Effects of the AT1 Antagonist HR 720 in Comparison to Losartan on Stimulated Sympathetic Outflow, Blood Pressure, and Heart Rate in Pithed Spontaneously Hypertensive Rats

Haüser, Winfried; Dendorfer, Andreas; Nguyễn, Thị Nhạn; Dominiak, Peter

doi:10.1159/000025840

Cited by 23 publications

(8 citation statements)

References 24 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Angiotensin II enhances noradrenaline release from sympathetic nervous terminals as well as adrenaline release from the adrenal medulla. These effects are mediated by AT 1 receptors and losartan is therefore able to prevent them (Soltis et al, 1993;Häuser et al, 1998;Nakata et al, 1998). To determine if circulating Ang II was involved in the mediation in the pressor response EE of the MPFC, we pretreated animals with losartan (1 mg/kg, i.v.).…”

Section: Discussionmentioning

confidence: 99%

Pressor effects of electrical stimulation of medial prefrontal cortex in unanesthetized rats

Tavares

Antunes‐Rodrigues

Corrêa

2004

J of Neuroscience Research

View full text Add to dashboard Cite

The medial prefrontal cortex (MPFC) is involved in central nervous system (CNS)-mediated cardiovascular modulation. We compared the cardiovascular effects of electrical stimulation (EE) of the MPFC in unanesthetized rats to those observed after stimulation of the same area in urethane-anesthetized rats. Electrical stimulation (35, 106, 177, 247, 318, and 389 microA rms/10 sec, 60-Hz sine wave) of the MPFC of urethane-anesthetized rats caused depressor responses of stimulus-related intensity. The cardiovascular response to electrical stimulation of the MPFC in unanesthetized rats was characterized by stimulus-related pressor responses. No significant heart rate changes were observed during the EE period in any case. The pressor response to electrical stimulation (106 microA rms/10 sec, 60-Hz sine wave) of the MPFC was not affected by intravenous pretreatment with the vasopressin antagonist dTyr(CH(2))(5)(Me)AVP (50 microg/kg, intravenously), by hypophysectomy, or by intravenous pretreatment with the angiotensin II antagonist losartan (1 mg/kg, intravenously). The pressor response was blocked by intravenous pretreatment with the ganglionic blocker mecamylamine (2 mg/kg, intravenously) but was not affected by adrenal demedullation, thus suggesting involvement of the neural component of the sympathetic nervous system without a major involvement of its hormonal component. Our results confirmed the occurrence of depressor responses after electrical stimulation of the MPFC in urethane-anesthetized rats and evidenced that only pressor responses are observed after its stimulation in unanesthetized rats. The fact that the pressor response to the stimulation of the MPFC was blocked by a ganglioplegic suggests that the MPFC has functional excitatory actions over the sympathetic nervous system.

show abstract

Section: Discussionmentioning

confidence: 99%

Pressor effects of electrical stimulation of medial prefrontal cortex in unanesthetized rats

Tavares

Antunes‐Rodrigues

Corrêa

2004

J of Neuroscience Research

View full text Add to dashboard Cite

show abstract

“…First, it was recently shown that ACE inhibitors increase uptake-1 in heart failure (Kawai et al, 1999) and hypertension (Raasch et al, 2001), and second, ANG enhances catecholamine release via stimulation of presynaptic AT 1 receptors (Brasch et al, 1993;Balt et al, 2001a), so that AT 1 antagonists were able to diminish noradrenaline overflow in various in vitro and in vivo models (Dominiak et al, 1987;Minatoguchi et al, 1992;Dendorfer et al, 1998;Hä user et al, 1998;Balt et al, 2001a,b). However, it should be emphasized that the reversible or irreversible MAO inhibitors viloxazine or pargyline were found to increase biogenic amines in brains and livers due to their MAO inhibitory effects, underlining the importance of MAO for regulating tissue catecholamines (Martinez et al, 1986;Raasch et al, 1999b).…”

Section: Discussionmentioning

confidence: 99%

Angiotensin I-Converting Enzyme Inhibition Increases Cardiac Catecholamine Content and Reduces Monoamine Oxidase Activity via an Angiotensin Type 1 Receptor-Mediated Mechanism

Raasch¹,

Bartels²,

Gieselberg³

et al. 2002

J Pharmacol Exp Ther

View full text Add to dashboard Cite

Antihypertensive and cardioprotective effects of angiotensin I-converting enzyme (ACE) inhibitors are well established and have usually been attributed to the inhibition of angiotensin II (ANG)-mediated effects at vascular or ventricular (angiotensin type 1) AT 1 receptors. One other important mechanism involves ANG-induced interactions with the sympathetic nervous system, which might include alterations of cardiac catecholamine concentrations during ACE inhibition due to a modulation of monoamine oxidase (MAO) activity. Tissue catecholamines were studied in spontaneously hypertensive rats that were long-term treated with captopril (50 or 0.5 mg/kg/day), enalapril (10 or 0.1 mg/kg/day), an AT 1 receptor antagonist (candesartan-cilexetil, 3 mg/kg/day), or a calcium antagonist (mibefradil, 18 mg/kg/day). The kinetic parameters of MAO were then determined in vitro in the presence of ANG, captopril, enalaprilat, or candesartan. Noradrenaline and adrenaline contents were doubled in the left ventricle by captopril, enalapril, or candesartan independently of hypotensive potency but not in liver or cortex. In parallel, cardiac MAO activity was reduced by all doses of captopril (49/29%), enalapril (52/24%), or candesartan (38%). Mibefradil, which does not interact with the renin-angiotensin system, did not alter cardiac catecholamines or MAO activity when an equipotent antihypertensive dose was applied. In vitro MAO activity was not influenced by ANG, enalaprilat, or captopril at concentrations of up to 1 mM. It is concluded that diminished AT 1 receptor stimulation decreases cardiac MAO activity, probably by regulating MAO expression, since ANG, ACE inhibitors, and AT 1 antagonists had no effect on MAO activity in vitro. This action contributes to an increase in cardiac catecholamine content that may improve cardiac sympathetic control during therapy.Angiotensin I-converting enzyme (ACE) inhibitors are well established in the treatment of hypertension and heart failure. They decrease angiotensin II (ANG) generation by blocking the circulating and local renin-angiotensin systems (RAS) and by preventing the degradation of bradykinin. Both mechanisms seem to be involved in the antihypertensive and cardioprotective effects. Both ANG and bradykinin interact with other neurohumoral systems such as the sympathetic system. ANG increases noradrenaline release from sympathetic nerve endings by stimulating presynaptic AT 1 receptors (Brasch et al., 1993). Hence, inhibition of ANG biosynthesis by ACE inhibitors reduces the release of catecholamines (Majewski et al., 1984). In the past, many clinical trials evaluated the pronounced antihypertensive and cardioprotective effects of ACE inhibitors, and in this context, the contributions of diminished plasma noradrenaline levels to their antihypertensive and cardioprotective effects were discussed. The therapeutic significance of this action was revealed for the treatment of heart failure where a pathological sympathetic stimulation was associated with decreased cardiac noradren...

show abstract

“…16,17 Briefly, the animals were anesthetized with ether, and artificial respiration was initiated via an endotracheal tube. Pentobarbital (50 mg/kg IP) was used as an anesthetic in rats that were to be instrumented for renal sympathetic nerve activity (RSNA) determinations.…”

Section: Pithed Rat Preparationmentioning

confidence: 99%

Angiotensin II Induces Catecholamine Release by Direct Ganglionic Excitation

et al. 2002

View full text Add to dashboard Cite

Abstract-Angiotensin II (ANG) is known to facilitate catecholamine release from peripheral sympathetic neurons by enhancing depolarization-dependent exocytosis. In addition, a direct excitation by ANG of peripheral sympathetic nerve activity has recently been described. This study determined the significance of the latter mechanism for angiotensininduced catecholamine release in the pithed rat. Rats were anesthetized and instrumented for measuring either hemodynamics and renal sympathetic nerve activity or plasma catecholamine concentrations in response to successively increasing doses of angiotensin infusions. Even during ganglionic blockade by hexamethonium (20 mg/kg), angiotensin dose-dependently elevated sympathetic nerve activity, whereas blood pressure-equivalent doses of phenylephrine were ineffective. Independently of central nervous sympathetic activity and ganglionic transmission, angiotensin (0.1 to 1 g/kg) also induced an up-to 27-fold increase in plasma norepinephrine levels, reaching 2.65 ng/mL. Preganglionic electrical stimulation (0.5 Hz) raised basal norepinephrine levels 11-fold and further enhanced the angiotensin-induced increase in norepinephrine (4.04 ng/mL at 1 g/kg ANG). Stimulation of sympathetic nerve activity and norepinephrine release were suppressed by candesartan (1 mg/kg) or tetrodotoxin (100 g/kg), respectively. Angiotensin enhanced plasma norepinephrine, heart rate, and sympathetic nerve activity at similar threshold doses (0.3 to 1 g/kg), but raised blood pressure at a significantly lower dose (0.01 g/kg). It is concluded that direct stimulation of ganglionic angiotensin type 1 (AT 1 ) receptors arouses electrical activity in sympathetic neurons, leading to exocytotic junctional catecholamine release. In both the absence and presence of preganglionic sympathetic activity, this mechanism contributes significantly to ANG-induced enhancement of catecholamine release. Key Words: angiotensin II Ⅲ angiotensin antagonist Ⅲ catecholamines Ⅲ sympathetic nervous system Ⅲ electric stimulation Ⅲ rats A ngiotensin II (ANG) potently enhances catecholamine release from the peripheral sympathetic system, an action that implies important pathophysiological consequences. Catecholamines released by this mechanism contribute to the vasoconstricting and sodium-retaining properties of ANG. 1 In particular, the chronic effects of ANG at moderately elevated levels are promoted by adrenergic pathways that are significantly involved in the development of hypertension 2,3 and in the concomitant myocardial damage that has elsewhere been attributed to a stimulation of cardiac ␤-adrenoceptors. 4 ANG activates the sympathetic system via several mechanisms. Central nervous sympathetic tone is increased by circulating or locally produced ANG in nuclei responsible for autonomic control. 5 In the peripheral sympathetic system, the termini of adrenergic neurons are equipped with prejunctional angiotensin type 1 (AT 1 ) receptors whose activation enhances the efficacy of catecholamine discharge induced by each acti...

show abstract

Effects of the AT1 Antagonist HR 720 in Comparison to Losartan on Stimulated Sympathetic Outflow, Blood Pressure, and Heart Rate in Pithed Spontaneously Hypertensive Rats

Cited by 23 publications

References 24 publications

Pressor effects of electrical stimulation of medial prefrontal cortex in unanesthetized rats

Pressor effects of electrical stimulation of medial prefrontal cortex in unanesthetized rats

Angiotensin I-Converting Enzyme Inhibition Increases Cardiac Catecholamine Content and Reduces Monoamine Oxidase Activity via an Angiotensin Type 1 Receptor-Mediated Mechanism

Angiotensin II Induces Catecholamine Release by Direct Ganglionic Excitation

Contact Info

Product

Resources

About