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.
KeywordsNitric oxide Angiotensin II Brainstem Baroreceptor reflex Intracellular calcium
The study was supported by a British Heart Foundation programme grant awarded to JFRP and SK. JWP is supported by a British Heart Foundation project grant awarded to Professor A Wolf (PICU, Bristol Royal Infirmary, University of Bristol) and JFRP.
- 6.Paton JFR, Deuchars J, Ahmad Z, Wong L-F, Murphy D, Kasparov S (2001b) Adenoviral vector demonstrates that angiotensin II-induced depression of the cardiac baroreflex is mediated by endothelial nitric oxide synthase in the nucleus tractus solitarii of the rat. J Physiol 531:445–458PubMedCrossRefGoogle Scholar
- 8.Polson JW, Dampney RA, Boscan P, Pickering AE, Paton JFR (2007) Differential baroreflex control of sympathetic drive by angiotensin II in the nucleus tractus solitarii. Am J Physiol 293:R1954–R1960Google Scholar
- 10.Campagnole-Santos MJ, Diz DI, Ferrario CM (1988) Baroreceptor reflex modulation by angiotensin II at the nucleus tractus solitarius. Hypertension 11(Suppl I):I-167–I-171Google Scholar
- 13.Tan PS, Killinger S, Horiuchi J, Dampney RAL (2007) Baroreceptor reflex modulation by circulating angiotensin II is mediated by AT1 receptors in the nucleus tractus solitarius. Am J Physiol 293:R2267–78Google Scholar
- 26.Blackshaw S, Eliasson MJ, Sawa A, Watkins CC, Krug D, Gupta A, Arai T, Ferrante RJ, Snyder SH (2003) Species, strain and developmental variations in hippocampal neuronal and endothelial nitric oxide synthase clarify discrepancies in nitric oxide-dependent synaptic plasticity. Neurosci 119:979–990CrossRefGoogle Scholar
- 29.Wang S, Teschemacher AG, Paton JFR, Kasparov S (2006) The mechanism of nitric oxide action on inhibitory GABAergic signaling within the nucleus tractus solitarii. FASEB J 20:E821–E831Google Scholar
- 33.Bendall JK, Alp NJ, Warrick N, Cai S, Adlam D, Rockett K, Yokoyama M, Kawashima S, Channon KM (2005) Stoichiometric relationships between endothelial tetrahydrobiopterin, endothelial NO synthase (eNOS) activity, and eNOS coupling in vivo: insights from transgenic mice with endothelial-targeted GTP cyclohydrolase 1 and eNOS overexpression. Circ Res 97:864–871PubMedCrossRefGoogle Scholar
- 37.Cushing H (1901) Concerning a definitive regulatory mechanism of the vaso-motor centre which controls blood pressure during cerebral compression. Bull Johns Hopk Hosp 12:290–292Google Scholar
- 39.Dickinson CJ (1991) Neurogenic hypertension: A synthesis and review. Monograph. Chapman & Hall Medical p123Google Scholar