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W Linz

Publications and source records attributed to W Linz.

At least 37 records · Page 2Linked to original sources
PubMed1998

Nephroprotection by long-term ACE inhibition with ramipril in spontaneously hypertensive stroke prone rats.

BACKGROUND: The effect of life-long treatment with the ACE inhibitor ramipril on hypertension-induced histological changes in the kidney was tested in stroke-prone spontaneously hypertensive rats (SHR-SP). METHODS: One-month-old pre-hypertensive SHR-SP were randomized into three groups of 45 animals each, and exposed via drinking water for their lifetime to a dose of: 1 mg.kg-1.d-1 ramipril (antihypertensive dose, HRA); 10 micrograms.kg-1.d-1 slight dose of ramipril (non-antihypertensive dose, LRA); or placebo. Histological and biochemical assessments were conducted after 15 months in ten rats each, when about 80% of the placebo group had died. RESULTS: Kidneys from placebo treated SHR-SP showed pronounced arterial wall hypertrophy and sclerosis, arterial fibrinoid necrosis, glomerulopathy and tubular interstitial injury that were, in concert with normalized blood pressure, completely prevented by HRA treatment. LRA treatment did not affect any blood pressure increase, and also attenuated the development of arterial wall hypertrophy, sclerosis and arterial fibrinoid necrosis, though to a minor extent only, but did not change glomerular and tubulointerstitial degeneration. These effects of ramipril were associated with a dose-dependent inhibition of plasma and renal tissue ACE activities as well as lower serum concentrations of creatinine, but there were no changes in serum potassium. CONCLUSIONS: Life-long HRA-induced ACE inhibition protects against hypertension-induced renal damages in SHR-SP. This is associated with a doubling of the lifespan in these animals.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Regulation of aortic atrial natriuretic factor and angiotensinogen in experimental hypertension.

We investigated the relation between atrial natriuretic factor (ANF) gene expression and the status of the renin-angiotensin system (RAS) in aortic tissue in rats made hypertensive by either aortic banding or by deoxycorticosterone acetate (DOCA)-salt administration. These experimental models of hypertension are known to have differences in terms of the status of RAS. ANF messenger RNA (mRNA) levels were measured in aortic tissue by using a newly developed quantitative competitive reverse transcription polymerase chain reaction (QC-RT-PCR) technique. Changes in the proportions of alpha1 and alpha2 isoforms of Na+K+-adenosine triphosphatase (ATPase) mRNA levels were used as indicators of aortic hypertrophy. Treatment with DOCA alone, salt alone, or DOCA-salt for 5 weeks increased aortic-weight/body-weight ratio and aortic angiotensinogen mRNA levels, but did not change alpha1 or alpha2 Na+K+-ATPase mRNA levels. Aortic ANF mRNA levels had a tendency to increase after treatment with DOCA, salt, or DOCA-salt, but this change did not reach statistical significance. Suprarenal aortic banding for 6 weeks or 12 weeks increased aortic-weight/body-weight ratio (12 weeks), decreased alpha2 Na+K+-ATPase and angiotensinogen mRNA levels, but did not affect alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. Treatment with ramipril, an angiotensin-converting enzyme (ACE) inhibitor was carried out for 6 weeks just after aortic banding (prevention experiment) or after 6 weeks in rats that were banded for the previous 6 weeks (regression experiment). High-dose ramipril (1 mg/kg)--a treatment known to inhibit both tissue and circulating RAS--normalized aortic-weight/body-weight ratio, and also normalized alpha2 Na+K+-ATPase mRNA levels. Aortic angiotensinogen mRNA levels of banded rats treated with high-dose ramipril was higher than those of the normal control, sham operated, and banded rats. Treatment with high-dose ramipril did not affect alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. Low-dose ramipril (10 microg/kg)--a treatment that selectively inhibits tissue RAS--normalized aortic-weight/body-weight ratio but did not normalize alpha2 Na+K+-ATPase mRNA levels (regression experiment) or angiotensinogen mRNA levels (prevention experiment) and did not change either alpha1 Na+K+-ATPase mRNA levels or ANF mRNA levels. The results suggest that, in contrast to previous findings in heart and kidney, the regulation of ANF mRNA levels in aortic tissue is largely independent of pressure load, volume load, and plasma or tissue RAS. It is suggested that any antihypertrophic actions of ANF may be mediated by the increased circulating ANF levels and its interaction with its receptor or through CNP.

Angiotensinogen↗
PubMed1998

Dose-dependent reduction of myocardial infarct mass in rabbits by the NHE-1 inhibitor cariporide (HOE 642).

The aim of this study was to investigate the dose-dependent effect of pretreatment with the selective sodium-hydrogen exchange NHE-subtype 1 inhibitor cariporide on myocardial infarct mass in a rabbit model of coronary ligation and reperfusion. Furthermore, in a second part of the study, we tested the effect of cariporide in the rabbits when given prior to reperfusion. Rabbits (n=49) were randomized in 7 groups: saline vehicle, cariporide: 0.01, 0.03, 0.1 and 0.3 mg/kg, and subjected to a 30 min occlusion of a branch of the left coronary artery followed by 2 h reperfusion. Cariporide was given as a bolus intravenously 10 min before occlusion or 5 min before reperfusion. After reperfusion, myocardial infarct mass was determined by triphenyl tetrazolium chloride staining and expressed as a percent of area at risk. Cariporide given intravenously 10 min before occlusion in doses of 0.01, 0.03, 0.1, 0.3 mg/kg, led to a dose-dependent reduction in infarct mass from 58+/-6% in controls to 48+/-4% (-17%, NS), 36+/-5% (-38%, p<0.05), 26+/-6% (-55%, p<0.05), 11+/-4% (-81%, p<0.05) respectively, whereas area at risk did not differ in between the groups. The effect of the lowest dose of 0.01 mg/kg did not reach significance. Plasma levels at different doses of cariporide were correlated to the respective infarct mass. After coronary occlusion left ventricular end-diastolic pressure (LVEDP) significantly increased throughout occlusion and reperfusion. Cariporide in the doses of 0.3, 0.1 and 0.03 mg/kg normalized LVEDP when measured after 2 h reperfusion. In controls hemodynamic parameters such as mean arterial blood pressure (MAP), heart rate (HR), left ventricular pressure (LVP) and LV dP/dt(max) were not significantly changed by ischemia/reperfusion with the exception of MAP, LVP and LV dP/dt(max) which were significantly decreased after 120 min reperfusion. Cariporide at doses of 0.1, 0.03 and 0.01 mg/kg did not significantly influence these parameters, whereas the highest dose of 0.3 mg/kg prevented the decrease of MAP and LVP. Cariporide (0.3 mg/kg i.v.) administered 5 min before reperfusion significantly reduced infarct mass by 31%. Under these conditions the increase of LVEDP after coronary occlusion was not influenced by cariporide. As in the pretreatment experiments, the decrease of MAP and LVP was prevented when measured 2 h after reperfusion. The results show that pretreatment with the NHE-subtype 1 inhibitor cariporide is cardioprotective by reducing infarct mass in rabbits in a dose-dependent manner. While the cardioprotective effect of pretreatment could be demonstrated over a broad range of doses, the efficacy of the compound when given only on reperfusion was significant but more limited.

Animals↗
PubMed1997

Long-term ACE inhibition doubles lifespan of hypertensive rats.

BACKGROUND: We compared the outcome of lifelong treatment with the ACE inhibitor ramipril in young prehypertensive stroke-prone spontaneously hypertensive rats (SHR-SP) and age-matched normotensive Wistar-Kyoto (WKY) rats. Ramipril was given in an antihypertensive and subantihypertensive dose. In addition to the primary end point, lifespan, surrogate parameters such as cardiac left ventricular hypertrophy, cardiac function and metabolism, and endothelial function were studied. METHODS AND RESULTS: One-month-old SHR-SP and WKY rats, 135 of each, were randomized into 3 groups. Each group was treated via drinking water with an antihypertensive high dose of ramipril (HRA, 1 mg x kg(-1) x d(-1)), a nonantihypertensive low dose of ramipril (LRA, 10 microg x kg(-1) x d(-1)), or placebo. Body weight and blood pressure were determined every 3 months. Molecular, biochemical, and functional data were assessed in SHR-SP and WKY rats after 15 and 30 months, respectively. These were the times when approximately 80% of the corresponding placebo group had died. Early-onset long-term ACE inhibition with HRA doubled lifespan to 30 months in SHR-SP, which was identical to the lifespan of placebo-treated normotensive WKY rats. LRA treatment prolonged lifespan from 15 to 18 months. In SHR-SP, left ventricular hypertrophy was completely prevented by HRA but not by LRA treatment. Cardiac function and metabolism as well as endothelial function were significantly improved by both doses of ramipril. Carotid expression of endothelial NO synthase was moderately enhanced, whereas cardiac ACE expression and activity were decreased to values of placebo-treated WKY rats. CONCLUSIONS: Lifelong ACE inhibition doubles lifespan in SHR-SP, matching that of normotensive WKY rats. This effect correlated with preservation of endothelial function, cardiac function/size, and metabolism. Thus, these data predict a beneficial outcome on survival in high-risk patients with hypertension and associated cardiovascular diseases by ACE inhibition.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Beneficial effects of bradykinin on myocardial energy metabolism and infarct size.

There is growing evidence for a local kallikrein-kinin system in the heart. In the ischemic heart the enhanced generation and release of kinins seem to have cardioprotective actions. In isolated rat hearts with ischemia-reperfusion injuries, perfusion with bradykinin reduces the duration and incidence of ventricular fibrillations, improves cardiodynamics, reduces release of cytosolic enzymes, and preserves energy-rich phosphates and glycogen stores. In anesthetized animals, intracoronary infusion of bradykinin is followed by comparable beneficial changes and limits infarct size. Inhibition of breakdown of bradykinin and related peptides induces similar beneficial cardiac effects. Treatment with angiotensin-converting enzyme (ACE) inhibitors such as ramipril increases cardiac kinins and reduces postischemic reperfusion injuries in isolated rat hearts as well as infarct size and remodeling in postinfarcted animals, respectively. Blockade of B2 kinin receptors increases ischemia-induced effects. In isolated hearts, ischemia-reperfusion injuries intensify with the B2 kinin receptor antagonist icatibant, which also abolishes the cardioprotective effects of ACE inhibitors and of exogenous bradykinin. Infarct size reduction by ACE inhibitors and bradykinin in anesthetized animals is reversed by icatibant. Kinins contribute to the cardioprotective effects associated with ischemic preconditioning. Preconditioning or bradykinin-induced antiarrhythmic and infarct size-limiting effects are attenuated by icatibant.

Animals↗
PubMed1997

Kinins and cardioprotection.

During the past decade it was recognised that kinins are potent endogenous vasoactive peptides with important cardioprotective actions which are of therapeutic relevance in the acute and chronic beneficial effects of ACE inhibitors. The effect of kinins is mediated through the release of autocoids from the endothelium, particularly nitric oxide (NO). In this review article the cardioprotective effects of kinins and their importance for the therapeutic effects of ACE inhibitors are highlighted.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Myocardial angiotensin receptor type 1 gene expression in a rat model of cardiac volume overload.

To investigate the regulation of the angiotensin receptor type 1 (AT1) in different organs in cardiac volume overload, we measured AT1 mRNA content in the atria, left and right ventricle, kidney and liver of rats with an aortocaval shunt, produced by infrarenal aortocaval puncture 4 weeks earlier. For angiotensin receptor mRNA quantitation a novel quantitative PCR procedure based on liquid phase hybridization was used that allowed the determination of absolute AT1 mRNA copy numbers and its comparison in different organs. Glyceraldehydephosphate dehydrogenase (GAPDH) mRNA was measured by RT-PCR to control externally equal mRNA content and quality of RNA extraction in shunt animals and controls. Heart weight was increased in the shunt animals, with the greatest increase in the atria. Blood pressure, plasma renin activity, plasma angiotensin I and II and aldosterone concentrations were not significantly altered. The AT1 mRNA content was significantly increased in the atria (shunt: 1167 +/- 350 copies AT1 mRNA/ng RNA vs controls: 803 +/- 240; p < 0.05). No change was found in the right or left ventricle, in the kidney and liver. The findings document that atrial hypertrophy in cardiac volume overload parallel with a significant increase in atrial AT1 mRNA content.

Animals↗
PubMed1997

Antihypertensive and cardioprotective effects after angiotensin-converting enzyme inhibition: role of kinins.

Kinins are potent bioactive peptides formed by the enzymatic action of kallikrein on kininogens. The discovery that angiotensin-converting enzyme, which generates angiotensin II, is also a major degrading enzyme of kinins, gave rise to the hypothesis that kinin potentiation, in addition to angiotensin II reduction, may be involved in the therapeutic actions of angiotensin-converting enzyme inhibitors. Angiotensin-converting enzyme inhibitors have become important drugs in the treatment of hypertension, congestive heart failure, postmyocardial infarction, and diabetic nephropathy. Although angiotensin II reduction appears to be the predominant mechanism of the antihypertensive effect of chronic angiotensin-converting enzyme inhibitor treatment, the role of kinins in the antihypertensive effects of angiotensin-converting enzyme inhibitors seems to be renin dependent and cannot be generalized for all models of hypertension. On the other hand, at least under experimental conditions, various cardioprotective effects of angiotensin-converting enzyme inhibitors appear to be due to the potentiation of endogenous kinins, including improved cardiac function, structural changes following myocardial ischemia, and induction of capillary growth in hypertension-induced left ventricular hypertrophy.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1997

Hypercholesterolemia is associated with enhanced angiotensin AT1-receptor expression.

Low-density lipoprotein increases the AT1-receptor gene expression in vascular smooth muscle cells. To elucidate whether elevated cholesterol serum levels upregulate the AT1 receptor and its functional response to angiotensin II in vivo, we compared 1) the vasoconstrictive effect of angiotensin II and 2) the level of expression of the vascular AT1 receptor in aortas of normocholesterolemic and hypercholesterolemic rabbits. Contraction experiments on isolated aortic rings showed that the angiotensin II-induced vasoconstriction was increased in hypercholesterolemic New Zealand White rabbits compared with normocholesterolemic New Zealand White rabbits. This difference in the angiotensin II-induced vasoconstriction was caused by a twofold increase in the density of cell surface AT1 receptors in hypercholesterolemic rabbits, as assessed by radioligand binding assays. The enhanced expression of AT1 receptors on the surface of these vascular cells was caused by elevated steady-state levels of the AT1-receptor mRNA to 220 +/- 35% in aortas excised from hypercholesterolemic rabbits compared with levels in aortas from normocholesterolemic rabbits, as measured by Northern blot analysis. These data indicate that hypercholesterolemia is associated with upregulation of expression and function of vascular AT1 receptors in vivo. This suggests a novel mechanism by which hypercholesterolemia could be involved in the onset and progression of chronic vascular diseases such as hypertension and arteriosclerosis if the phenomenon is confirmed in humans.

Angiotensin II↗
PubMed1997

Increased brain transcription factor expression by angiotensin in genetic hypertension.

A stimulated brain renin-angiotensin system has been implicated in genetic hypertension. We compared the effects of an intracerebroventricular injection of angiotensin II (100 ng) on the expression of inducible transcription factors c-Fos, c-Jun, and Krox-24 in the brain of spontaneously hypertensive rats (SHR). in Wistar rats with nephrogenic hypertension induced by aortic banding, and in normotensive Wistar-Kyoto and Wistar rats immunohistochemically. Generally, the angiotensin II-induced transcription factor expression was strictly confined to four distinct forebrain areas: the subfornical organ, median preoptic area, paraventricular nucleus, and supraoptic nucleus. In SHR, the angiotensin II-induced c-Fos and c-Jun expressions were significantly enhanced compared with those in normotensive control strains as well as in secondary hypertensive Wistar rats. Krox-24 expression in the subfornical organ, median preoptic area, and paraventricular nucleus of SHR was also significantly increased compared with that in all control strains. In the supraoptic nucleus, significant differences could be discriminated between SHR and secondary hypertensive Wistar rats. Injection of isotonic saline or arginine vasopressin (100 ng) as controls did not induce any expression of c-Fos, c-Jun, or Krox-24. Our findings demonstrate an enhanced sensitivity of SHR to angiotensin II-induced transcription factor expression in distinct brain areas involved in central blood pressure and osmotic control that is independent of blood pressure.

Angiotensin II↗
PubMed1997

Endothelial dysfunction coincides with an enhanced nitric oxide synthase expression and superoxide anion production.

We investigated the effects of aortic banding-induced hypertension on the endothelium-dependent vasodilator responses in the aorta and coronary circulation of Sprague-Dawley rats. We studied the influence of hypertension on the endothelial nitric oxide synthase (NOS III) expression, assessed by Western blot and reverse transcription-polymerase chain reactions experiments, and on the superoxide anion (O2-) production. Two weeks after aortic banding, the endothelium-dependent relaxations were not altered. At this time, the expression of NOS III in the aorta and in confluent coronary microvascular endothelial cells (RCMECs) exhibited no marked changes, whereas O2- production was enhanced 1.9-fold in aortas from aortic-banded rats. Six weeks after aortic banding, the endothelium-dependent dilations were markedly impaired in the heart (50% decrease) and aorta (35% decrease). Analysis of NOS III protein and mRNA levels revealed marked increases in both aortas and confluent RCMECs (2.6- to 4-fold) from aortic-banded compared with sham-operated rats. There was no further increase in O2production in both the aorta and confluent RCMECs from aortic-banded rats. An enhanced nitrotyrosine protein level was also detected in the aorta from 6-week aortic-banded rats. These findings indicate that in hypertension induced by aortic banding, an enhanced O2- production alone is not sufficient to produce endothelial dysfunction. Endothelial vasodilator hyporesponsiveness was observed only when NOS III expression and O2- production were increased and was associated with the appearance of enhanced nitrotyrosine residues. This would suggest that the development of endothelial dysfunction is linked to an overproduction of not one, but two, endothelium-derived radicals that might lead to the formation of peroxynitrite.

Animals↗
PubMed1997

Angiotensin-converting enzyme inhibition alters nitric oxide and superoxide release in normotensive and hypertensive rats.

Young (approximately 1 month old) male normotensive Wistar-Kyoto rats (n=26) and spontaneously hypertensive rats (n=38) were randomized into three groups treated via drinking water for approximately 2 years with, respectively, placebo, low doses, or high doses of an angiotensin-converting enzyme inhibitor, ramipril (10 microg x kg[-1] x d[-1], non-blood pressure-lowering dose, or 1 mg x kg[-1] x d[-1], blood pressure-lowering dose). Relative to placebo treatment in each respective rat strain, both ramipril dosages increased endothelial constitutive nitric oxide synthase expression (Western blot) and resultant synthesis of nitric oxide (porphyrinic sensor) in freshly excised carotids and thoracic aortas, respectively. Paradoxically, this activity was associated with an increased/decreased superoxide accumulation (chemiluminescence) in freshly excised aortas from 24-/22-month-old normotensive/hypertensive rats. In normotensive rats, relative to placebo treatment, the threefold increase in superoxide accumulation with antihypertensive ramipril treatment is most likely from the >300% increase in endothelial constitutive nitric oxide synthase expression (some of which may be disarranged by local insufficiencies in L-arginine or tetrahydrobiopterin). In hypertensive rats, relative to placebo treatment, the 35% increase in nitric oxide availability by long-term antihypertensive ramipril treatment may contribute to the preservation of the endothelium and prevent its dysfunction by inhibiting superoxide production. Increased nitric oxide production with concomitant decreased superoxide accumulation (approximately one third of placebo levels) correlates positively with the previously reported +40% life span extension for rats with genetic hypertension that were treated with antihypertensive doses of ramipril.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Evidence for load-dependent and load-independent determinants of cardiac natriuretic peptide production.

BACKGROUND: In hypertension with cardiac hypertrophy, the specific contributions to increased production of the cardiac natriuretic peptides (NP) atrial natriuretic factor (ANF) and brain natriuretic peptide (BNP) by load and the hypertrophic process are not known. In the present work we determine ANF and BNP synthesis and secretion in the aortic-banded rat treated with dosage schedules of the ACE inhibitor ramipril that result in the prevention or regression of both hypertension and hypertrophy (high dosage) or in the prevention or regression of hypertrophy alone with persistent hypertension (low dosage). Myosin heavy chain (MHC) isoform switch was studied as an indicator of ventricular cardiocyte hypertrophy as well as the levels of collagen III mRNA as a measure of changes in extracellular matrix. METHODS AND RESULTS: Ramipril was administered for 6 weeks just after suprarenal aortic banding, or rats were banded for 6 weeks, after which ramipril was administered during the following 6 weeks. Banding caused an increase in blood pressure, left ventricular weight-to-body weight ratio, plasma and ventricular NP, ventricular NP mRNA, collagen III, and beta-MHC mRNA. Ramipril at 1 mg/kg normalized all these parameters while ramipril at 10 micrograms/kg normalized left ventricular weight-to-body weight ratio but not blood pressure. Plasma and ventricular NP content and mRNA levels were partially normalized by ramipril (10 micrograms/kg). Ramipril (10 micrograms/kg) prevented increased collagen III mRNA levels but did not affect beta-MHC mRNA levels. CONCLUSIONS: (1) NP production and secretion in aortic-banded rats are independently related to increased blood pressure and hypertrophy. (2) A load-dependent component is more important than a load-independent component in regulating left ventricular NP production. (3) ANF production is more sensitive than BNP production to the load-independent component. (4) Low-dose ramipril treatment reverses hypertrophy and the increased collagen III expression but does not reverse the increased beta-MHC isoform expression, suggesting that these are independently regulated processes. (5) Aortic banding and ACE inhibition do not affect atrial NP production and content.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

Differences in acetylcholine- and bradykinin-induced vasorelaxation of the mesenteric vascular bed in spontaneously hypertensive rats of different ages.

The present study examined whether alterations of endothelium-dependent vasorelaxation in spontaneously hypertensive rats (SHR) in response to the endothelium-dependent vasodilators acetylcholine and bradykinin ran parallel. We tried to find out the age at which endothelium-dependent vasorelaxation in response to each agonist became impaired and compared three different groups of SHR aged 7, 21 and 51 weeks. To be able to separate hypertension-induced alterations from age-dependent changes age-matched normotensive Wistar rats were included. Endothelium-dependent vasorelaxation was studied in the mesenteric vascular bed precontracted with noradrenaline, a typical resistance vessel, which showed relaxation to both acetylcholine and bradykinin, and the precontracted thoracic aorta, which only responded to acetylcholine. There were major differences in the agonist-dependent vasorelaxation between bradykinin and acetylcholine in SHR as a function of age. A surprising finding was that acetylcholine-induced relaxation was preserved, even slightly improved not only in young SHR (7 weeks) with developing hypertension but also in adult SHR (21 weeks) with established hypertension, which can be interpreted as a compensatory mechanism. As expected, in old SHR (51 weeks) acetylcholine-induced vasorelaxation was impaired as a consequence of the detrimental effects of long-term hypertension on endothelium. The parallel changes observed with acetylcholine in the mesenteric vascular bed and thoracic aorta provided mutual confirmation. In clear contrast to acetylcholine bradykinin-induced vasorelaxation was already imparied in young SHR with developing hypertension suggesting that bradykinin-induced vasorelaxation is either much more sensitive to detrimental effects of (even slightly) increased blood pressure or, more likely, that there is a basic deficiency in the action of bradykinin in SHR. Thus, our study allows to conclude that impairment of acetylcholine-induced endothelium-dependent vasorelaxation in the mesenteric vascular bed of SHR is a secondary phenomenon developing as a consequence of long-term hypertension while the impaired bradykinin-induced vasorelaxation seems to be a primary phenomenon that could be closely related to the development of hypertension.

Acetylcholine↗
PubMed1996

Cardiac and vascular effects of long-term losartan treatment in stroke-prone spontaneously hypertensive rats.

In previous studies in stroke-prone spontaneously hypertensive rats (SHRSP), we demonstrated that early-onset, long-term angiotensin-converting enzyme inhibitor treatment improved cardiac function and metabolism and increased aortic cGMP content even at sub-antihypertensive doses. These effects could be prevented by bradykinin type 2 (B2) receptor blockade with icatibant. In the present study, we studied the effects of long-term oral treatment with the angiotensin type 1 (AT1) receptor antagonist losartan (30 mg/kg per day) on functional and biochemical parameters of the heart and on cGMP content in the aorta in SHRSP treated prenatally and subsequently up to the age of 20 weeks. Losartan prevented the development of hypertension and left ventricular hypertrophy. Cardiac function measured ex vivo in isolated perfused hearts was improved, as demonstrated by significant increases in left ventricular pressure (22.4%), differentiated left ventricular pressure (dP/dtmax) (35.1%), and coronary flow (38%). The release of the intracellular enzymes lactate dehydrogenase and creatine kinase and of lactate into the coronary effluent was reduced by 46.4%, 47.2%, and 63.6%, respectively. In myocardial tissue, the concentrations of glycogen and the energy-rich phosphates ATP and creatine phosphate were increased by 43.2%, 33.1%, and 42.4%, respectively, whereas lactate was decreased by 57.0%. The aortic tissue content of cGMP was increased fivefold. Our results demonstrate that chronic blockade of AT1 receptors with losartan improved cardiac function and metabolism and increased aortic cGMP content in SHRSP to an extent similar to that observed previously after long-term angiotensin-converting enzyme inhibitor treatment at a comparably antihypertensive dose. Prevention of hypertension and cardiac hypertrophy as well as stimulation of non-AT1 receptors are discussed to explain the cardiac and vascular actions of losartan.

Angiotensin Receptor Antagonists↗
PubMed1996

Role of kinins in the pathophysiology of myocardial ischemia. In vitro and in vivo studies.

In ischemia, the heart generates and releases kinins as mediators that seem to have cardioprotective actions. Kinin-generating pathways are present in the heart. Kininogen, kininogenases, kinins, and B2 kinin receptors can be measured in cardiac tissue. Kinins are released under conditions of ischemia. In anesthetized rats and dogs with coronary artery ligation and in human patients with myocardial infarction, kinin plasma levels are increased. In isolated rat hearts, the outflow of kinins is enhanced during ischemia but markedly attenuated after deendothelialization, pointing to the coronary vascular endothelium as the main possible source. Kinins administered locally exert beneficial cardiac effects. In isolated rat hearts with ischemia-reperfusion injuries, perfusion with bradykinin (BK) reduces the duration and incidence of ventricular fibrillation, improves cardiodynamics, reduces release of cytosolic enzymes, and preserves energy-rich phosphates and glycogen stores. In anesthetized animals, intracoronary BK is followed by comparable beneficial changes and limits infarct size. Inhibition of breakdown of BK and related peptides induces beneficial cardiac effects. Treatment with ACE inhibitors such as ramipril increases cardiac kinin levels and reduces post-ischemic reperfusion injuries in isolated rat hearts and infarct size in anesthetized animals. The importance of an intact endothelium that continuously generates kinins is supported by observations that basal and ramipril-induced release of kinins and PGI2 is markedly reduced after deendothelialization of isolated hearts. Blockade of B2 kinin receptors increases ischemia-induced effects. Endothelial formation of NO and PGI2 by ACE inhibition is prevented by the specific B2 kinin receptor antagonist icatibant. In isolated hearts, ischemia-reperfusion injuries deteriorate with icatibant, which also abolishes the cardioprotective effects of ACE inhibitors and of exogenous BK. Infarct size reduction by ACE inhibitors and by BK in anesthetized animals is reversed by icatibant. Kinins contribute to the cardioprotective effects associated with ischemic preconditioning because preconditioning or BK-induced antiarrhythmic and infarct size-limiting effects are attenuated by icatibant. In conclusion, kinins may act as mediators of endogenous cardioprotective mechanisms. Kinins are generated and released during ischemia, with subsequent formation of PGI2 and NO probably derived mainly from the coronary vascular endothelium. Their cardioprotective profile resembles that of ACE inhibitors.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1996

ACE inhibition decreases postoperative mortality in rats with left ventricular hypertrophy and myocardial infarction.

UNLABELLED: In male Sprague Dawley rats with left ventricular hypertrophy (LVH) and hypertension induced by aortic constriction (AC) and subsequent myocardial infarction (MI) by occlusion of the left coronary artery the effects of ACE inhibition with ramipril (RA 1 mg/kg/day via the drinking water during 6 weeks) on survival as well as cardiac function and metabolism were investigated. Respective groups (sham AC; AC; AC + sham MI; normotensive animals with sham MI; MI; MI + RA) served as comparisons. Following MI hypertensive rats with AC and LVH revealed an increased postoperative mortality (68%) when compared to normotensives without AC (28%). ACE inhibition with ramipril significantly reduced mortality in hypertensive rats by 26%. Untreated hypertensive animals with LVH clearly showed reduced MI size (6.2 +/- 2.3%) in comparison with untreated normotensive animals and MI (31.0 +/- 3.3%). In hypertensive rats with MI which died during the study a significant increase in infarct size was found compared to those which survived MI. In normotensive animals ramipril reduced infarct size by 50%. Due to the quite small infarct size observed in hypertensive rats, ACE inhibition did not further reduce MI in these animals. LVH as well as hydroxyproline/proline ratio was diminished by ACE inhibitor treatment. In the isolated hearts of ramipril treated rats contractility was improved when compared to the respective untreated groups with MI. In the coronary effluent of isolated hearts from rats with AC and MI lactate dehydrogenase and creatine kinase activities as well as lactate levels were increased. Ramipril treatment starting one week before MI normalized these parameters and in addition increased prostacyclin output. Hearts with MI from treated normotensive animals contained increased energy rich phosphates when compared to hearts from untreated rats with MI. CONCLUSIONS: Hypertensive rats with LVH undergoing MI experience increased postoperative mortality probably due to a reduced tolerance to myocardial ischemia and occurrence of arrhythmias. In these animals ACE inhibition with ramipril increased survival. Both, increased survival in hypertensive and reduction in infarct size in normotensive rats by ACE inhibition with ramipril was accompanied by an improved myocardial metabolism.

Angiotensin-Converting Enzyme Inhibitors↗