Biomedical subjects

T Unger

Publications and source records attributed to T Unger.

At least 127 records · Page 7Linked to original sources

PubMed1997

Antihypertensive and cardioprotective effects after angiotensin-converting enzyme inhibition: role of kinins.

Kinins are potent bioactive peptides formed by the enzymatic action of kallikrein on kininogens. The discovery that angiotensin-converting enzyme, which generates angiotensin II, is also a major degrading enzyme of kinins, gave rise to the hypothesis that kinin potentiation, in addition to angiotensin II reduction, may be involved in the therapeutic actions of angiotensin-converting enzyme inhibitors. Angiotensin-converting enzyme inhibitors have become important drugs in the treatment of hypertension, congestive heart failure, postmyocardial infarction, and diabetic nephropathy. Although angiotensin II reduction appears to be the predominant mechanism of the antihypertensive effect of chronic angiotensin-converting enzyme inhibitor treatment, the role of kinins in the antihypertensive effects of angiotensin-converting enzyme inhibitors seems to be renin dependent and cannot be generalized for all models of hypertension. On the other hand, at least under experimental conditions, various cardioprotective effects of angiotensin-converting enzyme inhibitors appear to be due to the potentiation of endogenous kinins, including improved cardiac function, structural changes following myocardial ischemia, and induction of capillary growth in hypertension-induced left ventricular hypertrophy.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

[Palliative intraoperative irradiation of recurrent neck lymph node metastases in the head and neck area].

BACKGROUND: In the course of a malignant tumor disease, metastases in the regional lymph nodes commonly are linked with poor prognosis. Especially in cases of recurrence after surgery and radiation therapy, curative management of the disease can rarely be achieved. Therefore several palliative treatment modalities have been developed. Intraoperative radiation therapy represents one of them it allows a single high-dose irradiation of a region which, in light of the global tumor disorder, cannot be cured by surgical intervention. METHODS/ PATIENTS: Between 1989 and 1994, 70 patients with recurrent metastases in the head and neck lymph nodes were treated with IORT in the ENT Department of the University Hospital Aachen in collaboration with the Radiation Department. Since some patients were irradiated up to four times, 91 operations (77 under general anesthesia and 14 under local anesthesia) and irradiations were performed. During the procedure each, patient had to be transported twice from the standard operating suite to the radiation unit and back. RESULTS: Regarding the palliative intention of IORT in these cases, we mainly evaluated parameters which had an influence on quality of life of the patients: duration of hospitalization, pain treatment, removal of necrotic tumor mass, and safety of treatment. Depending on the general condition, the patients stayed in the hospital for 3-56 days (median: 10 days). In almost every case, mental and to some extent physical integrity was restored for some time after the disfiguring tumor on the neck had been removed. In nearly 90%, pain treatment could be reduced (e.g., discontinuation of opiate treatment) or further progression could be avoided (74%). Despite the transportation only few complications occurred, which primarily involved healing disturbances (n = 8), fistulas (n = 3), and edemas of the arm (n = 2; after primary treatment of breast cancer). There was no serious infection observed under prophylactic antibiotic treatment in 74% of the cases. Local tumor control (LTC), which only was of minor interest in this treatment group, was possible depending on the extent of tumor resection that could be achieved during the surgical approach: R0 resection = > 50% LTC/R1 resection = > 40% LTC/R2 resection (72.5% of the cases) = > 24.8% LTC. Follow-up of the surviving patients lasted 6-26 months (mean: 14.4 months) but generally did not allow an exact assessment of the time of tumor control. CONCLUSIONS: IORT of recurrent metastases in the head and neck region in our opinion represents an effective alternative for palliative treatment. Important aspects of the patients' quality of life could be improved, and patients were then able to take part in social life again for some time. On the other hand tumor control was not to be expected since in most of the cases only an incomplete tumor resection was achieved. However, the extent of resection substantially affects local tumor control in the head and neck region.

Combined Modality Therapy↗

PubMed1997

Hypertension caused by chronic intermittent hypoxia--influence of chemoreceptors and sympathetic nervous system.

BACKGROUND: The sleep apnea syndrome (SAS) is a common health problem with a 30% prevalence among patients with so-called essential hypertension. OBJECTIVE: Prompted by this epidemiologic link we tried to find out whether there is a cause-effect relationship between SAS and systemic hypertension. DESIGN: We developed an animal model to simulate defined aspects of the SAS. Rats were exposed to chronic repetitive hypoxia for 7 h per day and their blood pressure was measured by invasive methods. RESULTS: We found that 30 days of intermittent hypoxia sufficed for the development of a significant elevation of blood pressure. The co-exposure to hypoxia and hypercapnia had no additional effect. Surgical denervation of peripheral chemoreceptors prevented the increase in arterial blood pressure. Adrenal demedullation and chemical denervation of the peripheral sympathetic nervous system by 6-hydroxy dopamine also prevented the increase. CONCLUSIONS: Our data imply that repetitive hypoxemia in SAS is probably the cause of the high prevalence of systemic hypertension in this population and that peripheral chemoreceptors and the sympathetic nervous system play important roles in this pathophysiologic process.

Adrenal Medulla↗

PubMed1997

Renal expression of two rat kallikrein genes under diabetic conditions.

OBJECTIVE: We have reported that bradykinin (BK) excretion is increased in severely diabetic rats, independent of the activity of the main renal kinin-forming enzyme, true kallikrein (KLK). To further investigate the relationship between renal BK excretion and renal KLK in diabetes we studied the regulation of the renal kallikrein-like gene, rat kallikrein 7 (rKLK7), as well as of the KLK encoding gene, rKLK1, in streptozotocin-induced (STZ) diabetic rats. METHODS: Experiments were performed in STZ-induced diabetic male Wistar rats and their non-diabetic controls (n = 7 each group). Twelve weeks after STZ injection, urinary KLK activity, glomerular filtration rate and total protein excretion were determined. After extraction of total renal cortical RNA, specific oligonucleotides were used to generate a reverse transcription-polymerase chain reaction (RT-PCR) products of renal cortical rKLK1 and rKLK7 messenger (m)RNA. Southern blot analysis of these RT-PCR products were hybridized with appropriate gene-specific oligonucleotide probes. RESULTS: After 12 weeks, the rats showed hyperglycemia, proteinuria and a reduced glomerular filtration rate. Renal kininogenase was reduced, as indicated by a reduction in the expression of rKLK1, as well as of the KLK-related gene, rKLK7. CONCLUSIONS: Our data show that the expression of the two principal renal KLK genes is downregulated in the renal cortex of STZ-diabetic rats. We suggest that under severe diabetic conditions the rise in urinary BK excretion is not related to activation of the renal kinin-forming enzyme system.

Actins↗

PubMed1997

Effects of bradykinin and icatibant on renal hemodynamics in conscious spontaneously hypertensive and normotensive rats.

We investigated the effects of bradykinin (BK) and icatibant (HOE 140), a highly selective bradykinin-B2-receptor antagonist, on mean arterial blood pressure (MAP), heart rate (HR), renal blood flow (RBF), and renal vascular resistance (RVR) in conscious Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Experiments were performed in conscious male WKY rats and SHRs instrumented over the long term with arterial and venous catheters and a transit-time flow probe for measurement of RBF. In WKY rats (n = 16), intraaortic (i.a.) bolus injections of BK (0.1, 1.0, and 10 microg) produced dose-dependent decreases in MAP and RBF with reciprocal increases in RVR. Intrarenal (i.r.) injections of BK (10 microg; n = 6) induced the same hemodynamic response pattern, although the increase in RVR was higher compared with i.a. injections (p < 0.05). Neither vasopressin V1-receptor nor alpha1-adrenoceptor blockade had an effect on the renal vasoconstrictor responses on i.a. BK. The i.a. injections of icatibant (0.1, 1.0, 5.0, and 10 microg; n = 6-10 for each dose) led to a dose-dependent blockade of the hemodynamic responses to BK (10 microg, i.a.). Icatibant (10 microg, i.a) had no effect on resting MAP and HR but induced a biphasic response in RBF and RVR with significant changes compared with basal values (p < 0.05). In SHRs (n = 9), after injection of increasing i.a. doses of BK (0.1, 1.0, and 10 microg), dose-dependent decreases in MAP were proportionately greater compared with those in WKY rats. In contrast to WKY rats, RBF and RVR exhibited a biphasic response pattern on BK in SHRs. Neither vasopressin V1-receptor nor alpha1-adrenoceptor blockade had an effect on the renal vasoconstrictor responses on i.a. BK. The i.a. injections of icatibant (10 microg) almost completely blocked the hemodynamic responses on BK in SHRs (n = 13). Icatibant (10 microg, i.a.) itself induced an increase in resting MAP and HR (p < 0.05) and a biphasic response in RBF and RVR with significant changes of basal values (p < 0.05). Our results provide evidence that BK exhibits renal vasoconstrictor and vasodilator properties in vivo, both mediated by B2-receptors. Furthermore, we demonstrated that SHRs display an increased B2-receptor-mediated vasodilatory responsiveness to BK. Finally we showed that blockade of B2 receptors leads to an increase of MAP in SHRs in contrast to WKY rats, suggesting an important role of the kallikrein/kinin system in the regulation of high blood pressure in SHRs.

Adrenergic alpha-1 Receptor Antagonists↗

PubMed1997

Circulating Na+/K+-ATPase inhibitors: effects of neuropeptides, volume expansion and salt loading in conscious rats.

1. In mammalian plasma, many different inhibitors of Na+/K(+)-ATPase are present, but it is not clear whether their net effect on NA+/K(+)-ATPase activity changes during the regulation of electrolyte and fluid balance. We studied Na+/K(+)-ATPase inhibition by plasma extracts in conscious rats during short- and long-term body fluid regulation. 2. Male, adult, conscious, freely moving Wistar rats were subjected to one of the following protocols: (i) intracerebro-ventricular (i.c.v.) injections of angiotension II (AngII; 1, 10 and 100 ng), the AngII receptor antagonist losartan (1 microgram), atrial natriuretic peptide (ANP-III; 1 microgram) or isotonic saline (IS); (ii) intra-arterial (i.a.) injections of IS (6 or 10 mL), hypertonic saline (HS; 1.2% NaCl, 5 mL) or hypertonic plasma expander (HPS; 3.5% hetastarch in HS, 5 mL); or (iii) a low salt-high salt-low salt diet sequence (0.18/1.8/0.18% NaCl chow for 5 days each with controls receiving 0.18% NaCl on all days). Bodyweight, the intake of food and water, urine volume and Na+ concentration and weight of faeces were determined daily. Plasma samples were withdrawn repeatedly throughout the respective protocols, extracted on C18-reversed phase columns and assayed for their effect on the activity of different Na+/K(+)-ATPase preparations. 3. The inhibition of rat brain Na+/K(+)-ATPase by plasma extracts was not significantly changed by i.c.v. injection of AngII, losartan, ANP-III and IS within the observation period (30 min from respective stimuli). Similarly, no significant changes occurred after acute volume expansion by i.a. injection of IS or HS within 120 min; upon HPS, however, Na+/K(+)-ATPase inhibition was decreased by approximately 20% (P < 0.05), probably due to passive dilution. During the high-salt diet, fluid retention was effectively counteracted by an adaptive increase of urinary sodium excretion. Throughout the protocol, inhibition of pig brain Na+/K(+)-ATPase by plasma extracts did not differ significantly between groups. 4. It is concluded from these results that the short- or long-term control of body fluids in conscious rats is not associated with systematic changes in Na+/K(+)-ATPase inhibition by plasma factors.

Angiotensin II↗

PubMed1997

Effect of chronic volume overload on baroreflex control of heart rate and sympathetic nerve activity.

Baroreceptor-heart rate reflex sensitivity is decreased in congestive heart failure. The reflex control of heart rate and sympathetic nerve activity in rats with chronic volume overload, an established model for moderate heart failure, is still unknown. Therefore, we investigated the regulation of humoral and neuronal sympathetic activity and the baroreflex control of heart rate and sympathetic nerve activity in conscious, unrestrained rats with aortocaval shunt. Rats with aortocaval shunts had larger hearts (388 +/- 11 vs. 277 +/- 4 mg/100 g body wt), elevated central venous pressures (14 +/- 4 vs. 4 +/- 3 mmHg), and higher atrial natriuretic peptide plasma levels (87 +/- 16 vs. 25 +/- 3 pmol/l) than controls but had similar systemic blood pressure and heart rate values. Plasma epinephrine (0.63 +/- 0.16 vs. 0.21 +/- 0.08 pmol/l, P < 0.05) and norepinephrine concentrations (0.27 +/- 0.03 vs. 0.16 +/- 0.02 pmol/l, P < 0.05) were elevated in shunted rats compared with controls. Nitroprusside-induced hypotension led to a significantly greater increase in efferent splanchnic sympathetic nerve activity in shunted rats than in controls (0.9 +/- 0.1 vs. 2.6 +/- 0.6 microV, P < 0.05), whereas the heart rate responses were not different between the groups. These results indicate that the regulation of the autonomic nervous system is altered in chronically volume-overloaded rats. The arterial baroreflex control of efferent splanchnic sympathetic nerve activity was dissociated from the control of heart rate. Therefore, analysis of the activation of sympathetic nervous system assessed by direct measurements of efferent sympathetic nerve activity appears to be more sensitive for the detection of altered autonomic nervous system function than the analysis of baroreflex control of heart rate.

Animals↗

PubMed1997

Blockade of bradykinin B2 receptors prevents the increase in capillary density induced by chronic angiotensin-converting enzyme inhibitor treatment in stroke-prone spontaneously hypertensive rats.

We investigated the mechanism of action of the ACE inhibitor-induced increase in cardiac capillary length density. Stroke-prone spontaneously hypertensive rats were treated prenatally and up to the age of 20 weeks with the ACE inhibitor ramipril (0.01 and 1 mg/kg per day PO) and the AT1 receptor antagonist losartan (30 mg/kg per day PO). The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment with the bradykinin B2-receptor antagonist Icatibant (0.5 mg/kg per day, SC via osmotic minipumps) from 6 to 20 weeks of age. At the end of the treatment period, cardiac capillary length density was measured stereologically using the orientator method. The development of hypertension and left ventricular hypertrophy was prevented by high- but not low-dose ramipril and was not affected by chronic bradykinin B2-receptor blockade. Low- and high-dose ramipril significantly increased cardiac capillary length density (3577 +/- 279, n = 11 and 3988 +/- 300 mm/mm3; n = 10; P < .05) compared with vehicle-treated animals (2935 +/- 137 mm/mm3; n = 13). These effects were abolished by chronic bradykinin B2-receptor blockade. The bradykinin antagonist alone was without effect on cardiac capillary length density. Losartan prevented hypertension and left ventricular hypertrophy but did not significantly alter cardiac capillary length density (3429 +/- 309 mm/mm3; n = 7). Our results demonstrate that chronic ACE inhibitor treatment can increase cardiac capillary length density in stroke-prone spontaneously hypertensive rats independently of a reduction in blood pressure or left ventricular hypertrophy. This effect is related to the ACE inhibitor-induced potentiation of endogenous bradykinin since it was prevented by chronic bradykinin B2-receptor blockade and was not observed following antihypertensive treatment with the AT1-receptor antagonist losartan.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

Increased brain transcription factor expression by angiotensin in genetic hypertension.

A stimulated brain renin-angiotensin system has been implicated in genetic hypertension. We compared the effects of an intracerebroventricular injection of angiotensin II (100 ng) on the expression of inducible transcription factors c-Fos, c-Jun, and Krox-24 in the brain of spontaneously hypertensive rats (SHR). in Wistar rats with nephrogenic hypertension induced by aortic banding, and in normotensive Wistar-Kyoto and Wistar rats immunohistochemically. Generally, the angiotensin II-induced transcription factor expression was strictly confined to four distinct forebrain areas: the subfornical organ, median preoptic area, paraventricular nucleus, and supraoptic nucleus. In SHR, the angiotensin II-induced c-Fos and c-Jun expressions were significantly enhanced compared with those in normotensive control strains as well as in secondary hypertensive Wistar rats. Krox-24 expression in the subfornical organ, median preoptic area, and paraventricular nucleus of SHR was also significantly increased compared with that in all control strains. In the supraoptic nucleus, significant differences could be discriminated between SHR and secondary hypertensive Wistar rats. Injection of isotonic saline or arginine vasopressin (100 ng) as controls did not induce any expression of c-Fos, c-Jun, or Krox-24. Our findings demonstrate an enhanced sensitivity of SHR to angiotensin II-induced transcription factor expression in distinct brain areas involved in central blood pressure and osmotic control that is independent of blood pressure.

Angiotensin II↗

PubMed1997

Contribution of bradykinin to the cardioprotective action of angiotensin converting enzyme inhibition in hypertension and after myocardial infarction.

Angiotensin converting enzyme (ACE) is identical with kininase II. Besides reducing the production of angiotensin II, inhibition of ACE potentiates the biological actions of endogenous kinins. In hypertension-induced left ventricular hypertrophy, potentiation of endogenous kinins contributes to the improvement of cardiac function and energy metabolism and to capillary proliferation effected by ACE inhibitors. In myocardial infarction (MI), the potentiation of kinins has been shown to be involved in the reduction of infarct size and improvement of cardiac function by ACE inhibition. The cardioprotective actions of ACE inhibition in MI seem to be, in part, mediated by the augmentation of myocardial blood flow, especially in the ischemic region of the heart.

Angiotensin-Converting Enzyme Inhibitors↗

PubMed1997

Extrarenal aspects of angiotensin II function.

The cloning of angiotensin II (Ang II) receptor genes and the availability of specific receptor ligands allows characterization of Ang II receptor-mediated actions. Most of the well-known Ang II effects such as vasoconstriction, drinking response and cell proliferation are mediated through the AT1 receptor. Little is known about the physiological effect of the AT2 receptor, though there are some reports describing the involvement of the AT2 receptor in blood pressure regulation. Recent data demonstrate that the AT2-mediated actions are inhibitory to AT1- and mitogen-induced growth effects, indicating a balancing mechanism for Ang II-controlled mechanisms. It has also been demonstrated that AT2 receptor inactivation induces endothelial cell proliferation in the presence of Ang II. Additionally, AT2 receptor activation enhances nerve growth factor-induced differentiation of PCI2W cells and a role in apoptotic changes has also been reported. Based on recent findings, this article focuses on the role of Ang II in growth and differentiation processes with respect to the AT2 receptor in these events.

Angiotensin II↗

PubMed1997

The role of angiotensin receptors in cardiovascular diseases.

As an antihypertensive regimen, angiotensin I-converting enzyme (ACE) inhibition appears to have an antiproliferative cardiovascular effect that is not caused by blood pressure reduction alone. On the other hand, ACE inhibition has been shown to induce neocapillarization in hypertrophied myocardium. The possible mechanisms behind these beneficial cardiovascular effects of ACE inhibition are the suppression of angiotensin II formation and the potentiation of bradykinin. Angiotensin II receptor antagonism appears to have a similar antiproliferative effect on myocardium and vascular smooth muscle as ACE inhibition. This suggests that the antiproliferative action of both regimens is due only to the reduction of the pressor and growth effects of angiotensin II, or that both regimens have an additional, similarly effective antiproliferative action. Recently, knowledge about angiotensin II receptors has almost exponentially expanded. The two main classes of angiotensin II receptors, type 1 and 2 (AT1 and AT2), have been shown to belong to the same receptor family. However, their signal transduction and function seem to differ totally. The function and signal transduction of AT1 are to a large extent known. All the well-known physiological and pathophysiological effects of angiotensin II have been attributed to AT1. On the other hand, AT2 has quite recently been shown to mediate antiproliferation and differentiation at least in some tissues and cells, e.g. in vascular endothelial cells and some cells of neuronal origin. This review highlights the recent findings on angiotensin II receptors, and discusses the mechanisms behind the beneficial cardiovascular effects of interfering with the renin-angiotensin system.

Animals↗

PubMed1997

Effect of tachykinin receptor inhibition in the brain on cardiovascular and behavioral responses to stress.

The neurokinins, substance P (SP) and neurokinin A (NKA) represent natural, nonspecific ligands of NK1 and NK2 receptors. In our study in conscious rats, we tested the hypothesis that neurokinins, especially SP, are used by neuronal circuits to generate cardiovascular and behavioral responses to stress by using the selective, high-affinity, nonpeptide antagonists of NK1 and NK2 receptors, CP-96, 345, RP 67580 and SR 48968, respectively, Formalin injected s.c. through a chronically implanted catheter in the region of the lower leg was used as a stress stimulus. The antagonists and their inactive enantiomers, RP 68651 and SR 48965, as a control for nonspecific activity, were injected intracerebroventricularly (i.c.v.) 10 min before the s.c. injection of formalin. Formalin (2.5%, 50 microliters, s.c.) induced a marked increase in mean arterial pressure (MAP) and heart rate (HR) as well as hind limb grooming/biting (HG) as the dominant behavioral manifestation. Pretreatment with the NK1 receptor antagonist, CP-96,345 (5 nmol, i.c.v.), significantly attenuated only the HR (-54%; P < .01) but not the MAP response to formalin. The NK1 receptor antagonist, RP 67580, injected i.c.v. at doses of 100, 500 and 2500 pmol significantly reduced both, the MAP and HR responses to formalin by maximally 63% (P < .01) and 52% (P < .01), respectively. In a separate set of experiments, we compared the effect of the individual and simultaneous blockade of central NK1 and NK2 receptors on the cardiovascular and behavioral responses to formalin stress. Pretreatment with RP 67580 (100 pmol, i.c.v.) attenuated the MAP (-30%; P < .05), HR (-40%; P < .01) and HG (P < .05) responses to formalin. The NK2 receptor antagonist, SR 48968 (650 pmol, i.c.v.), affected neither the cardiovascular nor the behavioral responses. i.c.v. pretreatment with both tachykinin receptor antagonists (RP 67580: 100 pmol; SR 48968: 650 pmol) reduced the MAP, HR and HG responses to formalin to the same extent as RP 67580 alone. Pretreatment with the inactive enantiomers, RP 68651 (100 pmol, i.c.v.) and SR 48965 (650 pmol, i.c.v.) did not alter the cardiovascular and behavioral responses to formalin. Our results demonstrate that centrally administered NK1 receptor antagonists inhibit the cardiovascular and behavioral reactions in response to a noxious stimulus. They provide first pharmacological evidence that endogenous SP acts as mediator of stress responses in the brain.

Animals↗

PubMed1996

Complex activation of inducible transcription factors in the brain of normotensive and spontaneously hypertensive rats following central angiotensin II administration.

The effects of intracerebroventricular (i.c.v.) injections of angiotensin II (Ang II) on the expression of inducible transcription factors (ITF) (c-Fos, FosB, c-Jun, JunB, JunD, Krox-20 and Krox-24) in the brain of conscious rats were assessed immunohistochemically using polyclonal antisera. Ang II (1, 10, 100 ng) induced after 90 min a dose-dependent expression of c-Fos, FosB, c-Jun, JunB and Krox-24, which was confined to four specific brain areas, namely the subfornical organ (SFO), median preoptic area (MnPO), paraventricular nucleus (PVN) and supraoptic nucleus (SON). In the above-mentioned regions, JunD exhibited a high basal staining which was not visibly altered by Ang II. Krox 20 was not induced by AnG II. FosB was only induced 4 h after i.c.v. injection of 100 ng Ang II in the MnPO and PVN. The Ang II-AT1 receptor antagonist, losartan, applied i.c.v. 5 min prior to Ang II (100 ng, i.c.v.) prevented the Ang II-induced ITF expression. In spontaneously hypertensive rats (SHR) but not in Wistar rats with nephrogenic hypertension due to aortic banding (WIab), the Ang II-induced expression of c-Fos, and c-Jun was enhanced in all four areas when compared to normotensive Wistar Kyoto (WKY)- and Wistar (WI) rats. The Ang II-induced expression of Krox-24 in the SFO, MnPO and PVN in SHR was also significantly increased when compared to WKY, WI and WIab rats. Our data demonstrate that a stimulation of periventricular Ang II-AT1 receptors induces a temporally and spatially highly differentiated expression pattern of ITFs restricted to four distinct regions of the forebrain involved in blood pressure regulation and body fluid homeostasis. The points to a strictly regulated expression of target genes in the respective regions. The enhanced Ang II-induced expression of ITFs in SHR compared to normotensive controls is not due to elevated blood pressure itself, since it was not observed in secondary hypertensive rats WIab. Thus, the increased sensitivity to Ang II in SHR appears to be genetically determined. The target genes regulated by Ang II-induced ITFs will have to be identified.

Angiotensin II↗

PubMed1996

The angiotensin II AT2 receptor inhibits proliferation and promotes differentiation in PC12W cells.

Angiotensin II (ANG II) has been implicated in cell growth and differentiation. We investigated the effect of AT2 receptor stimulation on proliferation and morphological differentiation in cells of neuronal origin by using the pheochromocytoma derived cell line, PC12W. ANG II (10(-8)-10(-6) M) inhibited fetal calf serum (FCS)-induced cell proliferation in a concentration dependent manner. In half of the experiments, the epidermal growth factor (EGF) exerted a mitogenic action which was concentration-dependently inhibited by ANG II. In the other half of the experiments, EGF had an antimitogenic effect which was further enhanced by ANG II (maximally at 10(-6) M). Treatment with nerve growth factor (NGF) induced an inhibition of [3H]thymidine incorporation, which was enhanced by ANG II, maximally 25% at the highest concentration. The effects of ANG II on [3H]thymidine incorporation were reflected by those on cell number and were prevented by the AT2 receptor antagonist, PD123177, but not influenced by the AT1 receptor antagonist, losartan. The ANG II-induced inhibition of cell proliferation was paralleled by morphological differentiation in response to daily treatment with ANG II. ANG II also enhanced low-dose NGF-induced neurite formation. Again, these effects of ANG II were abolished by the AT2 receptor antagonist, PD123177. Our data in PC12W cells show that the AT2 receptor not only inhibits growth factor-induced proliferation and enhances the NGF-mediated growth arrest but also induces morphological differentiation in cells of neuronal origin. These findings strongly support the hypothesis that the AT2 receptor promotes differentiation in neuronal cells.

Angiotensin II↗

PubMed1996

Effect of angiotensin AT2 and muscarinic receptor blockade on osmotically induced vasopressin release.

Recently, we have shown that angiotensin II-induced AT1 receptor-mediated vasopressin release can be potentiated by blockade of periventricular AT2 receptors. In the present study, we investigated whether the AT2 receptor also exerts an inhibitory effect on osmotically induced vasopressin release. In addition, we tested the effect of the muscarinic receptor antagonist, atropine, on hyperosmolar saline-induced vasopressin release. Plasma vasopressin levels were determined 90 s after intracerebroventricularly applied hyperosmolar saline (0.2, 0.3 and 0.6 M, 5 microliters) with or without intracerebroventricular pretreatment with 1 nmol of the selective AT2 receptor antagonist, PD 123177 (1-(4-amino-3-methylphenyl)methyl-5-diphenylacetyl-4,5,6,7-tetrahy dro- 1H-imidazo[4,5-c]pyridine-6-carboxylic acid-2HCl), or with 15 nmol of the muscarinic receptor antagonist, atropine. PD 123177 potentiated 0.2 M saline-induced vasopressin release (4.7 +/- 0.8 pg/ml vs. 2.2 +/- 0.3 in vehicle-pretreated controls, P < 0.05), did not affect 0.3 M saline-induced vasopressin release (4.3 +/- 0.7 pg/ml vs. 5.4 +/- 0.6 pg/ml in vehicle-pretreated controls) and reduced 0.6 M saline-induced vasopressin release (10.0 +/- 2.3 pg/ml vs. 17.9 +/- 1.8 pg/ml in vehicle-pretreated controls, P < 0.05). Pretreatment with atropine reduced 0.3 M (2.3 +/- 0.6 pg/ml vs. 5.4 +/- 0.9 pg/ml in vehicle-pretreated controls, P < 0.05) and 0.6 M saline-induced AVP release (4.0 +/- 1.5 pg/ml vs. 18.4 +/- 2.4 pg/ml in vehicle-pretreated controls, P < 0.05) but did not affect 0.2 M saline-induced vasopressin release (2.1 +/- 0.4 pg/ml vs. 3.2 +/- 0.8 pg/ml in vehicle-pretreated controls). Our results suggest that the low saline concentration-induced, AT1 receptor-mediated, vasopressin release is under inhibitory control by periventricular AT2 receptors. Following high saline concentrations, a muscarinic mechanism seems to be predominant on which AT2 receptor stimulation acts in a facilitating manner.

Angiotensin Receptor Antagonists↗

PubMed1996

Bradykinin excretion is increased in severely hyperglycemic streptozotocin-diabetic rats.

The renal kallikrein-kinin system (KKS) was studied in pair-fed streptozotocin (STZ)-induced diabetic rats and compared with age-matched controls. Twelve weeks after STZ injection, rats were normotensive, showed hyperglycemia, proteinuria, polydipsia and reduced glomerular filtration rate (GFR) and body weight. The activities of urinary prekallikrein (PKLK) and kallikrein (KLK) were reduced accompanied by an up to 3-fold increase of bradykinin (BK) excretion compared to controls. The increased BK excretion suggests that the renal KKS in STZ-diabetes is activated and that the reduction in urinary PKLK and KLK activity may be due to an increased consumption of these enzymes or to a negative feedback mechanism. The stimulation of the renal KKS in STZ-diabetes could reflect an attempt of the organism to balance glomerular hypertension.

Animals↗

PubMed1996

Cardiac and vascular effects of long-term losartan treatment in stroke-prone spontaneously hypertensive rats.

In previous studies in stroke-prone spontaneously hypertensive rats (SHRSP), we demonstrated that early-onset, long-term angiotensin-converting enzyme inhibitor treatment improved cardiac function and metabolism and increased aortic cGMP content even at sub-antihypertensive doses. These effects could be prevented by bradykinin type 2 (B2) receptor blockade with icatibant. In the present study, we studied the effects of long-term oral treatment with the angiotensin type 1 (AT1) receptor antagonist losartan (30 mg/kg per day) on functional and biochemical parameters of the heart and on cGMP content in the aorta in SHRSP treated prenatally and subsequently up to the age of 20 weeks. Losartan prevented the development of hypertension and left ventricular hypertrophy. Cardiac function measured ex vivo in isolated perfused hearts was improved, as demonstrated by significant increases in left ventricular pressure (22.4%), differentiated left ventricular pressure (dP/dtmax) (35.1%), and coronary flow (38%). The release of the intracellular enzymes lactate dehydrogenase and creatine kinase and of lactate into the coronary effluent was reduced by 46.4%, 47.2%, and 63.6%, respectively. In myocardial tissue, the concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 43.2%, 33.1%, and 42.4%, respectively, whereas lactate was decreased by 57.0%. The aortic tissue content of cGMP was increased fivefold. Our results demonstrate that chronic blockade of AT1 receptors with losartan improved cardiac function and metabolism and increased aortic cGMP content in SHRSP to an extent similar to that observed previously after long-term angiotensin-converting enzyme inhibitor treatment at a comparably antihypertensive dose. Prevention of hypertension and cardiac hypertrophy as well as stimulation of non-AT1 receptors are discussed to explain the cardiac and vascular actions of losartan.

Angiotensin Receptor Antagonists↗