Influence of captopril treatment on angiotensin II receptors and angiotensinogen in the brain of spontaneously hypertensive rats.

Abstract

SUMMARY The brain renin-angiotensin system (RAS) has been suggested as contributing to the pathogenesis of spontaneous hypertension in rats. Brain angiotensinogen-and angiotensin II (AII)-sensitive neurons were therefore investigated in stroke-prone spontaneously hypertensive rats (SHRsp) and in Wistar-Kyoto (WKY) rats with and without treatment by captopril (CAP). Angiotensinogen was decreased in the anterior hypothalamus but increased in the cortex, the hippocampus, and cerebellum of SHR-sp. There were no differences between SHR-sp and WKY rats concerning the angiotensinogen content of posterior hypothalamus, brain stem, and septum. The sensitivity of the septal neurons to microiontophoretically applied AH was elevated, however, in SHR-sp as compared to WKY rats with regard to threshold and maximal response for All-evoked neuronal discharges. The excitation characteristics did not change with the age of animals in both WKY rats and SHR-sp. The treatment of SHR-sp with CAP (50 mg/kg/day per os) starting in weanlings kept animals normotensive and reduced the high sensitivity of septal neurons to AH. Simultaneously angiotensinogen content was increased in the anterior hypothalamus and suppressed in the hippocampus. The same treatment of WKY rats reduced blood pressure somewhat and increased the angiotensinogen content in the anterior hypothalamus without affecting the neuronal sensitivity to AH. Thus, malfunction of the brain RAS may participate in the hypertension of SHR-sp, since converting enzyme blockade with CAP inhibited the blood pressure rise, augmented the angiotensinogen content of the anterior hypothalamus, and decreased the sensitivity of AH receptors in the brains of these rats. (Hypertension 5: 935-942, 1983) KEY WORDS • brain renin angiotensin system • chronic captopril treatment • microiontophoresis • septal area • stroke-prone spontaneously hypertensive rats • Wistar-Kyoto rats T HE spontaneously hypertensive rat (SHR) 1 has been used as a model for human essential hypertension, and several hypotheses have been formulated about the pathogenesis of the high blood pressure in these rats. Recently, Ganten and colleagues 2 have applied the term "peptidergic stimulation syndrome" to the observation that rats of the stroke-prone substrain of SHR (SHR-sp) 3 demonstrate an exaggerated response, e.g., of blood pressure, to several peptide hormones after their intracerebral application. Much interest was addressed to the brain renin-angiotensin system (RAS) in this respect, since all components needed for a functional system, includ-

Brain angiotensin II and baroreceptor reflex function in spontaneously hypertensive rats.

“…These findings are in agreement with our previous observations, 22 which also showed that lifetime-captopril-treated SHR had decreased brain Ang II binding, suggesting a depressed angiotensinergic system in the brain. Our results are also consistent with those of Schelling and Felix, 32 who showed a decrease in the sensitivity of Ang II receptors to iontophoretically applied Ang II in septal neurons of SHRSP with lifetime captopril treatment. 32 In summary, lifetime oral captopril treatment prevented the development of hypertension in spontaneously hypertensive rats.…”

“…In addition, the observation that the drinking response to Ang II was also depressed suggested that decreased responsiveness may be related to a reduction in Ang II receptors in the brain. This was our finding in Ang II binding studies in the hypothalamus of captopril-treated SHR as compared with control rats and is consistent with findings of Schelling and Felix, 32 who reported that captopril treatment decreased Ang II receptor sensitivity to iontophoretically applied Ang II. In contrast to the central effects, peripheral responsiveness to Ang II and receptor binding kinetics of the peptide were significantly enhanced as a result of lifetime captopril treatment.…”

“…Using high-performance liquid chromatography-controlled radioimmunoassay for angiotensin peptides in tissues, these same investigators were able to demonstrate a reduction in tissue Ang II concentration in brain after oral administration of converting enzyme inhibitors. 31 Studies of Schelling and Felix 32 showed that, when SHRSP were treated daily with captopril (given orally) during their lifespan beginning with treatment of pregnant females, blood pressure remained at normotensive levels, and the Ang II-evoked neuronal responses in the septum were similar to Ang II-related neuronal sensitivity found in WKY rats. This is in contrast to higher sensitivity to Ang II in neurons from untreated SHRSP as compared with WKY rats.…”

Long-term captopril treatment. Angiotensin II receptors and responses.

“…However, the observations that the drinking responses to Ang II were also depressed suggest that the decreased responsiveness may be related to the reduction of Ang II receptors in the brain. The results are consistent with those of Schelling and Felix,7 who reported that lifetime captopril treatment decreased Ang II receptor sensitivity to iontophoretically applied AngLI.…”

“…2 Vasopressin and adrenocorticotropic hormone (ACTH) secretion and sympathetic tone are also enhanced. 3 - 4 Additional reports indicate that the pressor effects of centrally administered Ang II are increased in SHR, 3 6 the sensitivity to iontophoretically applied Ang II is enhanced, 7 and increases in the number of Ang II receptors are observed in areas of the brain that are integral to cardiovascular control. 8 •' The strongest evidence that brain Ang II may play a role in the pathogenesis of hypertension is that both short-term or long-term intracerebroventricular (i.c.v.)…”