Janus Kinase 2/Signal Transducers Of Activated Transcription (Jak/Stat) Pathway In Angiotensin Ii (Ang Ii)-Mediated Elevations In Blood Pressure : Peripheral Vs. Centrally Mediated Effects

ANG II mediates both central and peripheral effects on blood pressure. ANGII activates the JAK2/STAT signaling pathway in peripheral blood vessels and kidney cortex and is critical for ANG II-induced hypertension. AG490, a JAK2 inhibitor can theoretically cross the blood brain barrier, thus we inquired whether Ang II-mediated effects via JAK2/STAT centrally or peripherally to modulate blood pressure. In male Sprague Dawley rats radiotelemetry transmitters, or intravenous (iv) catheters were implanted for MAP and HR measures. Rats were placed on a 2% salt diet 7 days prior to ICV cannulae to administer AG490 (1nmol/L; or aCSF) or iv infusion (10ng/kg/min) and peripheral Ang II infusion (150 ng/kg/min;minipump) for 14 days. In a separate study iv catheters peripherally delivered ANG II and AG490 (10 ng/kg/min) as well as an arterial catheter to measure mean arterial pressure (MAP). Centrally AG490 had no effect on mean arterial pressure (MAP) compared to aCSF/Ang II control rats. However, peripheral AG490 significantly reduced the MAP (160 +9 mm Hg ANG II vs 121 +5 mm Hg ANG II/AG490). Western analyses confirmed no central activation of JAK2, however, there was significant activation of JAK2 in thoracic aorta and kidney cortex homogenates. In conclusion, JAK2 mediates Ang II-mediated increases in blood pressure via a peripheral not centrally mediated mechanism. Funded by: NIH R00HL087927 (CAN) and R00HL91177 (ABB).