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Biomedical subjects

T Unger

Publications and source records attributed to T Unger.

At least 217 records · Page 12Linked to original sources
PubMed1992

Cardiac and vascular effects of chronic angiotensin converting enzyme inhibition at subantihypertensive doses.

AIM: We performed two sets of experiments in order to prevent or to regress cardiac and vascular hypertrophy, using antihypertensive and subantihypertensive doses of the angiotensin converting enzyme inhibitor zabicipril. METHODS AND RESULTS: Spontaneously hypertensive rats (SHR) begin to develop hypertension at less than 4 weeks of age and reach stable hypertension levels after 12-14 weeks. The blood pressure increase is accompanied by the development of cardiac and vascular hypertrophy. Treatment of SHR in utero and up to the age of 20 weeks with an antihypertensive dose of zabicipril (1 mg/kg per day) not only prevented the development of high blood pressure but also the development of cardiac and vascular hypertrophy. This effect was demonstrated by a significant decrease in left ventricular weight and the number of smooth muscle cell layers in the vascular media, media thickness and the media:lumen ratio in mesenteric arteries. In contrast, antihypertensive treatment with the Ca2+ antagonist verapamil (100 mg/kg per day) and the subantihypertensive dose of zabicipril (0.01 mg/kg per day) did not affect the development of cardiac and vascular hypertrophy. We found a significant increase in the length and surface density of myocardial capillaries after treatment with zabicipril at 1 mg/kg per day, indicating that the capillary density had improved and therefore that the oxygen supply of the heart was improved. Similar findings were observed with the low dose of zabicipril in SHR, although these rats had high blood pressure and cardiac and vascular hypertrophy. CONCLUSIONS: Treatment of adult SHR for 16 weeks with zabicipril at 1 mg/kg per day completely normalized their blood pressure levels. This effect was accompanied by a regression of left ventricular but not of vascular hypertrophy. Treatment with an antihypertensive dose of verapamil or with a subantihypertensive dose of zabicipril had no effect on cardiac and vascular hypertrophy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

ACE inhibitor effect on bradykinin metabolism in the vascular wall.

In the isolated rabbit thoracic aorta the ACE inhibitor ramiprilat attenuated bradykinin degradation by enzymes localized on vascular endothelial cells as well as on vascular smooth muscle cells by 26% and 32%, respectively. We conclude that the ACE inhibitor can attenuate vascular bradykinin degradation not only by inhibition of endothelial ACE but also by inhibition of other bradykinin degrading enzymes in deeper layers of the vascular wall.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

Involvement of adrenergic and angiotensinergic receptors in the paraventricular nucleus in the angiotensin II-induced vasopressin release.

The role of hypothalamic paraventricular adrenoceptors and angiotensin II (ANG II)-AT 1 receptors in mediating the vasopressin (AVP) release into the plasma in response to i.c.v. and local paraventricular ANG II injections was investigated in conscious chronically instrumented rats. Noradrenaline (NA) administered bilaterally into the paraventricular nucleus (PVN) dose-dependently stimulated AVP release. Bilateral PVN microinjections of the alpha 1 adrenoceptor agonists methoxamine and phenylephrine, or of the alpha2 adrenoceptor agonist clonidine, did not affect plasma AVP when given alone, but increased plasma AVP when methoxamine and clonidine were given in combination. In contrast, PVN microinjections of both the beta 1 adrenoceptor agonist dobutamine and the beta 2 adrenoceptor agonist salbutamol significantly reduced basal plasma AVP. Bilateral PVN pretreatment with the alpha 1 and alpha 2 adrenergic antagonists prazosin, idazoxan and rauwolscine, but not of the beta 1 and beta 2 adrenoceptor antagonists atenolol and ICI 118 551, significantly attenuated the i.c.v. ANG II-induced AVP release. ANG II injected bilaterally into the PVN dose-dependently increased plasma AVP. Bilateral PVN pretreatment with the specific ANG II-AT 1 receptor antagonist losartan partially inhibited the i.c.v. ANG II-induced AVP release. We conclude: 1) Beta 1 and beta 2 adrenoceptors in the PVN exert an inhibitory action on basal AVP secretion. 2) ANG II can release AVP by directly stimulating its ANG II-AT 1 receptors in the PVN. 3) PVN mediated AVP release in response to periventricular ANG II-AT 1 receptor stimulation is at least partially effected through ANG II-AT 1 receptors in the PVN impinging on alpha adrenergic terminals.

Angiotensin II↗
PubMed1991

Angiotensin II-induced noradrenaline release from anterior hypothalamus in conscious rats: a brain microdialysis study.

Interaction with aminergic transmitter substances has been implicated in the central actions of angiotensin II (ANG II). We used the novel technique of brain microdialysis in conscious rats to investigate whether ANG II influences the release of endogenous catecholamines (CA) from the anterior hypothalamus (AH). Intracerebroventricular (i.c.v.) administration of ANG II (1 ng and 100 ng) increased mean arterial pressure. ANG II at 1 ng had no effect on the release of noradrenaline (NA) from the AH but ANG II at 100 ng significantly increased NA release. Intracerebroventricular pretreatment with the ANG II-receptor antagonist sarilesin (Sar1, Ile8-ANG II; 3 micrograms) prevented the ANG II-induced NA release. The release of the intraneuronal NA and dopamine (DA) metabolites 3,4-dihydroxyphenylethyl glycol (DOPEG) and 3,4-dihydroxyphenylacetic acid (DOPAC) from the AH was not altered by i.c.v. ANG II. Our results provide the first in vivo evidence for NA release from the hypothalamus induced by periventricular ANG II receptor stimulation. They support the hypothesis that hypothalamic noradrenergic mechanisms are involved in the central actions of this peptide.

1-Sarcosine-8-Isoleucine Angiotensin II↗
PubMed1991

Distribution of angiotensin II receptor subtypes in rat brain nuclei.

Angiotensin II (ANG II) receptor subtypes in rat brain were characterized and quantified by competitive radioligand binding using [125I]Sar1 Ile8 angiotensin II ([125I]sarilesin) as a tracer and ANG II, sarilesin and the subtype selective ligands DuP 753 (AT1) and CGP 42112A (AT2) as competitors. The distribution of AT1 and AT2 receptors was determined in midbrain, brainstem, hypothalamus as well as in individual hypothalamic and periventricular nuclei. Whereas in midbrain and brainstem the AT1: AT2 ratio was 40%: 60% and 70%: 30% respectively, the AT1 receptors were by far predominant in hypothalamus and in the nuclei investigated. Interestingly, we found that approximately 25% of the ANG II receptors in hypothalamus did not bind DuP 753 even at 0.1 mM. These sites which bind CGP 42112A, ANG II and sarilesin may represent a third ANG II receptor subtype.

Angiotensin II↗
PubMed1991

Are renal mechanisms involved in primary hypertension? Evidence from kidney transplantation studies in rats.

Previous renal transplantation experiments in genetically hypertensive and normotensive rat strains indicated that a genetic defect in the kidney may be primarily involved in the pathogenesis of primary hypertension. In order to investigate whether this is also true for the most widely used animal model of primary hypertension, the spontaneously hypertensive rat (SHR), we performed renal transplantations using SHR and normotensive Wistar-Kyoto rats (WKY) as kidney donors and bilaterally nephrectomized F1 hybrids, bred from SHR x WKY parents as renal graft recipients. Our studies were also designed to differentiate between primary and secondary renal mechanisms as a possible cause of posttransplantation hypertension. Recipients of renal grafts from adult, naive SHR but not from adult normotensive WKY kidney donors developed posttransplantation hypertension. Permanent blood pressure normalization by antihypertensive treatment in adult SHR kidney donors and prehypertensive, young age of SHR kidney donors reduced, but did not prevent, posttransplantation hypertension. Increasing renal perfusion pressure in WKY kidney donors (2-kidney 1-clip hypertension) also resulted in posttransplantation hypertension in recipients of the non-clipped kidneys. Blood pressure remained normal in recipients of renal grafts from young WKY kidney donors. These data suggest that SHR kidneys carry a genetic defect which may be primarily involved in the pathogenesis of primary hypertension.

Animals↗
PubMed1991

Localization of the substance P-induced cardiovascular responses in the rat hypothalamus.

Intracerebroventricular injection of substance P (SP) has been reported to induce a typical cardiovascular defense response characterized by an increase in blood pressure, heart rate, sympathetic efferent activity, hindlimb vasodilatation and mesenteric vasoconstriction. In this study we employed microinjections of SP to localize the hypothalamic areas in which SP elicits the activation of the cardiovascular system. SP (550 pmol) injected into the anterior hypothalamus (AH) produced, after a short latency, a marked increase in mean arterial pressure and heart rate. In the ventromedial hypothalamus, the magnitude of the cardiovascular response to SP was identical to that in the AH, but the response was delayed. SP injected into the posterior hypothalamus failed to induce any cardiovascular response. These results suggest that the anterior and ventromedial parts of the hypothalamus are responsible for eliciting the central cardiovascular effects of SP in conscious rats.

Animals↗
PubMed1991

HOE 140, a new highly potent and long-acting bradykinin antagonist in conscious rats.

The inhibitory effects of the new bradykinin antagonist HOE 140 (D-Arg-Arg-Pro-Hyp-Gly-Thi-Ser-D-Tic-Oic-Arg) on depressor responses to exogenous bradykinin were investigated in conscious rats and compared with those of the bradykinin antagonist B4146 (D-Arg-Hyp-Pro-Gly-Thi-Ser-D-Pro-Thi-Arg). HOE 140 showed a 250-700-fold higher potency in vivo and a much longer biological half-life than B4146. Plasma catecholamines were not increased after application of HOE 140, indicating that this compound did not interfere with catecholamine release. HOE 140 proved to be a highly potent, specific and long-acting bradykinin B2-receptor antagonist.

Amino Acid Sequence↗
PubMed1991

From tissue angiotensin converting enzyme inhibition to antihypertensive effect.

The renin-angiotensin system (RAS) has long been regarded as a classical hormonal system, with angiotensin II (ANG II) being the circulating effector peptide. In recent years, evidence for additional RAS in various organs, including vascular wall, kidney, adrenal gland, heart, and brain, has been obtained. Drugs interfering with the RAS such as the converting enzyme (CE) inhibitors may, therefore, not only inhibit the plasma RAS but also inhibit these tissue RAS. Such a "tissue" RAS inhibition has been repeatedly demonstrated in animal experiments, and in some cases it correlated better with the cardiovascular actions of the CE inhibitors than did inhibition of plasma RAS. In the vascular wall, a local inhibition of ANG II synthesis may contribute not only to the reduction of vascular tone but also to the marked regression of media hypertrophy seen after CE inhibitor treatment. Vascular ANG II generation by CE appears to occur almost exclusively at the luminal surface of the endothelium. Locally formed ANG II may then contribute to the pool of circulating ANG II (endocrine ANG II) or feed back to adjacent cells without being transported by the blood (paracrine ANG II). Thus, CE inhibitors may not have to penetrate into deeper layers of the vascular wall to inhibit the vascular RAS, but may rather prevent the paracrine actions of locally generated ANG II.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Central effects of atrial natriuretic factor on renal salt excretion.

Atrial natriuretic factor (ANF) has been localized in periventricular brain areas involved in cardiovascular and fluid control. We investigated the effect of intracerebroventricular (icv) ANF (alpha-rat atriopeptin III) on renal sodium excretion in unilaterally nephrectomized, conscious unrestrained rats fitted with a chronic ureteral catheter. Isotonic NaCl (1 ml/h) was infused intravenously. ANF injected at doses (icv) of 1 ng (n = 6), 100 ng (n = 7), and 1 microgram (n = 7) reduced urinary sodium excretion (all values mumol/45 min, means +/- SE) from 111.6 +/- 24.4 to 83 +/- 20 (P less than 0.05), from 96.9 +/- 25.2 to 55 +/- 14 (P less than 0.01), and from 90.8 +/- 14.2 to 51 +/- 9 (P less than 0.01), respectively, whereas urinary flow rate did not change. The antinatriuretic effect was immediate in onset and lasted for greater than or equal to 60 min. Blood pressure remained unaltered. ANF (100 ng icv) increased efferent sympathetic renal nerve activity (+36%; n = 6, P less than 0.05), plasma renin activity (4.6 +/- 0.6 to 7.5 +/- 0.5 pmol angiotensin I.ml-1.h-1; n = 9, P less than 0.01), plasma angiotensin II (68.7 +/- 2.5 to 84.7 +/- 3.4 fmol/ml; n = 8, P less than 0.01), and aldosterone (22.3 +/- 3.6 to 37.2 +/- 4.0 ng/ml; n = 9, P less than 0.02). Renal denervation reduced the antinatriuretic effect of ANF by 37%. We conclude that brain ANF has antinatriuretic actions, which may be partly explained by activation of renal nerves.

Aldosterone↗
PubMed1991

Tissue renin-angiotensin systems: fact or fiction?

The discovery of the components of the renin-angiotensin system (RAS) in various tissues gave rise to the idea that functional "tissue" RASs exist that are more or less independent of the hormonal RAS. Further support for this notion came from the recent demonstration of the mRNA for the protein components of the RAS in a number of organs. Last but not least, the introduction of the converting-enzyme (CE) inhibitors, generating an enormous scientific interest in the role of the RAS, has contributed to the concept of "tissue" RASs, since some of the effects of these drugs were thought to be reconciled better with "tissue" than with plasma RAS inhibition. However, this model of plasma vs. "tissue" RAS still suffers from a number of conceptual problems. For instance, with respect to the "tissue" RAS in the vascular wall, it is not clear at present whether angiotensin-converting enzyme (ACE) is at all active inside endothelial cells. In addition, all evidence available speaks against its localization in the vascular media, while there may be some activity of the enzyme in the adventitial layer. Concerning the heart, there is at present no unequivocal evidence for a local angiotensin II (Ang II) production through ACE in cardiac tissue outside the coronary vessels. The localization of Ang II generation within tissue RASs in the adrenal gland or in the kidney, where Ang II may be generated through CE at the tubular brush border, are far from being elucidated.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Post-transplantation hypertension in recipients of renal grafts from hypertensive donor rats.

Renal transplantations were performed using stroke-prone spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) as kidney donors and bilaterally nephrectomized F1 hybrids, bred from SHR x WKY parents as renal graft recipients. Recipients of renal grafts from adult, naive SHR but not from adult normotensive WKY kidney donors developed post-transplantation hypertension. Permanent blood pressure normalization by antihypertensive treatment in adult SHR kidney donors, as well as the young, prehypertensive age of SHR kidney donors reduced but did not prevent the development of post-transplantation hypertension. Increasing renal perfusion pressure in WKY kidney donors (chronic 2-kidney 1-clip renovascular hypertension) also resulted in post-transplantation hypertension in recipients of the non-clipped kidneys. Blood pressure remained normal in recipients of renal grafts from young WKY kidney donors. These data suggest that SHR kidneys carry a genetic defect which can give rise to post-transplantation hypertension and which therefore may also play a role in the development of hypertension in naive SHR. In addition, secondary hypertension-induced renal damage may also contribute to post-transplantation hypertension in recipients of renal grafts from hypertensive donors.

Animals↗
PubMed1991

[Relations between pharmacokinetics and effectiveness of ACE inhibitors].

While being similar to each other with respect to their pharmacodynamic effects, the various ACE inhibitors may differ considerably concerning their pharmacokinetic properties. Pharmacokinetic features that may influence the clinical choice for or against a particular ACE inhibitor include its oral bioavailability, plasma protein binding, tissue distribution, metabolization, and excretion. It should be kept in mind, however, that there may be considerable discrepancies between pharmacokinetic parameters in the plasma and the clinical effects (e.g., on blood pressure) of the same substance. These differences may be due to the fact that ACE inhibitors, especially upon chronic administration, predominantly act on local (paracrine/intracrine) renin-angiotensin-systems (RAS) rather than on the plasma RAS (endocrine RAS).

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1990

Central vasopressin pretreatment sensitizes phosphoinositol hydrolysis in the rat septum.

Previous in vivo and in vitro studies have demonstrated that exposure of the brain to arginine vasopressin (AVP) can potentiate various responses to a second central challenge with AVP. To determine whether this sensitization is mediated by changes at the receptor level, we investigated the effects of AVP on the phosphoinositide metabolism in septal slices prepared from rats centrally pretreated with saline or AVP. Addition of vasopressin (10(-7) M, 10(-6) M) to septal slices from saline-pretreated rats failed to elicit a significant stimulation of inositol-1-phosphate (IP1). In contrast, AVP (10(-7) M) significantly stimulated IP1 release in septal slices prepared from rats pretreated intracerebroventricularly (i.c.v.) 24 h earlier with 10 or 100 ng AVP. Pretreatment with the same i.c.v. doses of AVP also induced a significant enhancement of the carbachol-induced stimulation of IP1 release, but i.e.v. pretreatment with carbachol did not stimulate the IP1 release in response to AVP. Our results suggest that a novel facilitation of phosphoinositide metabolism can be induced by central AVP pretreatment.

Animals↗
PubMed1990

Tissue renin-angiotensin systems in the heart and vasculature: possible involvement in the cardiovascular actions of converting enzyme inhibitors.

The existence of independently functioning local renin-angiotensin systems in a number of tissues has been firmly established by biochemical and functional evidence and, most recently, by the demonstration of genetic messages for components of the renin-angiotensin systems, such as renin and angiotensinogen, in several organs. In this review, local renin-angiotensin systems in the heart and vascular walls are described and the contribution of a local inhibition of converting enzymes to the cardiovascular actions of converting enzyme inhibitors is discussed. Most of the studies cited support the hypothesis that an inhibition of cardiac converting enzyme may be involved in the beneficial hemodynamic and metabolic actions of converting enzyme inhibitors in cardiovascular disease, such as hypertension and congestive heart failure, independent of the circulating renin-angiotensin system. Local effects on cardiac converting enzyme may contribute to the ability of converting enzyme inhibitors to reduce cardiac hypertrophy. Similarly, local converting enzyme inhibition in the vascular wall may not only constitute a mechanism involved in the antihypertensive effects of converting enzyme inhibitors, but may also contribute to the regression of hypertension-induced vascular hypertrophy. In addition to reduced local angiotensin II generation, converting enzyme inhibition may engender a potentiation of the local effects of kinins. This mechanism may be more important to the cardiovascular actions of converting enzyme inhibitors than initially thought.

Angiotensin II↗