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Biomedical subjects

A Dendorfer

Publications and source records attributed to A Dendorfer.

At least 19 recordsLinked to original sources
PubMed2006

Effects of candesartan and enalaprilat on the organ-specific microvascular permeability during haemorrhagic shock in rats.

BACKGROUND: To counteract the contribution of angiotensin II to shock-induced ischaemic organ damage pharmacologic blockade of the renin-angiotensin-system (RAS) is currently under investigation. To evaluate potential side-effects of RAS blockade regarding capillary leak, we studied alterations in microvascular permeability in various organs during haemorrhagic shock (HS) in rats pretreated with candesartan (AT(1)-receptor antagonism) or enalaprilat (ACE-inhibition). METHODS: Thirty-eight instrumented and anaesthetized animals received either candesartan, enalaprilat or placebo. Within each of the three groups 6-7 animals were exposed to HS and 6 animals of each group served as normovolaemic controls. After 30 min of shock, 50 mg kg(-1) Evans blue (EB) was injected i.v. followed by a distribution period of 20 min. Exsanguination was performed with saline, before harvesting organs to quantify albumin-bound EB extravasation. RESULTS: To reduce cardiac output from 37.5 (1.3) to 20.4 (1.1) ml min(-1) [mean (SEM)] in the shock groups, withdrawal of 4.0 (0.25) ml [mean (SEM)] blood was necessary. Simultaneously mean arterial pressure decreased from 77.5 (3.2) to 36.1 (2) mm Hg. Serum lactate increased significantly from 1.3 (0.1) to 3.5 (0.24) mmol litre(-1). Treatment with candesartan increased EB extravasation in the kidney in normovolaemic controls. Specific AT(1) and ACE-blockade before acute non-resuscitated HS significantly increased EB extravasation in the rat ileum by 53 and 66%, respectively. CONCLUSION: This observation of increased microvascular albumin extravasation should be borne in mind for any interventional use of candesartan or enalaprilat during circulatory stress.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2005

ACE inhibitors and angiotensin II receptor antagonists.

The biological actions of angiotensin II (ANG), the most prominent hormone of the renin-angiotensin-aldosterone system (RAAS), may promote the development of atherosclerosis in many ways. ANG aggravates hypertension, metabolic syndrome, and endothelial dysfunction, and thereby constitutes a major risk factor for cardiovascular disease. The formation of atherosclerotic lesions involves local uptake, synthesis and oxidation of lipids, inflammation, as well as cellular migration and proliferation--mechanisms that may all be enhanced by ANG via its AT1 receptor. ANG may also increase the risk of acute thrombosis by destabilizing atherosclerotic plaques and enhancing the activity of thrombocytes and coagulation. After myocardial infarction, ANG promotes myocardial remodeling and fibrosis, and its many pathological mechanisms deteriorate the prognosis of these high-risk patients in particular. Therapeutically, inhibitors of the angiotensin I-converting enzyme (ACEI) and AT1 receptor blockers (ARB) are available to suppress the generation and cellular signaling of ANG, respectively. Despite major differences in the efficacy of ANG suppression and the modulation of other hormones and receptors, both classes of drugs are generally effective in attenuating numerous pathomechanisms of ANG in vitro, and in diminishing the development of atherosclerotic lesions and restenosis after angioplasty in various animal models. In clinical therapy, ACEI and ACE are well-tolerated antihypertensive drugs that also improve the prognosis of heart failure patients. After myocardial infarction and in stable coronary heart disease, ACEI have been shown to reduce mortality in a manner independent of hemodynamic alterations. However, there is little evidence that inhibitors of the RAAS may be effective against arterial restenosis, and a possible benefit of these substances compared to other antihypertensive drugs in the primary prevention of coronary heart disease in hypertensive patients is still a matter of debate, possibly depending on the specific substance and condition being investigated. As such, the general clinical efficacy of ACEI and ARB may be due to a positive influence on hemodynamic load, vascular function, myocardial remodeling, and neuro-humoral regulation, rather than to a direct attenuation of the atherosclerotic process. Further therapeutic advances may be achieved by identifying optimum drugs, patient populations, and treatment protocols.

Angiotensin II Type 1 Receptor Blockers↗
PubMed2003

A miniature self-inflating bag-mask ventilator for rats.

Respiratory depression and apnoea during anaesthesia may lead to hypoxia and myocardial ischaemia. A self-inflating miniature bag-mask device was assembled combining characteristics from the Ambu-bag and the Kuhn-system. This bag-mask device permitted ventilation during anaesthesia-induced apnoea in rats until a safe airway by tracheotomy was achieved.

Anesthesia, General↗
PubMed2002

[Therapy relevant differences in beta blockers and ACE inhibitors. Innovation or plagiarism?].

As exemplified by the two classes of substance beta blockers and ACE inhibitors, the question is considered as to when new developments within a drug family can be termed innovations and when they must be seen purely as plagiarisms ("me-too" preparations). It is noted that in principle no innovations are to be expected from generics, since these substances are are not the subject of specific research. Although large-scale clinical studies in recent years have identified a new indication--cardiac insufficiency--for the beta blockers metoprolol, bisoprolol and carvedilol, this must not be considered an innovation in the sense of a new development. The translatability of the study results to uninvestigated substances is uncertain. In contrast to the beta blockers, the indications for the ACE inhibitors have long been known, but again, the new generic preparations that have come onto the market are not innovations.

Adrenergic beta-Antagonists↗
PubMed2001

Effects of intracoronary low-dose enalaprilat as an adjunct to primary percutaneous transluminal coronary angiography in acute myocardial infarction.

Bradykinin accumulation is a potent cardioprotective mechanism underlying angiotensin-converting enzyme (ACE) inhibition in ischemia and/or reperfusion injury. There is, however, concern about treatment with ACE inhibitors in the very early phase of acute myocardial infarction (AMI) due to adverse systemic hemodynamic effects. We tested the hypothesis that cardiac bradykinin metabolism can be influenced by very low doses of intracoronary ACE inhibitors without harmful systemic effects in patients with AMI. Twenty-two patients with AMI in Killip classes II to III who underwent primary percutaneous transluminal coronary angiography (PTCA) were randomized to intracoronary enalaprilat (50 microg) or saline, given immediately after reopening of the infarct-related artery. Hemodynamics and electrocardiograms were monitored continuously and samples for determination of ACE activity, angiotensin II, bradykinin, kininogen, and cardiac marker proteins were collected from pulmonary arterial and central venous blood. Enalaprilat had no adverse effects on systemic hemodynamics, but rather stabilized arterial pressure and cardiac rhythm during reperfusion. Enalaprilat induced a 70% reduction of ACE activity and a significant increase of bradykinin in pulmonary arterial blood. Angiotensin II was not significantly affected by enalaprilat either in pulmonary arterial or in central venous blood. Myoglobin release was lower and the duration of reperfusion arrhythmias was significantly reduced in the enalaprilat group (p <0.05). Thus, in this pilot study, intracoronary enalaprilat infusion in the infarct-related artery is feasible in the setting of primary angioplasty and is safe and well tolerated. Effective cardiac ACE inhibition can be achieved by low-dose intracoronary enalaprilat, which primarily causes a potentiation of bradykinin.

Angioplasty, Balloon, Coronary↗
PubMed2001

Apstatin, a selective inhibitor of aminopeptidase P, reduces myocardial infarct size by a kinin-dependent pathway.

1. Inhibitors of the angiotensin converting enzyme (ACE) have been shown to exert their cardioprotective actions through a kinin-dependent mechanism. ACE is not the only kinin degrading enzyme in the rat heart. 2. Since aminopeptidase P (APP) has been shown to participate in myocardial kinin metabolism to the same extent as ACE, the aims of the present study were to investigate whether (a) inhibition of APP leads to a reduction of myocardial infarct size in a rat model of acute ischaemia and reperfusion, (b) reduction of infarct size is mediated by bradykinin, and (c) a combination of APP and ACE inhibition leads to a more pronounced effect than APP inhibition alone. 3. Pentobarbital-anaesthetized rats were subjected to 30 min left coronary artery occlusion followed by 3 h reperfusion. The APP inhibitor apstatin, the ACE-inhibitor ramiprilat, or their combination were administered 5 min before ischaemia. Rats receiving HOE140, a specific B(2) receptor antagonist, were pretreated 5 min prior to enzyme inhibitors. Myocardial infarct size (IS) was determined by tetrazolium staining and expressed as percentage of the area at risk (AAR). 4. IS/AAR% was significantly reduced in rats that received apstatin (18+/-2%), ramiprilat (18+/-3%), or apstatin plus ramiprilat (20+/-4%) as compared with those receiving saline (40+/-2%), HOE (43+/-3%) or apstatin plus HOE140 (49+/-4%). 5. Apstatin reduces IS in an in vivo model of acute myocardial ischaemia and reperfusion to the same extent than ramiprilat. Cardioprotection achieved by this selective inhibitor of APP is mediated by bradykinin. Combined inhibition of APP and ACE did not result in a more pronounced reduction of IS than APP-inhibition alone.

Aminopeptidases↗
PubMed2001

Relation of cerebral energy metabolism and extracellular nitrite and nitrate concentrations in patients after aneurysmal subarachnoid hemorrhage.

In a prospective clinical investigation on neurochemical intensive care monitoring, the authors' aim was to elucidate the temporal profile of nitric oxide metabolite concentrations-that is, nitrite and nitrate (NO(x))--and compounds related to energy-metabolism in the cerebral interstitium of patients after aneurysmal subarachnoid hemorrhage (SAH). During aneurysm surgery, microdialysis probes were implanted in cerebral white matter of the vascular territory most likely affected by vasospasm. Temporal profiles of NO(x) were analyzed in a subset of 10 patients (7 female, 3 male, mean age = 47 +/- 14 years). Microdialysis was performed for 152 +/- 63 hours. Extracellular metabolites (glucose, lactate, pyruvate, glutamate) were recovered from the extracellular fluid of the cerebral parenchyma. NO(x) was measured using a fluorometric assay. After early surgery, SAH patients revealed characteristic decreases of NO(x) from initial values of 46.2 +/- 34.8 micromol/L to 23.5 +/- 9.0 micromol/L on day 7 after SAH (P < 0.05). Decreases in NO(x) were seen regardless of development of delayed ischemia (DIND). Overall NO(x) correlated intraindividually with glucose, lactate, and glutamate (r = 0.58, P < 0.05; r = 0.32, P < 0.05; r = 0.28, P < 0.05; respectively). After SAH, cerebral extracellular concentrations of NO metabolites decrease over time and are associated with concomitant alterations in energy-or damage-related compounds. This could be related to reduced NO availability, potentially leading to an imbalance of vasodilatory and vasoconstrictive factors. On the basis of the current findings, however, subsequent development of DIND cannot be explained by a lack of vasodilatory NO alone.

Adult↗
PubMed2001

Angiotensin converting enzyme inhibition improves cardiac neuronal uptake of noradrenaline in spontaneously hypertensive rats.

OBJECTIVES: It has been shown that a diminished sympathetic activity contributes to the hypotensive and cardioprotective actions of angiotensin converting enzyme (ACE) inhibitors (ACEI). Besides an inhibition of central sympathetic tone and peripheral noradrenaline release, we hypothesized that the interactions of ACEI with the sympathetic system may include a modulation of neuronal catecholamine uptake by peripheral nerves. DESIGN: We investigated the influence of fosinopril on noradrenergic uptake into cardiac neurones in vitro and in vivo in acute and chronic models. METHODS AND RESULTS: Acute administration of fosinoprilat to isolated perfused rat hearts increased the extraction of [3H]-noradrenaline from the perfusate by 39%. Treatment (14 days) of spontaneously hypertensive rats (SHR) with fosinopril (20 mg/kg per day) enhanced the cardiac uptake of i.v. administered [3H]-noradrenaline by 28%. The endogenous left ventricular content of noradrenaline was increased by 49% after an antihypertensive treatment of SHR with fosinopril (20 mg/kg per day). Identical increases in cardiac noradrenaline stores (53%) were observed in SHR treated with a blood pressure ineffective dose of fosinopril (0.2 mg/kg per day). The myocardial content of adrenaline was increased in parallel to noradrenaline after both dose regimes. CONCLUSIONS: It is concluded that ACEI increases neuronal uptake of catecholamines in SHR in a blood pressure-independent manner. This effect occurs acutely and is independent of central sympathetic activity. Therefore, we hypothesize that ACEI modulate the activity of the cardiac noradrenaline transporter by direct activation. The improved uptake of noradrenaline may contribute to the antihypertensive and cardioprotective effects of ACEI.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Pathways of bradykinin degradation in blood and plasma of normotensive and hypertensive rats.

Kinins are vasoactive peptide hormones that can confer protection against the development of hypertension. Because their efficacy is greatly influenced by the rate of enzymatic degradation, the activities of various kininases in plasma and blood of spontaneously hypertensive rats (SHR) were compared with those in normotensive Wistar-Kyoto rats (WKY) to identify pathogenic alterations. Either plasma or whole blood was incubated with bradykinin (10 microM). Bradykinin and kinin metabolites were measured by high-performance liquid chromatography. Kininase activities were determined by cumulative inhibition of angiotensin I-converting enzyme (ACE), carboxypeptidase N (CPN), and aminopeptidase P (APP), using selective inhibitors. Plasma of WKY rats degraded bradykinin at a rate of 13.3 +/- 0.94 micromol x min(-1) x l(-1). The enzymes ACE, APP, and CPN represented 92% of this kininase activity, with relative contributions of 52, 25, and 16%, respectively. Inclusion of blood cells at physiological concentrations did not extend the activities of these plasma kininases further. No differences of kinin degradation were found between WKY and SHR. The identical conditions of kinin degradation in WKY and SHR suggest no pathogenic role of kininases in the SHR model of genetic hypertension.

Aminopeptidases↗
PubMed2001

Potentiation of kinin analogues by ramiprilat is exclusively related to their degradation.

The potentiation of kinin actions represents a cardioprotective property of ACE inhibitors. Although a clear contribution to this effect is related to the inhibition of bradykinin (BK) breakdown, the high efficacy of potentiation and the ability of ACE inhibitors to provoke a B(2)-receptor-mediated response even after receptor desensitization has also triggered hypotheses concerning additional mechanisms of kinin potentiation. The application of kinin analogues with enhanced metabolic stability for the demonstration of degradation-independent mechanisms of potentiation, however, has yielded inconsistent results. Therefore, the relation between the susceptibility of B(2)-agonists to ACE and the potentiation of their actions by ACE inhibitors was investigated with the use of minimally modified kinin derivatives that varied in their degree of ACE resistance. The B(2)-agonists BK, D-Arg-[Hyp(3)]-BK, [Hyp,(3) Tyr(Me)(8)]-BK, [DeltaPhe(5)]-BK, [D-NMF(7)]-BK, and [Phe(8)psi(CH(2)-NH)Arg(9)]-BK were tested for degradation by purified rabbit ACE and for their potency in contracting the endothelium-denuded rabbit jugular vein in the absence and presence of ramiprilat. Purified ACE degraded D-Arg-[Hyp(3)]-BK and [Hyp,(3) Tyr(Me)(8)]-BK at 81% and 71% of BK degradation activity, respectively, whereas other peptides were highly ([DeltaPhe(5)]-BK) or completely ([D-NMF(7)]-BK, [Phe(8)psi(CH(2)-NH)Arg(9)]-BK) resistant. The EC(50) of BK-induced venoconstriction (1.15+/-0.2 nmol/L) was reduced by a factor of 5.7 in the presence of ramiprilat. Likewise, D-Arg-[Hyp(3)]-BK and [Hyp,(3) Tyr(Me)(8)]-BK were both significantly potentiated by a factor of 4.4, whereas the activities of the other agonists were not affected. Ramiprilat exerted no influence on the maximum contraction induced by any of the agonists. It is concluded that the potentiation of kinin analogues during ACE inhibition correlates quantitatively with the susceptibility of each substance to degradation by ACE. As such, no evidence of degradation-independent potentiating actions of ACE inhibitors could be obtained.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Prepro-orexin and orexin receptor mRNAs are differentially expressed in peripheral tissues of male and female rats.

Orexins are produced specifically by neurons located in the lateral hypothalamus. Recent results suggested peripheral actions of orexins. Therefore, we analyzed the mRNA expression of prepro-orexin and the orexin receptor subtypes OX(1) and OX(2) in peripheral rat tissues. Using real-time quantitative RT-PCR we detected significant amounts of prepro-orexin mRNA in testis, but not in ovaries. OX(1) receptor mRNA was highly expressed in the brain and at lower levels in the pituitary gland. Only small amounts of OX(1) receptor mRNA were found in other tissues such as kidney, adrenal, thyroid, testis, ovaries, and jejunum. Very high levels of OX(2) receptor mRNA, 4-fold higher than in brain, were found in adrenal glands of male rats. Low amounts of OX(2) receptor mRNA were present in lung and pituitary. In adrenal glands, OX(2) receptor mRNA was localized in the zona glomerulosa and reticularis by in situ hybridization, indicating a role in adrenal steroid synthesis and/or release. OX(1) receptor mRNA in the pituitary and OX(2) receptor mRNA in the adrenal gland were much higher in male than in female rats. In the hypothalamus, OX(1) receptor mRNA was slightly elevated in female rats. The differential mRNA expression of orexin receptor subtypes in peripheral organs indicates discrete peripheral effects of orexins and the existence of a peripheral orexin system. This is supported by the detection of orexin A in rat plasma. Moreover, the sexually dimorphic expression of OX(1) and OX(2) receptors in the hypothalamus, pituitary, and adrenal glands suggests gender-specific roles of orexins in the control of endocrine functions.

Adrenal Glands↗
PubMed2001

Interactions of ligands at angiotensin II-receptors and imidazoline receptors.

Ligands for angiotensin II-(AT)-receptors and imidazoline receptors have structural similarities and influence blood pressure via various mechanisms. The goal of this study was to study the specificity of various ligands by displacement experiments. Antazoline, cimetidine, clonidine, efaroxan, guanabenz, guanethidine, idazoxan, moxonidine and rilmenidine up to a concentration of 100 microM failed to displace the specific binding of [125I]Sar1,Ile8 angiotensin II at the AT1-receptor characterized by losartan (IC50 = 26 +/- 12 nM) in liver homogenate. The same substances up to 100 microM produced no reduction of specific [125I]Sar1,Ile8 angiotensin II binding to the AT2-receptor of phaeochromocytoma cell membranes characterized by PD123319 (IC50 = 20 +/- 5 nM). Displacement experiments at the imidazoline I1-receptors were performed on bovine adrenal medulla membranes using [3H]clonidine after characterization by the I1-ligand clonidine (IC50 = 459 +/- 13 nM) and the I2-ligand idazoxan (IC50 = 3.29 +/- 0.88 microM). The investigated AT-receptor ligands angiotensin II, losartan, EXP 3174 and PD123319 revealed no displacement of [3H]clonidine up to a concentration of 100 microM. The I2-receptor in liver homogenate was characterized by displacement of [3H]idazoxan by cold idazoxan and clonidine (IC50 = 0.37 +/- 0.17 and 68 +/- 31 microM, respectively). The investigated AT-receptor ligands angiotensin II, losartan and PD123319 failed to displace [3H]idazoxan specifically up to 100 microM. Hence, the tested substances showed no cross-reactivity at the corresponding AT- and I-receptors up to 100 microM, a concentration markedly higher than the plasma concentrations achieved after therapeutic application.

Adrenal Medulla↗
PubMed2001

Tissue kallikrein KLK1 is expressed de novo in endothelial cells and mediates relaxation of human umbilical veins.

Bradykinin released by the endothelium is thought to play an important local role in cardiovascular regulation. However, the molecular identity of endothelial proteases liberating bradykinin from its precursors remained unclear. Using RT-PCR and Southern blotting techniques we detected mRNA for tissue kallikrein (KLK1) in human umbilical vein endothelial cells and in bovine aortic endothelial cells. Protein expression was confirmed by precipitation of KLK1 from lysates of endothelial cells pre-labeled with [35S]-cysteine/methionine. Partial purification of tissue kallikrein from total endothelial cell extracts resulted in a protein triplet of about 50 kDa in Western blots using specific anti-KLK1 antibodies. The immunodetection of tissue kallikrein antigen in the fractions from ion exchange chromatography correlated with the presence of amidolytic tissue kallikrein activity. Stimulation of endothelial cells with angiotensin II (ANG-II), which recently has been shown to activate the vascular kinin system and to cause vasodilation, resulted in the release of bradykinin and kallidin. ANG-II-dependent relaxation of pre-constricted rings from human umbilical veins was abolished in the presence of a specific tissue kallikrein inhibitor. We conclude that endothelial cells de novo express significant amounts of tissue kallikrein, which likely serves in the local generation of vasoactive kinins.

Amino Acid Sequence↗
PubMed2000

Potentiation of the vascular response to kinins by inhibition of myocardial kininases.

Inhibitors of angiotensin I-converting enzyme (ACE) are very efficacious in the potentiation of the actions of bradykinin (BK) and are able to provoke a B(2) receptor-mediated vasodilation even after desensitization of this receptor. Because this activity cannot be easily explained only by an inhibition of kinin degradation, direct interactions of ACE inhibitors with the B(2) receptor or its signal transduction have been hypothesized. To clarify the significance of degradation-independent potentiation, we studied the vasodilatory effects of BK and 2 degradation-resistant B(2) receptor agonists in the isolated rat heart, a model in which ACE and aminopeptidase P (APP) contribute equally to the degradation of BK. Coronary vasodilation to BK and to a peptidic (B6014) and a nonpeptidic (FR190997) degradation-resistant B(2) agonist was assessed in the presence or absence of the ACE inhibitor ramiprilat, the APP inhibitor mercaptoethanol, or both. Ramiprilat or mercaptoethanol induced leftward shifts in the BK dose-response curve (EC(50)=3.4 nmol/L) by a factor of 4.6 or 4.9, respectively. Combined inhibition of ACE and APP reduced the EC(50) of BK to 0.18 nmol/L (ie, by a factor of 19) but potentiated the activity of B6014 (EC(50)=1.9 nmol/L) only weakly without altering that of FR190997 (EC(50)=0.34 nmol/L). Desensitization of B(2) receptors was induced by the administration of BK (0.2 micromol/L) or FR190997 (0.1 micromol/L) for 30 minutes; the vascular reactivity to ramiprilat or increasing doses of BK was tested thereafter. After desensitization with BK, but not FR190997, an additional application of ramiprilat provoked a B(2) receptor-mediated vasodilation. High BK concentrations were still effective at the desensitized receptor. The process of desensitization was not altered by ramiprilat. These results show that in this model, all potentiating actions of ACE inhibitors on kinin-induced vasodilation are exclusively related to the reduction in BK breakdown and are equivalently provoked by APP inhibition. The desensitization of B(2) receptors is overcome by increasing BK concentrations, either directly or through the inhibition of ACE. These observations do not suggest any direct interactions of ACE inhibitors with the B(2) receptor or its signal transduction but point to a very high activity of BK degradation in the vicinity of the B(2) receptor in combination with a stimulation-dependent reduction in receptor affinity.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2000

Positive inotropic effects of imidazoline derivatives are not mediated via imidazoline binding sites but alpha1-adrenergic receptors.

Imidazoline-binding sites are non-adrenergic receptors and classified into I11/I2 subtypes. There is strong evidence that I1-binding sites, located in the rostro-ventrolateral medulla, are involved in regulation of blood pressure. However, less is known about the peripheral participation of I1-binding sites in cardiovascular reactions. Therefore, the aim of this study was to investigate whether specific imidazoline derivatives influence myocardial contractility and whether imidazoline binding sites are expressed in rat heart. Agmatine, clonidine and idazoxan failed to alter inotropy in left atria within the whole concentration range tested (1 nM - 100 microM), whereas cirazoline (1- 100 microM) and moxonidine (100 microM) increase inotropy by about 20-30%. After preincubation with the alpha1-adrenoceptor antagonist prazosin, the cirazoline and moxonidine stimulated inotropy was antagonized, indicating more an alpha1-adrenergic and less an imidazoline binding site mediated mechanism. Radioligand-binding studies in membranes of left ventricles using [3H]-clonidine to specify I1-binding yielded KD values of 12.7 microM, confirming the functional results of an absence of I1-binding sites in ventricles of rats. However, the existence of low affinity I2-binding sites determined by [3H]-idazoxan labeling could not be excluded since a KD of 0.5 microM was calculated and since competition studies with guanabenz (Ki = 0.1 microM), clonidine (Ki = 58.1 microM) and moxonidine (Ki = 129 microM) confirmed the specificity of the I2-binding.

Agmatine↗
PubMed1999

Mechanisms of bradykinin-induced catecholamine release in pithed spontaneously hypertensive rats.

Kinins have the potential to modulate the sympathetic system. However, the kinin receptor subtypes and secondary mediators involved in vivo are not fully characterized. Earlier studies failed to show complete inhibition by B1- or B2-antagonists of bradykinin-induced catecholamine release, and were impeded by direct stimulatory actions of those substances. Such effects may arise from the involvement of histamine, the release of which is known to be stimulated by bradykinin and kinin-receptor antagonists. The present study was designed to evaluate the significance of B2-receptors and histamine in the bradykinin-induced enhancement of plasma catecholamines in pithed spontaneously hypertensive rats. The effects of bradykinin, the B2-receptor antagonist HOE 140, histamine and the H1-receptor antagonist mepyramine were tested. Administration of histamine dose-dependently increased catecholamine release whereby a marked preference for adrenaline over noradrenaline was seen. The H1-receptor antagonist mepyramine (0.3 mg/kg) prevented this effect. Bradykinin (7.2 microg/kg) enhanced plasma adrenaline and noradrenaline. In doses > or = 10 microg/kg, HOE 140 completely suppressed the bradykinin-induced increase in plasma noradrenaline, while a slight stimulation of adrenaline that even persisted after a high dose of HOE 140 (100 microg/kg), was only abolished by additional administration of mepyramine (0.3 mg/kg). The H1-receptor antagonist at this dose did not influence the effectivity of bradykinin. It is concluded that the bradykinin-induced enhancement of catecholamine release during electrical stimulation is completely (noradrenaline) or predominantly (adrenaline) mediated by B2-receptors. A minor stimulating effect of bradykinin on plasma adrenaline is provoked independently of B2-receptors via histamine acting on H1-receptors.

Adrenergic beta-Antagonists↗
PubMed1999

Is bradykinin a mediator of renal neuropeptide Y effects?

We have previously reported that the bradykinin receptor antagonist icatibant attenuates the neuropeptide-Y-induced diuresis and natriuresis in anaesthetized rats (Am J Physiol 275:F502-F509, 1998). Therefore, we have now determined whether bradykinin mimics tubular responses to neuropeptide Y in acutely pentobarbital-anaesthetized rats. Infusion of the neuropeptide Y receptor agonist peptide YY (2 micrograms kg-1 min-1) enhanced diuresis and natriuresis approximately equal to 2- and 4-fold, respectively, but did not increase urinary bradykinin excretion. Intrarenal infusion of bradykinin (100 ng kg-1 min-1) reduced renal blood flow by approximately equal to 12% and this was abolished by concomitant administration of icatibant (200 ng kg-1 min-1). However, intrarenal bradykinin infusion did not affect creatinine clearance, urine flow rate or sodium excretion (basal values: 0.8 ml min-1, 111 microliters/15 min and 7.7 mumol/15 min, respectively). These data do not support our original hypothesis that bradykinin mediates the renal effects of neuropeptide Y.

Animals↗