Jahshan S, Dayan L, Jacob G. Nitric oxide-sensitive guanylyl cyclase signaling affects CO2-dependent but not pressure-dependent regulation of cerebral blood flow. Cerebrovascular CO2 reactivity is affected by nitric oxide (NO). We tested the hypothesis that sildenafil selectively potentiates NO-cGMP signaling, which affects CO2 reactivity. Fourteen healthy males (34 Ϯ 2 yr) were enrolled in the study. Blood pressure (BP), ECG, velocity of cerebral blood flow (CBF; measured by transcranial

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... r), and end-tidal CO2 (EtCO2) were assessed at baseline (CO2~39 mmHg), during hyperventilation (CO2 24 mmHg), during hypercapnia (CO2~46 mmHg), during boluses of phenylephrine (25-200 g), and during graded head-up tilting (HUT). Measurements were repeated 1 h after 100 mg sildenafil were taken. Results showed that sildenafil did not affect resting BP, heart rate, CBF peak and mean velocities, estimated regional cerebrovascular resistance (eCVR; mean BP/mean CBF), breath/min, and EtCO2: 117 Ϯ 2/67 Ϯ 3 mmHg, 69 Ϯ 3 beats/min, 84 Ϯ 5 and 57 Ϯ 4 cm/s, 1.56 Ϯ 0.1 mmHg·cm Ϫ1 ·s Ϫ1 , 14 Ϯ 0.5 breaths/min, and 39 Ϯ 0.9 mmHg, respectively. Sildenafil increased and decreased the hypercapnia induced in CBF and eCVR, respectively. Sildenafil also attenuated the decrease in peak velocity of CBF, 25 Ϯ 2 vs. 20 Ϯ 2% (P Ͻ 0.05) and increased the eCVR, 2.5 Ϯ 0.2 vs. 2 Ϯ 0.2% (P Ͻ 0.03) during hyperventilation. Sildenafil did not affect CBF despite significant increases in the eCVRs that were elicited by phenylephrine and HUT. This investigation suggests that sildenafil, which potentiates the NO-cGMP signaling, seems to affect the cerebrovascular CO2 reactivity without affecting the static and dynamic pressure-dependent mechanisms of cerebrovascular autoregulation. autoregulation; cerebral blood flow; CO2 reactivity; PDE5 inhibitor; sildenafil