Delayed Cerebroventricular Metabolism of [¹²⁵I]Angiotensins in the Spontaneously Hypertensive Rat

Abstract

This study was designed to evaluate the hypothesis that impaired brain angiotensin signal termination contributes to the sustained blood pressure elevations noted in the genetically hypertensive rat model of human essential hypertension. A technique that combined the intracerebroventricular injection of [125I]angiotensins, followed by focused microwave fixation to stop all peptidase activity and subsequent HPLC analyses, was used for determining half-lives of [125I]angiotensin II and [125I]angiotensin III in the ventricular space. The results indicate that the spontaneously hypertensive rat evidenced significantly longer half-lives for intracerebroventricularly injected [125I]angiotensin II over those measured for the Wistar-Kyoto and Sprague-Dawley normotensive rat strains: 45.0, 27.2, and 25.0 s, respectively. This was also true for intracerebroventricularly administered [125I]angiotensin III: 19.5, 11.4, and 9.0 s, respectively. These results support the notion that a dysfunction in central aminopeptidase activity in the spontaneously hypertensive rat may result in prolonged half-lives of endogenously synthesized angiotensins II and III, which are known to serve as ligands at central angiotensin receptors responsible for the control of cardiovascular function. The extended half-lives of these ligands may contribute to the sustained elevations in blood pressure observed in this animal model.

Metabolism of Angiotensin Peptides by Neuronal and Glial Cultures from Rat Brain

“…The longer half-life of [Ile'l-Ang I1 in neuron-enriched cells from SHR is in good agreement with findings of delayed cerebroventricular metabolism of "'I-labeled Ang I1 in SHR (Harding et al, 1986;Wright et al, 1987). In contrast to these studies, we could not confirm the very short half-lives (<1 min in our preparation) of intracerebroventricularly administered 251-labeled Ang I1 and I11 (Harding et al, 1986;Wright et al, 1987). Differences in the experimental protocols, such as the use of intact animals, 12'I-labeled peptides, and substrate enzyme ratios influencing the kinetics, may be critical in this regard.…”

“…This finding is in contrast to previous work reporting a faster turnover of Ang I1 in SHR after central CE inhibition (Ganten et al, 1983). The longer half-life of [Ile'l-Ang I1 in neuron-enriched cells from SHR is in good agreement with findings of delayed cerebroventricular metabolism of "'I-labeled Ang I1 in SHR (Harding et al, 1986;Wright et al, 1987). In contrast to these studies, we could not confirm the very short half-lives (<1 min in our preparation) of intracerebroventricularly administered 251-labeled Ang I1 and I11 (Harding et al, 1986;Wright et al, 1987).…”

Physiological Role of Brain Angiotensin III in Drinking Behavior in the Rat

“…Considerable evidence suggests that dysfunction of the central renin-angiotensin system, in particular the degradation of angiotensin [45,46], contributes to the observed increase in arterial pressure [12,40,47], foodrelated drinking [20], drinking response to i.c.v. adminis tered AIII [40,47] and salt appetite [11,28] in this strain.…”

“…This hypothesis was evaluated in the present study, utilizing a treatment schedule we designed previously [3,6,7,22,23] for the evaluation of endogenous neuropep tide activity. We also delineated whether differential responses existed in the spontaneously hypertensive (SH) and its normotensive control rats, since a dysfunction of central aminopeptidase activity, leading to an impair ment of the termination of angiotensin signals, has been suggested to contribute to the blood pressure abnormality of the SHRs [45][46][47]. Our results revealed that the endog enous brain AIII may not be tonically involved in fluid homeostasis.…”

Focus on Brain Angiotensin III and Aminopeptidase A in the Control of Hypertension

“…We suspected a disruption in brain aminopeptidase activity in the SHR [87, 88]. To test this hypothesis replacement Glu-AP was i.c.v.-infused in order to promote the hydrolysis of AngII to AngIII.…”