Central hypotensive effect of L-3,4-dihydroxyphenylalanine in the rat

Abstract

Mean arterial blood pressure was recorded through in-dwelling arterial catheters in conscious normotensive Sprague-Dawley rats. L-3,4-Dihydroxyphenylalanine (L-dopa) was given in various doses intraperitoneally, alone and after pretreatment with an inhibitor of dopa decarboxylase, α-hydrazino-α-methyl-β-(3,4-dihydroxyphenyl) propionic acid (MK 485) or seryl-2,3,4-trihydroxybenzylhydrazine (Ro 4–4602). L-Dopa (50 mg/kg) produced a hypertensive response which was abolished by MK 485 (100 mg/kg). A larger dose of L-dopa (200 mg/kg) after MK 485 caused a significant lowering of blood pressure after 15–20 min. After Ro 4–4602 (400 + 200 mg/kg), injection of L-dopa (200 mg/kg) had no significant effect on blood pressure. The hypotensive response to L-dopa (200 mg/kg) after MK 485 was not influenced by the central dopamine receptor blocking agent, spiroperidol (0.1 mg/kg), but could be completely inhibited by the dopamine β-hydroxylase inhibitor, bis-(4-methyl-1-homopiperazinyl-thiocarbonyl)disulphide (FLA 63) (40 mg/kg). Pretreatment with protripty-line (10 mg/kg) completely blocked the hypotensive effect of L-dopa after MK 485. In correlative biochemical experiments, levels of noradrenaline and dopamine were determined in brain, heart and femoral muscle. L-Dopa (200 mg/kg) alone caused a significant increase of dopamine levels in all tissues. After MK 485 and Ro 4–4602 L-dopa did not significantly increase the levels of dopamine in heart or femoral muscle; however, brain dopamine levels were increased more than after L-dopa alone, but brain dopamine levels after Ro 4–4602 were significantly lower than after MK 485, indicating some central decarboxylase inhibition by Ro 4–4602. L-Dopa alone reduced the noradrenaline content of the heart and this effect was prevented by MK 485 and Ro 4–4602. The results show that decarboxylation of L-dopa in both the central and the peripheral nervous system leads to an increase in blood pressure. Decarboxylation of L-dopa in the central nervous system only results in a hypotensive response, provided that high amounts of dopamine are formed in the brain. This effect was prevented by an inhibitor of dopamine β-hydroxylase but not by a dopamine receptor blocker. Therefore, a central noradrenaline mechanism seems to be involved. The presence of an intact membrane pump in noradrenaline neurons may be essential since protriptyline also blocked the hypotensive action.