Intranasal angiotensin II directly influences central nervous regulation of blood pressure

Derad, Inge; Willeke, Karen; Pietrowsky, Reinhard; Born, Jan; Fehm, Horst L.

doi:10.1016/s0895-7061(98)00095-8

Cited by 36 publications

(18 citation statements)

References 26 publications

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“…The results indicated that a direct pathway from nose to brain existed. Derad et al (1998) evaluated the effect of angiotensin II on the central nervous functions of cardiovascular control after nasal and intravenous administration in 12 volunteers in a balanced cross-over design study. For intravenous and nasal administration of angiotensin II similar plasma levels were seen and both methods of administration resulted in comparable acute raises in blood pressure.…”

Section: Human Studiesmentioning

confidence: 99%

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Is nose-to-brain transport of drugs in man a reality?

Illum¹

2004

Journal of Pharmacy and Pharmacology

399

262

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The blood-brain barrier that segregates the brain interstitial fluid from the circulating blood provides an efficient barrier for the diffusion of most, especially polar, drugs from the blood to receptors in the central nervous system (CNS). Hence limitations are evident in the treatment of CNS diseases, such as Parkinson's and Alzheimer's diseases, especially exploiting neuropeptides and similar polar and large molecular weight drugs. In recent years interest has been expressed in the use of the nasal route for delivery of drugs to the brain, exploiting the olfactory pathway. A wealth of studies has reported proof of nose-to-brain delivery of a range of different drugs in animal models, such as the rat. Studies in man have mostly compared the pharmacological effects (e.g. brain functions) of nasally applied drugs with parenterally applied drugs and have shown a distinct indication of direct nose-to-brain transport. Recent studies in volunteers involving cerebrospinal fluid sampling, blood sampling and pharmacokinetic analysis after nasal, and in some instances parenteral administration of different drugs, have in my opinion confirmed the likely existence of a direct pathway from nose to brain.

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Section: Human Studiesmentioning

confidence: 99%

“…); Adrenocorticotropin 4±10 (nˆ54) (Derad et al 1998); Insulin (nˆ12) ; Diazepam ((nˆ8) ? (Lindhardt et al 2001).…”

Section: Ratunclassified

Is nose-to-brain transport of drugs in man a reality?

Illum¹

2004

Journal of Pharmacy and Pharmacology

399

262

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“…28,32 In addition, the interaction between the renin-angiotensin system and the sympathetic nervous system might be mediated through central AT 1 receptors in the brain. [33][34][35] (4) Facilitation of norepinephrine release by presynaptic AT 1 -receptor activation might be counteracted by presynaptic AT 1 receptors, which can inhibit norepinephrine release and are downregulated in cardiomyocytes of patients with chronic heart failure. 22,23,36 …”

Section: Intracoronary Angiotensin II Infusion and Norepinephrine Relmentioning

confidence: 99%

Exogenous Angiotensin II Does Not Facilitate Norepinephrine Release in the Heart

et al. 2002

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Abstract-Studies on the effect of angiotensin II on norepinephrine release from sympathetic nerve terminals through stimulation of presynaptic angiotensin II type 1 receptors are equivocal. Furthermore, evidence that angiotensin II activates the cardiac sympathetic nervous system in vivo is scarce or indirect. In the intact porcine heart, we investigated whether angiotensin II increases norepinephrine concentrations in the myocardial interstitial fluid (NE MIF ) under basal conditions and during sympathetic activation and whether it enhances exocytotic and nonexocytotic ischemia-induced norepinephrine release. In 27 anesthetized pigs, NE MIF was measured in the left ventricular myocardium using the microdialysis technique. Key Words: norepinephrine Ⅲ angiotensin II Ⅲ renin-angiotensin system Ⅲ sympathetic nervous system A ctivation of the sympathetic nervous system simultaneously leads to activation of the renin-angiotensin system via stimulation of ␤-adrenergic receptors within the kidney, resulting in an increased renin release. There is also evidence, albeit conflicting, that the sympathetic nervous system is activated by the renin-angiotensin system. 1-13 This activation supposedly occurs through stimulation of angiotensin II receptors within the central nervous system and/or stimulation of presynaptic angiotensin II receptors located at sympathetic nerve terminals. When investigating the sympathetic nervous system and its interaction with the renin-angiotensin system, the heart is of particular interest. First of all, the mammalian heart has a dense sympathetic innervation. Second, all components of the renin-angiotensin system are present in the heart, and most angiotensin II in the heart is formed from locally synthesized angiotensin I. 14 Third, in conditions like hypertension, ischemia, and especially heart failure, the renin-angiotensin system and sympathetic nervous system are both activated, and this activation likely contributes to the deterioration of cardiac function. [15][16][17] Evidence that angiotensin II activates the cardiac sympathetic nervous system in vivo is scarce 4 or indirect. 7,18 In a recent study, Teisman et al 4 have shown with the use of the microdialysis technique that "pharmacological" (10 Ϫ6 mol/L) concentrations of locally applied angiotensin II were associated with an increase in norepinephrine concentrations in the myocardial interstitial fluid (NE MIF ) of the in vivo rat heart. In the present study, we determined whether "physiological" (10 Ϫ10 mol/L) to "pathophysiological" (10 Ϫ8 mol/L) concentrations of angiotensin II modulate NE MIF in the intact porcine heart. The pig is especially suitable as a model for studying the cardiac sympathetic nervous system because, unlike the rat, the prevailing parasympathetic control of cardiac function is very similar to that in man, which allows for a more reliable extrapolation of the experimental results to the reality of human patients.To exclude a masking effect of neuronal norepinephrine reuptake and negative feedback through pr...

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“…The dosing of ANGII was adopted from a previous study of ours establishing dose-response curves for the effects of ANGII on blood pressure and for blood ANGII concentrations, which revealed that the intranasal administration of 400 μg ANGII and the intravenous infusion of 2.5 μg ANGII led to equivalent blood ANGII concentrations. 30 Before each test session, the AT1 receptor blocker valsartan (80 mg) was administered orally twice (12 and 6 hours before the intranasal substance), and blood pressure was controlled by oscillometric measurements at the upper arm to adjust and control continuous blood pressure recording via the 2-finger Portapress system (model 2 with a height correction system, TNO Institute of Applied Physics). Measurements switched automatically from one finger to the other after 30-minute periods.…”

Section: Design and Proceduresmentioning

confidence: 99%

“…In a previous study, we found that the intranasal administration of ANGII in humans induced the release of vasopressin, whereas the prolonged neurogenic blood pressure increase was blocked. 30 Those findings led us to suspect that within the brain, ANGII might act to decrease blood pressure, although such an effect was masked in that study because of ANGII that, after intranasal administration, spilled over into the bloodstream to activate angiotensin receptors in the circumventricular organs. With this knowledge, the present study aimed to investigate whether intranasal ANGII reduces blood pressure in healthy humans, whereas any afferent angiotensinergic effects via the blood were selectively blocked by the AT1 receptor blocker valsartan.…”

mentioning

confidence: 95%

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

et al. 2014

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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...

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Intranasal angiotensin II directly influences central nervous regulation of blood pressure

Cited by 36 publications

References 26 publications

Is nose-to-brain transport of drugs in man a reality?

Is nose-to-brain transport of drugs in man a reality?

Exogenous Angiotensin II Does Not Facilitate Norepinephrine Release in the Heart

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

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