Intranasal Angiotensin II in Humans Reduces Blood Pressure When Angiotensin II Type 1 Receptors Are Blocked

Abstract

T he peptide hormone angiotensin II (ANGII) displays a wide range of regulatory actions on blood pressure. Besides its systemic effects on the blood vessels and different organ systems, local ANGII is crucially involved in the central nervous regulation of blood pressure.1-6 ANGII receptors, mainly type 1 receptors (AT1) and also type 2 receptors (AT2), are expressed in several cerebral nuclei where they mediate effects of locally produced ANGII.7-10 Inhibition of central nervous ANGII synthesis reversed hypertension in spontaneously hypertensive rats. 11The differentiation of central nervous and peripheral actions of ANGII is important for understanding blood pressure homeostasis and the development of essential hypertension in humans. Peripheral ANGII increases blood pressure but cannot surpass the blood-brain barrier, except via the circumventricular organs (area postrema, organum vasculosum laminae terminalis).12,13 These structures express a magnitude of AT1 receptors and seem to serve as an interface gating effects of circulating ANGII to brain stem and hypothalamic nuclei (ie, nucleus tractus solitarius, supraoptic nucleus, and paraventricular nuclei). Such humoral ANGII input is known to increase tonic blood pressure levels by an upward resetting of the sympathetic baroreceptor reflex activity 2,14-17 and may also activate intrinsic hypothalamic neurohypophysial fiber pathways, inducing the release of vasopressin. 3,[18][19][20] When ANGII is directly injected into the nucleus tractus solitarius, the baroreceptor reflex is suppressed via activation of AT1 receptors. After intracerebral administration, however, pressor effects of ANGII were revealed to be variable and even contradictory depending on dose and location of the injection, therefore suggesting differential effects on blood pressure regulation. 3,4,9,10,19,[21][22][23][24] The intranasal administration of small peptide molecules represents an established approach to bypass the bloodbrain barrier in humans and to achieve direct central nervous effects. [25][26][27][28][29] These studies demonstrate that peptide molecules such as ANGII directly enter the cerebrospinal fluid after their intranasal administration without previous uptake to the blood but instead via diffusion along neuronal clefts in the nasal mucosa. Importantly, because of the relatively great amounts of substance administered to achieve central nervous effects of the peptide, it cannot be prevented that, rather than directly accessing the cerebrospinal fluid compartment, some portion of the substance spills over into the circulation. Peptide that enters the circulation might then mask direct central nervous effects after intranasal peptide administration. Thus, a viable approach to unravel direct brain effects of intranasal peptide administration is to combine this treatment with a peripherally acting receptor blocker of the peptide.Abstract-Intranasal administration of angiotensin II (ANGII) affects blood pressure in a mode different from intravenously administered ANGII via a d...

The Upper Nasal Space: Option for Systemic Drug Delivery, Mucosal Vaccines and “Nose-to-Brain”

“…Kurve’s ViaNase technology is still being advanced for treating psychiatric conditions, post-stroke and cognitive impairment in multiple sclerosis, with six separate programs delivering insulin in mild cognitive impairment, five programs delivering polyclonal antibodies in neurodegenerative disease, and five other programs featured on their corporate website. Other N2B delivery projects have looked at cholecystokinin [ 91 ], erythropoietin [ 92 ], melanocortin [ 93 ], glutathione [ 94 ], perillyl alcohol [ 95 ], angiotensin II [ 96 ] and neurotrophic factors [ 97 ] all with promising preclinical, or clinical case study results but have yet to be subjected to large scale, randomized clinical trial investigation.…”