Leucine aminopeptidase M-induced reductions in blood pressure in spontaneously hypertensive rats.

Abstract

Leucine aminopeptidase M significantly reduced blood pressure for up to 40 minutes when infused intracerebroventricularly into anesthetized spontaneously hypertensive rats (SHR) from a mean±SEM of 190±4 to 94±7 mm Hg and also in normotensive Wistar-Kyoto (WKY) rats from 138±5 to 68±8 mm Hg. Cerebrospinal fluid levels of angiotensin II (Ang II) and III were measured by radioimmunoassay and indicated drops with leucine aminopeptidase M infusion in SHR (from 36±6 to 11±1 pg/100 fil) and in WKY rats (from 33±9 to 13±1 pg/100 A»1). Pretreatment with the specific angiotensin receptor antagonist [Sar',Thr 8 ]Ang II (sarthran) significantly diminished the subsequent leucine aminopeptidase M-induced decreases in blood pressure in SHR and facilitated recovery to base level blood pressure and heart rate in both strains. Thus, exogenous application of leucine aminopeptidase M into the brain lateral ventricles of SHR is temporarily effective at reducing blood pressure, and this effect appears dependent on the brain angiotensinergic system. This treatment also reduced blood pressure in WKY rats; however, pretreatment with sarthran was reasonably ineffective at preventing subsequent leucine aminopeptidase M-induced decreases in blood pressure. (Hypertension 1989;13:910-915) S pontaneously hypertensive rats (SHR) and the stroke-prone SHR (SHRSP) appear to possess a dysfunctional brain reninangiotensin system that contributes to their hypertension.1 Schelling and colleagues 2 measured elevated levels of renin in brain areas associated with catecholaminergic nuclei in SHR, and Ganten et al 3 observed greater turnover of brain angiotensin than in normotensive rats. Our laboratory has measured deficiencies in brain aminopeptidase activity in SHR, 4 which may explain their heightened sensitivity to intracerebroventricularly injected angiotensin II (Ang II) 5 and angiotensin III (Ang III). 6Electrophysiological studies also indicate a significantly increased sensitivity to microiontophoretically injected Ang II and Ang HI in the paraventricular nucleus of SHR as compared with WistarKyoto (WKY) normotensive rats. 7From the

Biochemical and enzymatic properties of the M1 family of aminopeptidases involved in the regulation of blood pressure

“…In this review, we will describe the enzymatic properties of the M1 family of aminopeptidases, which mediate the metabolism of BP regulatory peptides and may thus function as regulators of BP in physiological and/or pathological conditions. hypertensive rats (SHR) by Wright et al [4][5][6]. While the injection of APA significantly increased BP, that of APN(M) caused a decrease of BP.…”

Role of angiotensin III in hypertension

“…Consistent with these data, Wright et al [16] showed that, despite the high molecular mass of APA and APN (∼ 120-130 kDa for the monomer), the ICV infusion of APA results in a significant increase in BP, whereas the ICV injection of APN into SHR decreases BP [52]. The hypertensive effect probably results from higher levels of brain Ang III production, whereas the hypotensive effect may be related to an increase in Ang III metabolism.…”

Aminopeptidase A inhibitors as centrally acting antihypertensive agents

“…infusion of APA results in a significant increase in BP [68] whereas the i.c.v. injection of APN into SHR decreases BP [65]. The hypertensive effect probably results from higher levels of brain AngIII production, whereas the hypotensive effect may be related to an increase in AngIII metabolism.…”

“…AngII and AngIII injected separately i.c.v. into normotensive Wistar Kyoto (WKY) rats or SHR, cause similar dose-dependent pressor responses [52,64,65]. In addition, AngIII, applied by microiontophoresis, induces an increase in firing rate of neurons higher than AngII in two brain structures involved in the control of BP, the SFO [66], and Heart Fail Rev (2008) 13:311-319 313 the PVN [53].…”