Signalling across the blood brain barrier by angiotensin II: novel implications for neurogenic hypertension.
Angiotensin II (AngII) is a major culprit in essential hypertension. Based on a genetic rodent model of hypertension, we review here evidence that AngII may signal across the blood brain barrier to affect neuronal circuits within the nucleus tractus solitarii (NTS) of the brainstem, a pivotal region regulating both the baroreceptor reflex and set point control of arterial pressure. We have termed this form of signalling as vascular-neuronal signalling. We describe that the depressant action of AngII in NTS on the baroreceptor reflex is mediated via activation of endothelial nitric oxide synthase (eNOS) releasing NO that promotes release of the inhibitory transmitter-GABA. This could shunt the incoming excitatory baroreceptor afferent traffic impinging on NTS neurones. Chronic studies recording arterial pressure in conscious unrestrained rats using radio-telemetry have revealed that eNOS in NTS plays an endogenous physiological role in the homeostatic regulation of the gain of the cardiac baroreceptor reflex. However, in the spontaneously hypertensive rat, eNOS mRNA was higher (compared to normotensive rats), and its chronic blockade in NTS restored the abnormally depressed cardiac baroreceptor reflex to levels akin to normotensive rats, improved heart rate variability and lowered arterial pressure. Hence, it seems that excessive eNOS activity in NTS of the SHR contributes to the pathological state of this animal model's cardiovascular autonomic nervous system. We speculate on why eNOS activity may be up regulated in the NTS of the SHR and propose that it is a consequence of high cerebral vascular resistance and inadequate blood perfusion of the brainstem.
Paton
Julian F R
JF
Department of Physiology & Pharmacology, Bristol Heart Institute, School of Medical Sciences, University of Bristol, Bristol, UK. Julian.F.R.Paton@Bristol.ac.uk
Wang
Sheng
S
Polson
Jaimie W
JW
Kasparov
Sergey
S
D000804:Angiotensin II / Q000378:metabolism*; D000818:Animals; D017704:Baroreflex; D001812:Blood-Brain Barrier / Q000378:metabolism*; D006801:Humans; D006973:Hypertension / Q000201:enzymology / Q000378:metabolism*; D015398:Signal Transduction; D017552:Solitary Nucleus / Q000201:enzymology / Q000378:metabolism
D000804:Angiotensin II