Natriuretic peptides receptors in human aldosterone-secreting adenomas.

Atrial natriuretic peptide (ANP) and B-type or brain natriuretic peptide (BNP) inhibit aldosterone secretion in humans both in vitro and in vivo. Unresponsiveness of aldosterone-secreting adenomas (aldosteronomas) to ANP in vitro and in vivo, might be due to reduced expression of the biologically-active natriuretic peptide receptor type A (NPr-A) and/or increased expression of the clearance receptor for natriuretic peptides (NPr-C). Therefore, we have analyzed NPr gene expression and ANP binding sites in human adrenals and aldosteronomas. Using reverse transcription and polymerase chain reaction, we cloned and characterized cDNAs for NPr-A, NPr-C, and the receptor (NPr-B) for the C-type natriuretic peptide (CNP). Total RNA from three normal human adrenals (obtained at surgery from patients with renal cancer) and five aldosteronomas were used for Northern analysis. NPr-A mRNA (approximately 4 kb) and NPr-B mRNA (approximately 4 kb) were expressed without significant differences in adrenals and in aldosteronomas except in an aldosteronomas that contained only very low amounts of NPr mRNAs. The gene expression of NPr-C was barely detectable both in adrenals and in aldosteronomas. ANP binding sites were analyzed by autoradiography with 125I-labeled ligand in other six aldosteronomas. Only one of the adenomas analyzed showed ANP binding sites with density of granules similar to nonadenomatous glomerulosa, whereas the others had significantly reduced densities. In summary, aldosteronomas express the genes encoding for NPr but mainly NPr-A, similarly to control adrenals. On the contrary, the binding sites for ANP are greatly reduced in most aldosteronomas. A somatic mutation or a post-transcriptional defect that reduces ANP binding sites might be present in some aldosteronomas.

[The role of ACE inhibitors in heart failure. Lessons of CONSENSUS, SOLVD and V-HeFTII]. / Il ruolo degli ACE-inibitori nell'insufficienza cardiaca. Lezioni dal CONSENSUS, SOLVD e V-HeFTII.

Heart failure is today one of the most serious health problems of modern industrialized societies. The increase in the mean age of the population is an additional factor which favours a high incidence of episodes of heart failure. Age is also a relevant factor in mortality linked with heart failure. On this basis more emphasis has been given by researchers and physicians to improve a preventive and therapeutic approach to heart failure. For many years the pharmacological treatment of heart failure patients was based on the increase in inotropism through the digitalis and on the reduction in sodium-water retention through diuretics, while less importance was given to the improvement of the afterload. We have had knowledge of vasodilatory drugs in chronic heart failure for at least 20 years but only 10 years ago with the Vasodilator-Heart Failure Trial (V-HeFTI), it was proved that the combination of hydralazine and nitrates in addition to the conventional treatment, improved the survival of patients affected by moderate-severe heart failure. With the advent of the ACE-inhibitors, in the '80s, the first studies concerning the role of such drugs in heart failure were carried out. In the Cooperative North Scandinavian Enalapril Survival Study (CONSENSUS I) it was proved for the first time that an ACE-inhibitor (enalapril), added to the conventional heart failure therapy, improved the survival of patients with severe congestive heart failure (NYHA class IV). The result was so extraordinary that the study was interrupted for ethical reasons. However, it has raised a considerable interest in the study of the ACE-inhibitors in heart failure and now it has been proved that such drugs are a milestone in a correct pharmacological approach to heart failure.

Hyperplastic growth of aortic smooth muscle cells in renovascular hypertensive rabbits is characterized by the expansion of an immature cell phenotype.

Smooth muscle cells (SMCs) of rabbit aorta undergo marked changes in myosin isoform content during development. Analysis of nonmuscle myosin composition at the protein level has permitted the identification of three phases in the SMC differentiation process: fetal, postnatal, and adult. Using monoclonal antibodies specific for smooth muscle and nonmuscle myosins and extra domain A of fibronectin as well as cDNA probes for platelet-derived growth factors (PDGF) and various procollagens, we have evaluated the differentiation pattern of aortic SMCs in two-kidney, one-clip hypertensive rabbits. Morphometric and bromo-deoxyuridine studies indicate that hypertrophy of aortic media along with intimal thickening occurring in hypertensive animals is due to SMC hyperplasia. Western blotting experiments performed on aortic specimens from hypertensive animals with antimyosin antibodies revealed the appearance of a myosin isoform pattern of the "immature" type. Immunofluorescence tests showed that these cells are localized in the thickened intima or distributed in the underlying media (sparsely or in groups). Similarly, the fibronectin variant showing the extra domain A, peculiar to "phenotypically modulated" SMCs, appeared in intimal thickening, and its expression followed the time course of nonmuscle myosin expression. Counting of postnatal-type SMCs in the aortic media revealed that this cell population increases markedly with hypertension (2- up to 15-fold at 4 months) and then declines to near control level in 8-month hypertensive rabbits. Diminution of postnatal-type SMCs at later stages of hypertension was temporally correlated with the slowing down of aortic wall hypertrophy. Average levels of mRNAs, as determined by densitometric analysis in aortas from 1- and 2.5-month hypertensive rabbits, showed an increased expression for PDGF beta receptor (up to twofold), procollagen type I (alpha 1, threefold), procollagen type III (alpha 1, twofold), and fibronectin (up to threefold) compared with controls. Conversely, the steady-state levels of mRNAs for PDGF (A and B chain), PDGF alpha receptor, TGF-beta 1, and procollagen type IV (alpha 1) did not increase significantly. These results provide evidence that in adult renovascular hypertensive rabbits, the hyperplastic growth of aortic SMCs is accompanied by the expansion of an "immature" cell phenotype characteristic of the early stages of development.