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T Unger

Publications and source records attributed to T Unger.

At least 163 records · Page 9Linked to original sources
PubMed1995

The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells.

Angiotensin II (ANG II) is known to be a potent growth promoting factor for vascular smooth muscle cells and fibroblasts but little is known about its influence on growth in endothelial cells. We studied the effects of ANG II on endothelial growth and the role of the angiotensin receptor subtypes involved. Proliferation of rat coronary endothelial cells (CEC) and rat vascular smooth muscle cells (VSMC) was determined by [3H]thymidine incorporation, the MTT-test and by directly counting cells in a coulter counter. Angiotensin AT1- and AT2-receptors were demonstrated by binding studies and by the presence of their respective mRNA through reverse transcription polymerase chain reaction (RT-PCR). In contrast to VSMC, which in culture only express the AT1-receptor, CEC express both, AT1- and AT2-receptors simultaneously up to the third passage. Whereas ANG II stimulated growth of quiescent VSMC, an effect abolished by pretreatment with the AT1-receptor antagonist, losartan, ANG II did not induce proliferation in quiescent CEC. However, after pretreatment of quiescent endothelial cells (< passage 4) with the AT2-receptor antagonist, PD 123177, ANG II induced proliferation. This effect was reversed by additional pretreatment with losartan. ANG II significantly inhibited the proliferation of bFGF-stimulated CEC in a dose-dependent manner by maximally 50%. This effect was prevented by PD 123177 while losartan was ineffective. The AT2-receptor agonist, CGP 42112, mimicked the antiproliferative actions of ANG II, confirming the specificity of the effect. Our results show that the growth modulating actions of ANG II depend on the type of angiotensin receptor present on a given cell. In coronary endothelial cells, the antiproliferative actions of the AT2-receptor offset the growth promoting effects mediated by the AT1-receptor.

Angiotensin I↗
PubMed1995

ACE inhibitors. Drug interactions of clinical significance.

ACE inhibitors are used widely in the treatment of hypertension and congestive heart failure, but there is only limited information on adverse interactions between ACE inhibitors and other cardiovascular or noncardiovascular drugs. The present article provides an overview of this issue, with emphasis on those interactions having the greatest clinical implications. In patients who have been sodium and/or volume depleted by thiazide or loop diuretics, the additional use of ACE inhibitors can lead to an excessive reduction in blood pressure and symptomatic hypotension. An increase in serum potassium levels may occur after coadministration of potassium-sparing diuretics and ACE inhibitors, resulting in hyperkalaemia especially in patients with renal insufficiency. The incidence of acute renal failure may be associated with ACE inhibitor therapy when these drugs are combined with nonsteroidal anti-inflammatory agents and given to patients whose renal function becomes increasingly dependent on angiotensin II and prostaglandins. There is some evidence, albeit scant, linking ACE inhibitors with the induction of lithium toxicity in patients maintained on lithium, and with the occurrence of severe hypersensitivity reactions in patients undergoing haemodialysis, venom immunisation or concomitant allopurinol therapy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1995

Angiotensin II induces the expression of c-fos mRNA in the central nervous system of the rat.

We have investigated the effects of intracerebroventricular injections of angiotensin II in conscious rats on the expression of c-fos messenger RNA (mRNA) in the caudate nucleus, hypothalamus, midbrain and brainstem using semi-quantitative polymerase chain reaction and Northern Blots. RNA analysis revealed the presence of c-fos transcripts in the midbrain and brainstem following icv injections of ANG II. ANG II (1, 10, 100 ng) induced a substantial increase in c-fos mRNA in the brainstem which was significant after 10 ng ANG II, and less after 100 ng. This effect was time-dependent being detectable within 15 minutes and maximal after 60 minutes. This ANG II-induced c-fos mRNA expression was totally inhibited by icv pretreatment with the ANG II-AT1 receptor antagonist, losartan. Our data show for the first time that stimulation of central periventricular AT1 receptors induces the expression of c-fos mRNA in the brain. Thus, ANG II, in addition to its short-term regulatory actions, can participate through transcription factors in neuroplastic processes.

Angiotensin II↗
PubMed1995

Moexipril, a new angiotensin-converting enzyme (ACE) inhibitor: pharmacological characterization and comparison with enalapril.

The pharmacodynamic profile of the new angiotensin-converting enzyme (ACE) inhibitor moexipril and its active diacid, moexiprilat, was studied in vitro and in vivo. In vitro, moexiprilat exhibited a higher inhibitory potency than enalaprilat against both plasma ACE and purified ACE from rabbit lung. Upon oral administration of moexipril (10 mg/kg/day) to spontaneously hypertensive rats, plasma angiotensin II concentration decreased to undetectable levels, plasma ACE activity was inhibited by 98% and plasma angiotensin I concentration increased 8.6-fold 1 h after dosing. At 24 h, plasma angiotensin I and angiotensin II concentrations had returned to pretreatment levels, whereas plasma ACE activity was still inhibited by 56%. Four-week oral administration of moexipril (0.1-30 mg/kg/day) to spontaneously hypertensive rats lowered blood pressure and differentially inhibited ACE activity in plasma, lung, aorta, heart and kidney in a dose-dependent fashion. Equidose treatment (10 mg/kg/day) with moexipril and enalapril over 4 weeks led to comparable decreases in blood pressure, inhibition of plasma ACE and reduction of plasma angiotensinogen and to a similar attenuation of the pressor responses to angiotensin I and potentiation of the depressor responses to bradykinin. In contrast, ACE inhibition in aorta, heart and lung was significantly greater with moexipril than with enalapril, whereas in the kidney both drugs inhibited ACE activity to a similar extent. In summary, moexipril is an orally active ACE inhibitor that is comparable to enalapril in potency and duration of antihypertensive activity. The results of the present study demonstrate that 1) the antihypertensive potency of a given ACE inhibitor cannot be predicted from its in vitro characteristics and 2) the degree of blood pressure reduction does not correlate with tissue ACE inhibition.

Angiotensin I↗
PubMed1995

Experimental evidence for effects of ramipril on cardiac and vascular hypertrophy beyond blood pressure reduction.

In renal hypertensive rats with pressure overload left ventricular hypertrophy the angiotensin converting enzyme inhibitor ramipril, given in a high blood pressure lowering dose as well as in a low, non-antihypertensive dose, prevented and regressed left ventricular hypertrophy. These beneficial effects were abolished by coadministration of the specific bradykinin receptor antagonist (HOE 140) in the prevention--but not in the regression studies. Vascular function of rats with pressure overload left ventricular hypertrophy was impaired, whereas treated animals showed a reversal to normal. The angiotensin II subtype AT1 receptor antagonist, losartan, was barely active in the prevention, however markedly active in the regression of left ventricular hypertrophy. From these experimental studies in rats with pressure overload left ventricular hypertrophy and vascular dysfunction we conclude that inhibition of bradykinin degradation induced by ramipril may contribute to the antihypertrophic action during the prevention phase, whereas attenuation of angiotensin II formation may be more important during the regression period. In another model, the spontaneously hypertensive rat (SHR and stroke prone SHR)--a non-renal hypertensive model--cardiac left ventricular hypertrophy could be reduced by chronic high-dose ramipril treatment in prevention and regression studies, whereas the low dose regimen only reduced left ventricular hypertrophy in the regression experiments. In addition, both doses improved the myocardial capillary supply to the heart leading to improved function and metabolism. In comparison, vascular hypertrophy of the mesenteric artery could only be prevented by early-onset high dose treatment with the angiotensin converting enzyme inhibitor but not once hypertrophy has been established.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1995

Patient-doctor interactions in hypertension.

The interaction between doctors and their hypertensive patients still suffers from a number of shortcomings owing to ignorance and misconceptions on both sides as well as poorly defined mutual goals. In this paper, an attempt is made to define common goals of doctors and patients and to describe the information status of both the patient and the doctor concerning the disease. Problems associated with the management/treatment of hypertension for patient and doctor are addressed, and expectations, attitudes and considerations on 'both sides of the needle' are discussed. Finally, the individual concern of patients and doctors with anti-hypertensive drug treatment is related to frequent problems such as inadequate drug selection on the doctor's side or non-compliance on the patient's side.

Goals↗
PubMed1995

Contribution of kinins to the cardiovascular actions of angiotensin-converting enzyme inhibitors.

From pharmacological investigations and clinical studies, it is known that ACE inhibitors exhibit additional local actions that are not related to hemodynamic changes and that cannot be explained only by interference with the renin-angiotensin system by means of an inhibition of ANG II formation. Because ACE is identical to kininase II, which inactivates the nonapeptide BK and related kinins, potentiation of kinins might be responsible for these additional effects of ACE inhibitors. ACE inhibition, concentration, and time dependently increased the formation of NO and PGI2 in cultured endothelial cells of different origin and from different species, including humans. The specific B2 kinin receptor antagonist, icatibant, suppressed the ACE inhibitor-induced increase in endothelial cyclic GMP accumulation index for NO-formation and, in parallel, attenuated the increase in PGI2 release. In renovascular models of hypertension associated with a stimulated renin-angiotensin system (two-kidney, one-clip), blood pressure reduction by ACE inhibitors was attenuated by icatibant, whereas in rats with genetic hypertension with normal to low plasma renin, blood pressure reduction through ACE inhibitors was not affected. In experimental atherosclerosis in rabbits, ACE inhibitors were able to preserve endothelial function and vascular reactivity and to reduce surface involvement. In the balloon denudation model of carotid arteries in rats, it was found that ACE inhibition markedly reduced neointima formation. However, when the ACE inhibitor was given together with icatibant, its effect was significantly blunted. Perfusion with ACE inhibitors induced a reduction of the incidence, as well as of the duration, of ventricular fibrillation and improved cardiodynamics and myocardial metabolism. BK perfusion induced comparable cardioprotective effects. In addition, perfusion with ACE inhibitors markedly increased the outflow of BK and related kinins from isolated rat hearts. The antiischemic effect of ACE inhibitors and BK were abolished by the addition of L-NNA (1 x 10(-6) mol/l) or icatibant (1 x 10(-9) mol/l). Similar results were found in dogs and rabbits with myocardial infarction. BK and related kinins also seem to be involved in preconditioning and remodeling. The effect of ACE inhibition in LVH was investigated in rats made hypertensive by aortic banding. ACE inhibition with ramipril, in the antihypertensive dose of 1 mg/kg/day for 6 weeks, prevented the increase in blood pressure and the development of LVH. A lower, nonantihypertensive dose of the ACE inhibitor (10 micrograms/kg/day for 6 weeks) had no effect on the increase in blood pressure or on plasma ACE activity, but also prevented LVH after aortic banding.4+ off

Amino Acid Sequence↗
PubMed1995

Osmotically induced natriuresis and blood pressure response involves angiotensin AT1 receptors in the subfornical organ.

OBJECTIVE: In the present study we tested the hypothesis of whether the centrally induced natriuresis and blood pressure increase after intracerebroventricular injection of hypertonic saline involves the subfornical organ, as suggested by the occurrence of osmosensitive cells as well as a high concentration of angiotensin II receptors in this brain area. METHODS: All experiments were performed in conscious Wistar rats. A chronic cannula was inserted into the lateral brain ventricle for intracerebroventricular injection and a chronic indwelling intracranial guide cannula for microinjection was placed in the subfornical organ. In addition, the rats were provided with ureter catheters for urine collection. RESULTS: Intracerebroventricular injections of hypertonic saline (0.3 mol/l; n = 7) increased renal sodium excretion from 180.0 +/- 30.0 to 279.0 +/- 34.0 mol/l/60 min (P < 0.001) accompanied by an increase in mean arterial pressure of 8.3 +/- 1.2 mmHg (P < 0.01). No change in urinary volume was observed. After injection of the specific AT1 receptor antagonist, losartan, into the subfornical organ (5 micrograms/200 nl; n = 8) the natriuresis and blood pressure response to intracerebroventricular hypertonic saline was completely abolished. Control injections of losartan into areas adjacent to the subfornical organ had no effect on the responses to hypertonic saline. CONCLUSION: Our results suggest that the centrally induced natriuresis and blood pressure responses to hypertonic saline are mediated by an angiotensinergic mechanism involving the subfornical organ.

Animals↗
PubMed1995

Growth or antigrowth: angiotensin and the endothelium.

AIM: Antihypertensive drugs that interfere with the renin-angiotensin system, such as angiotensin converting enzyme (ACE) inhibitors and angiotensin II receptor antagonists, are increasingly being perceived to exert effects beyond blood pressure control, for instance on vascular structure and function. In a recent study we demonstrated that early-onset treatment of spontaneously hypertensive rats with an ACE inhibitor induced an increase in myocardial capillary length density independently of the antihypertensive and antihypertrophic actions of the drug. The aim of the present work was to focus on the growth-modulating effects of angiotensin II on vascular cells and the differential role played by the two angiotensin II receptor subtypes, AT1 and AT2, in the regulation of cell growth and differentiation. RESULTS: Recent findings indicate that angiotensin II exerts different growth-modulating actions depending on the presence or absence of angiotensin II receptor subtypes on a given cell. The growth-promoting effect of angiotensin II is mediated by the AT1 receptor and is associated with the increased expression of growth factors and immediate early genes. In endothelial cells, this effect is counteracted by the antiproliferative actions of the AT2 receptor. Angiotensin II may also be involved in the process of angiogenesis and development mediated by AT1 and AT2 receptors expressed in various tissues.

Animals↗
PubMed1994

Further localization of cardiovascular and behavioral actions of substance P in the rat brain.

Cardiovascular and behavioral actions of substance P (SP) were examined after microinjection into the medial preoptic area (MPO), anterior hypothalamic area (AH), and ventral tegmental area (VTA) in conscious unrestrained rats. SP elicited marked increases in mean arterial pressure and heart rate as well as stereotyped behaviors of excessive grooming and exploring when injected into the MPO or AH. In the MPO, the latencies to the cardiovascular responses were observed after SP injection into the VTA. These results, together with our previous results, suggest that SP acts as transmitter or modulator in the rostral hypothalamic areas to elicit cardiovascular defense responses. In contrast, SP may not be involved in causing a defense reaction in the more caudal areas of the defense center.

Animals↗
PubMed1994

Release of angiotensin in the paraventricular nucleus in response to hyperosmotic stimulation in conscious rats: a microdialysis study.

Angiotensin peptides are thought to act as neurotransmitters or neuromodulators in central osmoregulation. We tested the hypothesis that angiotensin peptides are released in the paraventricular nucleus (PVN) of the hypothalamus upon local osmotic stimulation. Brain microdialysis and radioimmunoassay (RIA) techniques were used to measure the release of immunoreactive angiotensin II (irANG II) in the PVN following direct stimulation of this area with hyperosmotic solutions. In conscious rats, perfusion of the PVN with 0.3 M and 0.6 M NaCl in artificial cerebrospinal fluid (aCSF) elicited concentration-dependent increases in irANG II release to 5.52 +/- 0.53, (P < 0.01, n = 8) and 9.01 +/- 1.03 pg/100 microliters, (P < 0.001, n = 7), respectively, from basal values of 3.04 +/- 0.46 pg/100 microliters. Local perfusion of the PVN with 1.2 M glucose in aCSF also resulted in an increased release of irANG II from 3.07 +/- 0.87 to 6.24 +/- 0.45 pg/100 microliters (P < 0.05, n = 5). Fractionization of angiotensin peptides by HPLC followed by RIA revealed that ANG II (1-8) and ANG III (2-8) were released in similar amounts in the perfusate collected during 0.6 M NaCl stimulation (4.79 +/- 0.69 and 3.45 +/- 0.76 pg/100 microliters, respectively). Our results show that both, ANG II and ANG III are released in the PVN in response to local hyperosmotic stimulation. They support the concept that angiotensin peptides in the PVN are involved as neurotransmitters in central osmotic control.

Angiotensin II↗
PubMed1994

Inhibition by morphine of the cardiovascular and behavioral responses evoked by centrally administered substance P in conscious rats.

The effect of endogenous opioid receptor stimulation on the central cardiovascular and behavioral actions of substance P (SP) was examined in conscious rats. SP (55 pmol) injected intracerebroventricularly (i.c.v.) elicited increases in mean arterial pressure, heart rate, and stereotyped behavioral activation such as exploring and grooming, which were considered to be parts of the cardiovascular defense reaction. Intravenous (i.v.) pretreatment with morphine (2.5 and 5.0 mg/kg) attenuated the cardiovascular and behavioral responses produced by SP i.c.v. dose-dependently. The i.v. pretreatment with naloxone (10 mg/kg) had no effect on the central SP-induced response. Pressor responses elicited by i.c.v. injection of corticotropin-releasing factor or angiotensin II were also attenuated by pretreatment with i.v. morphine (5.0 mg/kg). Our results showed that endogenous opioid receptor stimulation antagonizes the central cardiovascular and behavioral actions of SP. Morphine may not influence the primary site of action of SP but does influence the central neural pathway which conveys the SP-induced sympathetic activation signal.

Analysis of Variance↗
PubMed1994

Effect of low-dose treatment with perindopril on cardiac function in stroke-prone spontaneously hypertensive rats: role of bradykinin.

Angiotensin-converting enzyme (ACE) inhibitors can improve cardiac function independent of their blood pressure (BP)-lowering actions. We investigated the effect of chronic subantihypertensive ACE inhibitor treatment on functional and biochemical cardiac parameters in stroke-prone spontaneously hypertensive rats (SHRSP). Animals were treated in utero and subsequently to age 20 weeks with the ACE inhibitor perindopril (0.01 mg/kg/day). The contribution of endogenous bradykinin (BK) potentiation to the actions of the ACE inhibitor was assessed by cotreatment with the BK beta 2-receptor antagonist Hoe 140 (500 micrograms/kg/day subcutaneously, s.c.) from age 6 to 20 weeks and by measurement of myocardial prostacyclin and cyclic GMP concentrations. Chronic low-dose perindopril treatment had no effect on development of hypertension and left ventricular hypertrophy (LVH), but perindopril improved cardiac function, as demonstrated by increased LV pressure (LVP) (19.4%) and LVdp/dtmax (27.8%) but no change in heart rate (HR). The activities of lactate dehydrogenase (LDH) and creatine kinase (CK) as well as lactate concentrations in the coronary venous effluent were reduced by 39.3, 50, and 60.6%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and CK were increased by 16.3, 33.1, and 28.2%, respectively. All ACE inhibitor-induced effects on cardiac function and metabolism were abolished by concomitant chronic BK receptor blockade. Cardiac prostacyclin concentrations were threefold elevated in perindopril-treated animals whereas cardiac cyclic GMP concentration remained unchanged as compared with that of controls. Our data demonstrate that chronic low-dose ACE inhibitor treatment can improve cardiac function and metabolism by potentiating endogenous BK.(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗
PubMed1994

Modulation of autonomic nervous system adjustments to heat stress by central ANG II receptor antagonism.

The purpose of this study was to determine whether central angiotensin II (ANG II) participates in mediating selected sympathetic nervous system and neuroendocrine adjustments to heat stress in conscious freely moving rats. Mean arterial pressure (MAP), heart rate (HR), splanchnic sympathetic nerve activity (SpNA), plasma arginine vasopressin (AVP) concentration, and colonic temperature were measured before and during whole body heating (42 degrees C ambient temperature). Heating was stopped when a colonic temperature of 41 degrees C was attained. On consecutive days, rats received an intracerebroventricular (icv) injection of saline (0.9%) or 25 micrograms of the ANG II AT1-selective receptor antagonist losartan 20 min before the start of heating. Neither treatment influenced control levels of any parameter. The increase above baseline for MAP at the end of heating was attenuated by > 50% in the losartan, compared with the saline trial (P < 0.05), while HR remained unchanged from control values for both trials. Pretreatment with losartan icv eliminated the increase in SpNA observed during the heating period in the saline trial. Furthermore, the magnitude of change in plasma AVP during heating was significantly elevated in rats after icv administration of saline compared with losartan. These findings indicate that central ANG II receptor antagonism significantly attenuates the heating-induced elevations in MAP, sympathetic neural activity to visceral regions, and plasma AVP and suggest that the central nervous system actions of endogenous ANG II are required for full expression of the sympathoexcitatory, pressor, and neuroendocrine responses associated with nonexertional heat stress in the conscious rat.

Angiotensin II↗
PubMed1994

Angiotensin-converting enzyme inhibition improves cardiac function. Role of bradykinin.

The effect of chronic low- and high-dose treatment with the angiotensin-converting enzyme (ACE) inhibitor ramipril (0.01 and 1 mg/kg per day) on the development of hypertension and left ventricular hypertrophy as well as on functional and biochemical alterations of the heart was studied in stroke-prone spontaneously hypertensive rats treated prenatally and subsequently up to the age of 20 weeks. The contribution of endogenous bradykinin potentiation to the ACE inhibitor actions was assessed by cotreatment of rats with the bradykinin B2-receptor antagonist Hoe 140 (500 micrograms/kg per day SC) from 6 to 20 weeks of age. High- but not low-dose ACE inhibitor treatment prevented the development of hypertension and left ventricular hypertrophy. Chronic bradykinin receptor blockade did not attenuate the antihypertensive and antihypertrophic actions of ramipril. High-dose ramipril treatment improved cardiac function, as demonstrated by an increase in left ventricular pressure (29.9%), dP/dtmax (34.9%), and coronary flow (22.1%), without a change in heart rate. The activities of lactate dehydrogenase and creatine kinase and lactate concentration in the coronary effluent were reduced by 39.3%, 55.5%, and 66.7%, respectively. Myocardial tissue concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 31.3%, 39.9%, and 73.7%, respectively, whereas lactate was decreased by 20.8%. Chronic low-dose ACE inhibitor treatment led to a pattern of changes in cardiodynamics and cardiac metabolism similar to that observed with the high dose. All ACE inhibitor-induced effects on cardiac function and metabolism were abolished by chronic bradykinin receptor blockade.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗