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T Unger

Publications and source records attributed to T Unger.

At least 181 records · Page 10Linked to original sources
PubMed1994

Angiotensin-converting enzyme inhibition in infarct-induced heart failure in rats: bradykinin versus angiotensin II.

BACKGROUND: The beneficial effects of angiotensin-converting enzyme (ACE) inhibitors in the prevention of heart failure following myocardial infarction are widely accepted. However, the underlying mechanisms are still a matter of discussion. We therefore investigated the relative contribution of the breakdown of bradykinin and of the inhibition of angiotensin-II synthesis to the beneficial actions of ACE inhibitors in chronic heart failure following myocardial infarction. METHODS: We compared the effects pretreatment with the ACE inhibitor moexipril with those of the type 1 angiotensin (AT1)-receptor antagonist losartan on structural and functional cardiac parameters after myocardial infarction in rats. In addition, the bradykinin B2-receptor antagonist icatabant was used to investigate the role of bradykinin in the cardioprotective effects of ACE inhibition. Rats underwent a sham operation or surgery to induce myocardial infarction. Treatment was started 1 week before myocardial infarction and continued for another 6 weeks after the procedure. RESULTS: Moexipril reduced infarct size (100 +/- 9mm2 compared with 165 +/- 8mm2), the ratio of total heart weight to body weight (2.6 +/- 0.1 g/kg compared with 2.9 +/- 0.1 g/kg) and end-diastolic pressure (8.2 +/- 1.5 mmHg compared with 14.0 +/- 1.7 mmHg). All of these effects of the ACE inhibitor were blocked by concomitant treatment with icatibant. Losartan did not affect any of these cardiac parameters. CONCLUSION: The cardioprotective effects of the ACE inhibitor moexipril administered before myocardial infarction in the present study were a result of the reduced breakdown of kinins rather than of the reduced synthesis of angiotensin II.

Adrenergic beta-Antagonists↗
PubMed1994

[Cardioprotective effects by ramipril after ischemia and reperfusion in animal experiment studies].

ACE inhibitors induce an increase in kinin levels with subsequent release of nitric oxide (NO) and prostacyclin, as shown in cultured endothelial cells and isolated rat hearts. Isolated perfused working rat hearts continuously release kinins and prostacyclin. During ischemia after ligation of the left coronary artery kinin and prostacyclin concentrations in the venous effluent of the hearts are increased. ACE inhibition with ramiprilat increases kinin concentrations during normoxia, ischemia and reperfusion, whereas deendothelialization markedly reduces kinin and prostacyclin outflow in controls as well as in ACE inhibitor-treated hearts. Rat hearts with postischemic reperfusion arrhythmias are protected by ramiprilat- and bradykinin perfusion, cardiodynamics and metabolism of treated hearts are improved. These effects are observed in concentrations too low to increase coronary flow. The cardioprotective effects of ramiprilat and bradykinin are abolished by the specific B2-kinin receptor antagonist icatibant and by an inhibitor of NO-synthase. Long-term treatment (20 weeks) with ramipril in a blood-pressure-lowering dose (1 mg/kg/day) and a subantihypertensive dose (10 micromg/kg/day) protects spontaneously hypertensive rats (stroke prone) against hypertension and left ventricular hypertrophy in the high dose. In addition, both treatment regimens induce myocardial capillary growth. Isolated hearts of these animals show increased myocardial contractility and coronary flow, reduced release of cytosolic enzymes into the coronary effluent, and improved myocardial metabolism. These changes are observed even at a dose of ramipril which does not affect blood pressure and left ventricular hypertrophy. They are abolished by chronic blockade of kinin receptors with icatibant.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

The renin-angiotensin system in the heart and vascular wall: new therapeutic aspects.

Traditionally, the renin-angiotensin system (RAS) has been viewed as an endocrine system. Recently, independent tissue RASs have been postulated that are believed to act in a paracrine/autocrine fashion. Elements of the RAS have been shown to exist in many peripheral tissues. Angiotensin-converting enzyme (ACE), a key element of the RAS, is found mainly in the vascular endothelium and therefore represents the main target site for inhibition of the local and circulating RASs. In the heart, angiotensin II exerts a direct positive inotropic and chronotropic effect. More recently, it was also found that angiotensin II may act as a growth factor in several cell types. Angiotensin II is also thought to be partially responsible for structural remodeling in cardiac hypertrophy. The role of ACE inhibitors has been established in the treatment of hypertension and congestive heart failure. Recent multicenter trials revealed a beneficial role of ACE inhibitors in reduction of mortality rates in patients with congestive heart failure and a low ejection fraction. Mechanisms that include reduction of myocardial oxygen demand, improvement of coronary blood flow, induction of capillary proliferation, reduction of blood pressure and ventricular wall tension without reflex tachycardia, and impairment of myocardial contractility are the basis for the beneficial effects of ACE inhibitors. In addition to a reduction of angiotensin II generation, these effects appear to be largely brought about by the inhibition of endogenous kinin degradation. Recent studies suggest that a deletion polymorphism in the gene encoding ACE is a risk factor in myocardial infarction (MI).(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1994

The carboxy-terminal serine 392 phosphorylation site of human p53 is not required for wild-type activities.

Wild-type p53 functions in the G1 DNA damage checkpoint pathway by activating gene transcription and preventing cell cycle progression. Others reported that mutation of the serine 386 codon in mouse p53 abolished its ability to suppress growth. Serine 386 of murine p53 and the homologous residue of human p53, serine 392, are phosphorylated in vivo and can be phosphorylated in vitro by casein kinase II (CKII). We constructed mutants that changed serine 392 of human p53 to alanine (p53-S392A) or aspartic acid (p53-S392D); cotransfection of both these mutants with a reporter gene carrying a p53-responsive element into the p53-null Saos-2 cell line activated transcription as well as did wild-type p53. Furthermore, both mutants blocked cell cycle progression after transient transfection in these cells. A stable derivative of the T98G human glioblastoma cell line was established that expressed p53-S392A in response to dexamethasone. Overexpression of this mutant activated transcription of the endogenous waf1 (also called cip1) and mdm2 genes to the same extent as wild-type p53 and also produced growth arrest. Finally, p53-S392A and p53-S392D suppressed foci formation by activated ras and adenovirus E1A oncogenes as efficiently as did wild-type p53. Thus, unlike mutants that altered the serine 15 phosphorylation site, elimination of the serine 392 phosphorylation site had no discernible effect on p53 function. We conclude that neither phosphorylation nor RNA attachment to serine 392 are required for human p53's ability to suppress cell growth or to activate transcription in vivo.

Adenovirus E1A Proteins↗
PubMed1993

Effects of tachykinins on phosphoinositide metabolism in the hypothalamus: is the NK1 receptor involved?

Substance P (SP) has been shown to stimulate the hydrolysis of inositol phospholipids in peripheral tissues and in the brain. In mammalian peripheral tissues, three tachykinin receptor subclasses, neurokinin 1 (NK1), neurokinin 2 (NK2) and neurokinin 3 (NK3), have been identified. The purpose of our study was to pharmacologically characterize the SP receptors in the hypothalamus using phosphoinositide breakdown as a functional response. SP, previously described as a NK1 agonist, and Neurokinin A (NKA), previously described as a NK2 agonist, stimulated phosphoinositide breakdown in the hypothalamus in a dose-dependent fashion, with SP being more potent than NKA. The NK2-selective antagonist L-659,877, at a dose of 10(-6) M, abolished the effect of SP (10(-8) M) without affecting basal phosphoinositide breakdown. However, this NK2-selective antagonist did not inhibit the NKA-induced stimulation in phosphoinositide metabolism. The NK1-selective antagonist L-668,169 stimulated phosphoinositide metabolism at a concentration of 10(-6) M, but not at 10(-8) M. This NK1-receptor antagonist did not significantly inhibit the effect of SP on phosphoinositide metabolism. Spantide II, another NK1-selective antagonist, also stimulated phosphoinositide metabolism at a dose of 10(-6) M. Like L-668,169, spantide II failed to inhibit the SP-induced stimulation of phosphoinositide metabolism, and even potentiated the response to SP.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Substance P and neurokinin A induced desensitization to cardiovascular and behavioral effects: evidence for the involvement of different tachykinin receptors.

Desensitization and cross-desensitization to the cardiovascular and behavioral effects elicited by intracerebroventricular (i.c.v.) substance P (SP) and neurokinin A (NKA) injections were examined in conscious, freely moving rats. The cardiovascular responses to equimolar doses of both peptides were identical, however, the pattern of the behavioral responses differed. Relative to SP, NKA was weaker in eliciting hindquarter grooming but more effective in eliciting wet dog shakes. SP pretreatment (50 pmol) desensitized the cardiovascular and behavioral responses to both, subsequent injections of SP (50 pmol) as well as of NKA (50 or 500 pmol) injected 30 or 60 min after SP, indicating cross-desensitization. NKA pretreatment (50 pmol) partly reduced the cardiovascular but not the behavioral responses to subsequent equimolar doses of NKA. The cardiovascular responses to SP (50 pmol) were reduced only 30 min but not 60 min after pretreatment with a 10 times higher dose of NKA (500 pmol). Of all behavioral manifestations to i.c.v. SP, only hindquarter grooming was attenuated by pretreatment with either dose of NKA. The equal potency of SP and NKA in eliciting the cardiovascular effects but different pattern of behavioral responses to these peptides suggest an involvement of different types of tachykinin receptors in mediating the central effects of the two peptides. The fact that NKA induced cross-desensitization selectively to one type of behavioral manifestations elicited by SP, indicates the existence of two subtypes of SP (NK1) receptors in the rat brain.

Animals↗
PubMed1993

Vascular remodeling in systemic hypertension.

It is now well accepted that treatment of hypertension must extend beyond the mere control of blood pressure. Among the objectives "beyond blood pressure control" is the remodeling of resistance and compliance vessels that have usually undergone a process of hypertrophy and/or hyperplasia. Salutary vascular remodeling by antihypertensive treatment not only implies structural changes of the vascular wall, but also functional improvements, including diminished contractile responses to endogenous vasoconstrictors and enhanced relaxation to endogenous vasodilators. We have treated spontaneously hypertensive rats with the angiotensin-converting enzyme (ACE) inhibitors zabicipril, perindopril, and ramipril at antihypertensive and sub-antihypertensive doses and have analyzed vascular morphology and function. Chronic oral treatment was begun before hypertension developed (prevention study). Remodeling of mesenteric vessels with, inter alia, a reduction of the media:lumen ratio was achieved by antihypertensive doses of the drugs. Further, vascular function was improved not only after high-dose, but also after low-dose ACE inhibitor treatment, as tested in the aortic vessels: an inhibition of vascular ACE was associated with attenuated vasoconstrictor responses to norepinephrine and enhanced dilator responses to acetylcholine. In addition, low and high doses significantly increased aortic cyclic guanosine monophosphate (cGMP) content, suggesting an improved vasodilator capacity. Our data demonstrate that improvements of vascular function can be achieved by ACE inhibitors, independently of structural changes and of the antihypertensive action exerted by these drugs.

Acetylcholine↗
PubMed1993

[Autoregulation of kidney circulation, glomerular filtration rate and plasma renin activity in spontaneously hypertensive rats and normotensive Wistar rats].

The autoregulation of renal blood flow (RBF), glomerular filtration rate (GFR) and the pressure dependent renin release into the circulation were studied in conscious chronically instrumented spontaneously hypertensive rats (SHR) and normotensive Wistar rats. Renal perfusion pressure was lowered by means of a suprarenal inflatable cuff on the abdominal aorta and was lowered in pressure steps of 10 mm Hg. Breakoff points for RBF- and GFR-autoregulation as well as the threshold for renin release were calculated using non-linear regression (breakpoint analysis). Wistar rats autoregulated RBF and GFR in a range between 110 and 90 mm Hg (breakoff points: RBF 88 +/- 2 mm Hg; GFR 92 +/- 3 mm Hg). Plasma-renin activity (PRA) showed a threshold of activation at 89 +/- 8 mm Hg. Breakoff points and threshold of renin release did not differ significantly from each other. SHR autoregulated RBF and GFR in a range between 160 and 100 mm Hg (breakoff points: RBF 104 +/- 6 mm Hg; GFR 99 +/- 4 mm Hg). The PRA increase had a threshold at 119 +/- 6 mm Hg. Breakoff points of RBF- and GFR-autoregulation did not differ significantly. In SHR the threshold of renin release was at a significantly higher pressure than the breakoff point of GFR-autoregulation. The comparison between Wistar rats and SHR revealed a significant shift of the RBF-autoregulation curve and the pressure-dependent renin release of SHR towards higher pressures (p < 0.05). The early increase of PRA in SHR suggests a role of the renin-angiotensin-system (RAS) in the autoregulation of GFR in SHR. Wistar rats seem to autoregulate GFR independently of the RAS. An activation of the sympathetic nervous system might take part in the rightward shift of the RBF- and GFR-autoregulation curve in SHR. The role of this altered autoregulatory pattern in the development of genetic hypertension remains to be investigated.

Animals↗
PubMed1993

Functional domains of wild-type and mutant p53 proteins involved in transcriptional regulation, transdominant inhibition, and transformation suppression.

The wild-type (wt) p53 protein has transcriptional activation functions which may be linked to its tumor suppressor activity. Many mutant p53 proteins expressed in cancers have lost the ability to function as transcriptional activators and furthermore may inhibit wt p53 function. To study the mechanisms by which mutant forms of p53 have lost their transactivation function and can act in a dominant negative manner, a structure-function analysis of both mutant and engineered truncated forms of p53 was carried out. We show that different mutant p53 proteins found in cancers vary in the ability to inhibit the transcriptional transactivation and specific DNA binding activities of wt human p53. This transdominant effect was mediated through the carboxy-terminal oligomerization region. The role of the transactivation activity in transformation suppression by wt p53 was also examined by constructing an N-terminal deletion mutant lacking the transactivation domain. This mutant was unable to transactivate but could bind specifically to DNA. Although it was impaired in its ability to suppress transformation of primary rat embryo fibroblasts by adenovirus E1A plus activated ras, the N-terminal deletion mutant still had some suppression activity, suggesting that additional functions of p53 may contribute to transformation suppression.

Animals↗
PubMed1993

Cardiovascular and renal effects of hypoxia in conscious carotid body-denervated rats.

The contribution of peripheral arterial chemoreceptors to cardiovascular and renal responses to acute hypocapnic hypoxia is currently not well understood. We compared the effects of normobaric hypoxia on mean arterial blood pressure (MABP), heart rate, glomerular filtration rate (GFR), renal blood flow (RBF), and renal volume and electrolyte excretion in conscious unilaterally nephrectomized carotid body-denervated (n = 10) and sham-operated (n = 10) control rats. Thirty minutes of normobaric hypoxia (12.5% O2) resulted in significant reductions in arterial PO2 and PCO2 as well as decreases in MABP, GFR, RBF, and renal sodium, potassium, and water excretion. These effects occurred more rapidly and/or were significantly more pronounced in carotid body-denervated than in sham-operated rats. These data indicate that moderate acute hypocapnic hypoxia has profound effects on systemic and renal hemodynamics as well as on renal excretory function in conscious rats. We conclude that stimulation of the peripheral arterial chemoreceptors can partially offset the hypoxia-induced decreases in MABP, RBF, GFR, urine flow, and urinary sodium and potassium excretion, thereby helping to maintain cardiovascular as well as fluid and electrolyte homeostasis.

Animals↗
PubMed1993

Long-term low-dose angiotensin converting enzyme inhibitor treatment increases vascular cyclic guanosine 3',5'-monophosphate.

We investigated functional changes in aortic preparations of spontaneously hypertensive rats treated in utero and subsequently up to 20 weeks of age with the angiotensin converting enzyme (ACE) inhibitors ramipril (0.01 and 1 mg/kg per day) and perindopril (0.01 mg/kg per day). Early-onset treatment with the high dose of ramipril inhibited aortic ACE activity, prevented the development of hypertension, increased aortic vasodilator responses to acetylcholine (10(-8) to 10(-6) mol/L), decreased vasoconstrictor responses to norepinephrine (10(-8) mol/L), and increased aortic cyclic GMP content by 160%. Low-dose ramipril inhibited aortic ACE activity and attenuated the aortic vasoconstrictor response to norepinephrine but had no effect on blood pressure. Low-dose treatment with ramipril and perindopril resulted in a significant increase in aortic cyclic GMP content by 98% and 77%, respectively. Long-term coadministration of the bradykinin B2-receptor antagonist Hoe 140 abolished the ACE inhibitor-induced increase in aortic cyclic GMP. Our data demonstrate that long-term treatment with ACE inhibitors can alter vascular function of compliance vessels independently of the antihypertensive action. The increase in aortic cyclic GMP was due to bradykinin potentiating the action of the ACE inhibitors.

Aging↗
PubMed1993

Angiotensin II-induced vasopressin release is mediated through alpha-1 adrenoceptors and angiotensin II AT1 receptors in the supraoptic nucleus.

The central actions of angiotensin II (ANG II) include the release of vasopressin (AVP) from the supraoptic nucleus (SON) via the pituitary gland into the blood. In conscious rats, we investigated whether catecholamines in the SON are involved in this release process. It was found that i.c.v. injections of ANG II (100 ng) selectively increased the release of norepinephrine (NA) from the SON. Like the ANG II i.c.v.-induced AVP release, this effect was prevented by i.c.v. pretreatment with the ANG II AT1 receptor antagonist, losartan (5 micrograms). The alpha-1 adrenoceptor antagonist, prazosin (0.7 nmol), injected bilaterally into the SON, significantly reduced the ANG II 100-ng i.c.v.-induced AVP release. Pretreatment with the alpha-2, beta-1 and beta-2 adrenoceptor antagonists, idazoxan, atenolol and ICI 118551, respectively, had no effect. Injections of NA into the SON increased plasma AVP at doses up to 10 nmol but not at higher doses (30-100 nmol). The effects of NA were mimicked by the alpha-1 adrenoceptor agonist, methoxamine (1-5 nmol). Bilateral pretreatment of the SON with losartan (5 micrograms) markedly inhibited the i.c.v. ANG II 100 ng-induced AVP release. The increase in AVP release after ANG II injections into the SON was also inhibited by losartan pretreatment into the SON, whereas prazosin had no effect. These results demonstrate that the ANG II-induced release of AVP is initiated through periventricular ANG II AT1 receptors and involves postsynaptic alpha-1 adrenoceptor stimulation in the SON. In addition, ANG II AT1 receptors in the SON can contribute to AVP release after periventricular ANG II receptor stimulation.

Adrenergic alpha-1 Receptor Antagonists↗
PubMed1992

Identification of the central tachykinin receptor subclass involved in substance P-induced cardiovascular and behavioral responses in conscious rats.

To identify the tachykinin receptor subclass involved in the central cardiovascular and behavioral actions of substance P (SP), we compared the central actions of SP with those of neurokinin A (NKA) and senktide in conscious chronically instrumented rats. Intracerebroventricular (i.c.v.) injection of SP (an NK1 agonist) and NKA (an NK2 agonist) increased mean arterial pressure (MAP) and heart rate (HR) dose dependently and these cardiovascular responses were associated with the behavioral responses, comprising excessive grooming and exploring. Both peptides were equipotent to produce the cardiovascular and the behavioral responses. Senktide (a highly selective NK-3 agonist), injected i.c.v. increased the HR markedly. The behavioral response, 'wet dog shakes', was observed most frequently after senktide and was dissociated from the HR response. Pretreatment with a peripheral NK-1-selective antagonist, L-668,169, attenuated the NKA-induced cardiovascular and behavioral responses but not the SP-induced responses. However, pretreatment with a peripheral NK-2-selective antagonists, L-659,877, attenuated the SP-induced responses but not the NKA-induced responses. These results suggest that the central cardiovascular and behavioral actions of SP and NKA are mediated by different subclasses of receptors and that the receptor subclasses which are specific for the central nervous system differ from those which mediate the peripheral actions of the two tachykinins.

Animals↗
PubMed1992

Angiotensin II evokes noradrenaline release from the paraventricular nucleus in conscious rats.

In vitro and in vivo experiments have provided indirect evidence that some of the central actions of angiotensin II (ANG II) involve catecholaminergic pathways in the brain. In this study in conscious rats we investigated the effect of stimulation of periventricular ANG II receptors on blood pressure and on catecholamine release (microdialysis and HPLC) from the paraventricular nucleus (PVN), a hypothalamic area thought to be instrumental in the central pressor responses to ANG II through the release of vasopressin into the blood. Intracerebroventricular (i.c.v.) injections of pressor doses of ANG II (1 ng and 100 ng) led to significant dose-dependent increases of the noradrenaline (NA) release in the PVN (1 ng: 30.95 +/- 6.01 to 47.38 +/- 6.79 pg/sample, P less than or equal to 0.01; 100 ng: 32.93 +/- 5.38 to 73.18 +/- 11.4 pg/sample, P less than or equal to 0.01). These changes coincided in extent and duration with the respective pressor responses. A subpressor dose of ANG II (100 pg) did not release catecholamines from the PVN. Dopamine (DA) and the NA and DA, metabolites 3,4-dihydroxyphenylethylglycol and 3,4-dihydroxyphenylacetic acid, were not influenced by i.c.v. injections of ANG II at any dose. Pretreatment with the novel non-peptide ANG II-AT 1 receptor antagonist DuP 753 (5 micrograms, i.c.v.) abolished the effect of 100 ng ANG II on blood pressure and on NA release. Our results show for the first time in vivo that stimulation of periventricular ANG II-AT 1 receptors induces a selective NA release in the PVN. They further support the hypothesis that ANG II engages a noradrenergic pathway in the PVN to release vasopressin.

3,4-Dihydroxyphenylacetic Acid↗