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Biomedical subjects

W Linz

Publications and source records attributed to W Linz.

At least 109 records · Page 6Linked to original sources
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

Atrial natriuretic factor protects the isolated working ischaemic rat heart against the action of angiotensin II.

The interaction between atrial natriuretic factor [synthetic human ANF-(103-126)] and angiotensin II (Ang II) and its influence on reperfusion arrhythmias, cardiodynamics, enzyme loss and metabolic changes were investigated in isolated ischaemic working rat hearts. Acute regional myocardial ischaemia was induced by coronary artery occlusion which was associated with ventricular fibrillation. Perfusion with 1 X 10(-9) mol/l Ang II markedly aggravated these arrhythmias. Perfusion with 1 X 10(-7) mol/l ANF, in contrast, gave protection against ventricular fibrillation and prevented Ang II-induced aggravation of ventricular fibrillation. Atrial natriuretic factor improved cardiodynamics, in particular, during reperfusion, whereas Ang II impaired cardiodynamics and increased the release of creatine kinase and lactate dehydrogenase. These adverse effects of Ang II were absent when ANF was simultaneously perfused. Compared with control hearts, myocardial tissue levels of glycogen, ATP and creatine phosphate were increased in hearts perfused with either ANF or ANF plus Ang II, whereas lactate levels decreased. Perfusion with Ang II alone led to deterioration in these metabolic parameters. These results in isolated working rat hearts suggest that ANF protects against the consequences of ischaemia and reperfusion and that functional antagonism between ANF and Ang II may contribute to this.

Angiotensin II↗
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↗
PubMed1988

[Pharmacologic modification of the converting enzyme--local and systemic effects on the heart and blood vessels].

The renin-angiotensin system (RAS) has long been perceived as basically humoral. Since recent findings in molecular biology extended this view to local, possibly independent, tissue-RAS, both the RAS and the kallikrein-kinin cascade are understood as mixed local-systemic interacting systems, which explains local and systemic effects of converting enzyme (CE) inhibitors well. The key enzyme of both systems, CE, catalyzes the activation of the vasopressor and possibly trophic peptide, angiotensin II, and also inactivates the vasodilatory and, according to our observations, cardioprotective bradykinin. Thus, it is consistent that CE-inhibitors lower blood pressure, reduce cardiac hypertrophy, improve metabolic state and attenuate arrhythmias, particularly in ischemic hearts. It is evident from animal experiments that the tight binding favours new oral CE inhibitors, such as ramipril, not only for prevention but also for treatment of tissue injuries due to hypertension or ischemia.

Animals↗
PubMed1988

Influence of the thromboxane synthetase inhibitor HOE 944, prostacyclin and indomethacin on reperfusion arrhythmias, cardiodynamics and metabolism in isolated ischemic rat hearts.

We investigated the influence of the thromboxane (TX) synthetase inhibitor HOE 944 (6-(5-Methylimidazol-1-yl)methyl-2-naphthoic acid-Hydrochloride), prostacyclin (PGI2) and indomethacin on reperfusion arrhythmias in isolated perfused ischemic rat hearts. HOE 944, PGI2 and indomethacin were perfused in a concentration of 1 x 10(-6), 5 x 10(-8) and 1 x 10 (-6) mol/l respectively (in vitro). In another set up rats were pretreated p.o. with a daily dose of 30 mg/kg for 7 days (ex vivo). Acute regional myocardial ischemia was induced in isolated working rat hearts by occlusion of the left coronary artery. Reperfusion commenced upon release of this occlusion which was invariably associated with ventricular fibrillations (VF). Perfusion with 1 x 10(-6) mol/l HOE 944 did not affect these arrhythmias. In contrast hearts from HOE 944 pretreated rats were protected against fibrillations (p less than 0.01). PGI2 perfusion was also protective against VF (p less than 0.01) whereas indomethacin perfusion aggravated VF. In the ischemic period cardiodynamics like left ventricular pressure (LVP), dp/dt max and coronary flow (CF) were improved in HOE 944 pretreated rat hearts. In the venous effluent the enzyme activities of lactate dehydrogenase (LDH) and creatine kinase (CK) as well as lactate production were decreased in the ischemic and reperfusion period. Myocardial tissue levels of ATP were distinctly increased and lactate levels decreased in HOE 944 pretreated rats, whereas glycogen and creatine phosphate did not change.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Synthesis and biological activity of new leukotriene antagonists (racemates and enantiomerically pure compounds).

Two series of structural analogues of leukotrienes C4, D4 and E4 (LTC4, LTD4, LTE4) were prepared. The compounds were evaluated for their ability to antagonize leukotriene-induced contractions of guinea pig lung strips. In comparison to FPL-55712, compounds 1a and 2h were more potent antagonists against LTC4 (2- and 3fold, respectively) and LTD4 (6- and 60fold respectively). Moreover, in vivo compounds 1a and 2h exhibited antagonism against leukotrienes (C4, D4, E4) and PAF, the most potent mediators in bronchial asthma. 2h also showed antagonistic activity when tested by inhalation.

Animals↗
PubMed1988

Intracardiac generation of angiotensin and its physiologic role.

The emerging recognition of the existence and potential biological significance of local tissue renin-angiotensin systems in a number of organs has fostered interest in a possible intrinsic cardiac renin-angiotensin system. Evidence for such a system was first provided by biochemical measurements of components of the renin-angiotensin system in cardiac tissue. It has recently been demonstrated that the genes coding for renin and angiotensinogen are expressed in all regions of the heart, an essential prerequisite for the postulated intracardiac biosynthesis of these proteins. Moreover, we have shown the presence of a functional and physiologically active pathway for the conversion of angiotensin I to angiotensin II in the beating mammalian heart. This conversion appears to be catalyzed by a specific cardiac converting enzyme that is susceptible to systemically administered converting-enzyme inhibitors. Evidence for the physiologic importance of the cardiac renin-angiotensin system comes from experimental data as well as indirect clinical evidence. The potent coronary vasoconstrictor properties of angiotensin II underscore its possible significance in myocardial ischemia and ischemic heart disease, in particular when viewed in the context of selective local activation. The long-known positive inotropic effects of angiotensin II are based on its direct myotropic properties and on its facilitatory effects on sympathetic neurotransmission and may be of added significance in metabolically compromised states. We have recently demonstrated that locally generated angiotensin may be a dominant etiologic factor in the pathogenesis of reperfusion arrhythmias. In addition, we have found experimental evidence for a deleterious effect of angiotensin II on myocardial metabolism in the setting of regional myocardial ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin II↗
PubMed1987

Effects of nicainoprol on reperfusion arrhythmia in the isolated working rat heart and on ischemia and reperfusion arrhythmia and myocardial infarct size in the anesthetized rat.

The effect of the novel antiarrhythmic agent nicainoprol on coronary occlusion and reperfusion arrhythmia was investigated in isolated working rat hearts and in anesthetized rats. In isolated working rat hearts nicainoprol (10(-6) M, 5 X 10(-6) M and 10(-5) M) induced concentration-related protection against reperfusion arrhythmia without changing the cardiodynamics, with the exception of a decrease in heart rate at the highest concentration. Enzyme levels (lactate dehydrogenase and creatine kinase) in the coronary venous effluent, and cardiac tissue concentrations of glycogen, lactate, ATP and creatine phosphate were not affected by nicainoprol. Given to anesthetized rats, nicainoprol (5 and 10 mg/kg i.v.) reduced dose dependently in the early post occlusion (0-30 min) period, the percentage of animals with premature ventricular complexes (PVCs) and ventricular tachycardia while completely preventing the occurrence of ventricular fibrillation. In the reperfusion period no animal treated with 5 mg/kg and 12% of the rats treated with 10 mg/kg showed PVCs (the only form of arrhythmia observed in this period) versus 60% of the control rats. Both doses of nicainoprol induced a decrease in heart rate, blood pressure and myocardial oxygen consumption. The ratio of infarct mass to ventricular mass was significantly reduced by 20% at a dose of 5 mg/kg and by 28% at the dose of 10 mg/kg. Nicainoprol could be useful in the prevention and treatment of arrhythmias associated with acute myocardial infarction.

Anesthesia↗
PubMed1987

Influence of local converting enzyme inhibition on angiotensin and bradykinin effects in ischemic rat hearts.

To investigate the influence of local cardiac converting enzyme (CE) inhibition on the effects of angiotensin I (ANG I), ANG II, and bradykinin (BK), experiments were performed in ischemic isolated perfused working rat hearts. Acute regional myocardial ischemia was induced by 15 min occlusion of the left coronary artery followed by reperfusion. In ischemic isolated rat hearts, perfusion with ramiprilat (100 ng/ml, 2.58 x 10(-7) mol/l), the active moiety of the CE inhibitor ramipril, after coronary occlusion protected against ventricular fibrillation that invariably occurred in untreated control hearts in the reperfusion period. Addition of ANG I and ANG II to the perfusate enhanced, whereas BK reduced postischemic reperfusion arrhythmias, which were almost abolished in the hearts from ramipril (1 mg/kg p.o.) pretreated rats. Perfusion with ANG I and ANG II reduced cardiac function and coronary flow, increased the activities of lactate dehydrogenase and creatine kinase in the perfusate, and decreased high-energy-rich phosphates and glycogen in the myocardium. In contrast, BK reduced the enzymatic activities in the perfusate and improved the metabolic parameters in the myocardium. In hearts from ramipril pretreated animals, the ANG I effects were abolished, whereas the ANG II actions remained unchanged. The results of these experiments are consistent with the hypothesis that the beneficial effects of CE inhibitors on ventricular arrhythmias, cardiac function, and metabolism are due to local interference with CE in the coronary vascular wall or heart tissue and subsequent reduction of local ANG II generation and BK degradation.

Angiotensin II↗
PubMed1986

Beneficial effects of the converting enzyme inhibitor, ramipril, in ischemic rat hearts.

Components of the renin-angiotensin system (RAS) have been found in heart tissue and it is likely that angiotensin II (ANG II) is generated locally in the heart as in other organs. Pharmacological interference with converting enzyme (CE) inhibitors reduced CE activity and ANG II generation in the heart. To investigate whether local inhibition of CE in the heart with the CE inhibitor ramipril might contribute to the therapeutic effects, experiments were performed in isolated perfused working rat hearts. Acute regional myocardial ischemia was induced by occlusion of the left coronary artery followed by reperfusion. In ischemic isolated rat hearts, both single oral pretreatment with ramipril (1 mg/kg) or perfusion with the active moiety, ramiprilat (10 micrograms/ml), protected against ventricular fibrillation, which invariably occurred in control hearts during reperfusion. Reperfusion arrhythmias were aggravated by perfusion with ANG I and ANG II, but prevented by bradykinin. ANG I-enhanced ventricular fibrillations were completely eliminated during local CE inhibition with ramipril. The CE inhibitor also improved cardiodynamics. Coronary flow, left ventricular pressure, dp/dtmax, and myocardial oxygen consumption were increased in comparison to controls without changes in heart rate. In the perfusate of treated hearts, lactate dehydrogenase, and creatine kinase activities and lactate production, were reduced. Myocardial tissue levels of glycogen, ATP, and creatine phosphate were increased in ramipril-pretreated hearts whereas lactate was decreased. The results of these experiments in rat hearts suggest that local inhibition of CE by ramipril exerts protective effects after ischemia and reperfusion by reducing arrhythmias and improving cardiac function and metabolism, thus probably contributing to the therapeutic effects of CE inhibitors in cardiovascular diseases.

Angiotensin-Converting Enzyme Inhibitors↗
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↗
PubMed1985

Effects of converting enzyme inhibitors: ramipril and enalapril on peptide action and sympathetic neurotransmission in the isolated heart.

The role of converting enzyme (CE) in heart function was studied by assessing the inhibition of CE activity in rat heart tissue and in isolated perfused hearts from rat, guinea-pig and rabbit (Langendorff technique). Angiotensin I (ANG I) added to the perfusate reduced coronary flow (FLO) in all species, increased force of contraction (CON) in rats, decreased CON in guinea-pigs and had no effect on CON in rabbits. In contrast, bradykinin (BK) increased FLO in all species, decreased CON in rats, increased CON in guinea-pigs and had no effect on CON in rabbits. The CE inhibitors ramipril (HOE498) 1 mg/kg and enalapril (MK421) 30 mg/kg given orally 1 h prior to killing of the animals inhibited the ANG I effects and potentiated the BK effects but had no effects on the action of ANG II. The same doses of the two CE inhibitors produced up to 24 h inhibition of CE activity measured biochemically in the heart after single oral doses. Electrical sympathetic stimulation of the cardiac nerves (SNS) in isolated rabbit heart resulted in an increase of HR and CON and in an initial decrease and subsequent increase of FLO. The effects of SNS on HR and FLO were significantly reduced following HOE498 (1 mg/kg) pretreatment. The results suggest that local CE is involved in the regulation of peptide effects in the heart, including the ANG II-mediated facilitation of neurotransmission.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1983

Vascular effects of piretanide. Studies on extrarenal action in several animal models.

4-Phenoxy-3-(1-pyrrolidinyl)-5-sulfamoyl benzoic acid (piretanide, Arelix) was studied for its vasoactive effects in several experimental models. In rat and rabbit thoracic aorta strips, piretanide dose-dependently attenuated contractions induced by norepinephrine (noradrenaline). When contractions were induced by KCl no concentration response curve could be established. Piretanide inhibited the vasoconstrictor response to norepinephrine and to KCl in the rat mesenteric vascular bed. IC50's of 0.5 mmol/l and 4.9 mmol/l, resp., were calculated. In bovine coronary artery strips piretanide caused a marked relaxation. The vasoconstrictor response to PGE2 in piretanide superfused preparations was attenuated in a concentration related manner. Infusion of piretanide (1 mg X ml-1 X min-1) in the isolated guinea pig heart produced a reversible increase of coronary flow. In both normotensive and spontaneously hypertensive bilaterally nephrectomized pithed rats piretanide caused a significant reduction of diastolic blood pressure. The results contribute to the understanding of the antihypertensive effect of piretanide.

Animals↗
PubMedDate not supplied

Angiotensin converting enzyme inhibitors, left ventricular hypertrophy and fibrosis.

From pharmacological investigations and clinical studies, it is known that angiotensin converting enzyme (ACE) inhibitors exhibit additional local actions, which are not related to hemodynamic changes and which cannot be explained only by interference with the renin angiotensin system (RAS) by means of an inhibition of angiotensin II (ANG II) formation. Since ACE is identical to kininase II, which inactivates the nonapeptide bradykinin (BK) and related kinins, potentiation of kinins might be responsible for these additional effects of ACE inhibitors. a) In rats made hypertensive by aortic banding, the effect of ramipril in left ventricular hypertrophy (LVH) was investigated. Ramipril in the antihypertensive dose of 1 mg/kg/day for 6 weeks prevented the increase in blood pressure and the development of LVH. The low dose of ramipril (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. The antihypertrophic effect of the higher and lower doses of ramipril, as well as the antihypertensive action of the higher dose of ramipril, was abolished by coadministration of the kinin receptor antagonist icatibant. In the regression study the antihypertrophic actions of ramipril were not blocked by the kinin receptor antagonist. Chronic administration of BK had similar beneficial effects in a prevention study which were abolished by icatibant and NG-nitro-L-arginine (L-NNA). In a one year study the high and low dose of ramipril prevented LVH and fibrosis. Ramipril had an early direct effect in hypertensive rats on the mRNA expression for myocardial collagen I and III, unrelated to its blood pressure lowering effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Angiotensin-Converting Enzyme Inhibitors↗