Cerebral Vasodilator Property of Poly(ADP-Ribose) Polymerase Inhibitor (PJ34) in the Neonatal and Adult Mouse Is Mediated by the Nitric Oxide Pathway

Figures

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  Figure 1. Representative Doppler velocity waveforms recorded in the basilar trunk (BT) in a control (A) and a PJ34-treated (B) adult mouse. Recordings were performed under light anaesthesia (isoflurane 0.5%) limiting the movement of the animal without any cardiorespiratory depression: (1) under air; (2) 3–5 min after breathing a gas mixture (CO2 5%, O2 16%, and N2 79%) known to provoke a normoxia-hypercapnia in order to evaluate the cerebral arteriolar vasodilation mediated by the increase in metabolic demand and the NO-pathway named the cerebral vasodilation reserve; (3) under air; and (4) under air and 2–5 min after sublingual administration of a exogenous NO-donor in order to evaluate the cerebral vasodilation unmediated by the NO-pathway. (A) (Top) In the control mouse, the mean blood flow velocity (mBFV, blue line on the Doppler velocity waveform) increased under CO2 allowing the calculation of the cerebral vasodilation reserve in percentage (difference of mBFV under CO2 and air reported to mBFV under air). (Bottom) The mBFV under exogenous NO-donor decreased compared to only air condition representative of the BT dilation without any modification downstream of the arteriolar…

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  Figure 2. Vasoreactivity during development (P10 to P365) and effect of PJ34 on the maximal cerebral vasodilation in P10 (A), P90 (B) and P365 (C) mice. Data are represented as mean blood flow velocities (mBFVs) related to the maximal cerebral vasodilation under CO2 in basal (control-naive and PBS-treated) P10, P90, and P365 mice and 1 and 48 h after PJ34 administration. PJ34 induced a recruitment on the cerebral vasodilation reserve at each stage of development. At P365, the PJ34 vasodilator effect was lowered compared to P10 and P90. (* p < 0.005, ** p < 0.001 vs. basal, # p < 0.005, vs. PBS, § p < 0.005, §§ p < 0.001 PJ34 at +H1 or at +H48 between ages, NS: not significant).

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  Figure 3. NOS activity in brain tissues from neonatal and adult mice in control conditions and after PJ34 administration (at 1 and 24 h). NOS activity in pup (A) and adult (B) mice is reported in nmol/min/mg protein and data were presented as the median and 25th–75th percentiles (n = 5–7). (*** p < 0.001 vs. the control (CTL) group).

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  Figure 4. Relative changes in mean blood flow velocities (mBFVs) recorded in the basilar trunk (BT) versus basal states 1 h after PBS or specific or non-specific NOS inhibitors followed 1 h after by PJ34 injection. In P10 (A) and P90 (B) mice, L-NMMA was responsible of a decrease in mBFVs. L-NMMA as well as L-NIO abolished the increase in mBFVs consecutive to the PJ34 injection as shown in the PBS injected mice. In contrast, 7-NI did not prevent of this increase. Altogether, these finding lead to the mediation of the endothelial more than the neuronal NOS into the dynamic effects of PJ34. (* p < 0.005, ** p < 0.001 PBS + PJ34 vs. NOS inhibitors + PJ34; # p < 0.005 each NOS inhibitors + PJ34 between them, NS: not significant).

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  Figure 5. In an arterial network, the level of the hemodynamic resistance (Rh) inversely sets the value of the blood flow volume (BFVol) in the upstream conduit artery at each level of arterial blood pressure (BP) through the Poiseuille law. The level of the Rh is dependent of the inner diameter (d) of arterioles (resistive arteries). The BFVol determined, the mean blood flow velocity (mBFV) is adapted in relation to the section of the conduit artery. In pup (A) and adult (B) mice, CO2 gas mixture exposure provokes an arteriolar dilation with the consecutive upstream increase in the BFVol. Even if the conduit artery moderately dilates (5–8%, endothelial function), mBFVs increase illustrative of the downstream arteriolar dilation (20–40%, endothelial function) mediated by the metabolic command, representative of the cerebral vasoreactivity and the cerebral vasodilation reserve. In adults (B), an exogenous NO-donor provokes a dilation of the conduit artery without any modification of the level of Rh, thus of the BFVol, with a consecutive decrease in the mBFVs. In absence of metabolic modification, regulation of the microvascular tone is maintained by the sympathetic nervous system (SNS),…

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  Figure 6. Outline of the experimental procedure in C57Bl/6j mice subjected to cerebral vasoreactivity in absence and/or presence of PJ34 and in presence of NOS inhibitors.