Selective downregulation of the angiotensin II AT1-receptor subtype in failing human ventricular myocardium.

BACKGROUND: The regulation of angiotensin II receptors and the two major subtypes (AT1 and AT2) in chronically failing human ventricular myocardium has not been previously examined. METHODS AND RESULTS: Angiotensin II receptors were measured by saturation binding of 125I-[Sar1,Ile8]angiotensin II in crude membranes from nonfailing (n = 19) and failing human left ventricles with idiopathic dilated cardiomyopathy (IDC; n = 31) or ischemic cardiomyopathy (ISC; n = 21) and membranes from a limited number of right ventricles in each category. The AT1 and AT2 fractions were determined by use of an AT1-selective antagonist, losartan. beta-Adrenergic receptors were also measured by binding of 125I-iodocyanopindolol with the beta 1 and beta 2 fractions determined by use of a beta 1-selective antagonist, CGP20712A, AT1 but not AT2 density was significantly decreased in the combined (IDC + ISC) failing left ventricles (nonfailing: AT1 4.66 +/- 0.48, AT2 2.73 +/- 0.39; failing: AT1 3.20 +/- 0.29, AT2 2.70 +/- 0.33 fmol/mg protein; mean +/- SE). The decrease in AT1 density was greater in the IDC than in the ISC left ventricles (IDC: 2.73 +/- 0.40, P < .01; ISC: 3.89 +/- 0.39 fmol/mg protein, P = NS versus nonfailing). beta 1 but not beta 2 density was decreased in the failing left ventricles. AT1 density was correlated with beta 1 density in all left ventricles (r = .43). AT1 density was also decreased in IDC right ventricles. In situ reverse transcription-polymerase chain reaction in sections of nonfailing and failing ventricles indicated that AT1 mRNA was present in both myocytes and nonmyocytes. CONCLUSIONS: AT1 receptors are selectively downregulated in failing human ventricles, similar to the selective downregulation of beta 1 receptors. The relative lack of AT1 downregulation in ISC hearts may be related to differences in the degree of ventricular dysfunction.

Regulation of the mRNA-binding protein AUF1 by activation of the beta-adrenergic receptor signal transduction pathway.

In both cell culture based model systems and in the failing human heart, beta-adrenergic receptors ( beta-AR) undergo agonist-mediated down-regulation. This decrease correlates closely with down-regulation of its mRNA, an effect regulated in part by changes in mRNA stability. Regulation of mRNA stability has been associated with mRNA-binding proteins that recognize A + U-rich elements within the 3'-untranslated regions of many mRNAs encoding proto-oncogene and cytokine mRNAs. We demonstrate here that the mRNA-binding protein, AUF1, is present in both human heart and in hamster DDT1-MF2 smooth muscle cells and that its abundance is regulated by beta-AR agonist stimulation. In human heart, AUF1 mRNA and protein was significantly increased in individuals with myocardial failure, a condition associated with increases in the beta-adrenergic receptor agonist norepinephrine. In the same hearts, there was a significant decrease (approximately 50%) in the abundance of beta1-AR mRNA and protein. In DDT1-MF2 cells, where agonist-mediated destabilization of beta2-AR mRNA was first described, exposure to beta-AR agonist resulted in a significant increase in AUF1 mRNA and protein (approximately 100%). Conversely, agonist exposure significantly decreased (approximately 40%) beta2-adrenergic receptor mRNA abundance. Last, we demonstrate that AUF1 can be immunoprecipitated from polysome-derived proteins following UV cross-linking to the 3'-untranslated region of the human beta1-AR mRNA and that purified, recombinant p37AUF1 protein also binds to beta1-AR 3'-untranslated region mRNA.

Cardiac adrenergic receptor effects of carvedilol.

Carvedilol is an adrenoceptor antagonist which modulates the activity not only of beta 1 and beta 2 but also of alpha 1 adrenergic receptors present on the cell surface membrane of the human cardiac myocyte. In the heart, carvedilol has approximately 7 times higher potency for beta 1 and beta 2 adrenoceptors, but in the doses 50-100 mg . day-1 used in clinical practice, it is essentially non-selective. In human myocardial preparations and in cultured heart cells, carvedilol has no intrinsic sympathomimetic activity but is able to identify high affinity agonist-binding receptors whose pharmacological signature is reduction in binding by incubation with guanine nucleotides (guanine nucleotide-modulatable binding). This property is more prominent for the human beta 2 than for the beta 1 adrenoceptor. The property of gaunine nucleotide-modulatable binding for carvedilol and structurally related bucindolol correlates with their ability to directly down-regulate beta 1-like receptors present in cultured chick myocytes, and with a lack of reversal of down-regulation of cardiac beta-receptors in patients with heart failure. Carvedilol does not exhibit high levels of inverse agonist activity, which may contribute to its good tolerability in subjects with heart failure. These data indicate that carvedilol produces a high degree of adrenergic receptor blockade in the failing human heart, and does not re-sensitize the beta-receptor pathway to stimulation by adrenergic agonists.

[Differential diagnosis of chronic peripancreatic pseudocysts on the computerized tomogram. Possibility of error and pitfalls]. / Differentialdiagnose der chronischen peripankreatischen Pseudozyste im Computertomogramm. Fehlermöglichkeiten und Fallgruben.

Cystic masses within the pancreas and in its neighbourhood are often really pseudocysts. In most cases, centrally necrotic solid tumours or genuine cystic neoplasms are easy to differentiate from such pseudocysts. They are in fact rare pathologic conditions. The exclusion of a pseudocyst is sometimes more difficult, especially in peripancreatic cystic masses. Computed tomography has significantly improved the diagnostics of the upper abdomen. Nevertheless, it sometimes creates new problems. This study is a selection of cases pointing to differential diagnostic difficulties that may become pitfalls for the examiner. An image-imminent approximative diagnosis is attempted. The importance of the localisation of these lesions and of the topographical anatomy of the upper abdomen are pointed out.

[Present role of urethrocystography in the diagnosis of female stress incontinence]. / Stellenwert der Urethrozystographie bei der Diagnostik der weiblichen Stressharninkontinez heute.

Urethrocystography was performed in 72 women with stress urinary incontinence (SUI). The radiological findings were compared with the clinical diagnosis. 8 Patients with a normal radiological study had SUI grade I by clinical criteria. Explanations of this discrepancy are discussed. In 4 cases the interpretation interfered with a large cystocele. In 60 patients (83.5%) the radiological study confirmed the clinical diagnosis and supported the gynaecologist in the indication for operation on SUI. However this indication cannot be based on the radiological study by itself; it must in fact take into account all the other aspects of the disease.

[Picture of duodenal rupture following blunt abdominal trauma]. / Zum Bild der Duodenalruptur nach stumpfem Bauchtrauma.

The case of a 30-year-old woman who suffered a pneumoretroperitoneum due to blunt abdominal trauma is reported. The characteristic roentgen signs showing the source of the retroperitoneal air trappings are discussed. Exact analysis of simple abdominal plain films allows early diagnosis of an often life-threatening disease without expensive additional examinations.

[Intestinal lipodystrophy (M. Whipple). Synopsis of radiology, endoscopy and histology]. / Intestinale Lipodystrophie (M. Whipple). Synopsis von Radiologie, Endoskopie und Histologie.

The case of a 48 years old man with intestinal lipodystrophy (Whipple's disease) is clinically, roentgenologically, endoscopically and histologically documented. The diagnosis was established by endoscopic biopsy and laparatomy. The patho-histologic changes of the mucosa of the proximal small bowel are pathognomonic. Roentgenologically the characteristic mucosal and lymphadenoid changes can be demonstrated as well as the extent of the process.