Cardiovascular pharmacology of dopaminergic agents in humans: a review.

PURPOSE: To review the cardiovascular effects of pharmacologic dopamine receptor modulation in humans, organized by receptor subtype.

METHODS

Narrative review of human pharmacological, genetic, and clinical evidence linking dopamine receptor agonism and antagonism to blood pressure and heart rate changes in healthy volunteers and in patients with Parkinson disease, autonomic failure, psychiatric disorders, and selected cardiovascular conditions.

RESULTS

Dopaminergic receptor agonism generally lowers blood pressure, with the magnitude of hypotension tracking with intrinsic activity: full orthosteric agonists (bromocriptine, ropirinole, apomorphine) carry the highest risk of orthostatic hypotension, and partial agonists (tavapadon) produce attenuated but clinically relevant hypotension. Dopamine D3-preferring agents (PF-592379, mesdopetam, cariprazine) have neutral cardiovascular effects in short-term trials. Levodopa-induced orthostatic hypotension arises from at least five converging mechanisms whose clinical impact is amplified by underlying neurogenic orthostatic hypotension. A notable exception is mevidalen, a centrally acting dopamine D1 positive allosteric modulator that paradoxically raises blood pressure. Despite murine knockout models consistently predicting that dopamine receptor deletion produces hypertension, pharmacological antagonism in humans does not reliably raise blood pressure: dopamine D1, D2, and D3 antagonists show largely neutral cardiovascular profiles, while antipsychotic-associated orthostatic hypotension is driven primarily by α1-adrenergic blockade.

CONCLUSIONS

The cardiovascular response to dopaminergic agents depends on receptor selectivity, intrinsic activity, and baroreflex integrity. The discrepancy between murine-knockout-predicted hypertension and human pharmacological neutrality with antagonists, and the hypertensive effects of dopamine D1 positive allosteric modulators, represent key unresolved questions.