Biomedical subjects

Walter Raasch

Publications and source records attributed to Walter Raasch.

16 recordsLinked to original sources

PubMed2006

Angiotensin II inhibition reduces stress sensitivity of hypothalamo-pituitary-adrenal axis in spontaneously hypertensive rats.

Angiotensin II type 1 (AT(1)) receptors are expressed within organs of the hypothalamo-pituitary-adrenal (HPA) axis and seem to be important for its stress responsiveness. Secretion of CRH, ACTH, and corticosterone (CORT) is increased by stimulation of AT(1) receptors. In the present study, we tested whether a blockade of the angiotensin II system attenuates the HPA axis reactivity in spontaneously hypertensive rats. Spontaneously hypertensive rats were treated with candesartan (2 mg/kg), ramipril (1 mg/kg), or mibefradil (12 mg/kg) for 5 wk. In addition to baseline levels, CORT and ACTH responses to injection of CRH (100 microg/kg) were monitored over 4 h. mRNA of CRH, proopiomelanocortin, AT(1A), AT(1B), and AT(2) receptors was quantified by real-time PCR. All treatments induced equivalent reductions of blood pressure and had no effect on baseline levels of CORT and ACTH. However, both candesartan and ramipril significantly reduced CRH-stimulated plasma levels of ACTH (-26 and -15%) and CORT (-36 and -18%) and lowered hypothalamic CRH mRNA (-25 and -29%). Mibefradil did not affect any of these parameters. Gene expression of AT(1A), AT(1B), and AT(2) receptors within the HPA axis was not altered by any drug. We show for the first time that antihypertensive treatment by inhibition of AT(1) receptors or angiotensin-converting enzyme attenuates HPA axis reactivity independently of blood pressure reduction. This action is solely evident after CRH stimulation but not under baseline conditions. Both a reduced pituitary sensitivity to CRH and a down-regulation of hypothalamic CRH expression have the potential to reduce HPA axis activity during chronic AT(1) blockade or angiotensin-converting enzyme inhibition.

Angiotensin II↗

PubMed2005

Angiotensin I-converting enzyme-dependent and neutral endopeptidase-dependent generation and degradation of angiotensin II contrarily modulate noradrenaline release: implications for vasopeptidase-inhibitor therapy?

OBJECTIVES: Vasopeptidase inhibitors inhibit neutral endopeptidase (NEP) and angiotensin I-converting enzyme (ACE). Since angiotensin (ANG) II availability is decreased by ACE inhibition but is increased by NEP inhibition, we evaluated the influence of the vasopeptidase inhibitor omapatrilat on ANG II-dependent noradrenaline (NA) release. DESIGN: The functional relevance of ACE-dependent and NEP-dependent generation and degradation of ANG II on NA overflow was determined in pithed rats by applications of ANG I (0.1-100 microg/kg) or ANG II (0.01-10 microg/kg) after single injections of ramipril (1 mg/kg), the NEP inhibitor candoxatril (100 mg/kg), or the vasopeptidase inhibitor omapatrilat (30 mg/kg). RESULTS: Blood pressure was equipotently decreased by ramipril and omapatrilat, but not by candoxatril. NA overflow was increased after ANG I infusions in controls (EC50 = 9.0 microg/kgANG I, Emax = 5680 pg/ml), but almost completely suppressed by ramipril and omapatrilat. Candoxatril decreased EC50 (4.1 microg/kg) and increased Emax (7259 pg/ml). NA overflow after ANG II infusions was enhanced by candoxatril or omapatrilat. Ex vivo ACE activity was extensively inhibited by ramipril or omapatrilat, whereas ex vivo NEP activity was reduced by omapatrilat and candoxatril only. In vitro, omapatrilat inhibited NEP and ACE with similar potencies (IC50 NEP/IC50 ACE = 0.4). CONCLUSIONS: Vasopeptidase inhibitors influence ANG II-related NA release depending on their ability to modulate the availability of ANG II via ACE or NEP. After acute application, the vasopeptidase inhibitor suppresses NA release in response to ANG I due to a predominant reduction of ANG II formation. These results indicate that the ratio of ACE-inhibitory and NEP-inhibitory potencies of vasopeptidase inhibitors may be relevant for sympathetic activation in chronic therapy.

Angiotensin II↗

PubMed2005

Peripheral sympatholytic actions of four AT1 antagonists: are they relevant for long-term antihypertensive efficacy?

BACKGROUND: Angiotensin II causes hypertension not only by direct constriction of vascular smooth muscle, but also by facilitating the release of noradrenaline from sympathetic terminals and by enhancing vascular noradrenaline sensitivity. AT1 receptor antagonists attenuate all these actions, but display some evidence of substance-related selectivities. OBJECTIVE: The contribution of pre- or postsynaptic impairment of sympathetic transmission to long-term antihypertensive efficacy should be determined for four structurally different, clinically approved AT1 antagonists. DESIGN: Spontaneously hypertensive rats were treated with candesartan, eprosartan, irbesartan, or losartan via osmotic minipumps for 4 weeks at doses yielding identical reductions of blood pressure. Maximum efficacy was obtained with a tripled dose of candesartan. METHODS: In the pithed rat model, stimulus/response dependencies were determined for vasopressor effectivity of preganglionic electrical stimulation, and of intravenous bolus applications of noradrenaline and angiotensin II. RESULTS: Losartan, irbesartan, eprosartan, and candesartan at doses of 5, 40, 20, and 0.05 mg/kg per day, were equally effective in reducing basal systolic blood pressure (-42 mmHg), and the vasopressor potency of angiotensin II (approximately 10-fold). The efficacies of preganglionic stimulation and exogenous noradrenaline were unaltered, with the exception of irbesartan, which reduced vascular noradrenaline sensitivity. The tripled dose of candesartan further reduced basal and angiotensin II-stimulated blood pressures, and significantly attenuated vascular noradrenaline sensitivity. CONCLUSION: AT1 antagonists at doses that effectively reduce blood pressure in chronic therapy do not generally suppress peripheral sympathetic function. A potential interaction consists in a reduction of vascular noradrenaline sensitivity, which can be considered as a class effect of AT1 antagonists at high dosage.

Acrylates↗

PubMed2004

Reduction of vascular noradrenaline sensitivity by AT1 antagonists depends on functional sympathetic innervation.

Blockade of angiotensin II type-1 (AT1) receptors has been shown to reduce the magnitude of the blood pressure response to noradrenaline in pithed rats via an unidentified mechanism. Dose-response curves were established for the noradrenaline-induced (10(-12) to 10(-7) mol/kg) increase of diastolic blood pressure in pithed rats treated with tubocurarine, propranolol, and atropine. Candesartan (1 mg/kg) increased the ED50 of the noradrenaline response (1.3+/-0.1 nmol/kg) up to 20-fold. Vasopressor responsiveness to noradrenaline was attenuated specifically, whereas the vasopressin-induced increase in diastolic blood pressure was maintained. Specific involvement of AT1 receptors was confirmed by equivalent actions of losartan. Blockade of norepinephrine transporter or alpha2-adrenoceptors using desipramine or rauwolscine reduced the losartan-induced shifts in the ED50 values of noradrenaline by 63% and 21%, respectively. Combined blockade of norepinephrine transporter and alpha2-adrenoceptors eliminated the influence of losartan on noradrenaline sensitivity (ED50 5.5+/-1.3 versus 5.6+/-1.2 nmol/kg), a result also observed after sympathetic denervation by reserpine (ED50 7.1+/-0.8 versus 7.8+/-0.8 nmol/kg). Our experiments show that the reduction of vascular noradrenaline sensitivity by AT1 blockade is dependent on the intact functioning of both neuronal noradrenaline uptake via norepinephrine transporter and presynaptic alpha2-mediated autoinhibition, exclusively provided by the sympathetic innervation. These newly identified mechanisms may contribute to the antihypertensive and protective actions of AT1 blockers.

Adrenergic alpha-Antagonists↗

PubMed2004

Combined blockade of AT1-receptors and ACE synergistically potentiates antihypertensive effects in SHR.

OBJECTIVES AND DESIGN: To check whether antihypertensive effects are additive or synergistic upon blockade of both angiotensin (AT1)-receptors and angiotensin-converting enzyme (ACE), spontaneously hypertensive rats (SHR) were treated with candesartan-cilexetil (0.1-30 mg/kg per day), ramipril (0.03-10 mg/kg per day), the calcium-antagonist mibefradil (1-150 mg/kg per day) or combinations thereof. Systolic blood pressure (SBP), left ventricular weight (LVW) and the cardiac activity/mRNA levels of ACE were determined. RESULTS: SBP was decreased by candesartan-cilexetil [inhibitory concentration (IC50) (mg/kg): 2.47], ramipril (1.97), mibefradil (4.41), candesartan-cilexetil/ramipril (0.68), and candesartan-cilexetil/mibefradil (5.68). Combining candesartan-cilexetil with ramipril increased SBP reduction synergistically rather than additively, since the dose-response curve was shifted 6.6-fold leftwards compared to a hypothetically generated additive curve, calculated by summing up the doses and corresponding effects of the ramipril and candesartan-cilexetil monotreatment regimes. A total threshold dose < 5.14 mg/kg (derived from dose-response curves) was found to exert synergistic effects when candesartan-cilexetil was combined with ramipril. Antihypertensive effects of mibefradil can not be increased when combined with candesartan-cilexetil. When LVW was correlated with SBP reduction, regression lines of candesartan-cilexetil, ramipril and their combination were congruent, while that for mibefradil was significantly flatter and became steeper under candesartan-cilexetil co-administration. Cardiac ACE activity was greatly reduced by ramipril independently of SBP reduction and dosage. With SBP-ineffective doses of ramipril, cardiac ACE mRNA levels were doubled, indicating a positive feedback mechanism. The increase in ACE mRNA was renormalized when SPB-effective ramipril doses were applied, suggesting a blood pressure-dependent regulation of cardiac ACE expression. CONCLUSIONS: Since synergy was observed only after combining low doses of ramipril and candesartan-cilexetil, prospective clinical trials should be performed on a low-dose combination, revealing the antihypertensive/antiproliferative benefits.

Angiotensin II Type 1 Receptor Blockers↗

PubMed2003

Elevation of sympathetic activity by eprosartan in young male subjects.

BACKGROUND: Selective blockade of the type 1 angiotensin II receptors (AT1 receptors) reduced blood pressure (BP) elevation caused by sympathetic stimulation in the pithed rat model. This has been attributed to blockade of AT1 receptors located presynaptically on sympathetic nerve endings normally facilitating norepinephrine release. We examined the effects of AT1 receptor blockade on the sympathetic nervous system in humans. METHODS: Twenty-nine young white men with normal to mildly hypertensive BP values participated in a double-blind, placebo-controlled, randomized cross-over protocol receiving 600 mg/d of eprosartan or placebo for 1 week. At the last day of intake we measured hemodynamic parameters, muscle sympathetic nerve activity by microneurography, and plasma levels of norepinephrine, epinephrine, and angiotensin II during rest and cardiovascular stress. RESULTS: Eprosartan lowered resting mean arterial pressure (73.6 +/- 11.0 v 78.0 +/- 10.3 mm Hg, P <.05; Finapres, Ohmeda, Englewood, CO), and elevated heart rate (64.4 +/- 7.6 v 61.1 +/- 6.8 beats/min, P =.01), muscle sympathetic nerve activity (14.1 +/- 10.4 v 9.8 +/- 6.3 bursts/min, P <.05) and plasma angiotensin II (37.0 +/- 33.7 v 6.9 +/- 2.8 ng/L, P <.01), as well as norepinephrine levels (234.2 +/- 87.6 v 187.8 +/- 59.3 ng/L, P <.01). Eprosartan did not blunt sympathetic activation caused by lower body negative pressure or mental stress. CONCLUSIONS: These results contrast with animal data showing antiadrenergic properties of this drug. If any, it appeared, that eprosartan causes augmented central neural vasoconstrictor outflow paralleled by increased plasma levels of norepinephrine, which casts doubt on its ability to dampen norepinephrine release from peripheral sympathetic nerve endings in humans. We hypothesize that eprosartan leads to a resetting of the baroreflex, presumably by the markedly elevated circulating angiotensin II.

Acrylates↗

PubMed2003

Toxicity of kava pyrones, drug safety and precautions--a case study.

Kava pyrones have been sold in Germany as OTC anxiolytics until June 2002, when all preparations with a kava pyrone content of more than 10(-4) of a homeopathic stock solution were withdrawn. Other countries in which kava pyrones have been used as anxiolytics, namely GB and the USA, have not followed suit. Kava pyrone anxiolytics have been positively reviewed by the Cochrane Collaboration; also newer German clinical studies have indicated pharmacological anxiolysis at the recommended doses. To use the first choice of treatment, psychotherapy, for all uncomplicated cases of pathological fear does not appear to be realistic. Current data about kava pyrone toxicity are unclear. Judging from the few well documented cases of kava pyrone hepatotoxicity (appr. 2 out of 36) in Germany and Switzerland, an immunologically mediated idiosyncratic mechanism appears to be most likely, especially at higher doses, whereas a direct toxic mechanism is much less likely. No direct results are available for the incidence of kava pyrone-related adverse drug effects. From spontaneously reported cases the incidences of adverse drug reactions cannot be obtained, a rough estimation indicates the incidence of hepatotoxicity to be comparable to those of benzodiazepines. Taken together, the withdrawal of kava pyrone-based anxiolytics appears to be an ill founded over-reaction given the lack of superior therapeutic alternatives. Neither the case evaluations presented by the BfArM (Bundesamt für Arzneimittel und Medizinprodukte = Federal Office for Drugs and Medical Products) nor the complete rejection of proof for therapeutic efficacy of kava pyrone anxiolytics are scientifically well founded.

Adverse Drug Reaction Reporting Systems↗

PubMed2003

Modification of noradrenaline release in pithed spontaneously hypertensive rats by I1-binding sites in addition to alpha2-adrenoceptors.

It is known that moxonidine acts as an agonist at presynaptic alpha(2)-adrenoceptors of the postganglionic sympathetic nerve terminals and leads to a reduction in noradrenaline release. In addition, it is conceivable that I(1)-binding sites located in other regions of the pre- and postganglionic sympathetic neurons are involved in this effect. Our aim was to investigate whether and to what extent activation of the I(1)-binding sites contributes to the moxonidine-induced inhibition of noradrenaline release. Noradrenaline release was induced in pithed spontaneously hypertensive rats (pretreated with phenoxybenzamine/desipramine at 10/0.5 mg/kg) by stimulation of sympathetic overflow from the spinal cord. Noradrenaline overflow was reduced using moxonidine (0.18, 0.6, and 1.8 mg/kg) by 39.4, 70.4, or 78.7%, respectively, even when all alpha(1)-/alpha(2)-adrenoceptors were blocked effectively by phenoxybenzamine. In contrast, the I(1)-antagonist efaroxan (0.1, 1, and 3 mg/kg) increased noradrenaline overflow from 453 (control) to 1710, 1999, or 2754 pg/ml, suggesting an autoreceptor-like function of I(1)-binding sites. In consequence, moxonidine (0.18, 0.6, and 1.8 mg/kg) reduced the increase in noradrenaline overflow in efaroxan-treated animals (1 mg/kg) by 22.7, 41.7, and 50.5%, respectively. Agmatine (6 and 60 mg/kg), an endogenous agonist at I(1)-binding sites, reduced noradrenaline overflow (-36 or 53%), even under alpha(2)-adrenoceptor blockade. When 2-endo-amino-3-exo-isopropylbicyclo[2.2.1]heptane (AGN192403) (10 mg/kg) was injected, a selective blocker of I(1)-binding sites, noradrenaline overflow was not influenced by agmatine. It is concluded that moxonidine reduces noradrenaline overflow by acting at I(1)-binding sites in addition to its agonistic property at alpha(2)-adrenoceptors. The exact location of the I(1)-binding sites on the pre- or postsynaptic sympathetic neurons is unknown, but the location in the pre- or postsynaptic membrane of the sympathetic ganglion is the most plausible explanation.

Adrenergic alpha-Antagonists↗

PubMed2003

Moxonidine displays a presynaptic alpha-2-adrenoceptor-dependent synergistic sympathoinhibitory action at imidazoline-1 receptors.

The function of presynaptic imidazoline-1 receptors (I1-R) in the heart remains unclear. In rat hearts, UK14.304 and moxonidine reduced norepinephrine (NE) release. AGN192403 had no influence on NE, whereas rilmenidine, agmatine, rauwolscine, and efaroxan increased NE. These effects of moxonidine and rilmenidine were not affected by AGN192403 adminstration. Conversely, after pretreatment with UK14.304, only moxonidine displayed a pronounced inhibitory action on NE release (sensitive to AGN192403), indicating a synergistic inhibitory action at I1-R under conditions of a stimulated alpha2-adrenergic autoinhibition.

Adrenergic alpha-Agonists↗

PubMed2003

Norepinephrine release is reduced by I(1)-receptors in addition to alpha(2)-adrenoceptors.

In pithed spontaneous hypertensive rats, noradrenaline overflow was diminished by moxonidine even when alpha(2)-adrenoceptors were blocked quantitatively using phenoxybenzamine, suggesting an I(1)-receptor-mediated mechanism of noradrenaline release. This hypothesis was confirmed, since the noradrenaline overflow was (1) increased under alpha(2)-adrenoceptors blockade by the mixed I(1)/alpha(2)-antagonists efaroxan or idazoxan, (2) still reduced by moxonidine when both alpha(2)- and I(1)-receptors were blocked, and (3) diminished by agmatine after pretreatment with phenoxybenzamine, but not with AGN192403. An indirect ganglionic I(1)-receptor-mediated mechanism of noradrenaline release is supposed.

Adrenergic alpha-Antagonists↗

PubMed2002

Impaired coronary flow and left ventricular dysfunction after mechanical recanalization in acute myocardial infarction: role of neurohumoral activation?

BACKGROUND: Reopening of the infarct-related coronary artery is the treatment of choice in the clinical setting of acute myocardial infarction. Nevertheless the removal of the total occlusion obtained either by thrombolysis or by primary angioplasty is followed by the ischemia/reperfusion sequelae. One of many proposed mechanisms playing a role in ischemia/reperfusion damage is a persistent increase in vasoconstrictor tone, which reduces cardiac function and impairs myocardial blood flow during primary percutaneous coronary intervention in acute myocardial infarction (PAMI). METHODS: To investigate early neurohumoral changes during PAMI we enrolled 18 patients, who were collated to 13 patients with stable angina undergoing elective PTCA. To evaluate angiotensin II (AngII), endothelin-1 (ET-1), vasopressin (AVP), norepinephrine (NE), troponin T (TNT), creatinephosphate kinase (CPKM) and isoenzyme MB (CPKMB), we collected blood from the pulmonary artery before and immediately after the infarct-related artery (IRA; TIMI 0 --> 2-3) or culprit lesion revascularization. Hemodynamic and angiographic LV-function parameters were compared to biochemical data. Corrected TIMI-frame count (CTFC) was used as an index of coronary blood flow and correlated to the biochemical measurements. RESULTS: CTFC in the IRA correlated inversely (p = 0.03; r = -0.51) with left ventricular ejection fraction measured after 10 days, and positively (p = 0.03; r = 0.54) with the maximal amount of LDH released after onset of AMI. There was an abrupt and long lasting rise in ET-1 (+65 %; p < 0.001) and an instant short lasting increase in AVP (+37 %; p < 0.05), whereas NE concentrations were elevated prior to PAMI and remained elevated during reperfusion. Correlations with CTFC were found for ET-1 (p = 0.01; r = 0.61) and NE (p = 0.01; r = 0.58) during reperfusion. The extent of left ventricular dysfunction correlated with the concentrations of AVP and NE during reperfusion. CONCLUSIONS: There is evidence for a distinct pattern of neurohumoral activation during early reperfusion in acute myocardial infarction. In particular, we documented substantial increases in AVP and ET-1. Left ventricular wall-stress appears to be involved in the release of AVP. Elevated levels of ET-1 and NE are associated with impaired angiographic reperfusion and increased myocardial damage after mechanical recanalization.

Aged↗

PubMed2002

Agmatine, an endogenous ligand at imidazoline binding sites, does not antagonize the clonidine-mediated blood pressure reaction.

Since agmatine has been identified as a clonidine displacing substance (CDS), the aim of this study was to investigate whether agmatine can mimic CDS-induced cardiovascular reactions in organ bath experiments, pithed spontaneously hypertensive rats (SHR) and anaesthetized SHR. Intravenously-administered agmatine significantly reduced the blood pressure and heart rate of anaesthetized SHR at doses higher than 1 and 3 mg kg(-1), respectively. These effects are probably mediated via central mechanisms, since there was an approximate 8 fold rightward shift of the dose-response curve in the pithed SHR (indicating a weakened cardiovascular effect). Moreover, in organ bath experiments, agmatine failed to alter the contractility of intact or endothelium-denuded aortal rings. When agmatine was administered i.c.v. to anaesthetized SHR, blood pressure was increased without any alteration of heart rate, whereas blood pressure was unchanged and heart rate was increased after injection into the 4th brain ventricle. This suggests that haemodynamic reaction patterns after central application are related to distinct influences on central cardiovascular mechanisms. Agmatine reduces noradrenaline release in pithed SHR while alpha(2)-adrenoceptors are irreversibly blocked with phenoxybenzamine, but not while I(1)-binding sites are selectively blocked with AGN192403. This suggests that agmatine may modulate noradrenaline release in the same way that clonidine does, i.e. via imidazoline binding sites; this involves a reduction in sympathetic tone which in turn reduces blood pressure and heart rate. Finally, CDS-like cardiovascular activity appears not to be due to agmatine, since (i) blood pressure in anaesthetized SHR is decreased by agmatine and clonidine, and (ii) agmatine did not antagonize the blood pressure reaction to clonidine in pithed or anaesthetized SHR.

Adrenergic alpha-Agonists↗

PubMed2002

Comparison of the vascular and antiadrenergic activities of four angiotensin II type 1 antagonists in the pithed rat.

BACKGROUND: Angiotensin II is known to facilitate the release of catecholamines from peripheral sympathetic neurons by stimulating presynaptically located receptors. Although inhibitor studies have revealed these to be angiotensin II type 1 (AT1) receptors, they do in fact appear to display peculiar susceptibilities to various AT1 receptor antagonists, which might correspond to different neuronal and vascular receptor subtypes. OBJECTIVE: A direct comparison of the pre- and postsynaptic potencies of four AT1 antagonists was performed to characterize these receptors further. DESIGN: We studied angiotensin II-induced catecholamine release and vasoconstriction in pithed, spontaneously hypertensive rats under the influence of candesartan, eprosartan, EXP 3174, and irbesartan. The effect of AT1 blockade on postsynaptic vascular sensitivity to noradrenaline (NA) was also determined. METHODS: Pithed rats received repeated intravenous applications of either angiotensin II or NA, preceded by cumulatively increasing doses of the AT1 antagonists. Vasoconstriction and catecholamine release were quantified by the measurement of acute increases in blood pressure and plasma NA, respectively. RESULTS: All AT1 antagonists dose-dependently suppressed angiotensin II-induced vasoconstriction and release of NA. Although the antagonists differed greatly in their inhibitory potencies (ID50 range 7-445 microg/kg), each displayed a similar potency at both neuronal and vascular angiotensin receptors. In a higher dose range, all AT1 antagonists attenuated the blood pressure increase in response to NA by up to 70%. The order of potencies for all inhibitory effects was: candesartan > eprosartan > EXP 3174 > irbesartan. CONCLUSION: The AT1 antagonists tested do not discriminate between presynaptic neuronal and postsynaptic vascular angiotensin II receptors - a fact that refutes the existence of tissue-specific AT1 receptor subtypes. A marked reduction in vascular sensitivity to NA may contribute to the antihypertensive and cardioprotective mechanisms of AT1 antagonists.

Adrenergic Antagonists↗

PubMed2002

Regression of ventricular and vascular hypertrophy: are there differences between structurally different angiotensin-converting enzyme inhibitors?

OBJECTIVES: It is well established that angiotensin-converting enzyme (ACE) inhibitors (ACEI) reduce blood pressure (BP) and hypertrophy of the left ventricle and vessels. The aim of our study was to compare chemically different ACEIs regarding their ability to modulate left ventricular and media hypertrophy, ACE activity and plasma endothelin-1 concentrations in spontaneously hypertensive rats (SHRs). DESIGN: After establishing equi-effective dose regimes, SHRs were treated (3 months) with captopril, enalapril, fosinopril or ramipril (2 x 25, 10, 20 or 1 mg/kg per day or corresponding 1% doses for studying blood pressure-independent effects). METHODS AND RESULTS: Systolic blood pressure was reduced in SHRs receiving high doses of captopril, enalapril, fosinopril or ramipril (-61, -54, -35 and -47 mmHg), whereas low doses were ineffective. Left ventricular weight was decreased in animals treated with high doses (captopril/enalapril/fosinopril/ramipril: -17/-19/-17/-19%), but not low doses of agents. Media thickness of thoracal aorta was reduced by administering high doses (captopril/enalapril/fosinopril/ramipril: -31/-32/-27/-26%) and low doses (-16/-22/-22/-19%) of agents. ACE activity was reduced in heart, aorta and kidney of rats treated with high and low doses of all ACE inhibitors, whereby high doses showed more pronounced effects. Plasma endothelin-1 concentrations were not altered. A blood-pressure-ineffective treatment with an AT -antagonist revealed similar effects on cardiovascular hypertrophy. CONCLUSIONS: ACEIs reduce cardiovascular hypertrophy uniformly via an AT -receptor- mediated mechanism, reinforcing the opinion that ACEI effects are indeed class effects. The significance of local renin-angiotensin systems was confirmed by antihypertrophic effects in the aorta that were apparent in the absence of any blood pressure reduction.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed2002

Angiotensin I-converting enzyme inhibition increases cardiac catecholamine content and reduces monoamine oxidase activity via an angiotensin type 1 receptor-mediated mechanism.

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 II↗

PubMed2002

Angiotensin II induces catecholamine release by direct ganglionic excitation.

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 angiotensin-induced 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 microg/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 microg/kg ANG). Stimulation of sympathetic nerve activity and norepinephrine release were suppressed by candesartan (1 mg/kg) or tetrodotoxin (100 microg/kg), respectively. Angiotensin enhanced plasma norepinephrine, heart rate, and sympathetic nerve activity at similar threshold doses (0.3 to 1 microg/kg), but raised blood pressure at a significantly lower dose (0.01 microg/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.

Angiotensin II↗