Effects of an Orally Active Converting-Enzyme Inhibitor, SQ 14225, on Pressor Responses to Angiotensin Administered into the Brain Ventricles of Spontaneously Hypertensive Rats

Mann, Johannes F.E.; Rascher, Wolfgang; Dietz, Rainer; Schömig, Albert; Ganten, Detlev

doi:10.1042/cs0560585

Cited by 42 publications

(8 citation statements)

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“…This explanation does not account, however, for the failure of intracerebroventricular [Sar'/Thr'jAng II to lower blood pressure in the studies of Bruner et al 5 and Berecek et al 7 or for the failure of captopril to lower blood pressure in the study of Mann et al 8 ; and in the present study, we demonstrated blockade of the pressor response to intracerebroventricular Ang II with intracerebroventricular DuP 753. In our opinion, the absence of the metabolite does not explain why clearly demonstrable blockade of brain Ang II did not lower blood pressure in these studies.…”

Section: Discussionmentioning

confidence: 39%

Central DuP 753 does not lower blood pressure in spontaneously hypertensive rats.

et al. 1992

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and captopril) in spontaneously hypertensive rats (SHRs) has long puzzled many investigators, primarily because SHRs do not have elevated plasma renin or angiotensin. The explanation may be that angiotensin levels are high in one or more tissues critical for the maintenance of the hypertension. According to this hypothesis, the RAS antagonists are presumed to have their antihypertensive actions in these key tissues. Some authors (e.g., Unger et al 1 ) have suggested that one of these key tissues is the brain, proposing that the angiotensin receptors of the brain may be critical for the development and maintenance of hypertension. The evidence (reviewed in Unger et al 1 ) is 1) components of the RAS are found in the brain, although recent evidence indicates that the brain "angiotensin II" (Ang II) may not be authentic 2 ; 2) Ang II injected into the brain increases blood pressure; and 3) saralasin injection or captopril infusion into the brain lowers blood pressure.In the present study, we sought to determine whether Ang II subtype 1 (AT,) receptors protected by the blood-brain barrier are responsible for the efficacy and long duration of action of DuP 753. We determined that Ang II in the brain appears to increase blood pressure via AT, receptors but found that blockade of these receptors with DuP 753 had variable effects on blood pressure quite unlike the oral antihypertensive action of the compound. Methods AnimalsMale SHRs, 17-21 weeks of age, were sedated with xylazine (8 mg/kg s.c.) and anesthetized with ketamine (65 mg/kg s.c), and the left jugular vein and right carotid artery were cannulated. For intracerebroventricular injection, rats were also stereotaxically instrumented with a 22-gauge guide catheter in the lateral cerebral ventricle. Rats were allowed to recover 3-5 days for intracerebroventricular studies and 24 hours for oral dosing experiments. Mean arterial pressure (MAP) was monitored in the conscious rat via the carotid artery catheter. All intracerebroventricular injections delivered a total volume of 10 or 20 JAI at a rate of 10 jil/min. Proper intracerebroventricular catheter placement was confirmed at the end of a study by injection of 5 ^1 of 1% Evans blue and visual inspection of the sectioned tissue.Two groups of rats were used in the study: normal SHRs and furosemide-treated SHRs. The furosemidetreated SHRs were pretreated (10 mg/kg s.c.) at 22 and 4 hours before the experiment and were not allowed access to water the night before the study. The furosemide-treated rats were also maintained on a low sodium diet beginning on the day of diuretic treatment. Pharmacological AgentsDuP 753 was synthesized by the Medicinal Chemistry

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Section: Discussionmentioning

confidence: 39%

Central DuP 753 does not lower blood pressure in spontaneously hypertensive rats.

et al. 1992

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“…36 Similarly, converting enzyme inhibition attenuated pressor responses to centrally administered Al. 41 These reports make it probable that ACE is involved in the physiological function of central angiotensin-containing neurons. It is likely that the activity of these neurons might be altered in states of altered sodium appetite or fluid homeostasis such as occurs with changes in dietary sodium intake.…”

Section: Intracerebroventricular Infusion Of Angiotensin IImentioning

confidence: 99%

Modulation of brain angiotensin-converting enzyme by dietary sodium and chronic intravenous and intracerebroventricular fusion of angiotensin II.

Mendelsohn¹,

Csicsmann²,

Js³

et al. 1982

Hypertension

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SUMMARY Angiotensin-converting enzyme (ACE) in rat brain closely resembled that in lung in its kinetics with the substrate Hip-His Leu, the inhibitors SQ 20,881 and SQ 14,225, and in its Cl" activation profile. Modification of dietary NaCI intake was associated with marked changes in brain ACE activity. Sodium-loaded rats had lower activity of ACE in hypothalamus, striatum, and midbrain, and higher activity in spinal cord compared to controls. In sodium-restricted rats, ACE was elevated in pituitary and depressed in spinal cord. Chronic intravenous infusion of angiotensin (AH) was associated with a pattern of changes partly resembling sodium loading: ACE was depressed in hypothalamus and striatum but elevated in midbrain. After chronic intracerebroventricular infusion of AH, ACE was elevated in striatum and hippocampus, and depressed in spinal cord; a pattern of changes quite different from those associated with intravenous All. These results show that ACE in several brain regions is sensitive to dietary sodium intake and support the hypothesis that angiotensincontaining neurons in these areas might be responsive to NaCI status of the animal. The observed changes in brain ACE do not seem to be explained in any simple manner by changes in circulating or central angiotensin II. (Hypertension 4: 590-596, 1982) KEY WORDS • sodium status • kininase II • osmotic minipumps * renin-angiotensin system • thirst * blood pressure T HERE is strong evidence that the renin-angiotensin system may exist in the brain independently of the circulating system.

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“…4 Further, acute or chronic intracerebroventricular administration of either saralasin or captopril at doses that are minimally effective in lowering blood pressure when given intravenously markedly reduces blood pressure in adult SHR and attenuates the development of hypertension in young SHR but has a minimal effect on blood pressure in age-matched WKY rats. 5 -' 1 Previous studies have demonstrated that an anterior hypothalamic knife cut that isolates the anterior hypothalamic area (AHA) from other cardiovascular control areas in the brain stem and hypothalamus eliminates both the pressor response to centrally administered Ang II and the central component of the pressor response to intravenous Ang II in normotensive rats. 12 Thus, neurons in AHA appear to participate in the centrally mediated pressor response to exogenous Ang II.…”

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confidence: 99%

Depressor effect of blocking angiotensin subtype 1 receptors in anterior hypothalamus.

et al. 1992

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Previous studies have shown that the anterior hypothalamic area participates in the centrally mediated pressor response to exogenous angiotensin II. The current study was designed to test the hypothesis that endogenous anterior hypothalamic angiotensin II plays a significant role in blood pressure control. Type 1 angiotensin II receptors in the anterior hypothalamic area were blocked by local microinjection of DuP 753 (2-/i-butyl-4-chloro-5-(hydroxymethyl)-l-[(2'-(lH-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole, potassium salt), a highly selective nonpeptide antagonist. DuP 753 (20 or 40 fig; in 100 nl artificial cerebrospinal fluid) or vehicle alone was microinjected into the anterior hypothalamic area of conscious NaCI-sensitive spontaneously hypertensive rats and Wistar-Kyoto controls. DuP 753 caused significant dose-related decreases in mean arterial pressure (maximal decrease, 22.5 ±1.8 mm Hg) with unchanged heart rate in NaCI-sensitive spontaneously hypertensive rats but effected no change in Wistar-Kyoto rats. Injections of equal volumes of artificial cerebrospinal fluid into the anterior hypothalamic area had no effect in either strain. Further, microinjection of DuP 753 into the posterior hypothalamic area produced no significant effect on blood pressure or heart rate in NaCI-sensitive spontaneously hypertensive rats. Microinjection into the anterior hypothalamic area of the selective type 2 angiotensin II receptor antagonist PD 123319 did not affect blood pressure or heart rate in NaCI-sensitive spontaneously hypertensive rats. These data provide the first demonstration that endogenous angiotensin II in the anterior hypothalamic area participates in the tonic control of blood pressure in salt-sensitive spontaneously hypertensive rats but not in normotensive Wistar-Kyoto rats and that this effect is mediated by type 1 angiotensin II receptors. 3 Brain Ang II levels are significantly higher in SHR than in WKY rats even before the development of hypertension, suggesting that the increase in brain Ang II may play an etiologic role in the development of hypertension rather than being a consequence of the blood pressure elevation. 4 Further, acute or chronic intracerebroventricular administration of either saralasin or captopril at doses that are minimally effective in lowering blood pressure when given intravenously markedly reduces blood pressure in adult

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Effects of an Orally Active Converting-Enzyme Inhibitor, SQ 14225, on Pressor Responses to Angiotensin Administered into the Brain Ventricles of Spontaneously Hypertensive Rats

Cited by 42 publications

References 9 publications

Central DuP 753 does not lower blood pressure in spontaneously hypertensive rats.

Central DuP 753 does not lower blood pressure in spontaneously hypertensive rats.

Modulation of brain angiotensin-converting enzyme by dietary sodium and chronic intravenous and intracerebroventricular fusion of angiotensin II.

Depressor effect of blocking angiotensin subtype 1 receptors in anterior hypothalamus.

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