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

The effects of pretreatment with the potent and selective 5-HT1A receptor ligand, MDL 73005EF, on the cardiovascular responses to administration of the 5-HT1A 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-HT1A receptor antagonists. MDL 7300EF (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-HT1A receptors since it caused a decrease in blood pressure, but also reduced the cardiovascular responses to the 5-HT1A receptor agonists, 8-OH-DPAT, flesinoxan and 5-methylurapidil.