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Biomedical subjects

G Wiemer

Publications and source records attributed to G Wiemer.

At least 55 records · Page 3Linked to original sources
PubMed1992

Ramipril prevents left ventricular hypertrophy with myocardial fibrosis without blood pressure reduction: a one year study in rats.

1. Angiotensin converting enzyme (ACE)-inhibitors have been demonstrated to be effective in the treatment of cardiac hypertrophy when used in antihypertensive doses. The aim of our one year study with an ACE-inhibitor in rats was to separate local cardiac effects produced by a non-antihypertensive dose from those on systemic blood pressure when an antihypertensive dose was used. 2. Rats made hypertensive by aortic banding were subjected to chronic oral treatment for one year with an antihypertensive dose of the ACE inhibitor, ramipril 1 mg kg-1 daily, (RA 1 mg) or received a low dose of 10 micrograms kg-1 daily (RA 10 micrograms) which did not affect high blood pressure. 3. Chronic treatment with the ACE-inhibitor prevented left ventricular hypertrophy in the antihypertensive rats as did the low dose which had no effects on blood pressure. Similar effects were observed on myocardial fibrosis. Plasma ACE activity was inhibited in the RA 1 mg but not in the RA 10 micrograms group although conversion of angiotensin (Ang) I to Ang II in isolated aortic strips was suppressed in both treated groups. Plasma catecholamines were increased in the untreated control group, but treatment with either dose of ramipril normalized the values. The myocardial phosphocreatine to ATP ratio (an indicator of the energy state in the heart) was reduced in the vehicle control group whereas the hearts from treated animals showed a normal ratio comparable to hearts from sham-operated animals. 4. After one year, five animals were separated from each group, treatment withdrawn, and housed for additional six months. In the RA 1 mg group, blood pressure did not reach the value of the control vehicle group and surprisingly, left ventricular hypertrophy and myocardial fibrosis did not recur in animals during withdrawal of treatment.5. These data show that long term ACE inhibitor treatment with ramipril in antihypertensive and non-antihypertensive doses prevented cardiac hypertrophy and myocardial fibrosis. This protective effect was still present after 6 months treatment withdrawal.

Adenosine Triphosphate↗
PubMed1992

Production of cyclic GMP via activation of B1 and B2 kinin receptors in cultured bovine aortic endothelial cells.

The purpose of this study was to define the type of kinin receptors in bovine aortic endothelial cells. As a biochemical response we used the cyclic GMP production which can be attributed to the activation of the soluble guanylyl cyclase of the endothelial cells via endothelium-derived relaxing factor. For the first time we demonstrated that in addition to bradykinin (BK) the B1 kinin receptor agonist desArg9BK increased markedly the content of cyclic GMP. Similar to BK the desArg9BK-stimulated cyclic GMP production was transient and concentration dependent. The effects of both kinin agonists were inhibited by NG-nitro-L-arginine. The known B1 kinin receptor antagonist desArg9[Leu8] BK and the newly discovered antagonist desArg9D-Arg[Hyp3,Thi5,D-Tic7,Oic8]BK only inhibited the desArg9BK-stimulated cyclic GMP production. The B2 kinin receptor antagonists D-Arg[Hyp3,Thi5,D-Tic7,Oic8]BK and D-Arg[Hyp2,Thi5,8,D-Phe7]BK inhibited the production of cyclic GMP upon stimulation with BK and surprisingly also with desArg9BK. These findings indicate that bovine aortic endothelial cells possess B1 and B2 type kinin receptors which are associated with the production and/or release of endothelium-derived relaxing factor. Furthermore, it was shown for the first time that the B1 kinin receptor in bovine aortic endothelial cells seems to be quite different from that which exists in isolated tissue preparations. The functional importance of these B1 type receptors with regard to regulation of blood pressure and blood flow remains to be determined.

Animals↗
PubMed1992

Effects of converting enzyme inhibitors and the calcium antagonist nifedipine alone and in combination on precontracted isolated rabbit aortic rings.

The calcium antagonist nifedipine markedly relaxed intact rabbit aortic rings precontracted with low level potassium chloride while converting enzyme (CE) inhibitors, ramiprilat, enalaprilat, and captopril were only marginally effective. Either CE inhibitor combined with nifedipine, however, significantly accentuated this relaxation. The CE inhibitors increased vascular cyclic GMP content while nifedipine was not active. Thus, inhibition of potassium chloride-induced calcium influx by nifedipine may unmask the vasorelaxant potential of CE inhibitors that in turn may result from local accumulation of endothelium-derived bradykinin.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1992

DesArg10[Hoe 140] is a potent B1 bradykinin antagonist.

DesArg10[Hoe 140] and Des(D-Arg1, Arg10)[Hoe 140], desArg10-analogs of the potent and stable B2 bradykinin (BK) receptor antagonist Hoe 140 were found to be potent and stable antagonists of the B1 receptor in vitro and in vivo. They were, however, less selective than DesArg9[Leu8]BK, the metabolically unstable B1 prototype antagonist. Surprisingly, Hoe 140, which behaved as a pure B2 antagonist in several smooth muscle preparations, had a considerable inhibitory effect against the B1 agonist DesArg9-BK in bovine aortic endothelial cells. This finding for the first time suggests that B1 receptors are heterogenous.

Animals↗
PubMed1992

Converting enzyme inhibitor-stimulated formation of nitric oxide and prostacyclin in endothelial cells from bovine aorta is mediated by endothelium-derived bradykinin.

Like bradykinin the converting enzyme inhibitor ramiprilat concentration-dependently enhances the formation of nitric oxide and prostacyclin assessed by intracellular cyclic GMP accumulation and 6-keto prostaglandin F1. resp. Both ramiprilat-induced effects are completely suppressed by the specific kinin receptor antagonist Hoe 140. The ramiprilat-induced cyclic GMP increase is totally blocked by the stereospecific inhibitor of nitric oxide synthase, NG-nitro-L-arginine.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Hoe 140 a new potent and long acting bradykinin-antagonist: in vitro studies.

1. Hoe 140 (D-Arg-[Hyp3, Thi5, D-Tic7, Oic8]bradykinin) is a new bradykinin (BK)-antagonist. It was tested in several in vitro assays and compared with D-Arg-[Hyp2,Thi5,8,D-Phe7]BK. 2. In receptor binding studies in guinea-pig ileum preparations, Hoe 140 showed an IC50 of 1.07 x 10(-9) mol l-1 and a KI value of 7.98 x 10(-10) mol l-1. 3. In isolated organ preparations Hoe 140 and D-Arg-[Hyp2,Thi5,8, D-Phe7]BK inhibited bradykinin-induced contractions concentration dependently, with IC50-values in the guinea-pig ileum preparation of 1.1 x 10(-8) mol l-1 and 3 x 10(-5) mol l-1, respectively. pA2 values in this tissue were 8.42 and 6.18, respectively. In the rat uterus preparation the IC50 value was 4.9 x 10(-9) mol l-1 for Hoe 140. D-Arg-[Hyp2, Thi5,8, D-Phe7]BK showed an IC50 of 4.0 x 10(-6) mol l-1. The IC50 values in the guinea-pig isolated pulmonary artery were 5.4 x 10(-9) mol l-1 and 6.4 x 10(-6) mol l-1, respectively. In the rabbit aorta no inhibitory effects on Des-Arg9-BK induced contractions were observed. 4. In cultured bovine endothelial cells, Hoe 140 antagonized (IC50 = 10(-8) mol l-1) bradykinin-induced endothelium-derived relaxing factor (EDRF) release and the bradykinin-induced increase in cytosolic free calcium (IC50 = 10(-9) mol l-1). 5. Hoe 140 (10 -7mol I1) totally suppressed the bradykinin-induced (10 8 to 10- mol I') prostacyclin (PGI2) release from cultured endothelial cells of bovine aorta. D-Arg-[Hyp2, Thi5'8, D-Phe7]BK (10- 7 mol I1- ) showed a weaker antagonism. 6. Taken together these results show that Hoe 140 is a highly potent bradykinin antagonist. It was two to three orders of magnitude more potent than D-Arg-[Hyp2, Thi5 8, D-Phe7]BK.

Animals↗
PubMed1991

Ramiprilat enhances endothelial autacoid formation by inhibiting breakdown of endothelium-derived bradykinin.

We studied whether inhibition of angiotensin converting enzyme stimulates the formation of nitric oxide and prostacyclin in cultured human and bovine endothelial cells by an enhanced accumulation of endothelium-derived bradykinin. Nitric oxide formation was assessed in terms of intracellular cyclic GMP accumulation, prostacyclin release by a specific radioimmunoassay. Inhibition of angiotensin converting enzyme by ramiprilat dose- and time-dependently increased the formation of nitric oxide and prostacyclin. These increases, peaking within 10 minutes, were maintained for at least 60 minutes. The ramiprilat-induced cyclic GMP increase was completely abolished by the stereospecific inhibitor of nitric oxide synthase, NG-nitro-L-arginine. The B2-kinin receptor antagonist, Hoe 140 (0.1 microM), markedly attenuated the cyclic GMP accumulation and abolished the increase in prostacyclin release. The supernatant of endothelial cells, incubated with ramiprilat (0.3 microM) for 15 minutes, elicited a significant nitric oxide release (as assessed by a guanylyl cyclase assay) in untreated endothelial cells used as detector tissue. Preincubation of the detector cells with Hoe 140 completely abolished this nitric oxide release. These data indicate that cultured endothelial cells from different species are capable of producing and releasing bradykinin into the extracellular space in amounts that lead to a sustained stimulation of nitric oxide and prostacyclin formation, provided that bradykinin degradation is prevented by angiotensin converting enzyme inhibition. Thus, the protective effect of angiotensin converting enzyme inhibitors observed on endothelial vasomotor function in hypertension may be explained by the local accumulation of endothelium-derived bradykinin that acts in an autocrine and paracrine manner as potent stimulus for endothelial autacoid formation.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Low-dose felodipine treatment attenuates endothelial dysfunction in rabbits fed an atherogenic diet.

Loss of endothelium-dependent relaxation is an early step in atherogenesis. To test the effect of low-dose felodipine on the progression of this dysfunction, male New Zealand white rabbits were rendered hypercholesterolemic with a diet containing 0.25% cholesterol and 3% coconut oil. After a 1-month induction period on this diet, during which the rabbits were identified as low or normal responders to cholesterol, 0.46 mg/kg of felodipine (FELO) or placebo (CON) were given by gavage once daily for a further 3 months. This regimen established FELO plasma levels (14.2 +/- 1.3 nM, week 9) corresponding to therapeutic concentrations in humans and an average 13-fold increase in plasma cholesterol from below 1 mM. At the end of the treatment period, relaxation of norepinephrine (1 x 10(-8) M)-precontracted proximal thoracic aorta strips to acetylcholine (ACh: 1 x 10(-8)-1 x 10(-5) M) was determined. Cholesterol exposure was calculated as the area under the curve for serum cholesterol x time [AUC (mM x day 1)]. Despite equal cholesterol load [FELO (n = 17): 1,856 +/- 182 mM x day) and CON (n = 22): 1,851 +/- 167 mM x day], maximal relaxation to 1 x 10(-7) M ACh was well preserved in strips from FELO-treated rabbits (29.5 +/- 5.7%) but suppressed in strips from untreated rabbits (11.0 +/- 2.9%). For comparison, relaxation in strips from standard diet controls was 49.8 +/- 2.9% (n = 15). Moreover, there was a significant inverse correlation (r = -0.74) between percentage ACh relaxation and cholesterol exposure in FELO-treated rabbits.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1991

Preservation of endothelial function by ramipril in rabbits on a long-term atherogenic diet.

Hypertension and hypercholesterolemia predispose to atherosclerosis. Ramipril, known to lower blood pressure, was used to study the effect of converting-enzyme inhibition on impairment of endothelium-derived relaxation and changes in basal cGMP content in rabbits fed an atherogenic diet (0.25% cholesterol). The generation of cGMP in the presence of bradykinin and ramiprilat was studied in vitro in aortic segments from normal untreated rabbits as well as in bovine endothelial cells. The ability to relax in response to acetylcholine was almost abolished in aortic segments from the vehicle-treated rabbits fed the atherogenic diet for 4 months. The basal cGMP content was substantially reduced. Aortic segments from rabbits concomitantly treated with ramipril (0.3 and 3.0 mg/kg/day) for 3 months showed well-preserved relaxation and matching basal cGMP content compared to normal controls. The relaxation was not significantly greater in aortic segments from ramipril-treated rabbits fed the standard diet, but the cGMP content was more than doubled. In vitro studies in aortic segments and in endothelial cells showed that both the ramiprilat and bradykinin concentrations dependently stimulated cGMP formation, which serves as a biochemical marker of nitric oxide or EDRF release. Thus, the observed endothelial protection against hypercholesterolemia by ramipril may be the result of continuously increased cGMP formation due to preserved EDRF release. This is presumably produced by enhanced bradykinin activity through inhibition of degradation by converting-enzyme inhibition with ramipril.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1989

Effects of the novel compound, Hoe 065, upon impaired learning and memory in rodents.

The effects of Hoe 065 (n-octyl 2-[N-[(S)-1-ethoxycarbonyl-3-phenylpropyl]-L-alanyl]-(1S,3S, 5S)-2-azabicyclo [3.3.0]octane-3-carboxylate maleate salt) were studied on the performance of mice and rats in different learning tasks. Hoe 065 prevented the disruption of memory induced by scopolamine administered before training. The results indicate that Hoe 065 improves cognitive function in different tasks.

Animals↗
PubMed1989

Effects of Hoe 065, a compound structurally related to inhibitors of angiotensin converting enzyme, on acetylcholine metabolism in rat brain.

Hoe 065, a compound structurally related to inhibitors of angiotensin converting enzyme, caused a fall in the content of acetylcholine (ACh) in different brain areas of the rat following i.p. administration in the range 0.03-30 mg/kg. This effect occurred 0.5 h after a single injection and lasted for at least 6 h. Simultaneous administration of the choline uptake inhibitor hemicholinium-3 (HC-3) with Hoe 065 potentiated the decrease in ACh content induced by HC-3. In the same dose range Hoe 065 acutely enhanced the activity of the enzyme choline acetyltransferase as well as the capacity of the high-affinity choline uptake system which is considered as the rate-limiting step in the synthesis of ACh. Cholinesterase activity in vivo was not altered by the compound. Hoe 065 produced a concurrent elevation of brain cyclic GMP content. Taken together, these results suggest that Hoe 065 acutely increases cholinergic activity within its physiological range, probably by means of an enhanced release of ACh.

Acetylcholine↗
PubMed1989

Potentiation of the effects of atrial natriuretic factor on the cardiovascular system by amiloride.

Amiloride has previously been shown to facilitate receptor binding of atrial natriuretic factor (ANF) to membranes of adrenal cortex and to enhance ANF induced inhibition of steroid secretion in vitro. This interaction of amiloride and ANF also holds true for the cardiovascular system. In precontracted rabbit aortic strips the relaxing effect induced by the combination of ANF (10(-10) mol/l) and amiloride (10(-5) mol/l) was overadditional. The production of cyclic guanosine monophosphate (cGMP), which parallels ANF induced relaxations of vascular strips, was not affected by amiloride alone up to 10(-3) mol/l, but was concentration-dependently increased in the presence of ANF (10(-8) mol/l). In spontaneously hypertensive rats ANF-induced decreases in blood pressure were potentiated by amiloride. Post ischemia reperfusion arrhythmias in isolated rat hearts were reduced by ANF. Amiloride increased this effect. The binding experiments revealed an interaction of amiloride and ANF on the receptor level. Binding of labeled ANF to aortic tissue was concentration-dependently increased by amiloride. Addition of ATP had the opposite effect. Therefore it can be suggested that amiloride and ATP interfere with a mechanism regulating the sensitivity of the vascular ANF-receptor for its ligand regarding binding and signal transforming presumably by a kinase mediated phosphorylation/dephosphorylation process.

Amiloride↗
PubMed1988

Amiloride potentiates the vascular effects of atrial natriuretic factor.

We have demonstrated an interaction between the effects of amiloride and atrial natriuretic factor (ANF) on the vascular system. In precontracted rabbit aortic strips the relaxant effect of a combination of ANF (10(-10) mol/l) and amiloride (10(-5) mol/l) was synergistic. The production of cyclic (c)GMP, which parallels ANF-induced relaxation of the strips, was not affected by amiloride alone up to 10(-3) mol/l, but was concentration-dependently increased in the presence of 10(-8) mol/l ANF. In spontaneously hypertensive rats (SHR) ANF-induced decreases in blood pressure were potentiated by amiloride. Binding experiments revealed an interaction between amiloride and ANF at the receptor level; binding of labelled ANF to aortic tissue was increased by amiloride but decreased by ATP. These data show that amiloride and ATP influence a mechanism that determines the sensitivity of vessels to ANF and this interaction occurs both at receptor level and at the level of transduction.

Adenosine Triphosphate↗
PubMed1988

Effects of colforsin, trequinsin and isoprenaline on norepinephrine-induced contractions and cyclic nucleotide levels of isolated vascular tissue.

Recent observations imply the involvement of an endothelium-derived relaxing factor (EDRF) in the vasodilation of isolated vascular preparations accompanied by an increase of cyclic guanosine 3',5'-monophosphate (cGMP). To investigate the changes of cGMP and cyclic adenosine 3',5'-monophosphate (cAMP) in endothelium-dependent relaxation of isolated rabbit thoracic aortic rings we used colforsin (forskolin, FOR) as an adenylate cyclase stimulator, trequinsin (TRE) as a phosphodiesterase inhibitor and isoprenaline (ISO) as a beta-adrenoceptor agonist. Norepinephrine (NE, 10(-8) mol/l) evoked a contractile response in intact rings of rabbit aorta. In these precontracted rings with endothelium, acetylcholine (ACh) induced a concentration-dependent relaxation at 10(-8)-10(-6) mol/l. FOR, TRE and ISO reduced NE-vasoconstrictor responses in a concentration-dependent manner with an IC50 of 4.1 x 10(-8) mol/l, 8.5 x 10(-7) mol/l and 4.0 x 10(-7) mol/l, respectively, in rabbit aortic rings with endothelium. These effects were associated with elevations (p less than 0.05) in cAMP and cGMP in vascular tissue. In segments with disrupted endothelium the IC50 for FOR and TRE were increased about 3.5- and 2.3-fold, without changes in cyclic nucleotides. All three compounds attenuated ACh-induced relaxations of aortic rings in a concentration-dependent manner. High concentrations of FOR (10(-7) mol/l) and TRE (10(-5)) which increased cAMP even reversed ACh-induced relaxations, comparable to ACh effects in de-endothelialized vascular tissue. It is suggested that FOR-, TRE- and ISO-induced relaxations of isolated aortic preparations, accompanied by increased cAMP, interact with EDRF-dependent relaxations.

Acetylcholine↗
PubMed1986

Atriopeptin III induces endothelium-independent relaxation and increases cGMP levels in rabbit aorta.

Atriopeptin III (AP III) is a 24 amino acid synthetic peptide and a fragment of the atrial natriuretic factor. Using isolated rabbit aortic segments with intact or functionally destroyed endothelium, the effect of AP III on muscular relaxation was examined. cAMP- and cGMP levels were also determined. Aortic segments were pre-contracted with norepinephrine 10(-8) M, angiotensin II 10(-7) M or potassium chloride 20 mM. Addition of AP III (10(-10)-10(-7) M) to these pre-contracted segments exerted a concentration-dependent relaxation which was independent of intact endothelium, with EC50 values of 2.2 X 10(-9) M, 2.0 X 10(-9) M and 3.1 X 10(-8) M, respectively. In aortic segments with functionally destroyed endothelial surface, basal levels of cGMP were lower compared with intact vascular tissue. The process of relaxation, induced by AP III, was associated with marked increases of cGMP in intact vascular tissue. cAMP levels were unchanged in both preparations. Our results suggest that AP III elicits a direct, endothelium-independent vascular relaxation associated with increased levels of cGMP in tissue with intact endothelium. Extrusion of intracellular Ca++ by activation of cGMP-dependent protein-kinase may be part of the vasorelaxant profile of AP III.

Animals↗
PubMed1984

Simple and reliable radioreceptor assay for beta-adrenoceptor antagonists and active metabolites in native human plasma.

A radioreceptor assay (RRA) for the assay of beta-adrenoceptor antagonists in native human plasma is described. The hydrophilic antagonist 3H-CGP 12177 was used as the radioligand. In contrast to the hydrophobic radioligand 3H-dihydroalprenolol, which was investigated in parallel, the beta-adrenoceptor binding of 3H-CGP 12177 by rat reticulocyte membranes was found not to be affected by inclusion of increasing proportions (0-66% of incubation volume) of human plasma in the assay. Thus, solvent extraction of drug and/or active metabolites was not necessary to avoid binding of the radioligand tracer to plasma added in the RRA. The assay of unprocessed samples was possible. Drug concentrations in plasma after oral administration of propranolol (240 mg) or carteolol (30 mg) to 6 healthy volunteers were measured by the RRA and in parallel by a chemical method. The results from both methods agreed when the plasma concentration kinetics of propranolol were investigated (elimination half-life:3.9 h). In contrast, plasma concentrations of carteolol were consistently higher according to the RRA after oral administration of the drug. Identical concentrations, however, were found by the RRA and chemical method using plasma samples spiked with carteolol. Plasma concentrations of carteolol detected by the chemical method decline monoexponentially (elimination half-life: 5.4 h). A similar half-life of elimination for parent drug was found by the RRA (5.9 h), but an additional term describing the appearance of an active metabolite was necessary to account for the biphasic drug elimination (elimination half-life of metabolite: 17.3 h).(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic beta-Antagonists↗
PubMed1982

Energy-dependent extrusion of cyclic 3',5'-adenosine-monophosphate. A drug-sensitive regulatory mechanism for the intracellular nucleotide concentration in rat erythrocytes.

In reticulocyte-rich suspensions of red blood cells from rats extrusion of cAMP as a regulatory mechanism of intracellular cAMP was investigated. In response to isoprenaline and/or the phosphodiesterase inhibitors Ro 20-1724 and rolipram extrusion of cAMP increases dependent on the concentration of the drugs and time of exposure. However, these drugs exert their effects on the extrusion of cAMP only indirectly, i.e. via increased intracellular levels of cAMP, since the respective EC50-values of the drugs for intracellular accumulation and extrusion of cAMP are identical (isoprenaline: approximately 50 nM; rolipram: approximately 1 microM; Ro 20-1724: 15 microM). The dependence of the rate of extrusion on intracellular levels of cAMP is characterized by a typical concentration-effect relationship from which a maximal capacity of cAMP extrusion of 3-6 nmol/10 min/10(9) cells and a half maximal effective intracellular cAMP concentration of 40-50 nmol/10(9) cells can be derived. This relationship has been inferred from either kinetic or steady-state approaches. At rapidly changing intracellular levels of cAMP an apparent time lag of extracellular cAMP accumulation is obligatorily conditioned by this relationship. Vasodilating drugs which lower the ATP content of the cells as well as the uncoupler of oxidative phosphorylation, FCCP, inhibit the extrusive process (papaverine greater than FCCP greater than dipyridamole greater than dilazep much greater than hexobendine greater than or equal to carbocromene) leading to a 3-5-fold increase of the intrato extracellular concentration gradient of cAMP. It is concluded that extrusion of cAMP is a saturable and energy-dependent process which regulates the intracellular cAMP concentration independent of the activities of adenylate cyclase and phosphodiesterase.

Adenosine Triphosphate↗