A comparison of different regression models for the quantitative analysis of the combined effect of P2Y12 and P2Y1 receptor antagonists on ADP-induced platelet activation

Q3 · MEDICINE

Article

Author: Wzorek, Joanna ; Boncler, Magdalena ; Watala, Cezary ; Palma, Agnieszka

INTRODUCTIONThe combination index (CI), a common quantitative indicator of the degree of synergy/antagonism, may be determined using different regression methods. However, any analysis with constraints has the potential for underestimating the combined effect of multiple drugs.OBJECTIVESThis in vitro study describes the combined effects of selected platelet antagonists on ADP-induced platelet activation in different regression models.METHODSThe inhibitory effects of P2Y₁₂ receptor antagonists in combination with P2Y₁ receptor antagonists (i.e. cangrelor with MRS 2279, prasugrel metabolite with MRS 2179 and PSB 0739 with MRS 2179) were characterized with the aid of three software packages: CompuSyn (for linear regression with constraints), CISNE (for non-linear regression with constraints) and GraphPad Prism (for non-linear regression without constraints). The synergism between P2Y₁₂ and P2Y₁ inhibitors was quantified by CI and synergy area.RESULTSMRS 2279 and MRS 2179 were found to act synergistically with selected P2Y₁₂ receptor antagonists to potentiate their antiplatelet effect. The models of regression with constraints, linear regression in particular, demonstrated a worse fit for experimental data than non-linear regression without constraints; this resulted in an incorrect estimation of the combined effects of two antiplatelet drugs, i.e., underestimating the CI and overestimating the synergy area. Also, the synergy area was found to better reflect the differences among models than the CI.CONCLUSIONSThese findings suggest that non-linear regression without constraints offers more precise quantitative determination of combined effects between two drugs compared to the regression models with constraints.

01 Sep 2016·Purinergic SignallingQ3 · MEDICINE

Coupling switch of P2Y-IP3 receptors mediates differential Ca2+ signaling in human embryonic stem cells and derived cardiovascular progenitor cells

Q3 · MEDICINE

Article

Author: Zhang, Min ; Zhang, Peng ; Ouyang, Kunfu ; Liang, He ; Huang, Jijun ; Yang, Huang-Tian

Purinergic signaling mediated by P2 receptors (P2Rs) plays important roles in embryonic and stem cell development. However, how it mediates Ca(2+) signals in human embryonic stem cells (hESCs) and derived cardiovascular progenitor cells (CVPCs) remains unclear. Here, we aimed to determine the role of P2Rs in mediating Ca(2+) mobilizations of these cells. hESCs were induced to differentiate into CVPCs by our recently established methods. Gene expression of P2Rs and inositol 1,4,5-trisphosphate receptors (IP3Rs) was analyzed by quantitative/RT-PCR. IP3R3 knockdown (KD) or IP3R2 knockout (KO) hESCs were established by shRNA- or TALEN-mediated gene manipulations, respectively. Confocal imaging revealed that Ca(2+) responses in CVPCs to ATP and UTP were more sensitive and stronger than those in hESCs. Consistently, the gene expression levels of most P2YRs except P2Y1 were increased in CVPCs. Suramin or PPADS blocked ATP-induced Ca(2+) transients in hESCs but only partially inhibited those in CVPCs. Moreover, the P2Y1 receptor-specific antagonist MRS2279 abolished most ATP-induced Ca(2+) signals in hESCs but not in CVPCs. P2Y1 receptor-specific agonist MRS2365 induced Ca(2+) transients only in hESCs but not in CVPCs. Furthermore, IP3R2KO but not IP3R3KD decreased the proportion of hESCs responding to MRS2365. In contrast, both IP3R2 and IP3R3 contributed to UTP-induced Ca(2+) responses while ATP-induced Ca(2+) responses were more dependent on IP3R2 in the CVPCs. In conclusion, a predominant role of P2Y1 receptors in hESCs and a transition of P2Y-IP3R coupling in derived CVPCs are responsible for the differential Ca(2+) mobilization between these cells.

01 Dec 2014·DiabetologiaQ1 · MEDICINE

Autocrine activation of P2Y1 receptors couples Ca2+ influx to Ca2+ release in human pancreatic beta cells

Q1 · MEDICINE

Article

Author: Wu, Xichen ; Duong, Eric ; MacDonald, Patrick E. ; Yan-Do, Richard ; Cheley, Stephen ; Braun, Matthias ; Bautista, Austin ; Khan, Shara

AIMS/HYPOTHESISThere is evidence that ATP acts as an autocrine signal in beta cells but the receptors and pathways involved are incompletely understood. Here we investigate the receptor subtype(s) and mechanism(s) mediating the effects of ATP on human beta cells.METHODSWe examined the effects of purinergic agonists and antagonists on membrane potential, membrane currents, intracellular Ca(2+) ([Ca(2+)]i) and insulin secretion in human beta cells.RESULTSExtracellular application of ATP evoked small inward currents (3.4 ± 0.7 pA) accompanied by depolarisation of the membrane potential (by 14.4 ± 2.4 mV) and stimulation of electrical activity at 6 mmol/l glucose. ATP increased [Ca(2+)]i by stimulating Ca(2+) influx and evoking Ca(2+) release via InsP3-receptors in the endoplasmic reticulum (ER). ATP-evoked Ca(2+) release was sufficient to trigger exocytosis in cells voltage-clamped at -70 mV. All effects of ATP were mimicked by the P2Y(1/12/13) agonist ADP and the P2Y1 agonist MRS-2365, whereas the P2X(1/3) agonist α,β-methyleneadenosine-5-triphosphate only had a small effect. The P2Y1 antagonists MRS-2279 and MRS-2500 hyperpolarised glucose-stimulated beta cells and lowered [Ca(2+)]i in the absence of exogenously added ATP and inhibited glucose-induced insulin secretion by 35%. In voltage-clamped cells subjected to action potential-like stimulation, MRS-2279 decreased [Ca(2+)]i and exocytosis without affecting Ca(2+) influx.CONCLUSIONS/INTERPRETATIONThese data demonstrate that ATP acts as a positive autocrine signal in human beta cells by activating P2Y1 receptors, stimulating electrical activity and coupling Ca(2+) influx to Ca(2+) release from ER stores.

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