Existence of Quantum Pharmacology in Sartans: Evidence in Isolated Rabbit Iliac Arteries

International Journal of Molecular Sciences · 9 authors, 7 centres

AI SUMMARY

FIDELITY 92%

POPULATIONMale New Zealand White rabbits (iliac artery rings and conscious rabbits)

INTERVENTIONUltra-high dilutions of ARBs (candesartan, telmisartan, ACC519T, ACC519T(2), BV6(K^+)2) and nirmatrelvir

COMPARISONControl (no drug) or vehicle

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TL;DR

This study demonstrates that both commercially available and novel angiotensin II receptor blockers (ARBs) can inhibit vasoconstriction in isolated rabbit iliac arteries at ultra-high dilutions (as low as 10^-60 M), providing experimental evidence for quantum pharmacology. The novel ARB ACC519T lowered mean arterial pressure in conscious rabbits in a dose-dependent manner, while BV6(K^+)2 increased ACE2 activity at 10^-6 M. These findings suggest that quantum effects may contribute to the placebo effect observed in hypertension trials and indicate the therapeutic potential of these novel ARBs.

Full summary

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**Background:** The placebo effect in hypertension trials suggests that inert substances can produce biological effects, possibly through quantum mechanical phenomena. Ultra-high dilutions (beyond Avogadro's constant) have been reported to induce physiological effects, but the mechanism remains controversial. This study investigates whether angiotensin II receptor blockers (ARBs) can modulate vascular contraction at extremely low concentrations, providing evidence for quantum pharmacology. The authors also evaluate novel bisartans (ACC519T, ACC519T(2), BV6(K^+)2) as potential antihypertensive agents.

**Methods:** Iliac artery rings from male New Zealand White rabbits (n=10, two batches) were mounted in organ baths and pre-incubated with ARBs (candesartan, telmisartan, ACC519T, ACC519T(2), BV6(K^+)2) or nirmatrelvir at concentrations from 10^-5 M to 10^-60 M for 10 minutes. Dose-response curves to angiotensin II (AngII, 10^-11 M to 10^-5 M), phenylephrine (PE, 10^-9 M to 10^-5 M), and angiotensin A (AngA, 10^-11 M to 10^-5 M) were then performed. In separate experiments, conscious rabbits received intravenous ACC519T or telmisartan (10^-14 M to 10^-10 M) and mean arterial pressure (MAP) was measured via auricular artery catheterization. ACE2 activity was assessed by incubating BV6(K^+)2 (10^-6 M, 10^-24 M, 10^-60 M) with recombinant human ACE2 and measuring AngII metabolism to Ang(1-7) by HPLC.

**Key Results:** - ACC519T reduced MAP in a dose-dependent manner from 114.27 ± 2.20 mmHg to 96.33 ± 1.30 mmHg at the final dose; one rabbit required euthanasia after 10^-12 M due to severe hypotension (MAP 30.60 mmHg). Telmisartan did not significantly alter MAP (95.70 ± 3.53 to 95.90 ± 2.06 mmHg). - All ARBs inhibited AngII-mediated contraction at all tested doses (10^-6 M to 10^-60 M) with p < 0.0001. Nirmatrelvir had no effect. - ACC519T enhanced PE-induced contraction at 10^-6 M (p < 0.0001) and 10^-40 M (p < 0.0001), while ACC519T(2), low-dose BV6(K^+)2, candesartan, and telmisartan reduced PE contraction at various doses. - ACC519T, ACC519T(2), and BV6(K^+)2 inhibited AngA-mediated contraction at all doses (10^-6 M to 10^-60 M, p < 0.0001). - BV6(K^+)2 at 10^-6 M significantly increased ACE2 metabolism of AngII into Ang(1-7) (p < 0.001), but ultra-low concentrations (10^-24 M, 10^-60 M) had no effect.

**Clinical Implications:** This study provides experimental evidence that ARBs can exert biological effects at concentrations far below those predicted by classical pharmacology, supporting the concept of quantum pharmacology. The ability of ACC519T to lower MAP in conscious rabbits at extremely low doses (as low as 10^-14 M) suggests that current dosing regimens for ARBs may be unnecessarily high, potentially reducing side effects. The differential effects on PE contraction indicate complex receptor interactions, possibly involving biased agonism or compensatory mechanisms between AT1R and α1-adrenergic receptors. The lack of effect of nirmatrelvir on vascular contraction highlights the need for cardiovascular-protective agents in COVID-19 patients. These findings challenge traditional pharmacological assumptions and warrant further investigation into quantum effects in drug-receptor interactions.

PICO

PPOPULATION

Male New Zealand White rabbits (iliac artery rings and conscious rabbits)

IINTERVENTION

Ultra-high dilutions of ARBs (candesartan, telmisartan, ACC519T, ACC519T(2), BV6(K^+)2) and nirmatrelvir

OOUTCOME

Vascular contraction responses to angiotensin II, phenylephrine, and angiotensin A; mean arterial pressure; ACE2 activity

STUDY TYPE

other

SPECIALTY

ophthalmology

SUMMARISED BY

AI pipeline

FIDELITY CHECK

92% · A

ORIGINAL PAPER

PMC10744031

Existence of Quantum Pharmacology in Sartans: Evidence in Isolated Rabbit Iliac Arteries

International Journal of Molecular Sciences

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ABSTRACT

Quantum pharmacology introduces theoretical models to describe the possibility of ultra-high dilutions to produce biological effects, which may help to explain the placebo effect observed in hypertensive clinical trials. To determine this within physiology and to evaluate novel ARBs, we tested the ability of known angiotensin II receptor blockers (ARBs) (candesartan and telmisartan) used to treat hypertension and other cardiovascular diseases, as well as novel ARBs (benzimidazole- N -biphenyl tetrazole (ACC519T), benzimidazole- bis - N , N ′-biphenyl tetrazole (ACC519T(2)) and 4-butyl-N,N0-bis[[20-2Htetrazol-5-yl)biphenyl-4-yl]methyl)imidazolium bromide (BV6(K + ) 2 ), and nirmatrelvir (the active ingredient in Paxlovid) to modulate vascular contraction in iliac rings from healthy male New Zealand White rabbits in responses to various vasopressors (angiotensin A, angiotensin II and phenylephrine). Additionally, the hemodynamic effect of ACC519T and telmisartan on mean arterial pressure in conscious rabbits was determined, while the ex vivo ability of BV6(K + ) 2 to activate angiotensin-converting enzyme-2 (ACE2) was also investigated. We show that commercially available and novel ARBs can modulate contraction responses at ultra-high dilutions to different vasopressors. ACC519T produced a dose-dependent reduction in rabbit mean arterial pressure while BV6(K + ) 2 significantly increased ACE2 metabolism. The ability of ARBs to inhibit contraction responses even at ultra-low concentrations provides evidence of the existence of quantum pharmacology. Furthermore, the ability of ACC519T and BV6(K + ) 2 to modulate blood pressure and ACE2 activity, respectively, indicates their therapeutic potential against hypertension.

CITATION EXPORT

Laura Kate Gadanec, Jordan Swiderski, Vasso Apostolopoulos et al.. Existence of Quantum Pharmacology in Sartans: Evidence in Isolated Rabbit Iliac Arteries. International Journal of Molecular Sciences. (2023). https://doi.org/10.3390/ijms242417559

AUTHORS

9 · 7 CENTRES

Laura Kate Gadanec, Jordan Swiderski, Vasso Apostolopoulos, Kostantinos Kelaidonis, Veroniki P. Vidali, Aleksander Canko, Graham J. Moore, John M. Matsoukas, Anthony Zulli

1Institute for Health and Sport, Victoria University, Melbourne, VIC 3030, Australia; [email protected] (L.K.G.); [email protected] (J.S.); [email protected] (V.A.)
2Immunology Program, Australian Institute for Musculoskeletal Science (AIMSS), Melbourne, VIC 3021, Australia
3NewDrug PC, Patras Science Park, 26 504 Patras, Greece; [email protected]
4Institute of Nanoscience and Nanotechnology, National Centre for Scientific Research “Demokritos”, Ag. Paraskevi, 153 41 Athens, Greece; [email protected] (V.P.V.); [email protected] (A.C.)
5Pepmetics Inc., 772 Murphy Place, Victoria, BC V6Y 3H4, Canada; [email protected]
6Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB T2N 4N1, Canada
7Department of Chemistry, University of Patras, 265 04 Patras, Greece

EDITOR / REVIEWER

Peter Illes