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.
The effects of intravenous (i.v.) administration of four agonists at central 5-HT1A 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 i.v. injection of 1 mg/kg of flesinoxan caused a similar fall in blood pressure and heart rate in SHR and WKY. The i.v. 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 micrograms of 8-OH-DPAT or 100 micrograms of either flesinoxan or MDL 75,608A caused a decrease in blood pressure and heart rate. The icv injection of 100 micrograms of 5-methyl-urapidil caused only a decrease in blood pressure. Chronic pre-treatment with these compounds, by daily i.v. injection, did not significantly influence the hypotensive or bradycardic effects in an acute experiment. The involvement of alpha 1-adrenoceptors in the effects of these compounds was studied by administering phenylephrine (1 microgram/i.v.) at 5-min intervals before and after the i.v. 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 i.v. 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-HT1A receptor 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-HT1A receptor agonists, where as 5-methyl-urapidil and MDL 75,608A also seem to have an effect on peripheral alpha 1-adrenoceptors.
Buisson-Defferier
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S
Marion Merrell Dow Research Institute, Strasbourg Research Center, France.
Hibert
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M
van den Buuse
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M
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology*; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002319:Cardiovascular System / Q000187:drug effects*; D004146:Dioxanes / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy* / Q000503:physiopathology; D007276:Injections, Intraventricular; D008297:Male; D010656:Phenylephrine / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D018340:Receptors, Adrenergic, alpha-1 / Q000187:drug effects / Q000502:physiology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D013141:Spiro Compounds / Q000494:pharmacology*
D000317:Adrenergic alpha-Antagonists; D004146:Dioxanes; C085838:MDL 75608A; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D017366:Serotonin Receptor Agonists; D013141:Spiro Compounds; C057446:5-methylurapidil; D010656:Phenylephrine; C056895:flesinoxan; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin