On the mechanism of L-dopa-induced postural hypotension in the cat

1. The effects of L-DOPA on postural hypotension and carotid occlusion pressor effect were studied, mainly in cats; the recovery of the blood pressure upon tilting was used as a measure of postural hypotension.2. L-DOPA (30 mg/kg) partially depressed the carotid occlusion pressor effect and caused some degree of postural hypotension, L-DOPA (100 mg/kg) had more marked effects; the responses returned to control after 90 to 150 minutes. L-DOPA itself caused a pressor response in all cats.3. The dopa decarboxylase inhibitor N(1)-(DL-seryl)-N(2)-(2,3,4-trihydroxybenzyl) hydrazine (RO4-4602, 50 and 10 mg/kg) had no effect itself on the tilt response but completely prevented the effects of L-DOPA on the carotid occlusion pressor effect and postural hypotension.4. After RO4-4602 (3 and 1 mg/kg), L-DOPA (100 mg/kg) caused a brief rise of blood pressure followed by a longer lasting fall in horizontally-orientated cats (i.e. ;supine' hypotension). No postural hypotension was observed after L-DOPA under these conditions.5. Noradrenaline elicited only small and transient effects on postural hypotension, but dopamine's effects were more marked and longer lasting. Pressor dose-response relationships for noradrenaline were the same before and after L-DOPA, as well as in cats pretreated with L-DOPA for 4 days.6. In cats with kidneys and intestines removed, the tilt reflex was still present. Dose-response curves to L-DOPA were the same as in normal animals. RO4-4602 (3 mg/kg) prevented postural hypotension and block of the carotid occlusion pressor effect; supine hypotension was also observed after L-DOPA.7. The recovery response to tilting in spinal cats was markedly depressed or absent unless the blood pressure was elevated by angiotensin, in which experiments L-DOPA depressed the recovery upon tilting (i.e. induced postural hypotension).8. Blood pressure responses to tyramine were increased after 10 mg/kg of L-DOPA, but depressed after 100 mg/kg. The response to tyramine was not depressed, however, when RO4-4602 was given to block the dopa-dopamine conversion.9. The response to sympathetic stimulation in pithed rats was depressed after L-DOPA and dopamine, but not after alpha-methyldopa.10. alpha-Methyldopa (300 mg/kg) given acutely caused a moderate degree of postural hypotension and a more marked postural hypotension if given for two days.11. It is concluded that it is possible to differentiate between the supine and postural hypotension caused by L-DOPA and that supine hypotension is due to a central effect and postural hypotension to an extracerebral effect. Postural hypotension is discussed in relation to six hypotheses presented to explain its effect. Postural hypotension after L-DOPA is probably not due to a-adrenoceptor blockade, a central effect or any effect on the kidney. The most likely hypothesis is that L-DOPA forms dopamine which acts as a false transmitter in the peripheral sympathetic nervous system.