Prevention by a somatostatin analogue of the hypertensive and cardiovascular structural changes induced by blockade of adenosine receptors C. Calhau 1 , F. Martel 2 , M.N.M.P. Alc Ëada 2 & I. Azevedo 1 1 Institute of Pharmacology and Therapeutics and 2 Department of Biochemistry, Faculty of Medicine, 4200 Porto, Portugal 1 Long-term administration of the adenosine receptor antagonist, 1,3-dipropyl-8- sulfophenylxanthine (DPSPX), causes arterial hypertension and cardiovascular hypertrophic and hyperplastic changes (Matias, Albino-Teixeira, Polo nia & Azevedo, 1991). As somatostatin is a repressor of cell growth, and adenosine is a potent inducer of the somatostatin gene, we investigated the putative involvement of somatostatin in the cardiovascular eects of DPSPX. 2 DPSPX (90 mg kg 71 h 71 , i.p.) or saline and the somatostatin analogue, octreotide (75 mg kg 71 day 71 , s.c.), or saline were infused through Alzet minipumps to Wistar rats. Blood pressure was measured with the tail-cu technique. Seven days after implantation of the minipumps the rats were killed and the tissues prepared for microscopy. 3 DPSPX induced arterial hypertension and cardiovascular hypertrophic and hyperplastic changes as previously described (Matias et al., 1991). Treatment of the rats with octreotide alone had no eect either on blood pressure or in blood vessel morphology. However, octreotide prevented both the hypertensive and the cardiovascular morphologic eects of DPSPX. 4 The results are compatible with the involvement of somatostatin in the long-term cardiovascular eects of adenosine. Introduction The sympathetic nervous system modulates the phenotype of blood vessel and heart cells, repressing their nuclear activity (Branco, Albino-Teixeira, Azevedo & Osswald, 1984; Azevedo & Osswald, 1986; Sarmento, Soares-da-Silva, Albino-Teixeria & Azevedo, 1987). Adenosine was shown to be able to prevent the morphological changes induced by sympathetic denervation (Albino-Teixeira, Matias & Azevedo, 1989; Albino-Teixeria, Azevedo, Branco & Osswald, 1990a; Albino-Teixeira, Matias, Soares- da-Silva, Sarmento & Azevedo, 1990b), becoming a good candidate for the role of a main trophic factor of the sympathetic nervous system (Osswald & Azevedo, 1991). In agreement with this theory, long-term blockade of adenosine receptors through administration of 1,3- dipropyl-8-sulfophenylxanthine (DPSPX) caused marked morphological cardiovascular changes and arterial hypertension (Albino-Teixeira, Matias, Po- loÂnia & Azevedo, 1991; Matias et al., 1991; Karoon, Rubino & Burnstock, 1995). However, all of the above experiments and data did not allow us to determine whether the adenosine trophic eects were exerted directly (i.e. through the action of adenosine on the nucleus of eector cells), or indirectly (i.e. through the action of a second eector agent). Considering that adenosine is a potent inducer of the somatostatin gene (Montminy & Bilezikjian, 1987), and that somatostatin exists in the sympathetic nervous system (HoÈkefelt et al., 1977) and seems to be a universal blocker of cell growth (Siperstein, Levein, Gum & Clark, 1992; Reubi & Laissue, 1995), we tested the hypothesis that somatostatin is involved in the trophic eects of adenosine. As somatostatin is highly unstable, with a half-life of about 2 min (Harris, 1994; Shulkes, 1994), we tested the eect of octreotide, a somatos- tatin analogue with a higher stability and longer half- life (Reichlin, 1983a,b), on the cardiovascular eects of DPSPX. Methods Blood pressure measurement Systolic and diastolic blood pressures were measured in conscious restrained Wistar rats (250±300 g body weight, BioteÂrio do Instituto Gulbenkian de CieÃncias, Journal of Autonomic Pharmacology, 17, 243±247 Correspondence: I. Azevedo # 1997 Blackwell Science Ltd 243 Paper 459 MS # 1996 Blackwell Science Ltd, Journal of Autonomic Pharmacology, 16, xx±xx Ahed Bhed Ched Dhed Ref marker Fig marker Table marker Ref end Ref start