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Peter Dominiak

Publications and source records attributed to Peter Dominiak.

36 records · Page 2Linked to original sources
PubMed2003

Hypoxia rapidly activates HIF-3alpha mRNA expression.

The role of the hypoxia-inducible factor (HIF) subunits 1alpha and 1beta in cellular response to hypoxia is well established, whereas little is known about HIF-2alpha and HIF-3alpha with respect to organ distribution and transcriptional regulation by hypoxia. We investigated mRNA levels of all HIF subunits and of their target genes erythropoietin (EPO) and glucose-transporter 1 (GLUT1) in rats undergoing systemic hypoxia for 30 or 120 min by quantitative real-time RT-PCR. In normoxia, persistently high mRNA levels of all HIF subunits were detected in cerebral cortex, hippocampus, and lung; the heart contained the lowest amounts. Hypoxia did not affect mRNA levels of HIF-1alpha, -1beta, and -2alpha. HIF-3alpha mRNA levels increased in all organs examined after 2 h of hypoxia. A significant rise of EPO and GLUT1 mRNA levels occurred in cortex, heart, liver, and kidney after 2 h of hypoxia, indicating activation of the HIF system. Protein levels of all HIF subunits, determined in brain and lung by immunoblotting, showed a marked increase corresponding to the duration of hypoxia. Our results suggest that induction at the transcriptional level is a unique feature of HIF-3alpha, which therefore may represent a rapidly reacting component of the HIF system in protection against hypoxic damage.

Animals↗
PubMed2003

Differential expression of AT1 receptors in the pituitary and adrenal gland of SHR and WKY.

The renin-angiotensin (ANG) system has been implicated in the development of hypertension in spontaneously hypertensive rats (SHR). Because SHR are more susceptible to stress than normotensive Wistar-Kyoto rats (WKY), we measured the mRNA expression of AT1A, AT1B, and AT2 receptors in the hypothalamo-pituitary-adrenal (stress) axis of male SHR in comparison to age-matched WKY at prehypertensive (3 to 4 weeks), developing (7 to 8 weeks), and established (12 to 13 weeks) stages of hypertension. AT1A receptor mRNA was mainly expressed in the hypothalamus and adrenal gland. AT1B receptor mRNA was detected in the pituitary and adrenal gland. AT2 receptor mRNA was prominent only in the adrenal gland. When compared with WKY, SHR showed increased AT1A receptor mRNA levels in the pituitary gland at all ages in contrast to reduced pituitary AT1B receptor mRNA levels. In the adrenal gland of SHR, AT1B receptor mRNA levels were decreased at the hypertensive stages when compared with WKY. The reduced expression of adrenal AT1B receptor mRNA was localized selectively in the zona glomerulosa by in situ hybridization. No differences were observed between WKY and SHR in the expression of hypothalamic ANG receptors. ANG significantly increased plasma levels of adrenocorticotropic hormone (ACTH) and corticosterone in dexamethasone-treated SHR but not in WKY. The aldosterone response to ANG was similar in SHR and WKY. Our results suggest a differential gene expression of AT1A and AT1B receptors in the hypothalamo-pituitary-adrenal axis of SHR and normotensive WKY and imply the participation of AT1 receptors in an exaggerated endocrine stress response of SHR to ANG.

Adrenal Glands↗
PubMed2003

Kinin B2 receptor localization and expression in the hypothalamo-pituitary-adrenal axis of spontaneously hypertensive rats.

OBJECTIVE: An enhanced hypothalamo-pituitary-adrenocortical (HPA) activity has been demonstrated during onset of high blood pressure in spontaneously hypertensive rats (SHR). Furthermore, compared to normotensive Wistar-Kyoto (WKY) rats, SHR show hypersensitivity to bradykinin (BK)-induced pressor responses which may be caused by an upregulation of B(2) receptor expression in the brain. METHODS: We performed an immunohistochemical localization and measured gene expression of B(2) receptors in the hypothalamus, pituitary and adrenal glands of SHR at three ages corresponding to the development of hypertension, i.e. prehypertensive phase, onset of hypertension and established hypertension. Using reverse transcriptase polymerase chain reaction (RT-PCR) and Western blot technique, B(2) receptor mRNA and protein levels, respectively, were measured. RESULTS: A specific immunostaining for B(2) receptors was observed in the hypothalamic nuclei paraventricularis (PVN) and supraopticus (SON). In the pituitary and adrenal glands, a strong immunostaining was observed in neurohypophysis (NH) and adrenal medulla, respectively. At all ages tested, B(2) receptor mRNA and protein levels were higher in the hypothalamus and adrenal glands of SHR compared to age-matched WKY rats. Among SHR, the mRNA level was increased in neurohypophysis with age, and no difference was found in the adenohypophysis (AH) between SHR and WKY rats. CONCLUSION: The data demonstrate a specific localization and an upregulation of B(2) receptor expression in the hypothalamus and adrenal glands of SHR, providing an anatomical and molecular basis for a possible contributory role to bradykinin-induced hypersensitivity of cardiovascular responses. The increased B(2) receptor expression in the hypothalamus and adrenal glands may also play a role in the abnormalities of the HPA axis in SHR during the development of hypertension.

Aging↗
PubMed2003

Inhibition of kinin breakdown prolongs retention and action of bradykinin in a myocardial B2 receptor compartment.

1. The high efficacy of ACE inhibitors to potentiate the actions of kinins might be explained by a hypothetical compartment in which B(2)-receptors are colocalized with kinin degrading enzymes. To demonstrate the functional consequence of such a compartment we compared the myocardial uptake and the persistence of action of bradykinin under the influence of kininase inhibitors. 2. Bradykinin-induced vasodilation and uptake of tritiated bradykinin were studied in perfused rat hearts during inhibition of ACE and aminopeptidase P. B(2)-receptors were localized by immuno-gold labelling and electron-microscopy. 3. The EC(50) of bradykinin-induced vasodilation (5.1+/-0.8 nM) was shifted to 14 fold lower concentrations during inhibition of both kininases. The maximum persistence of vasodilation after termination of bradykinin application (half-life 112+/-20 s) was increased by kininase inhibitors to 398+/-130 s. This prolongation was reversed when B(2)-receptors were blocked simultaneously with the termination of bradykinin infusion. 4. Tritiated bradykinin (perfused for 1 min) was partially (1.7+/-0.24%) retained by the myocardium and consecutively released with a half-life of 70+/-9 s. Kinin uptake was increased during kininase inhibition (7.7+/-2.6%), and was normalized by HOE 140 (2.0+/-0.34%), or when a tritiated B(2)-receptor antagonist (NPC 17731) was used as label. 5. B(2)-receptors were localized in plasmalemmal and cytosolic vesicles of capillary endothelium. 6. Bradykinin is locally incorporated and can associate with B(2)-receptors repeatedly when kinin breakdown is inhibited. This is the kinetic and functional consequence of a colocalization of kininases and B(2)-receptors in a compartment constituted by endothelial membrane vesicles.

Aminopeptidases↗
PubMed2003

Influence of captopril on symptomatic and hormonal responses to hypoglycaemia in humans.

AIMS: Hypoglycaemic symptoms and hormonal counter-regulation are of high importance to avoid the risk of severe hypoglycaemia in patients with diabetes mellitus. Various antihypertensive drugs, such as angiotensin-converting enzyme (ACE) inhibitors, have been suspected for a long time to reduce this response to hypoglycaemia in diabetic subjects. Although ACE inhibitors are approved for controlling diabetic complications, previous investigations regarding this putative side-effect are controversial. METHODS: We performed clamp experiments in 16 healthy men lasting for 6 h each. The subjects were pretreated for 7 days with captopril 3 x 25 mg day-1 vs placebo in a randomized, double-blind, crossover study. Plasma glucose was decreased in a stepwise manner during a hypoglycaemic clamp session and counter-regulatory hormones [epinephrine (adrenaline), norepinephrine (adrenaline), ACTH, cortisol, glucagon], symptoms, and haemodynamic parameters (blood pressure, heart rate] were measured. RESULTS: Counter-regulatory hormone concentrations significantly increased in both sessions (ACE inhibitor vs placebo) during hypoglycaemia. The rise of counter-regulatory hormones as well as symptom scores were equal under both ACE inhibitor and placebo treatment. Systolic blood pressure and heart rate increased (from 110 +/- 3 vs 115 +/- 3 mmHg to 132 +/- 4 vs 133 +/- 4 mmHg) whereas diastolic blood pressure slightly decreased (from 63 +/- 2 vs 70 +/- 3 mmHg to 61 +/- 2 vs 64 +/- 2 mmHg) independent of pretreatment. Systolic and diastolic blood pressure were significantly lower in the captopril session vs placebo (P < 0.05). CONCLUSIONS: Our results demonstrate that subchronic treatment with captopril does not attenuate symptomatic and hormonal response to hypoglycaemia. Thus, to patients at risk of hypoglycaemia who require antihypertensive or nephroprotective treatment, we would continue giving an ACE inhibitor.

Adult↗
PubMed2003

Brain nitric oxide synthase activity in spontaneously hypertensive rats during the development of hypertension.

OBJECTIVES: Blockade of neuronal nitric oxide synthase (nNOS) in the brain induced an increase in mean arterial pressure of spontaneously hypertensive rats (SHR). We hypothesize that increased nitric oxide (NO) synthesis in the brain compensates for hypertension. Therefore, we measured NOS activity in different brain regions in SHR at prehypertensive, onset and established hypertension, and compared with age-matched Wistar-Kyoto (WKY) rats. METHOD: NOS activity was measured by the ability of tissue homogenate to convert [3H]l-arginine to [3H]l-citrulline in a Ca2+- and NADPH-dependent manner. RESULTS: NOS activity was impaired in the cerebral cortex and brainstem of prehypertensive SHR. At established hypertension, SHR showed an augmentation in NOS activity in hypothalamus and brainstem. Chronic treatment of SHR with the angiotensin-1 converting enzyme (ACE)-inhibitor, enalapril, and the AT(1) receptor antagonist, losartan, normalized NOS activity in the hypothalamus but not in the brainstem. Treatment with a peripheral vasodilator, hydralazine, did not affect NOS activity. CONCLUSION: Attenuated NOS activity in the cortex and brainstem of prehypertensive SHR may play a role in the pathogenesis of hypertension. The upregulated NOS activity in the hypothalamus and brainstem of SHR possibly serves to compensate for hypertension. Hypothalamic, but not brainstem, NO is involved in antihypertensive effects of ACE inhibition and AT(1) receptor blockade. Since a blood pressure decrease per se had no effect on NOS activity, it appears that central sympathetic activity influenced by endogenous angiotensin II, rather than blood pressure, represents the stimulus for the increased NOS activity in the hypothalamus of SHR.

Age Factors↗
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

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↗
PubMed2003

Gonadal steroids differentially regulate the messenger ribonucleic acid expression of pituitary orexin type 1 receptors and adrenal orexin type 2 receptors.

Hypothalamic prepro-orexin as well as pituitary and adrenal orexin receptors are gender-specifically expressed. To assess the regulation by gonadal steroids, we investigated the effect of 17beta-estradiol in female and of testosterone in male rats on prepro-orexin and orexin receptor mRNA expression. Rats were either sham-operated or gonadectomized and subsequently treated with placebo, 17beta-estradiol, or testosterone for 21 d. Tissue mRNA levels of prepro-orexin, orexin type-1 (OX(1)), and orexin type-2 (OX(2)) receptors were measured using quantitative real-time RT-PCR. In female rats, pituitary OX(1) receptor mRNA levels were increased 12-fold after ovariectomy compared with sham- operated rats. The increase of pituitary OX(1) receptor mRNA was inhibited by treatment with 17beta-estradiol. Adrenal mRNA levels of OX(2) receptors in ovariectomized rats were increased 2-fold compared with sham-operated rats and were also reduced by treatment with 17beta-estradiol. In male rats, orchidectomy increased the mRNA levels of pituitary OX(1) receptors compared with sham-operated rats. In contrast, adrenal OX(2) receptor mRNA was reduced after orchidectomy. Testosterone treatment reversed the effect of orchidectomy on pituitary OX(1) and adrenal OX(2) receptors. In the hypothalamus, no differences were found in the mRNA levels of prepro-orexin, OX(1), and OX(2) receptors between sham-operated, placebo-treated, and steroid-treated female or male rats. Our results indicate that gonadal steroids differentially regulate pituitary OX(1) receptors and adrenal OX(2) receptors in male and female rats and may contribute to specific sex- dependent neuroendocrine and endocrine actions of orexins.

Animals↗
PubMed2002

Remote preconditioning protects the heart by activating myocardial PKCepsilon-isoform.

OBJECTIVE: Myocardial protection can be achieved by brief ischemia-reperfusion of remote organs, a phenomenon described as remote preconditioning (RPC). Since the intracellular mechanisms of RPC are not known, we tested the hypothesis that RPC might activate myocardial PKCepsilon, an essential mediator of classical ischemic preconditioning. Furthermore, we tried to delineate the mechanisms by which RPC is transduced to the heart with respect to the possible contribution of kinins and neuronal reflexes. METHODS: Anesthetized rats were randomised to undergo either 30 min of waiting (controls) or RPC (brief mesenteric artery occlusion followed by reperfusion) in the absence or presence of chelerythrine (5 mg kg(-1)), a specific PKC inhibitor. Myocardial infarct size was measured by TTC staining after 30 min of coronary artery occlusion followed by 150 min of reperfusion. In separate sets of experiments RPC was performed with or without pretreatment with HOE140, a selective B(2)-antagonist or hexamethonium was used to explore the influence of ganglion blockade on RPC. Translocation of PKCepsilon from cytosol to the particulate fraction was measured by quantitative immunoblotting. RESULTS: RPC significantly reduced infarct size which was completely blocked by the PKC inhibitor. RPC shifted the ratio between cytosolic and particulate PKCepsilon, an indicator for PKC-activation, from 0.95+/-0.06 in controls to 0.41+/-0.09 (P<0.05), and this effect was abolished by HOE140. Activation of PKCepsilon could not be achieved after pretreatment with HEX (0.69+/-0.06 in HEX vs. 0.78+/-0.06 in HEX+RPC). CONCLUSIONS: RPC activates myocardial PKCepsilon through a neuronal and bradykinin-dependent pathway. We assume that activation of PKCepsilon is an important step in cardioprotection induced by remote preconditioning.

Adrenergic beta-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

Sexually dimorphic expression of prepro-orexin mRNA in the rat hypothalamus.

The neuropeptides orexin A and B are expressed in the lateral hypothalamic area and are involved in the regulation of energy homeostasis and arousal. Recent results showed gender differences in the expression of orexin receptor subtypes in rats. In the present study, we analyzed the mRNA expression of prepro-orexin (PPO) in the hypothalamus of male and female rats using quantitative real-time PCR. We found significantly higher levels of PPO mRNA in the hypothalamus of female rats compared to male rats. Our study indicates a sex-dependent regulation of hypothalamic PPO expression and suggests gender-specific functions of orexins.

Animals↗
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↗