, whereas post- junctional a 2 -adrenoceptors did not (Guimara ˜es et al.1994): the EC 30% values for UK-14,304 was reduced from 381 to 85 nM and its maximal effect, expressed as percent reduc- tion of noradrenaline-overflow increased from 45 to 61%, while in L-NAME-treated rats there was no change in either of these two parameters, and at postjunctional levels there