Role of nitric oxide in angiotensin IV-induced increases in cerebral blood flow
Introduction
An ischemic insult to the brain can lead to significant cell losses especially in the CA1 field of the hippocampus 1, 2, 3, 4. Within this field pyramidal neurons are lost in proportion to the severity of the ischemia, thus compromising this structure's ability to mediate learning acquisition and memory processing 5, 6, 7, 8, 9, 10. The CA1 field is also targeted during the progression of Alzheimer's disease (AD) with concomitant cognitive impairment 11, 12. These AD-associated cell losses have been attributed to insufficient microcirculation [13]. Thus, an understanding of the mechanisms regulating cerebral blood flow (CBF) may be relevant to these cognitive dysfunctions [3].
Earlier reports have suggested that the octapeptide, angiotensin II (AngII), may play a role in CBF regulation 14, 15, 16. Recent evidence supports the notion that an AngII degradative product, the hexapeptide angiotensin IV (AngIV), may also serve a critical function in the control of CBF 17, 18. Along these lines Näveri et al. [19]reported that intravenous infusions of AngIV in rats reversed the reduction in CBF resulting from experimentally-induced subarachnoid hemorrhage (SAH) by increasing CBF 45–80% above baseline over a 60-min period. Pretreatment with a non-selective AT1 and AT2 receptor antagonist, Sar1, Ile8 AngII (Sarile), failed to block this AngIV-induced vasodilation response, suggesting that AngIV-induced elevations in blood flow are mediated by a receptor subtype other than AT1 and AT2.
Our laboratory has discovered what may be a novel angiotensin receptor subtype, classified AT4 [20], that displays high affinity for AngIV 21, 22, however, the molecular structure of this receptor has not been determined. The initial discovery was made in bovine adrenal tissue but has since been extended to include other tissues such as cultured endothelial and smooth muscle cells 22, 23, 24. Therefore, it is possible that this receptor subtype is responsible for mediating the AngIV-induced increases in CBF reported by Näveri et al. [19]. The development and availability of Losartan (Dup 753), a specific AT1 receptor subtype antagonist [25], and a newly synthesized specific AT4 receptor subtype antagonist, Divalinal-AngIV [26], now makes it possible to differentiate the roles of AngII and AngIV. We have utilized laser-Doppler flowmetry to demonstrate that intra-arterial infusions of AngII reduced CBF by 23%, whereas, infusions of AngIV increased CBF in a dose-dependent fashion [27]. Further, these AngII-induced reductions in CBF could be inhibited by pre-treatment with Losartan, while pre-treatment with Divalinal-AngIV completely abolished the AngIV-induced vasodilation response. There were no receptor antagonist cross-over effects suggesting that AngII acts at the AT1 receptor to reduce CBF, while AngIV binds at the AT4 subtype to increase CBF.
As mentioned above, vascular endothelial cells possess AT4 receptors [24]. It has also been shown that a vascular endothelial cell nitric oxide (NO)-mediated mechanism decreased infarction volume after middle cerebral artery occlusion by increasing regional CBF in rats [30]. Taken together, we speculated that AngIV-induced vasodilation may be caused by AngIV directly (or indirectly) activating the synthesis and release of NO in vascular endothelial cells. Results from a recent study by Patel and Block [31]support this notion in that AngIV enhanced the catalytic activity of endothelial cell NO synthase (ecNOS) and the production of cGMP in porcine pulmonary artery endothelial cells (PAEC). These investigators predicted that Divalinal-AngIV would block ecNOS activation, and consequently NO production in PAEC (J.M. Patel, personal communication).
Given the recent findings on the effects of AngIV on cerebral circulation 19, 22it appears that AngIV participates in the regulation of CBF in the microvasculature. However, native AngIV possesses a short metabolic half-life (Harding, personal communication; [28]), consequently, there is a need to develop AngIV analogs that are resistant to systemic metabolic breakdown and display high-affinity binding at the AT4 receptor. Our laboratory has investigated the structure-binding characteristics of AngIV with the AT4 receptor [29], and we have recently synthesized several AngIV analogs. Thus, the purpose of the present study was to investigate the effects of AngIV and three AngIV analogs, Lysine1-AngIV (Lys1-AngIV), Norleucine1-AngIV (Nle1-AngIV) and Norleucinal on CBF regulation, and to evaluate the hypothesis that these compounds may stimulate the release of NO in cerebral circulation. We predicted that intra-arterial infusions of Lys1-AngIV, Nle1-AngIV and Norleucinal would increase CBF without influencing systemic blood pressure, and that an NO synthase inhibitor, Nw-nitro-l-arginine methyl ester (l-NAME), would block these AngIV- and AngIV analog-induced responses in the cerebral microvasculature.
Section snippets
Animals and maintenance
Female Sprague–Dawley rats (Taconic Farms, Germantown, NY, derived), weighing 250–350 g, were bred and housed in group cages in an American Association for Accreditation of Laboratory Animal Care-approved vivarium under a 12:12 h light/dark cycle initiated at 07:00 h at 22±1°C with free access to Purina laboratory chow and water.
Surgery and instrumentation
Each animal utilized in experiments 1 and 2 was initially pretreated with an intramuscular injection of diazepam (2.5 mg/kg, Parke Davis, St. Louis, MO) 10 min prior to
Experiment 1: AngIV analog-induced pressor and CBF effects
The maximum changes in systemic blood pressure during the infusion of AngIV and AngIV analogs in experiment 1 are listed for groups 1–5 in Table 2. The groups used to test for the effects of AngIV, and AngIV analogs, on systemic blood pressure and CBF did not differ regarding baseline blood pressure (overall mean±S.E.M.=110.0±1.3 mmHg; F=1.12, df 4/35, P>0.10). The maximum change in MAP during the pretreatment and treatment period was also shown to have no groups effect (F=1.17, df 5/36, P
Discussion
The recent discovery of an AT4 receptor subtype that binds AngIV has generated several investigations concerning its roles within the brain-renin angiotensin system. Initial studies revealed that this AT4 receptor is localized in species ranging from arthropods to mammals, and in a wide range of tissue beds including heart, lung, brain, bladder, spleen, thymus, adrenals, kidney, gut, spinal cord, pituitary and vascular endothelial and smooth muscle cells 23, 24, 33, 34. It appears that the AT4
Acknowledgements
We wish to extend our thanks to Bryan Slinker for statistical consultation. This investigation was supported by funds provided by Washington State University, Hedral Therapeutics, and The Laing Endowment for research on Alzheimer's Disease.
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