Vasodilator

The best-measured thing curine does.

Whole-cell patch clamp in A7r5 vascular smooth-muscle cells shows concentration-dependent inhibition of L-type Ca²⁺ current with a hyperpolarising shift of steady-state inactivation and reduced intracellular Ca²⁺ transients, unaffected by IBMX, dibutyryl-cAMP or 8-Br-cGMP — so not a PKA/PKG route ^{6Reference 6Medeiros MA et al. · 2011In vitroCurine, a bisbenzylisoquinoline alkaloid, blocks L-type Ca²⁺ channels and decreases intracellular Ca²⁺ transients in A7r5 cells — in vitroView study →}.

In rat mesenteric resistance arteries it relaxes noradrenaline- and KCl-precontracted rings at IC50 ≈ 4.8–6.0 µM independently of the endothelium, and also blocks noradrenaline-triggered contraction in Ca²⁺-free medium, i.e. it hits store release as well as influx ^{7Reference 7Dias CS et al. · 2002AnimalMechanisms involved in the vasodilator effect of curine in rat resistance arteries — ratsView study →}.

Ceiling: ex-vivo and patch clamp only — no in-vivo blood-pressure or hemodynamic study of curine exists, so “vasodilator” is a tissue-level property, not a demonstrated antihypertensive effect.

Reported from abuta.

(S)-reticuline reduces the peak L-type Ca²⁺ current in A7r5 vascular smooth-muscle cells in a concentration-dependent way and shifts the steady-state inactivation curve leftward — voltage-dependent Ca²⁺-channel blockade, explicitly demonstrated by patch clamp on the defined enantiomer ^{20Reference 20Medeiros MAA et al. · 2009Medeiros MAA, Nunes XP, Barbosa-Filho JM, Lemos VS, Pinho JF, Roman-Campos D, de Medeiros IA, Araújo DAM, Cruz JS. (2009). (S)-reticuline induces vasorelaxation through the blockade of L-type Ca²⁺ channels — patch-clamp and isolated-tissue study. Naunyn-Schmiedeberg’s Archives of Pharmacology, 379(2), 115–125. https://pubmed.ncbi.nlm.nih.gov/18825370/View study →}.

In endothelium-intact rat aortic rings, reticuline inhibited phenylephrine- and KCl-induced contractions (IC50s in the 10⁻⁴ M range), antagonized CaCl₂-induced contraction, and blocked noradrenaline-triggered intracellular-store contractions but not caffeine-triggered ones; endothelium removal, L-NAME and atropine each shifted the curve, marking a second, endothelium-dependent NO/muscarinic component ^{21Reference 21Dias KL et al. · 2004AnimalCardiovascular effects induced by reticuline in normotensive rats — animal studyView study →}.

Ceiling: 10⁻⁴ M is a high concentration, the work is rat aorta and one cell line, and there is no oral study. Reported from california-poppy, graviola.

Vincamine is the defining molecule of the selective cerebral vasodilator class — it relaxes cerebral arterial smooth muscle and raises regional cerebral blood flow with far less effect on systemic vasculature than a general vasodilator ^{22Reference 22Ren et al. · 2023ReviewVincamine, from an antioxidant and a cerebral vasodilator to its anticancer potential — reviewView study →}.

This is one of the rare plant-alkaloid vasodilator claims with a direct human measurement behind it: in a double-blind crossover study in multi-infarct dementia, oral vincamine significantly increased global cerebral blood flow by ¹³³Xe inhalation and reduced hemispheric asymmetry ^{23Reference 23Hagstadius et al. · 1984RCTThe effects of bromvincamine and vincamine on regional cerebral blood flow and mental functions in patients with multi-infarct dementia — double-blind crossover clinical trialView study →}.

It is a class property of the eburnamine–vincamine alkaloids rather than a vincamine peculiarity, and travels with an antihypoxic effect — improved neuronal tolerance of low oxygen — which is the mechanistically interesting half ^{1Reference 1Vas A · 2005Eburnamine derivatives and the brainView study →}.

Early Hungarian pharmacology established the systemic profile (blood-pressure lowering in rats, altered cerebral and coronary supply in the first clinical work) ^{24,25Reference 24Szporny et al. · 1962AnimalThe effect of vincamine on the blood pressure of the rat — animal pharmacologyView study →Reference 25Solti et al. · 1962Clinical trialSolti, F., et al. (1962). [The effect of Devincan on the blood supply of the brain and on the coronary vessels] — clinical study. Orvosi Hetilap. https://pubmed.ncbi.nlm.nih.gov/13915068/View study →}.

The ceiling is exposure and route. Vincamine is poorly water-soluble, its methyl ester is cleaved rapidly, and elimination is fast in every species studied ^{26,27Reference 26Vereczkey · 1985ReviewPharmacokinetics and metabolism of vincamine and related compounds — reviewView study →Reference 27Hasa et al. · 2013AnimalRationale of using Vinca minor Linne dry extract phytocomplex as a vincamine’s oral bioavailability enhancer — animal modelView study →} — which is why prolonged- release formulations were developed and why a Vinca minor extract matrix out-performs the isolate sevenfold on oral bioavailability in rats ^{27,28Reference 27Hasa et al. · 2013AnimalRationale of using Vinca minor Linne dry extract phytocomplex as a vincamine’s oral bioavailability enhancer — animal modelView study →Reference 28Emara et al. · 2000In vitroIn vitro-in vivo correlation and comparative bioavailability of vincamine in prolonged-release preparations — pharmaceuticsView study →}.

Note also that the vasoactivity is the same property implicated in ventricular arrhythmia with injected drug ^{29,30Reference 29Dany et al. · 1980Case reportDany, F., et al. (1980). [Severe ventricular arrhythmia following parenteral administration of vincamine: predisposing factors in 6 cases] — case series. Archives des Maladies du Cœur et des Vaisseaux. https://pubmed.ncbi.nlm.nih.gov/6779745/View study →Reference 30Dany et al. · 1981Case reportDany, F., et al. (1981). [Cardiac toxicity of vincamine: seven cases of ventricular arrhythmias by parenteral administration] — case reports. Thérapie. https://pubmed.ncbi.nlm.nih.gov/7233373/View study →}.

Reported from lesser-periwinkle (principal source), periwinkle (minor, variable).

Cycleanine is a potent, vascular-selective calcium antagonist: it inhibited KCl-induced contraction of rabbit aortic rings with an IC₅₀ of 0.8 nM — roughly nine-fold more potent than nifedipine in the same preparation — while barely touching noradrenaline-induced contraction, and it blocked L-type Ca²⁺ current in single rat ventricular myocytes voltage- and frequency-dependently (ventricular contraction was depressed far more weakly, IC₅₀ 3 µM) ^{8Reference 8Martínez JA et al. · 1998Calcium antagonist properties of the bisbenzylisoquinoline alkaloid cycleanineView study →}.

It also inhibits Na⁺,K⁺-ATPase non-competitively by a mechanism distinct from ouabain’s, though at ~620 µM ^{9Reference 9Satoh K et al. · 2003Inhibition of Na(+),K(+)-ATPase by the extract of Stephania cephararantha HAYATA and bisbenzylisoquinoline alkaloid cycleanine, a major constituentView study →}.

Ceiling: isolated tissue and single cells from one 1998 paper. No conscious-animal blood-pressure measurement exists for the free base — the blood-pressure literature belongs to the quaternary derivative cycleanine dimethobromide ^{10,11,12Reference 10Jin GZ et al. · 1984Controlled hypotensive effect of cycleanine dimethobromideView study →Reference 11Chen WZ et al. · 1980Chen WZ, Dong YL, Ding GS (1980). [Effects of dimethyl cycleanine bromide on cardiac hemodynamics of anesthetized dogs]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/6461170/View study →Reference 12Sun Z et al. · 1980Sun Z, Yang XY, Dai ZL, Jin GZ, Zhang ZD (1980). [Hypotensive effect of dimethyl cycleanine bromide]. Zhongguo Yao Li Xue Bao. https://pubmed.ncbi.nlm.nih.gov/6175170/View study →}, which is a different molecule. Reported from abuta.

Apovincamine is named in the Medicinal Research Reviews survey of eburnamine derivatives as one of the alkaloids — with vincamine, vinburnine, vindeburnol and vinpocetine — that “share modulatory effects on brain circulation and neuronal homeostasis” and carry antihypoxic and neuroprotective potency “to various degrees” ^{1Reference 1Vas A · 2005Eburnamine derivatives and the brainView study →}.

No receptor, channel or enzyme has been identified for apovincamine itself, and no cerebral-blood-flow measurement of it exists. Every primary study behind the class claim used an ester: ethyl apovincaminate raised cerebral blood flow in healthy volunteers on acute infusion ^{2Reference 2Lim CC et al. · 1980Clinical trialThe effect of an acute infusion of vincamine and ethyl apovincaminate on cerebral blood flow in healthy volunteersView study →}, showed a larger rise in vertebral than femoral flow in dogs (read as cerebral selectivity) ^{3Reference 3Caravaggi AM et al. · 1977Hemodynamic profile of a new cerebral vasodilator, vincamine and of one of its derivatives, apovincaminic acid ethylester (RGH-4405)View study →}, and lengthened cortical resistance time under ischemic anoxia in cats by EEG ^{4Reference 4Bíró K et al. · 1976Protective activity of ethyl apovincaminate on ischaemic anoxia of the brainView study →}.

Ceiling: the family’s own SAR work shows the side-chain ester is not a spectator — swapping ethyl for hydroxyethyl changed antioxidant and antiamnesic potency enough to pick a development candidate ^{5Reference 5Nemes A et al. · 2008Synthesis and evaluation of 2’-hydroxyethyl trans-apovincaminate derivatives as antioxidant and cognitive enhancer agentsView study →} — so the ethyl ester’s vasoactivity cannot be assumed for the methyl ester. This is a class inheritance, not a mechanism. Reported from lesser-periwinkle.

Weakest of the three and included only because “cerebral vasoactive agent” is how the drug was classified. l-Eburnamonine improved capillary circulation and raised cerebral oxygen supply in anaesthetised dogs ^{13Reference 13Linée P et al. · 1978Cerebral metabolic, hemodynamic and antihypoxic properties of l-eburnamonineView study →}, and in head-injury patients it lowered blood pressure less than papaverine while improving motor disorders, retrograde amnesia and vertigo ^{14Reference 14Facciolla D et al. · 1983Clinical trialClinical and electrophysiologic changes produced by (-)eburnamonine in acute and post-acute stages of head injuries — clinical trialView study →}.

No receptor, channel or second-messenger target has ever been identified for a vasodilator action of this molecule — unlike vinpocetine, whose PDE1 inhibition and sodium-channel block are characterized.

The honest position is that vasoactivity is an inference from the drug class, and much of what looks vasodilatory here is better explained by the 2,3-DPG/P50 oxygen-unloading mechanism above.

Treat as unresolved rather than supported.

Reported from lesser-periwinkle.

Dopamine is a dose-dependent, direct agonist across three receptor families: peripheral D1-like receptors in kidney and vasculature at low concentrations (vasodilation), β₁-adrenergic inotropy at intermediate, α₁-adrenergic vasoconstriction at high ^{15Reference 15Missale C et al. · 1998Dopamine receptors: from structure to functionView study →}.

This is textbook-grade receptor pharmacology with a large human evidence base — but entirely by continuous intravenous infusion: in SOAP II (n = 1,679) first-line dopamine gave no mortality advantage over noradrenaline and significantly more arrhythmic events ^{16Reference 16De Backer D et al. · 2010Comparison of dopamine and norepinephrine in the treatment of shock (SOAP II)View study →}.

The limit is decisive: the effect requires parenteral delivery precisely because oral dopamine is destroyed pre-systemically; the industry’s response was to synthesize ester prodrugs (ibopamine) to obtain oral activity dopamine itself lacks ^{17Reference 17Casagrande C et al. · 1986Synthesis and chemical properties of ibopamine and of related esters of N-substituted dopamines — synthesis of ibopamine metabolitesView study →}.

Correct mechanism, unreachable by mouth.

Reported from broom.

A Dioscorea deltoidea cell-culture furostanol-glycoside preparation (protodioscin + deltoside) at 1 mg/kg prevented hypertension after ovariectomy, cut the endothelial-dysfunction coefficient 1.75-fold, and raised eNOS mRNA 34.8% and NOx 45.6% in rats ^{18Reference 18Korokin M et al. · 2019AnimalStudies to elucidate the effects of furostanol glycosides from Dioscorea deltoidea cell culture in a rat model of endothelial dysfunction — [animal model]View study →}.

That is a genuine endothelial mechanism and it is the same pathway underlying the proerectile effect.

It stays minor because the tested article was a two-glycoside preparation, not protodioscin, and no isolate vasorelaxation study exists — indeed the one direct tissue-bath test of protodioscin found no relaxant activity at all ^{19Reference 19Adaikan PG et al. · 2000AnimalProerectile pharmacological effects of Tribulus terrestris extract on the rabbit corpus cavernosum — [animal model]View study →}.

Reported from tribulus, wild-yam.