Biomedical subjects

Carsten Tschöpe

Publications and source records attributed to Carsten Tschöpe.

27 records · Page 2Linked to original sources

PubMed2003

Cardiac kinin level in experimental diabetes mellitus: role of kininases.

Diabetes mellitus impairs the cardiac kallikrein-kinin system by reducing cardiac kallikrein (KLK) and kininogen levels, a mechanism that may contribute to the deleterious outcome of cardiac ischemia in this disease. We studied left ventricular (LV) function and bradykinin (BK) coronary outflow in buffer-perfused, isolated working hearts (n = 7) of controls and streptozotocin (STZ)-induced diabetic rats before and after global ischemia. With the use of selective kininase inhibitors, the activities of angiotensin I-converting enzyme, aminopeptidase P, and neutral endopeptidase were determined by analyzing the degradation kinetics of exogenously administered BK during sequential coronary passages. Basal LV function and coronary flow were impaired in STZ-induced diabetic rats. Neither basal nor postischemic coronary BK outflow differed between control and diabetic hearts. Reperfusion after 15 min of ischemia induced a peak in coronary BK outflow that was of the same extent and duration in both groups. In diabetic hearts, total cardiac kininase activity was reduced by 41.4% with an unchanged relative kininase contribution compared with controls. In conclusion, despite reduced cardiac KLK synthesis, STZ-induced diabetic hearts are able to maintain kinin liberation under basal and ischemic conditions because of a primary impairment or a secondary downregulation of kinin-degrading enzymes.

Aminopeptidases↗

PubMed2003

Kinins are involved in the antiproteinuric effect of angiotensin-converting enzyme inhibition in experimental diabetic nephropathy.

The present study examined non-insulin-treated streptozotocin (STZ)-induced diabetic rats to determine the role of kinins in diabetic nephropathy. Their involvement in the renoprotective effect of the angiotensin-converting enzyme inhibitor (ACEI) ramipril was investigated using the bradykinin (BK) B(2)-receptor antagonist, icatibant (HOE 140), or a combination of the two drugs.Although, none of the treatments prevented the decline of the glomerular filtration rate (GFR) in diabetic rats, ramipril (3 mg/kg/day), but not icatibant (HOE 140; 500 microg/kg/day), prevented proteinuria in these animals. However, the antiproteinuric effect of ramipril was reduced by 45% when combined with icatibant. To explore whether the renal kallikrein-kinin system (KKS) belongs to the underlying mechanisms of these findings, we also determined urinary BK levels, renal kallikrein (KLK) and angiotensin-converting enzyme (ACE) activity as well as renal cortical mRNA levels of neutral endopeptidase 24.11 (NEP) and low-molecular weight (LMW) kininogen. STZ led to a reduction of renal KLK and ACE activity and NEP expression and to a three-fold increase of urinary BK excretion and renal kininogen expression. Icatibant given alone had no effect on these parameters. In contrast, ramipril treatment normalized urinary protein and BK excretion as well as kininogen mRNA expression without affecting NEP mRNA expression or KLK and ACE activity. Our data demonstrate that renal BK is increased in severe STZ-induced diabetes mellitus, but may affect glomerular regulation only to a minor degree under this condition. However, kinins are partly involved in the antiproteinuric action of ACEI at this stage of diabetic nephropathy.

Actins↗

PubMed2002

Transgenic overexpression of the sarcoplasmic reticulum Ca2+ATPase improves reticular Ca2+ handling in normal and diabetic rat hearts.

Slowed relaxation in diabetic cardiomyopathy (CM) is partially related to diminished expression of the sarcoplasmic reticulum (SR) Ca2+-ATPase SERCA2a. To evaluate the impact of SERCA2a overexpression on SR Ca2+ handling in diabetic CM, we 1) generated transgenic rats harboring a human cytomegalovirus enhancer/chicken beta-actin promotor-controlled rat SERCA2 transgene (SERCA2-TGR), 2) characterized their SR phenotype, and 3) examined whether transgene expression may rescue SR Ca2+ transport in streptozotocin-induced diabetes. The transgene was expressed in all heart chambers. Compared to wild-type (WT) rats, a heterozygous line exhibited increased SERCA2 mRNA (1.5-fold), SERCA2 protein (+26%) and SR Ca2+ uptake (+37%). Phospholamban expression was not altered. In SERCA2-TGR, contraction amplitude (+48%) and rates of contraction (+34%) and relaxation (+35%) of isolated papillary muscles (PM) were increased (P2+ uptake and SERCA2 protein of SERCA2-TGR were 1.3-fold higher (P2+ uptake, accelerates relaxation and compensates, in part, for depressed Ca2+ uptake in diabetic CM. Therefore, SERCA2 expression might constitute an important therapeutic target to rescue cardiac SR Ca2+ handling in diabetes.

Animals↗

PubMed2002

Increased activity of the renal kallikrein-kinin system in autosomal dominant polycystic kidney disease in rats, but not in humans.

The kallikrein-kinin system (KKS) was investigated in autosomal dominant polycystic kidney disease (ADPKD)-affected rats (PKD) and compared to unaffected controls (SD) and 5/6 nephrectomized rats (5/6 Nx). In addition, patients with ADPKD compared to patients with nonpolycystic kidney disease and healthy controls have been investigated. Plasma and urine samples for determination of creatinine, protein, kallikrein (KAL) and bradykinin (BK) were taken in male 3- and 9-month-old PKD, SD and 9-month-old 5/6 Nx. The same parameters were determined in young (age: 20-40 years) and old (41-65 years) male patients with ADPKD and compared to age-matched patients with nonpolycystic kidney disease and age-matched healthy controls. Plasma and urine KAL were measured by chromogenic peptide substrate, and kininswere determined by radioimmunoassay. Urine KAL and BK levels were increased i n PKD compared to age-matched SD. No differences with respect to serum KAL were found between PKD and SD. In 5/6 Nx, urinary BK levels showed a trend towards higher compared to old SD (p = 0.06). KAL and BK were not increased in serum and urine of patients with ADPKD, in contrast to rats. Urinary KAL excretion was reduced in patients with ADPKD and advanced renal failure. Our results demonstrate an age-dependent activation of the renal KKS in rats with ADPKD, whereas the KKS is not activated in patients with ADPKD and advanced renal failure. These data indicate that there are fundamental differences in the factors influencing the course of the disease in human and rat ADPKD.

Adult↗

PubMed2002

Regulation of cardiac bradykinin B1- and B2-receptor mRNA in experimental ischemic, diabetic, and pressure-overload-induced cardiomyopathy.

Although kinins have been associated with the regulation of cardiovascular function in left ventricular hypertrophy (LVH) as a consequence of hypertension, myocardial infarction (MI), and/or diabetic cardiomyopathy, less is known about their receptor regulation under these conditions. We have therefore investigated the bradykinin B1-receptor (B1R) and B2-receptor (B2R) mRNA expression in rat models of MI, LVH and diabetes mellitus (DM). Sprague-Dawley rats (SD) were submitted to permanent ligation of the left descending coronary artery (LAD) to induce a MI, whereas DM was induced by a single injection of streptozotocin (STZ). LVH was induced after thoracic aortic banding (AB). Three weeks after MI, six weeks after STZ injection or six weeks after AB, left ventricular (LV) function was characterized using a Millar-tip catheter. Cardiac B1R- and B2R-mRNA expression were analyzed by specific RNase-protection assays (RPA). LV contractility (dP/dt max) was impaired by 40-48% in rats after induction of MI or DM compared to their controls. However, despite an enormous increase in LV end-diastolic pressure (LEVDP) to 310% after AB, LV contractility did not differ compared to the controls. These hemodynamic changes were accompanied by an up-regulation of cardiac B1R- (MI, 288%; STZ, 215%; AB, 4180%) and B2R-mRNA expression (MI, 122%; STZ, 288%; AB, 96%). Up-regulation of both BK-receptor (BKR) types in early stages of cardiac wound healing induced by ischemia and in chronic stages of cardiac remodeling induced by pressure-overload or by hyperglycemia indicates that kinins play a major role in the complex processes of cardiac tissue injury and repair.

Animals↗

PubMed2002

AT1 receptor blockade increases cardiac bradykinin via neutral endopeptidase after induction of myocardial infarction in rats.

ACE inhibition protects the heart against ischemic injury by reducing angiotensin II and promoting bradykinin (BK) accumulation. Since neutral endopeptidase (NEP) metabolizes BK, we determined its activity after induction of myocardial infarction (MI) and examined whether it is influenced by treatment with an ACE inhibitor or AT1 receptor blocker. Rats were studied 6 days and 3 wk after coronary occlusion. Starting 48 h after MI induction, additional animals were treated with the ACE inhibitor quinapril (2 mg x kg(-1) x day-1) or the AT1 blocker irbesartan (50 mg x kg(-1) x day-1). Animals were hemodynamically characterized. Finally, NEP-specific activity and BK concentrations were detected in homogenates of heart compartments. Quinapril and irbesartan treatment improved left ventricular function 6 days and 3 wk after MI induction, and NEP activity was elevated only in the infarcted area of untreated compared with sham-operated rats. After 6 days, irbesartan reversed this increase by 80% and quinapril by 35%. Quinapril had no effect after 3 wk, whereas irbesartan almost completely blocked the increased NEP activity in the infarcted area and concomitantly induced a further rise in the BK concentrations. These results indicate mechanisms of NEP regulation influenced by the AT1 receptor. Our data suggest that NEP is more decisive than ACE in mediating BK degradation and may indicate BK involvement in the cardioprotective effects of AT1 antagonists.

Angiotensin Receptor Antagonists↗

PubMed2002

Natriuretic peptide system in fetal heart and circulation.

Atrial natriuretic peptide, brain natriuretic peptide and C-type natriuretic peptide belong to a family of hormones that have diuretic, natriuretic and vasodepressor activity and play a part in pressure and volume homeostasis in adults. As little is known about the natriuretic peptides during cardiac maturation, this review summarizes current knowledge about the early expression of components of the natriuretic peptide system in the heart during embryonic and fetal development. The data indicate a functional importance of the fetal natriuretic peptide system, especially under pathophysiological conditions. Thus, in the fetus, the system fulfils important beneficial compensatory roles in cardiovascular disease, rather than in day-to-day pressure and volume homeostasis. In comparison with data on the relevance of natriuretic peptides in adults, those summarized here indicate a functional maturation of the natriuretic peptide system during ontogeny in mammals.

Animals↗

PubMed2002

Multiple interactions between the renin-angiotensin and the kallikrein-kinin systems: role of ACE inhibition and AT1 receptor blockade.

The investigation of therapeutic actions of angiotensin type 1 (AT1) receptor antagonists and ACE inhibitors (ACEI) demonstrated complex interactions between the renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS) in several experimental and clinical studies. They are evidenced by the fact that (1) ACE efficiently catabolizes kinins; (2) angiotensin-derivatives such as ANG-(1-7) exert kininlike effects; and (3) kallikrein probably serves as a prorenin-activating enzyme. (4) Several authors have demonstrated experimentally that the protective effects of ACEI are at least partly mediated by a direct potentiation of kinin receptor response on BK stimulation. (5) Furthermore, studies on AT1 antagonists, which do not directly influence kinin degradation, and studies on angiotensin-receptor transgenic mice have revealed additional interactions between the RAS and the KKS. There is mounting evidence that an autocrine cascade including kinins, nitric oxide, prostaglandins, and cyclic GMP is involved in at least some of the angiotensin type 2 receptor effects. This review discusses multiple possibilities of cross-talks between the RAS and KKS in vascular and cardiac physiology and pathology after ACE inhibition and AT1 receptor blockade.

Angiotensin Receptor Antagonists↗

PubMed2002

[Beta blockers in post-infarction state].

In the 80s, randomized clinical studies and overviews have shown that adjunctive therapy with beta blockers can be beneficial post-myocardial infarction (MI). Despite this evidence, the use of beta blockers in the post-MI setting is far from uniform and now lags considerably behind the routine use of angiotensin-converting enzyme inhibitors (ACEIs) in this clinical setting. Given the major advances in the management of myocardial infarction and its sequelae that have occurred in the last two decades (including the use of percutaneous transluminal coronary angioplasty [PTCA], thrombolysis, aspirin, ACEIs, and statins), there was clearly a need to revisit the issue of beta blocker therapy in patients with beta blockers in the setting of post-MI heart failure. For all these reasons, the CAPRICORN trial of carvedilol in post-MI left ventricular dysfunction was an important and eagerly awaited trial, which could show that carvedilol treatment post-MI on top of the so-called modern post-MI therapy reduces mortality. Further studies have to show whether this results can be repeated with other beta blockers.

Adrenergic beta-Antagonists↗