Why does L-DOPA cause hypotension?

Question

L-DOPA is administered in Parkinson's Disease as a prodrug to dopamine which it is converted to in the central nervous system.

However Dopamine is used as a vasopressor, and L-DOPA is associated with hypotension.

How does this work? I speculate that because L-DOPA conversion peripherally is usually blocked by co-administering a dopa decarboxylase inhibitor that peripheral dopamine levels stay low whilst central levels raise.

Why/how does centrally raised dopamine result in hypotension?

Thanks.

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Possible explanation

The dopamine agonist bromocriptine can produce hypotension by inhibiting the sympathetic nervous system. This causes arterial and venous vasodilation, lowering total peripheral resistance.

The authors of this paper ask whether bromocriptine exerts this effect by agonising dopamine receptors on smooth muscle cells directly or whether this is a suppressing effect of upstream dopamine receptors in the CNS reducing the activity of sympathetic fibres. I don't know the answer to this but it is intriguing! I suspect that directly activating dopamine receptors on smooth muscle cells does not cause vasodilation because dopamine itself is a vasopressor, but I am not sure about this. How does upstream modulation of the sympathetic nervous system by dopamine work?

This paper discussed how dopamine D2 receptors are present prejunctionally in the SNS and act antagonistically to reduce norepinephrine release from these cells.

Their pharmacological activation causes an inhibition of in vitro and in vivo norepinephrine (NE) release from sympathetic nerve terminals and an inhibition of in vitro epinephrine (E) release from the adrenal medulla. Endogenous DA, co-secreted with the other catecholamines (CA), modulates sympathetic-adrenal discharge only during high sympathetic stimulation through an autocrine mechanism, limiting excessive sympathetic adrenal discharge.

Perhaps this explains why L-DOPA produces orthostatic hypotension. Dopamine agonists only exert this modulating effect on the SNS at points of high sympathetic stimulation. This may explain why suddenly standing up, which should produce reflex tachycardia and thereby homeostasis of blood pressure fails in some patients causing a BP drop.

Answer 1

Interesting question. According to [1]:

Postural hypotension has been estimated to occur in some 15% of patients who take plain levodopa during the first year of treatment

So the hypotension side effect is postural (orthostatic) in nature, not general. This makes sense. Dopamine activates the sympathetic nervous system.

So let's say that dopamine already increased heart rate, vasoconstriction, and blood pressure. If someone on L-dopa stands up, they don't have a lot of homeostatic control mechanisms left to counteract the orthostatic pooling of blood in the legs. The result is a decrease in blood pressure of the brain. This could result in orthostatic hypotension, lightheadedness, and even collapse.

On the other hand, [1] also states:

it is doubtful whether the difference is significant.

In other words, patients that require L-dopa probably already have a high risk of postural hypotension. This is not an unreasonable statement because L-dopa is typically used in the treatment of Parkinson disease. And autonomic dysfunction is common in Parkinson disease.

[1] Aronson JK, et al. Meyler's side effects of drugs. 16th ed. Amsterdam. Page 4:545. Elsevier, 2016.