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Differential cardiovascular effects of 8‐hydroxy‐2‐(di‐n‐propylamino) tetralin (8‐OH‐DPAT), flesinoxan, 5‐methyl‐urapidil and MDL 75,608A in conscious spontaneously hypertensive rats
Author(s) -
BuissonDefferier S.,
Hibert M.,
Buuse M.
Publication year - 1993
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.1993.tb00254.x
Subject(s) - urapidil , blood pressure , heart rate , endocrinology , medicine , 8 oh dpat , tachycardia , spontaneously hypertensive rat , chemistry , receptor , 5 ht receptor , serotonin
Summary— The effects of intravenous (iv) administration of four agonists at central 5‐HT 1A receptors were investigated and compared. Acute iv injection of 0.1 mg/kg of 8‐OH‐DPAT induced a decrease in blood pressure both in spontaneously hypertensive rats (SHR) and normotensive Wistar‐Kyoto rats (WKY). The maximal hypotensive effect was observed 15 and 10 min after injection, respectively, but the effect was greater and longer‐lasting in the SHR. 8‐OH‐DPAT significantly decreased heart rate in WKY and, to a lesser extent, in SHR. The iv injection of 1 mg/kg of flesinoxan caused a similar fall in blood pressure and heart rate in SHR and WKY. The iv administration of 1 mg/kg of 5‐methyl‐urapidil or MDL 75,608A caused a fall in blood pressure which was significantly more pronounced in SHR than in WKY. 5‐methyl‐urapidil induced a significant tachycardia in WKY, but had little effect on heart rate in SHR. MDL 75,608A caused a short‐lasting tachycardia in SHR and WKY. In conscious SHR, the intracerebroventricular (icv) injection of 10 μg of 8‐OH‐DPAT or 100 μg of either flesinoxan or MDL 75,608A caused a decrease in blood pressure and heart rate. The icv injection of 100 μg of 5‐methyl‐urapidil caused only a decrease in blood pressure. Chronic pre‐treatment with these compounds, by daily iv injection, did not significantly influence the hypotensive or bradycardic effects in an acute experiment. The involvement of α 1 ‐adrenoceptors in the effects of these compounds was studied by administering phenylephrine (1 μg/iv) at 5‐ min intervals before and after the iv injection of the experimental compounds. The injection of phenylephrine reproducibly increased blood pressure by 35–40 mm Hg after saline pre‐treatment, and these responses were not affected by the iv injection of 0.1 mg/kg of either 8‐OH‐DPAT or 1 mg/kg of flesinoxan. In contrast, the phenylephrine‐induced pressor responses were markedly diminished at 5 min after treatment with 1 mg/kg of either 5‐methyl‐urapidil or MDL 75,608A, but slowly recovered thereafter. These results show that the 5‐HT 1A recptor agonists 8‐OH‐DPAT, flesinoxan, 5‐methyl‐urapidil and MDL 75,608A show antihypertensive properties in conscious SHR after iv or icv injection. However, the mechanism of action of the compounds differs: 8‐OH‐DPAT and flesinoxan may act predominantly as 5‐HT 1A receptor agonists, where as 5‐methyl‐urapidil and MDL 75,608A also seem to have an effect on peripheral α 1 ‐adrenoceptors.