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 microliters) and in WKY rats (from 33 +/- 9 to 13 +/- 1 pg/100 microliters). Pretreatment with the specific angiotensin receptor antagonist [Sar1, Thr8]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 blood 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.
Subject(s)
Blood Pressure/drug effects , Hypertension/physiopathology , Leucyl Aminopeptidase/pharmacology , Angiotensin II/analogs & derivatives , Angiotensin II/antagonists & inhibitors , Angiotensin II/cerebrospinal fluid , Angiotensin II/pharmacology , Animals , Cerebral Ventricles/physiology , Hypertension/metabolism , Injections, Intraventricular , Male , Rats , Rats, Inbred SHR , Rats, Inbred WKYABSTRACT
The purpose of this study was to test the hypothesis that intracarotid infusion of angiotensin via a brachial arterial catheter results in a heightened pressor response in the alert spontaneously hypertensive rat (SHR) as previously observed for intracerebroventricular (ICV) injection of angiotensin. We infused angiotensin II and III since these ligands are equivalently potent with respect to peak pressor effect when delivered ICV. We measured somewhat greater pressor responsiveness to AII than to AIII in the Wistar-Kyoto (WKY) normotensive control strain from a baselevel of 133.1 +/- 5.8 (mean +/- SEM) to 151.3 +/- 6.2 mmHg (+13.7%) at the 100 pmol/kg/min dose of AII, and from 132.5 +/- 5.8 to 146.0 +/- 6.1 mmHg (+10.2%) for AIII. The SHR revealed a heightened pressor sensitivity to AII, from a baselevel of 170.0 +/- 3.8 to 200.6 +/- 5.9 mmHg (+18%) while the response to AIII was less dramatic, from 171.3 +/- 2.1 to 189.8 +/- 2.4 mmHg (+10.8%). These findings suggest that a similar heightened pressor responsiveness occurs to peripheral infusion of angiotensin II in the SHR as previously observed to ICV injection.
Subject(s)
Angiotensin III/pharmacology , Angiotensin II/analogs & derivatives , Angiotensin II/pharmacology , Blood Pressure/drug effects , Animals , Carotid Arteries , Infusions, Intra-Arterial , Male , Rats , Rats, Inbred SHR , Rats, Inbred WKYABSTRACT
The angiotensin II competitive antagonist [125I]-Sar1, Ile8-angiotensin II was not transported from the vascular space to the cerebroventricular space in either intact or nephrectomized rats. In addition [125I]Sar1, Ile8-angiotensin II lacked the capacity to move in the opposite direction over a 20-min collection period following cerebroventricular infusion. These data suggest that angiotensins lack the capacity to move freely between the blood and cerebrospinal fluid compartments and are consistent with the notion that blood-borne and cerebroventricular angiotensins access different receptor populations.
Subject(s)
1-Sarcosine-8-Isoleucine Angiotensin II/metabolism , Angiotensin II/analogs & derivatives , Blood-Brain Barrier , Cerebral Ventricles/metabolism , 1-Sarcosine-8-Isoleucine Angiotensin II/blood , 1-Sarcosine-8-Isoleucine Angiotensin II/cerebrospinal fluid , Animals , Biological Transport , Chromatography, High Pressure Liquid , Iodine Radioisotopes , Male , Nephrectomy , Rats , Rats, Inbred StrainsABSTRACT
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.
