On the mechanism of l‐DOPA‐induced postural hypotension in the cat

Abstract

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 N¹-(dl-seryl)-N²-(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 α-methyldopa. 10 α-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 α-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.