Unravelling mechanisms of action of angiotensin II on cardiorespiratory function using in vivo gene transfer.
We review recent and ongoing work from our laboratory that has shed novel insights into the effects of angiotensin II (ANGII) on the baroreflex at the level of the nucleus of the solitary tract (NTS). The NTS is the site of termination for baroreceptor afferents and is a potentially powerful region for neuronal modulation. ANGII applied to this nucleus attenuated the cardiac vagal and cardiac sympathetic components of the baroreceptor reflex. This effect was antagonized by blockade of either gamma-amino butyric acid receptors or nitric oxide synthase within the NTS. Interestingly, nitric oxide donors microinjected into the NTS mimicked the effect of ANGII. Using an adenovirus we showed that ANGII activated the endothelial isoform of nitric oxide synthase. The NTS was transfected to express a dominant negative truncated mutant form of endothelial nitric oxide synthase that prevented the depressant effect of ANGII on the baroreflex. Endothelial nitric oxide synthase was present in both neurones and endothelium in the NTS. A possibility is that ANGII activation of endothelial nitric oxide synthase is calcium dependent. However, in most NTS neurones tested, ANGII failed to elevate intracellular calcium concentration. We conclude that ANGII activates endothelial nitric oxide synthase to release nitric oxide which enhances gamma-amino butyric acid transmission destined for circuitry mediating the baroreflex. We discuss the contribution of endothelial cells within the nucleus of the solitary tract as a potential target for both circulating and/or centrally produced ANGII. These data have relevance to patients with essential hypertension and left heart failure, conditions in which ANGII activity is elevated and the baroreceptor reflex is depressed.
Paton
J F
JF
Department of Physiology, School of Medical Sciences, University of Bristol, Bristol, UK.
Boscan
P
P
Murphy
D
D
Kasparov
S
S
D000256:Adenoviridae / Q000235:genetics; D000804:Angiotensin II / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D017704:Baroreflex / Q000502:physiology*; D018014:Gene Transfer Techniques; D019001:Nitric Oxide Synthase / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III; D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin / Q000378:metabolism; D017552:Solitary Nucleus / Q000502:physiology*
D044140:Receptor, Angiotensin, Type 1; D011945:Receptors, Angiotensin; D000804:Angiotensin II; D019001:Nitric Oxide Synthase; D052250:Nitric Oxide Synthase Type III