Cardiovascular effects of the 5-HT1A receptor ligand, MDL 73005EF, in conscious spontaneously hypertensive rats

doi:10.1016/0014-2999(92)94831-F

European Journal of Pharmacology

Volume 223, Issues 2–3, 17 November 1992, Pages 133-141

https://doi.org/10.1016/0014-2999(92)94831-F Get rights and content

Abstract

The effects of pretreatment with the potent and selective 5-HT_1A receptor ligand, MDL 73005EF, on the cardiovascular responses to administration of the 5-HT_1A receptor agonists, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), flesinoxan and 5-methylurapidil were studied in conscious spontaneously hypertensive rats (SHR) and compared with those of putative 5-HT_1A receptor antagonists. MDL 73005EF (0.1–3 mg/kg) induced a dose-dependent but transient decrease in mean arterial pressure (MAP). Pretreatment with doses of 1 or 3 mg/kg MDL 73005EF significantly inhibited the hypotensive and bradycardiac effects of 8-OH-DPAT (0.03-1 mg/kg). Pretreatment with 1 mg/kg MDL 73005EF similarly reduced the hypotensive actions of flesinoxan (0.3–1 mg/kg) and 5-methylurapidil (0.1 mg/kg). In contrast, MDL 73005EF did not significantly affect the decrease in blood pressure induced by administration of 0.01 mg/kg clonidine, 0.3 mg/kg hydralazine or 0.2 mg/kg nifedipine. The effect of 8-OH-DPAT (0.1 mg/kg) on MAP was also reduced by pretreatment with 1 mg/kg BMY 7378, buspirone or pindolol, but not NAN 190 or spiperone. BMY 7378, NAN 190, pindolol and spiperone induced a significant decrease in blood pressure. To rule out the possibility that the reduced baseline may have influenced responses to 8-OH-DPAT we showed that pretreatment with the vasodilator, hydralazine (0.3 mg/kg), had no effect on the MAP response to 8-OH-DPAT although it significantly reduced MAP. We conclude that MDL 73005EF acts as a mixed agonist/antagonist at 5-HT_1A receptors since it caused a decrease in blood pressure, but also reduced the cardiovascular responses to the 5-HT_1A receptor agonists. 8-OH-DPAT, flesinoxan and 5-methylurapidil.

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We studied the effect of treatment with the serotonin-1A (5-HT_1A) receptor ligands buspirone, 8-hydroxy-di-propyl-aminotetralin (8-OH-DPAT), and (8-[2-(2,3-dihydro-1,4-benzodioxin-2-yl-methylamino)ethyl]-8-azaspiro[4,5]decane-7,9-dione methyl sulphonate (MDL73,005EF) on blood pressure and heart rate increases to open field stress. We compared Spontaneously Hypertensive Rats (SHR), Fawn–Hooded (FH) rats, Wistar–Kyoto (WKY) rats, and Sprague–Dawley (SD) rats instrumented with radio-telemetry probes. Buspirone treatment reduced the blood pressure increase in SHR, FH rats, and WKY rats and heart rate increase in FH rats and WKY rats. 8-OH-DPAT treatment reduced the blood pressure increase in FH rats and WKY rats, but had no effect in SHR and enhanced the pressor response in SD rats. This treatment reduced the heart rate increase in FH rats and WKY rats only. Similarly, MDL73,005EF treatment reduced the blood pressure increase in FH rats and WKY rats, but had no effect in SHR and enhanced this response in SD rats. Little effect of this treatment was seen on heart rate changes. For comparison, diazepam treatment abolished the pressor response in SD rats and reduced it in FH rats and WKY rats, but not SHR. Differential effects of the treatments were also seen between strains for locomotor activity in the open field, although behavioural changes could not explain the effects of the drugs on cardiovascular responses. These data suggest that 5-HT_1A receptors are involved in cardiovascular stress responses; however, the extent of this involvement differs between rat strains and the drugs used. These results could be important for our understanding of possible anxiolytic properties of antipsychotic drugs with affinity for the 5-HT_1A receptor.
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Cardiovascular effects of the 5-HT1A receptor ligand, MDL 73005EF, in conscious spontaneously hypertensive rats

Abstract

J. Biol. Chem.

Brain Res.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Life Sci.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Neuropharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Pharmacol. Biochem. Behav.

Eur. J. Pharmacol.

Neuropharmacology

Eur. J. Pharmacol.

Eur. J. Pharmacol.

Cardiovascular effects of the 5-HT_1A receptor ligand, MDL 73005EF, in conscious spontaneously hypertensive rats