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F Ruschitzka

Publications and source records attributed to F Ruschitzka.

At least 19 recordsLinked to original sources
PubMed2006

Coxibs, non-steroidal anti-inflammatory drugs and cardiovascular risk.

The introduction of selective cyclooxygenase-2 inhibitors offered the promise of similar efficacy in pain control without the gastrointestinal effects associated with non-selective non-steroidal anti-inflammatory drugs (NSAIDs). By blocking prostacyclin formation but leaving platelet-derived thromboxane A2 generation unopposed, there is concern that the potential gastrointestinal benefit of cyclooxygenase-2-selective inhibitors may come at the cost of increased thrombotic risk. However, the differential effects of coxibs on blood pressure, endothelial function, oxidative stress, tissue factor expression, vascular smooth muscle proliferation and neointimal hyperplasia indicate a distinct heterogeneity among this class of drugs. Importantly, the observation of an excess cardiovascular risk with traditional NSAIDs in randomized clinical trials, meta-analysis and large-scale observational studies further highlights the need to scrutinize the entire class of anti-inflammatory drugs, including traditional NSAIDs, as rigorously as coxibs.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed2005

[The sweet secret of dark chocolate].

For centuries dark chocolate has been known for its taste as well as its beneficial effects on health. Mainly polyphenols, a heterogeneous group of molecules, have been associated with antioxidant and immunomodulatory properties. Furthermore they inhibit primary hemostasis and pathways associated with platelet activation and aggregation.

Administration, Oral↗
PubMed2001

Vasopeptidase inhibitors: a new therapeutic concept in cardiovascular disease?

The cardiovascular system is regulated by hemodynamic and neurohumoral mechanisms. These regulatory systems play a key role in modulating cardiac function, vascular tone, and structure. Although neurohumoral systems are essential in vascular homeostasis, they become maladaptive in disease states such as hypertension, coronary disease, and heart failure. The clinical success of ACE inhibitors has led to efforts to block other humoral systems. Neutral endopeptidase (NEP) is an endothelial cell surface zinc metallopeptidase with similar structure and catalytic site. NEP is the major enzymatic pathway for degradation of natriuretic peptides, a secondary enzymatic pathway for degradation of kinins, and adrenomedullin. The natriuretic peptides can be viewed as endogenous inhibitors of the renin angiotensin system. Inhibition of NEP increases levels of atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP) of myocardial cell origin, and C-type natriuretic peptide (CNP) of endothelial cell origin as well as bradykinin and adrenomedullin. By simultaneously inhibiting the renin-angiotensin-aldosterone system and potentiating the natriuretic peptide and kinin systems, vasopeptidase inhibitors reduce vasoconstriction, enhance vasodilation, improve sodium/water balance, and, in turn, decrease peripheral vascular resistance and blood pressure and improve local blood flow. Within the blood vessel wall, this leads to a reduction of vasoconstrictor and proliferative mediators such as angiotensin II and increased local levels of bradykinin (and, in turn, nitric oxide) and natriuretic peptides. Preliminary clinical experiences with vasopeptidase inhibitors are encouraging. Thus, the combined inhibition of ACE and neutral endopeptidase is a new and promising approach to treat patients with hypertension, atherosclerosis, or heart failure.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed2001

Endothelin 1 type a receptor antagonism prevents vascular dysfunction and hypertension induced by 11beta-hydroxysteroid dehydrogenase inhibition: role of nitric oxide.

BACKGROUND: The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD) prevents inappropriate activation of the nonselective mineralocorticoid receptors by glucocorticoids. Renal activity of 11beta-HSD is decreased in patients with apparent mineralocorticoid excess (SAME), licorice-induced hypertension, and essential hypertension. Although expressed in vascular cells, the role of 11beta-HSD in the regulation of vascular tone remains to be determined. METHODS AND RESULTS: lycyrrhizic acid (GA; 50 mg/kg IP, twice daily for 7 days) caused a significant inhibition of 11beta-HSD activity and induced hypertension in Wistar-Kyoto rats (157 versus 127 mm Hg in controls; P<0.01). After 11beta-HSD inhibition, aortic endothelial nitric oxide (NO) synthase (eNOS) protein content, nitrate tissue levels, and acetylcholine-induced release of NO were blunted (all P<0.05 versus controls). In contrast, vascular prepro-endothelin (ET)-1 gene expression, ET-1 protein levels, and vascular reactivity to ET-1 were enhanced by GA treatment (P<0.05 versus controls). Chronic ET(A) receptor blockade with LU135252 (50 mg. kg(-1). d(-1)) normalized blood pressure, ET-1 tissue content, vascular reactivity to ET-1, vascular eNOS protein content, and nitrate tissue levels and improved NO-mediated endothelial function in GA-treated rats (P<0.05 to 0.01 versus untreated and verapamil-treated controls). In human endothelial cells, GA increased production of ET-1 in the presence of corticosterone, which indicates that activation of the vascular ET-1 system by 11beta-HSD inhibition can occur independently of changes in blood pressure but is dependent on the presence of glucocorticoids. CONCLUSIONS: Chronic ET(A) receptor blockade normalizes blood pressure, prevents upregulation of vascular ET-1, and improves endothelial dysfunction in 11beta-HSD inhibitor-induced hypertension and may emerge as a novel therapeutic approach in cardiovascular disease associated with reduced 11beta-HSD activity.

11-beta-Hydroxysteroid Dehydrogenases↗
PubMed2001

Influence of aldosterone vs. endothelin receptor antagonism on renovascular function in liquorice-induced hypertension.

BACKGROUND: The enzyme 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor inactive 11-dehydro derivatives. Inhibition of 11beta-HSD2 by liquorice-derived glycyrrhizic acid (GA) therefore results in sodium retention and hypertension. The present study investigated the effect of the aldosterone receptor antagonist spironolactone in comparison with the endothelin ET(A) receptor antagonist darusentan on renovascular endothelial function in liquorice-induced hypertension. METHODS: GA, a recognized inhibitor of 11beta-HSD2 was supplemented to the drinking water (3 g/l) of Wistar Kyoto rats over a period of 21 days. From day 8 to 21, spironolactone (5.8+/-0.6 mg/kg/day), darusentan (45.2+/-6.5 mg/kg/day), or placebo was added to chow (n=7 per group). After the animals were killed, vascular function of isolated renal artery segments was assessed by isometric tension recording. RESULTS: Relaxation of pre-constricted renal artery segments in response to acetylcholine (10(-10) to 10(-5) mol/l) was impaired by GA as compared with controls (12+/-4% vs 98+/-5% of norepinephrine 3x10(-7) mol/l), whereas endothelium independent relaxations were unaffected. Endothelin receptor antagonism improved renovascular endothelium-dependent relaxation (32+/-4%, P<0.05 vs placebo) whereas endothelium-dependent relaxation was completely normalized by aldosterone receptor antagonism (85+/-4%, P<0.01 vs placebo). CONCLUSIONS: In GA-induced hypertension, both aldosterone receptor antagonism and endothelin receptor antagonism normalize blood pressure and improve renovascular function and, thus, may represent a new therapeutic approach in cardiovascular disease associated with impaired 11beta-HSD2 activity.

Animals↗
PubMed2001

Aldosterone receptor antagonism normalizes vascular function in liquorice-induced hypertension.

The enzyme 11beta-hydroxysteroid dehydrogenase (11beta-HSD2) provides mineralocorticoid receptor specificity for aldosterone by metabolizing glucocorticoids to their receptor-inactive 11-dehydro derivatives. The present study investigated the effects of the aldosterone receptor antagonists spironolactone and eplerenone on endothelial function in liquorice-induced hypertension. Glycyrrhizic acid (GA), a recognized inhibitor of 11beta-HSD2, was supplemented to the drinking water (3 g/L) of Wistar-Kyoto rats over a period of 21 days. From days 8 to 21, spironolactone (5.8+/-0.6 mg. kg(-1). d(-1)), eplerenone (182+/-13 mg. kg(-1). d(-1)), or placebo was added to the chow (n=7 animals per group). Endothelium-dependent or -independent vascular function was assessed as the relaxation of preconstricted aortic rings to acetylcholine or sodium nitroprusside, respectively. In addition, aortic endothelial nitric oxide synthase (eNOS) protein content, nitrate tissue levels, and endothelin-1 (ET-1) protein levels were determined. GA increased systolic blood pressure from 142+/-8 to 185+/-9 mm Hg (P<0.01). In the GA group, endothelium-dependent relaxation was impaired compared with that in controls (73+/-6% versus 99+/-5%), whereas endothelium-independent relaxation remained unchanged. In the aortas of 11beta-HSD2-deficient rats, eNOS protein content and nitrate tissue levels decreased (1114+/-128 versus 518+/-77 microgram/g protein, P<0.05). In contrast, aortic ET-1 protein levels were enhanced by GA (308+/-38 versus 497+/-47 pg/mg tissue, P<0.05). Both spironolactone and eplerenone normalized blood pressure in animals on GA (142+/-9 and 143+/-9 mm Hg, respectively, versus 189+/-8 mm Hg in the placebo group; P<0.01), restored endothelium-dependent relaxation (96+/-3% and 97+/-3%, respectively, P<0.01 versus placebo), blunted the decrease in vascular eNOS protein content and nitrate tissue levels, and normalized vascular ET-1 levels. This is the first study to demonstrate that aldosterone receptor antagonism normalizes blood pressure, prevents upregulation of vascular ET-1, restores NO-mediated endothelial dysfunction, and thus, may advance as a novel and specific therapeutic approach in 11beta-HSD2-deficient hypertension.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗
PubMed2000

Tissue endothelin-converting enzyme activity correlates with cardiovascular risk factors in coronary artery disease.

BACKGROUND: Endothelin-converting enzymes (ECEs) are the key enzymes in endothelin-1 (ET-1) generation. However, their pathophysiological role in patients with cardiovascular disease remains elusive. METHODS AND RESULTS: Vascular reactivity to big endothelin-1 (bigET-1; 10(-9) to 10(-7) mol/L) and ET-1 (10(-9) to 10(-7) mol/L) were examined in the internal mammary artery (IMA, n=33) and saphenous vein (SV, n=27) of patients with coronary artery disease with identified cardiovascular risk factors. Vascular ECE activity was determined by conversion of exogenously added bigET-1 to ET-1. Tissue contents of bigET-1 and ET-1 were measured by radioimmunoassay. In addition, the effects of LDL and oxidized LDL on ECE-1 protein levels were determined by Western blot analysis in human IMA endothelial cells. In the IMA, vascular ECE activity showed an inverse correlation with serum LDL levels (r=-0.76; P<0.01) and systolic and diastolic blood pressure and a positive correlation with fibrinogen (r=0.58; P<0.05). In the SV, fibrinogen was the only parameter to be correlated with vascular ECE activity. Vascular tissue content of bigET-1 was attenuated in the IMA of patients with hyperfibrinogenemia but increased in patients with elevated systolic blood pressure and increased serum LDL levels (P<0.05). Most interestingly, LDL and oxidized LDL downregulated ECE-1 protein levels in human IMA endothelial cells (P<0.05). CONCLUSIONS: These data demonstrate, for the first time, that vascular ECE activity is (1) inversely correlated with serum LDL levels and blood pressure and (2) positively associated with fibrinogen in human vascular tissue. Hence, ECE-1 activity may modulate cardiovascular risk in patients with coronary artery disease.

Aspartic Acid Endopeptidases↗
PubMed1999

Angiotensin converting enzyme inhibitors and vascular protection in hypertension.

Strategically located between the circulating blood and the vascular smooth muscle, endothelial cells release numerous vasoactive substances regulating the function of vascular smooth muscle and circulating blood cells. Endothelium-derived vasodilators include prostacyclin, nitric oxide and endothelium-derived hyperpolarizing factor. In particular, nitric oxide inhibits cellular growth and migration. In concert with prostacyclin, nitric oxide exerts potent antiatherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by vasoconstrictors, such as angiotensin II and endothelin (ET)-1, both of which exert prothrombotic and growth-promoting properties. In hypertension, elevated blood pressure causes vascular disease by inducing endothelial dysfunction. Hence, modern therapeutic strategies in human hypertension focus on preserving or restoring endothelial integrity. Beyond inhibiting the renin-angiotensin system, angiotensin-converting enzyme (ACE) inhibitors diminish the inactivation of bradykinin, thus leading to an augmentation of nitric oxide release. In addition, the compounds stabilize the B2-receptor, and reduce oxidative stress and tissue ET-1 levels. In patients with coronary artery disease, chronic ACE inhibition improves endothelial function. Further clinical studies are already under way which will prove whether these beneficial vascular effects of ACE inhibitors on endothelial dysfunction result in a clinical benefit for patients with hypertension.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1999

Endothelial dysfunction in acute renal failure: role of circulating and tissue endothelin-1.

The kidney is an important target and source of the potent vasoconstrictor and mitogen endothelin-1 (ET-1). However, its exact role in acute renal failure (ARF) remains to be determined. ARF was induced in male Wistar-Kyoto rats (n = 7) in a 2-kidney, 2-clip model of 30-min clamping. Twenty-four hours after clamp release, contractions to angiotensin I (Angl) and II, ET-1, and big ET-1 were studied in isolated aortic and renal artery rings. Endothelium-dependent and -independent relaxations were assessed by acetylcholine and sodium nitroprusside. ET-1 clearance, tissue uptake, plasma levels, and vascular and kidney content were investigated. In addition, ET(A) and Et(B) receptor mRNA expression was determined. Sham-operated animals served as controls (n = 7). In ARF, ET-1 plasma levels and tissue content of the renal artery, the aorta, and the kidney markedly increased (P<0.01). Plasma half-life of radiolabeled 125I-ET-1 was markedly prolonged, whereas 125I-ET-1 tissue uptake decreased in the kidney in ARF. Contractions to AngI and AngII were blunted (P<0.05) and those to KCl were unchanged, whereas vascular responses to big ET-1 and ET-1 were enhanced in the renal artery and also in the aorta in ARF (P<0.05 to 0.001). Correspondingly, ET(A) and Et(B) receptor mRNA expression significantly increased in both vascular beds. In addition, endothelium-dependent relaxation to acetylcholine was diminished and inversely correlated with vascular ET-1 protein levels in the renal artery (r = -0.827, P<0.001) and the aorta (r = -0.812, P<0.001). In conclusion, the present study demonstrates that increase of circulating and tissue ET-1 protein levels and ET(A) and Et(B) receptor gene expression occurs, which induces endothelial dysfunction and enhanced vasoconstriction in different vascular beds in ARF.

Acute Kidney Injury↗
PubMed1999

A rationale for treatment of endothelial dysfunction in hypertension.

Strategically located between the circulating blood and the vascular smooth muscle, endothelial cells release numerous vasoactive substances that regulate the function of vascular smooth muscle and circulating blood cells. Important endothelium-derived vasodilators are prostacyclin, bradykinin, nitric oxide (NO) and, independent of the former, endothelium-derived hyperpolarizing factor. In particular, NO inhibits cellular growth and migration. In concert with prostacyclin, NO exerts potent antiatherogenic and thromboresistant properties by preventing platelet aggregation and cell adhesion. These effects are counterbalanced by vasoconstrictors, angiotensin II and endothelin-1, both of which exert prothrombotic and growth-promoting properties. In hypertension, elevated blood pressure transmits into cardiovascular disease by causing endothelial dysfunction. Hence, modern therapeutic strategies in human hypertension focus on preserving or restoring endothelial integrity. Calcium antagonists counteract angiotensin II and endothelin-1 at the level of vascular smooth muscle by reducing the inflow of Ca2+ and facilitating the vasodilator effects of NO. Besides inhibiting the renin-angiotensin system, angiotensin-converting enzyme inhibitors diminish the inactivation of bradykinin, leading to an augmented release of NO. Newly developed vasopeptidase inhibitors induce potent antihypertensive effects in low-, normal-, and high-renin models of hypertension, not only because of the decreased breakdown of natriuretic peptides, but also because of the inhibition of endothelin-1 generation. Furthermore, experimental studies suggest that endothelin antagonists effectively lower blood pressure and prevent target-organ damage in salt-sensitive forms of hypertension. Further clinical studies are already underway to examine whether restoring endothelial dysfunction results in a clinical benefit in hypertension.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1998

Endothelial vasoconstrictor prostanoids, vascular reactivity, and acute renal failure.

The interaction of endothelium-derived vasoconstrictor prostaglandins, the angiotensins (Ang), and the sympathetic nervous system in acute renal failure still remains to be determined. In this study, acute renal failure (ARF) was induced in male Wistar Kyoto rats (N = 7) in a 2K/2C model of 30-minute clamping. Contractions to Ang I and II and norepinephrine (NE) were studied in isolated aortic and renal artery rings 24 hours after clamp release. Sham-operated animals served as controls (N = 7). In ARF, contractions to NE were increased in the aorta and even further enhanced in the renal artery (P < 0.05 to 0.001), whereas contractions to Ang I and II were blunted (P < 0.05). Contractions were inhibited by SQ 30741, a thromboxane A2 (TXA2)/prostaglandin H2 (PGH2) receptor antagonist. We conclude that ARF is characterized by abnormal vascular reactivity both in the renal as well as the systemic vasculature that is in part mediated by endothelium-derived vasoconstrictor prostaglandins.

Acute Kidney Injury↗
PubMed1998

Preventive strategies in endothelin-induced renal failure.

The endothelial vasoconstrictor endothelin (ET) can induce acute renal failure when fibrinolysis and vasodilatory prostanoids (PGs) are inhibited. This study compares therapeutic agents preventing ET-induced acute renal failure in anesthetized female pigs. We investigated the effect of four ET boli (1.5 microg/kg, i.v.) after pretreatment with indomethacin (2 mg/kg) and epsilon-aminocaproicacid (100 + 50 mg/kg) alone (controls, group 1) or during additional nifedipine (10 microg/kg/h; group 2), hirudin (0.5 mg/kg; group 3), or enalapril (2 x 0.15 mg; group 4) on coagulation, PGs, and renal function. The ET-induced blood pressure increase was lower in groups 2 to 4 (lowest in group 3, P < 0.05). PG synthesis was blocked in all groups. The initial hypercoagulability (controls) resulted in disseminated intravascular coagulation that was prevented by hirudin and was attenuated in groups 2 and 4. At the end of the experiment, creatinine clearance was significantly (P < 0.05) decreased. The recovery of renal function two hours after the last ET bolus was most pronounced in the hirudin group. All therapeutic drugs attenuated ET-induced impairment of renal function. Hirudin seems to be the most potent protective drug. Prevention of further ET release evoked by ET-mediated secretion of thrombin might explain this. These results suggest three important pathways for ET's hemodynamic and renal effects.

Acute Kidney Injury↗
PubMed1997

Different effects of thrombin receptor activation on endothelium and smooth muscle cells of human coronary bypass vessels. Implications for venous bypass graft failure.

BACKGROUND: Thrombin is implicated in coronary bypass graft disease; it cleaves its receptor's extracellular N-terminal domain and unmasks a new N-terminus as a tethered ligand. We studied the effects of thrombin receptor activation in human internal mammary artery (IMA) and saphenous vein (SV). METHODS AND RESULTS: To study the effects of thrombin receptor activation on vasomotion, isolated blood vessels were suspended for isometric tension recording, and the effects on cell proliferation were studied in cultured smooth muscle cells (SMCs) of IMA and SV. Thrombin receptor expression in IMA and SV was analyzed by reverse transcription polymerase chain reaction and immunohistology. Receptor function was studied by analyzing the activation of mitogen-activated protein kinase (p42MAPK). In IMA thrombin evoked endothelium-dependent relaxations (65 +/- 5%) that were mimicked by thrombin receptor agonist peptide (TRAP) and reduced by the thrombin inhibitors recombinant (r-) hirudin and D-Phe-Pro-Arg-chloromethyl ketone (PPACK) (P < .05). In SV thrombin caused contractions (36 +/- 5% of 100 mmol/L KCl) that were inhibited by r-hirudin or PPACK (P < .05) but not mimicked by TRAP. In SMCs thrombin induced more pronounced [3H]thymidine incorporation (inhibited by r-hirudin or PPACK) in SV than IMA (P < .05), but activation of p42MAPK was similar in both vessels. TRAP induced weaker activation of p42MAPK than thrombin and did not stimulate [3H]thymidine incorporation in SMCs of SV or IMA. Immunohistology and RT-PCR demonstrated that the endothelium and SMCs of IMA and SV express thrombin receptor. CONCLUSIONS: Functional thrombin receptors are present on endothelium and SMCs of IMA and SV. Endothelial thrombin receptors mediate relaxation in IMA but not SV. Thrombin causes much more pronounced contraction and proliferation in SMCs of SV than IMA independent of tethered receptors, suggesting other thrombin receptors exist. These differences of thrombin receptor activation in IMA and SV may be important in the development of and therapy for graft disease.

Amino Acid Chloromethyl Ketones↗