Bianchi Giuseppe Professore EmeritoMedicina

Bianchi Giuseppe

Biografia

Pubblicazioni

Biografia

Giuseppe Bianchi, MD, Milan University. Training in Pharmacology cardiovascular-renal pathophysiology, biochemistry and clinic in Pharma Companies, Universities of Milan, Parma, Padua, London and Glasgow, PhD in Pharmacology, Specialities in Cardiology and Nephrology. Honorary MD at the Universities of Berlin and Uppsala, awards from British, American, and Italian societies of Hypertension, National Kidney Foundation USA, International Union of Physiological Science USA, Accademia dei Lincei Rome, University of Naples and other scientific organizations.
Former Director of the Division of Nephrology, Dialysis and Hypertension, Chair and School of Nephrology, “Vita Salute” San Raffaele University, Milan University and past Scientific Director of the Prassis Sigma-Tau Cardiovascular Research Institute and of CVie Therapeutic Taiwan and China and past CSO at Windtree Therapeutics USA.
Present: Professor Emeritus at the “Vita Salute” San Raffaele University.
Past and present member of the Editorial Boards of 12 international journals and invited speaker or chairman at more than 600 national and international meetings. He has published more than 300 articles in peer-review journals (including Lancet, J Clin Invest, New Engl J med, PNAS, Science Trans Med etc.)  and more than 200 chapters in books or in meeting proceedings. Over the years, Prof. Bianchi has combined his academic and clinical experience with parallel work in collaboration with pharmaceutical companies (Lepetit S.p.A., Farmitalia Carlo Erba, Prassis Sigma-Tau S.p.A., CVie Therapeutics Taiwan and Windtree Therapeutics USA) in order to develop a targeted therapeutic approach to cardiovascular diseases through laboratory and clinical practice.

 

Precision Medicine is based on the principle that curative therapy must target the molecular abnormalities involved in the onset and/or maintenance of the disease. These molecular abnormalities may be triggered either by:

  1. primary genetic factors, or
  2. a variety of genetic, environmental, or biological factors, such as SERCA2a activity deficiency in cardiac failure in both animal models and patients.

The more potent and selective the novel drug is on these molecular targets, the greater the benefit-to-risk therapeutic ratio that may be achieved. The common strategy for both approaches consists of gathering findings from different contexts and then developing scientific hypotheses capable of accommodating them, after properly accounting for their specific context-dependent components.

Prof. Bianchi's clinical and research activities have been focused on the discovery or validation of both types of molecular abnormalities. These studies have addressed:

A) the genetic mechanisms regulating the activity of adducin and the synthesis and metabolism of endogenous ouabain that may affect hypertension with associated cardiac and renal damages.

B) the deficiency of SERCA2 activity in heart failure as the most important cause of cardiomyocyte Ca2+ abnormalities involved in cardiac mechanical abnormalities, arrhythmias, and metabolic dysfunction, including the increase of Reactive Oxygen Species (ROS) due to an increase in mitochondrial Ca2+.

 

Project A) Initially, this project aimed to find answers to the following questions: Can a "normal" kidney play a primary role in the development of "primary" or "essential" arterial hypertension? And if so, is it possible to develop a "causal" therapy for this form? The pursuit of these answers involved various fields including clinical medicine, pathophysiology, animal modeling, translational medicine, kidney physiology (including micro puncture), cell physiology, molecular biology, genetics, medicinal chemistry, molecular and clinical pharmacology. Naturally, this interdisciplinary approach necessitated collaboration among experts in different disciplines. Broadly, the strategy can be outlined in seven steps:

  1. Defining in an animal model and patients the temporal sequence of pathophysiological changes, along with responses to therapeutic interventions, associated with increased blood pressure following a known type of kidney injury such as renal artery constriction. Insights from these studies informed subsequent steps.
  2. Assessing, in appropriate animal model the Milan hypertensive rat (MHS) and in humans, whether a direct intervention like kidney cross-transplantation could influence blood pressure in primary or essential hypertension. These studies revealed that hypertension is influenced by the kidney.
  3. Identifying, in the MHS (an animal model sharing similarities with human patients in functional and biochemical abnormalities), the subcellular structures potentially responsible for subtle cellular abnormalities leading to hypertension despite an otherwise "normal" kidney. A membrane cytoskeleton abnormality was discovered, potentially speeding up ion transport across the basolateral membrane of kidney cells, leading to increased tubular Na+ reabsorption (as demonstrated by whole kidney studies in both species) via increased basolateral membrane expression of Na-K pump units.
  4. Through various genetic studies, pinpointing the "abnormal" cytoskeleton protein(s) and their association with cellular and whole-body abnormalities leading to hypertension in both animals and humans, along with associated organ damage. Adducin proteins and their gene variants emerged as prime candidates for these effects.
  5. Exploring other bodily mechanisms that could modulate the aforementioned constitutive kidney abnormalities. Many hormones play roles in adapting kidney function to bodily needs; endogenous ouabain, targeting the Na-K pump, emerged as a primary candidate for this function.
  6. Transitioning from association to validation, a highly selective, potent, and safe chemical compound (Rostafuroxin) was developed for use in animal models and patients. At a concentration of 10-11 M, Rostafuroxin selectively disrupts the binding of mutant adducin or ouabain-activated Na-K pumps to the SH2 domain of cSrc, selectively blocking the effects of mutant adducin and endogenous ouabain on Na-K pumps at both cellular and whole-body levels without affecting their normal functions.
  7. Validating the involvement of the two molecular mechanisms (mutant adducin and endogenous ouabain) through two phase II trials in patients. The effect of Rostafuroxin was tested in 518 Caucasians, carriers, and non-carriers of a combination of gene variants (gene profile) known to impact these two molecular mechanisms' effects on cellular and bodily physiopathology. In profile carriers with mild hypertension, Rostafuroxin at a daily oral dose of 0.06 mg resulted in a significant reduction in blood pressure (approximately 23 mmHg), compared to a negligible reduction (about 2 mmHg) observed in non-carriers. Conversely, the response to Losartan and HCTZ in 338 Caucasian patients was unaffected by the profile. Given that the profile is present in about 1/4 of hypertensive patients, these findings could be significant for optimizing blood pressure levels and preventing organ damage in a large number of patients. However, in 107 Chinese patients, the effect of Rostafuroxin was much lower, likely due to faster metabolic degradation in this population.


Project B) SERCA2a activation
Among a series of compounds synthetized to optimize their interaction with the Na-K pump, one molecule, subsequently named Istaroxime, has been characterized because its cardiac inotropic activity was associated to none or mild pro-arrhythmic activity, much lower than that of the known Na-K pump inhibitors. 

A series of appropriate studies in different contexts have demonstrated that Istaroxime, beside its Na-K pump inhibition sustaining its inotropic action, also displays a SERCA2a stimulatory activity that may mitigate the arrhythmias and favor diastolic relaxation with the associate improving of the heart pumping capacity. Moreover, during Istaroxime infusion there is the formation of a main and long-lasting metabolite, PST3093, endowed with the sole SERCA2a activity at plasma concentrations well above the ones stimulating SERCA2a in vitro.

Istaroxime has been investigated in vivo in animal models of HF, displaying safety and efficacy in improving the cardiac indexes of both systolic and diastolic function.  It was then developed for the in-hospital intravenous treatment of Acute Heart Failure patients. The results of the Phase I and II clinical trials, involving 350 patients, indicated that Istaroxime is a safe and effective luso-inotropic agent able to improve Pulmonary Capillary Wedge Pressure (PCWP), Cardiac Index (CI) (especially in patients with basal CI < 2.5 L/min/m2), without reducing, but even slightly enhancing SBP, and mildly reducing heart rate when intravenously infused for 6 hours. A Phase IIb clinical trial in patients with acute heart failure investigated the safety and efficacy of Istaroxime over a 24 hour at the intravenous infusion of 0.5 and 1 g/kg/min. It was shown that Istaroxime increased stroke volume index (SVI) and decreased the indexes of venous congestions, such as left atrium area (LAA) and inferior vena cava diameter (IVCD) after 24 hours infusion at the low dose of 0.5 g/kg/min, that persisted up to 48 hours from Istaroxime infusion start, when the parent compound is no more present in plasma, while the Istaroxime long-lasting metabolite PST3093 plasma concentrations are high enough to stimulate SERCA2a. As at 72 hours from the infusion start, the plasma concentration of the metabolite PST3093 is still in the concentration range able to stimulate SERCA2a, it is likely that an infusion of 24 hours may produce beneficial cardiac effect for 72 hours. Compared to the placebo treated patients, these beneficial effects occur without affecting plasma Hs-TnT and a decrease by 57% of the cardiovascular adverse events. These long term Istaroxime beneficial effects are very likely supported by the metabolic ones produced by the PST3093 SERCA2a activation mentioned above

With a medicinal chemistry program, a pure and very selective SERCA2a activator has been developed that, after intravenous or oral administration in an animal model of heart failure, demonstrated a pharmacological profile similar to that of PST3093.

 

Conclusions

Rostafuroxin and Istaroxime, along with its metabolites, are first-in-class drugs targeting specific molecular mechanisms underlying clinical symptoms. The available experimental and clinical data support the notion that they may be 'causal' drugs with an unprecedentedly high level of benefit-to-risk ratio, compared to that of the same class available drugs. This is because the available drugs target normal physiological mechanisms, aiming to mitigate the clinical symptoms caused by the pathological ones.

 

Update

The results with the corresponding conclusions described above were already available on December 2018, when these projects were transferred to Windtree Therapeutic (USA). Unfortunately, as of today (March 2024), the management of this company has not yielded significant results regarding the progression towards the use of these compounds in the clinical practice. This failure is mainly due to the choice of a business driven developmental strategy disregarding the previous scientific knowledge and skill needed to assess the causal mechanisms of clinical symptoms and how to correct them with a “causal” drug.  The choice of the vasoconstrictor effect of the higher doses of istaroxime for the cardiogenic shoch therapy is an example of this Windtree’ strategy. This. strategy ignores that. compared to the lower doses, the previous data showed a clear reduction of the patients’ benefits/risk ratio at the higher doses. After countless unsuccessful attempts to correct this wrong strategy, in April 2022 prof Bianchi rejected the Windtree ‘ proposal to continue the collaboration with Windtree.

Pubblicazioni

Pubblicazioni selezionate 

  1. MAFFII G, BIANCHI G. Effetti del 9-fluoro-prednisolone e di altri steroli sul contenuto in Na, K e glicogeno del diaframma isolato di ratto a riposo. Arch Inter Pharmacodyn 1958; 117: 30-43
  2. MAFFII G, BIANCHI G. Effetti del 9 alfa-fluoro-prednisolone, dell'idrocortisone e dell'l-desossicorticosterone sull'attività contrattile e il contenuto in Na e K del diaframma isolato di ratto. Arch Inter Pharmacodyn 1958; 117: 44-52
  3. MAFFII G, BIANCHI G. Anticholinergic activity of tropine-alfa-methyltropate. Nature 1960; 185: 844-845
  4. MAFFII G, SCHIATTI P, BIANCHI G, SERRALUNGA MG. Rifomycin. XVIII - Pharmacological studies with rifomycin SV. Il Farmaco (Ed. Sci) 1961; 16: 235-245
  5. MAFFII G, BIANCHI G, SCHIATTI P, SILVESTRINI B. Action of 5,5-diethyl-1,3-oxazine-2,4-dione (dioxone) on respiration and circulation. Brit J Pharmac Chemoter 1961; 16: 231-243
  6. MAFFII G, BIANCHI G. L'ipertensione sperimentale nel ratto nella valutazione dei farmaci ipotensivi. Arch Ital Sci Farmacol 1962; 12: 3-18
  7. MAFFII G, SCHIATTI P, BIANCHI G. Distribuzione della rifamicina SV nell'organismo animale. Aspetti farmacologici e orientamenti terapeutici. Chemioterapia 1963; 7: 158-169
  8. TESTA E, WITTGENS A, MAFFII G, BIANCHI G. Chemistry and pharmacology of azetidines. Res Progr in Organic Biol and Med Chemistry 1963; 1: 477-583
  9. BIANCHI G, PENSO G, AZZONE GF. Oxidation of glycerol l-phosphate by rat-liver mitochondria. Biochem Biophys Acta 1964; 92: 154-156
  10. BIANCHI G, AZZONE G.F. Oxidation of choline in rat-liver mitochondria. J Biol Chem 1964; 239: 3947-3955
  11. BIANCHI G, RIVA D. Prime determinazioni con due metodi di titolazione della renina nel plasma nei soggetti normali ed in alcune condizioni patologiche. Minerva Medica 1965; 56: 4239-4245
  12. BIANCHI G, RIVA D, VEGETO A. Ipertensione arteriosa da stenosi dell'arteria renale. Rass di Urologia e Nefrologia 1965; 3: 313-332
  13. BIANCHI G, BROWN JJ, LEVERR AF, ROBERTSON JIS. Concentrazione plasmatica della renina e pressione arteriosa nel cane sveglio. Minerva Nefrologica 1966; 13: 116-119
  14. BROWN JJ, DAVIES D, LEVER AF, ROBERTSON JIS, BIANCHI G, IMBS JL, JOHNSON VW, LAWRENCE M, FRAZER R, JAMES VHT. Renin and blood pressure. Proc. of 3rd Int. Congr. Nephrol., Washington 1966 (Karger, Basel/New York, 1967); l: 226-239
  15. BIANCHI G, BROWN JJ, LEVER F, ROBERTSON JIS, ROTH N. Changes of plasma renin concentration during pressor infusion of renin in the conscious dog: the influence of dietary sodium intake. Clin Sci 1968; 34: 303-314
  16. BIANCHI G, TENCONI LT, LUCCA R. Effect in the conscious dog of constriction of the renal artery to a sole remaining kidney on hemodynamics, sodium balance, body fluid volume, plasma renin concentration and pressor responsiveness to angiotensin. Clin Sci 1970; 38: 741-766
  17. BIANCHI G, CAMPOLO L, VEGETO A, PIETRA V, PIAZZA U. The value of plasma renin concentration per se, and in relation to plasma and extracellular fluid volume in diagnosis and prognosis of human renovascular hypertension. Clin Sci 1970; 39: 559-576
  18. BIANCHI G, PONTICELLI C, BARDI U, REDAELLI B, CAMPOLO L, DE PONTI G, GRAZIANI G. Role of the kidney in "salt and water dependent hypertension" of end-stage renal disease. Clin Sci 1972; 42: 47-55
  19. BIANCHI G, FOX U, DI FRANCESCO GF, BARDI U, RADICE M. The hypertensive role of the kidney in spontaneously hypertensive rats. Clin Sci Mol Med 1973; 45 (suppl I): 135s-139s
  20. BIANCHI G, FOX U, IMBASCIATI E. The development of a new strain of spontaneously hypertensive rats. Life Sci 1974; 14: 339-347
  21. BIANCHI G, FOX U, DI FRANCESCO GF, GIOVANETTI AM, PAGETTI D. Blood pressure changes produced by kidney cross-transplantation between spontaneously hypertensive rats and normotensive rats. Clin Sci Mol Med 1974; 47: 435-448
  22. BIANCHI G, FOX U, PAGETTI D, CARAVAGGI AM, BAER PG, BALDOLI E. Mechanisms involved in renal hypertension. Kidney Int 1975; 8: S165-S173
  23. BIANCHI G, BAER PG, FOX U, DUZZI L, PAGETTI D, GIOVANETTI AM. Changes in renin, water balance, and sodium balance during development of high blood pressure in genetically hypertensive rats. Circ Res 1975; 36&37 (suppl I): I153-I161
  24. CARAVAGGI AM, BIANCHI G, BROWN JJ, LEVER AF, MORTON JJ, POWELL-JACKSON JD, ROBERTSON JIS, SEMPLE PF. Blood pressure and plasma angiotensin II concentration after renal artery constriction and angiotensin in the dog (5-Isoleucine) angiotensin II and its breakdown fragments in dog blood. Circ Res 1976; 38: 315-321
  25. BROWN JJ, DAVIES DL, ROBERTSON JIS, LEVER AF, BIANCHI G, SCHALEKAMP MADH. Mechanisms of renal hypertension. Lancet 1976; I: 1219-1221
  26. HALLBACK M, JONES J, BIANCHI G, FOLKOW B. Cardiovascular control in the Milan strain of spontaneously hypertensive rat (MHS) at "rest" and during acute mental "stress". Acta Physiol Scand 1977; 99: 208-216
  27. BIANCHI G, BAER PG, FOX U, GUIDI E. The role of the kidney in the rat with genetic hypertension. Postgr Med J 1977; 53: suppl 2, 123-135
  28. BROWN JJ, CUESTA V, DAVIES DL, LEVER AF, MORTON JJ, PADFIELD PL, ROBERTSON JIS, TRUST P, BIANCHI G, SCHALEKAMP MADH. Can Angiotensin II cause renal hypertension when its plasma concentration is normal? Contr Nephrol 1977; 8: 57-60
  29. BROWN JJ, DAVIES DL, MORTON JJ, ROBERTSON JIS, CUESTA V, LEVER AF, PADFIELD PL, TRUST P, BIANCHI G, SCHALEKAMP MADH. Renal hypertension: role of renin. Postgr Med J 1977; 53: suppl 3, 31-34
  30. BAER PG, BIANCHI G. Renal micropuncture study of normotensive and Milan hypertensive rats before and after development of hypertension. Kidney Int 1978; 13: 452-466
  31. BIANCHI G, PICOTTI GB, BRACCHI G, CUSI D, GATTI M, LUPI GP, FERRARI P, BARLASSINA C, COLOMBO G, GORI D. Familial hypertension and hormonal profile, renal haemodynamics and body fluids of young normotensive subjects. Clin Sci Mol Med 1978; 55: suppl 4, 367s-371s
  32. BIANCHI G, CUSI D, GATTI M, LUPI GP, FERRARI P, BARLASSINA C, PICOTTI GB, BRACCHI G, COLOMBO G, GORI D, VELIS O, MAZZEI D. A renal abnormality as a possible cause of "essential" hypertension. Lancet 1979; I: 173-177
  33. DI PADOVA F, QUARTO DI PALO F, MORANDI E, BALDINI L, BIANCHI G, MAZZEI D, POLLI E. Is long term immunosuppressive treatment necessary to maintain good kidney graft function? Brit Med J 1979; 308: 421-423
  34. CUSI D, BARLASSINA C, FERRANDI M, PALAZZI P, CELEGA E, BIANCHI G. Relationship between altered Na-K cotransport and Na-Li countertransport in the erythrocytes of "essential" hypertensive patients. Clin Sci 1981; 61: 33s-36s
  35. FERRARI P, PICOTTI GB, MINOTTI E, BONDIOLOTTI GP, CARAVAGGI AM, BIANCHI G. Plasma concentrations of catecholamines in two strains of spontaneously hypertensive rats at different ages. Clin Sci 1981; 61: 199s-202s
  36. GUIDI E, BIANCHI G, DALL'OSTA V, CANTALUPI V, VALLINO F, POLLI E. The influence of familial hypertension of the donor on the blood pressure and antihypertensive therapy of kidney graft recipients. Nephron 1982; 30: 318-323
  37. FERRARI P, CUSI D, BARBER BR, BARLASSINA C, VEZZOLI G, DUZZI L, MINOTTI E, BIANCHI G. Erythrocyte membrane and renal function in relation to hypertension in rats of the Milan hypertensive strain. Clin Sci 1982; 63: 61s-64s
  38. CUSI D, BARLASSINA C, FERRANDI M, BREVI R, VAZZOLA A, BIANCHI G. Erythrocyte membrane transport systems as possible markers for essential hypertension. Clin Sci 1982; 63: 57s-59s
  39. BIANCHI G, CUSI D, GUIDI E. Renal hemodynamics in human subjects and in animals with genetic hypertension during the prehypertensive stage. Am J Nephrol 1983; 3: 73-79
  40. BIANCHI G, CUSI D, BARLASSINA C, LUPI GP, FERRARI P, PICOTTI GB, GATTI M, POLLI E. Renal dysfunction as a possible cause of essential hypertension in predisposed subjects. Kidney Int 1983; 23: 870-875
  41. BECK F, BIANCHI G, DORGE A, RICK R, SCHRAMM M, THURAU K. Sodium and potassium concentrations of renal cortical cells in two animal models of primary arterial hypertension. J Hypertens 1983; 1: (suppl.2), 38-39
  42. TRIZIO D, FERRARI P, FERRANDI M, TORIELLI L, Bianchi G. Expression at the hemopoietic stem cell level of the genetically determined erythrocyte membrane defects in the Milan hypertensive rat strain (MHS). J Hypertens 1983; 1: (suppl.2), 6-8
  43. BIANCHI G, FERRARI P, BARBER BR. The Milan Hypertensive strain. Handbook of hypertension.: Experimental and Genetic Models of hypertension. Ed. W. de Jong - Elsevier Science Publishers B.V, 1984; vol. 4: 328-349
  44. PERSSON AE, BIANCHI G, BOBERG U. Tubuloglomerular feedback in hypertensive rats of the Milan strain. Acta Physiol Scand 1985; 123: 139-146
  45. GUIDI E, BIANCHI G, RIVOLTA E, PONTICELLI C, QUARTO DI PALO F, MINETTI L, POLLI E. Hypertension in man with a kidney transplant: role of familial versus other factors. Nephron 1985; 41: 14-21
  46. BIANCHI G, FERRARI P, TRIZIO D, FERRANDI M, TORIELLI L, BARBER BR, POLLI E. Red blood cell abnormalities and spontaneous hypertension in the rat: A genetically determined link. Hypertension 1985; 7: 319-325
  47. BIANCHI G, SALVATI P, BARLASSINA C, FERRARI P, GUIDI E, TRIPODI MG, NIUTTA E, PATI C, POLLI E. The kidney in essential hypertension. Contr Nephrol (Karger, Basel) 1985; 49: 173-178
  48. VEZZOLI G, ELLI A, TRIPODI G, BIANCHI G, CARAFOLI E. Calcium ATPase in erythrocytes of spontaneously hypertensive rats of the Milan strain. J Hypertens 1985; 3: 645-648
  49. NIUTTA E, TRIPODI MG, CUSI D, PATI C, FOSSI F, ELLI A, BIANCHI G. Effects of captopril and of other antihypertensive drugs on cell membrane ion transport: a preliminary report. Postgrad Med J 1986; 62 (suppl l): 13-15
  50. BIANCHI G, FERRARI P, CUSI D, SALARDI S, NIUTTA E, TRIPODI G. Genetic and experimental hypertension in the animal model-similarities and dissimilarities to the development of human hypertension. J Cardiovasc Pharm 1986; 8 (suppl 5): S64-S70
  51. BRANDIS A, BIANCHI G, REALE E, HELMCHEN U, KUHN K, CLAUS H, DUZZI L. Age-dependent glomerulosclerosis and proteinuria occurring in rats of the Milan normotensive strain and not in rats of the Milan hypertensive strain. Lab Invest 1986; 55 (n. 2): 234-243
  52. PONTREMOLI S, MELLONI E, SALAMINO F, SPARATORE B, MICHETTI M, SACCO O, BIANCHI G. Characterization of the defective calpain-endogenous calpain inhibitor system in erythrocytes from Milan hypertensive rats. Biochem Bioph Res Co 1986; 139 (no. 1): 341-347
  53. HORIE R, KIHARA M, LOVENBERG W, BEN-ISHAY D, BIANCHI G, IWAI J, NAGAOKA A, RAPP JP, SASSARD J, SIMPSON FO, YAMORI Y. Comparison of various genetic hypertensive rat strains. J Hypertens 1986; 4(suppl 3): Sll-S14
  54. BIANCHI G, FERRARI P, SALVATI P, SALARDI S, PARENTI P, CUSI D, GUIDI E. A renal abnormality in the Milan hypertensive strain of rats and in humans predisposed to essential hypertension. J Hypertens 1986; 4 (suppl 3): S33-S36
  55. PARENTI P, HANOZET G, BIANCHI G. Sodium and glucose transport across renal brush-border membranes of Milan hypertensive rats. Hypertension 1986; 8: 932-939
  56. BIANCHI G. Ion transport across blood cell membrane in essential hypertension. Curr Opin Cardiol 1986; 1: 634-639
  57. VEZZOLI G, ELLI A, NIUTTA E, QUARTO DI PALO F, BIANCHI G, CARAFOLI E. Ca-ATPase in erythrocyte membrane ghost cells of MHS rats. Am J Nephrol 1986; 6 (suppl 1): 63-65
  58. FERRARI P, TORIELLI L, FERRANDI M, CIRILLO M, BIANCHI G. Volumes and Na transports in intact red blood cells, resealed ghosts and inside-out vesicles of Milan hypertensive rats. J Hypertens 1986; 4 (suppl 6): S379-S381
  59. BIANCHI G, BARBER BR, FERRARI P, DUZZI L. The Milan Hypertensive strain of rats and its control normotensive strain. Hypertension 1987; 9 (suppl I) n 1: I-30/I-33
  60. FERRARI P, FERRANDI M, TORIELLI L, CANESSA M, BIANCHI G. Relationship between erythrocyte volume and sodium transport in the Milan hypertensive rat and age-dependent changes. J Hypertens 1987; 5: 199-206
  61. HOLLAND S, MILLET J, ALAGHBAND-ZADEH J, DE WARDENER H, FERRARI P, BIANCHI G. Cytochemically assayable Na, K-ATPase inhibition by Milan hypertensive rat plasma. Hypertension 1987; 9: 498-503
  62. PONTREMOLI S, MELLONI E, SALAMINO F, SPARATORE B, VIOTTI P, MICHETTI M, DUZZI L, Bianchi G. Decreased level of Calpain inhibitor activity in kidney from Milan hypertensive rats. Biochem Bioph Res Co 1987; 145 (n.3): 1287-1294
  63. SALVATI P, FERRARIO RG, BIANCHI G. Natriuretic capacity in isolated kidneys of rats of the Milan strain before and after the development of hypertension: comparison with spontaneously hypertensive rats. J Hypertens 1987; 5 (suppl 5): S235-S237
  64. FERRARI P, BARBER BR, TORIELLI L, FERRANDI M, SALARDI S, BIANCHI G. The Milan hypertensive rat as a model for studying cation transport abnormality in genetic hypertension. Hypertension 1987; 10 (suppl I): I-32/I-36
  65. PARINI P, DIOP L, FERRARI P, BONDIOLOTTI GP, DAUSSE JP, BIANCHI G. Selective modification of renal alpha2-adrenergic receptors in Milan Hypertensive rat strain. Hypertension 1987; 10: 505-511
  66. GMAJ P, BIANCHI G, MURER H. Calcium transports in basolateral plasma membrane from kidney cortex of Milan hypertensive rats. Biochem Biophys Acta 1988; 941: 187-197
  67. BIANCHI G, CUSI D, VEZZOLI G. Role of cellular sodium and calcium metabolism in the pathogenesis of essential hypertension. Seminars in Nephrology 1988; 8, n. 2 (June): 110-119
  68. BIANCHI G, VEZZOLI G, CUSI D, COVA T, ELLI A, SOLDATI L, TRIPODI MG, SURIAN M, OTTAVIANO E, RIGATTI P, ORTOLANI S. Abnormal red-cell calcium pump in patients with idiopathic hypercalciuria. New Engl J Med 1988; 319: 897-901
  69. NIUTTA E, CUSI D, COLOMBO R, TRIPODI G, PELLIZZONI M, PATI P, CESANA B, ALBERGHINI E, BARLASSINA C, BIANCHI G. Antihypertensive effect of captopril, canreonate potassium, and atenolol; relations with red blood cell sodium transport and renin: Am J Hypertens 1988; 1: 364-371
  70. PONTREMOLI S, MELLONI E, SPARATORE B, SALAMINO F, PONTREMOLI R, TIZIANELLO R, BARLASSINA C, CUSI D, COLOMBO R, BIANCHI G. Erythrocyte deficiency in calpain inhibitor activity in essential hypertension. Hypertension 1988; 12: 474-478
  71. CAMUSSI A, BIANCHI G. Genetics of essential hypertension from the unimodal-bimodal controversy to molecular technology hypertension. Hypertension 1988; 12, 6, 620-628
  72. SALARDI S, MODICA R, FERRANDI M, FERRARI P, TORIELLI L, BIANCHI G. Characterization of erythrocyte adducin from the Milan hypertensve strain of rats. Journal of Hypertension; 1988; 6 (suppl. 4): S196-S198.
  73. BIANCHI G, NIUTTA E, FERRARI P, SALVATI P, SALARDI S, CUSI D, COLOMBO R, CESANA B, TRIPODI G, PATI P, ALBERGHINI E. A possible primary role for the kidney in essential hypertension. Am J Hypertens 1989; 2(2 pt 2): 2S-6S
  74. SALARDI S, SACCARDO B, BORSANI G, MODICA R, FERRANDI M, TRIPODI MG, SORIA M, FERRARI P, BARALLE FE, SIDOLI A, BIANCHI G. Erythrocyte adducin differential properties in normotensive and hypertensive rats of the Milan strain (charecterization of spleen adducin m-RNA). Am J Hypertens 1989; 2, 229
  75. CUSI D, ALBERGHINI E, PATI P, TRIPODI G, BARLASSINA C, COLOMBO R, COVA T, NIUTTA E, VEZZOLI G, BIANCHI G. Pathogenetic mechanisms in essential hypertension. Analogies between a rat model and the human disease. Int J Cardiol 1989; 25: S29-S36
  76. SALVATI P, FERRARIO RG, BIANCHI G: Diuretic effect of bumetanide in isolated perfused kidneys of Milan hypertensive rats. Kidney Int 1990; 37:1084-1089
  77. SALVATI P, CORRADO F, FERRARIO RG, LAMBERTI E, DUZZI L, BIANCHI G, REMUZZI G, PERICO N, BENIGNI A, BRAIDOTTI P, COGGI G, PUGLIESE F, PATRONO C. Role of enhanced glomerular synthesis of thromboxane A2 in progressive kidney disease. Kidney Int 1990; 38: 447-458
  78. NIUTTA E, CUSI D, COLOMBO R, PELLIZZONI M, CESANA B, BARLASSINA C, SOLDATI L, BIANCHI G. Predicting interindividual variations in anti-hypertensive therapy: the role of sodium transport systems and renin. J Hypertens 1990; 6 (suppl 4): S53-S58
  79. CUSI D, BARLASSINA C, STELLA P, POZZOLI E, BIANCHI G. Genetic polymorphism of Na-K cotransport in essential hypertension. J Hum Hypertens 1990; 4: 307-311
  80. SOLDATI L, MOLINARI I, SALARDI S, BARBER B, RUGGIERO M, SERRA F, BIANCHI G. Calpastatin level in spontaneously hypertensive rats. Biochem Bioph Res Co 1991; 175(2): 468-91.
  81. TRIPODI G, PISCONE A, BORSANI G, TISMINIETZKY S, SALARDI S, SIDOLI A, JAMES P, PONGOR S, BIANCHI G, BARALLE FE. Molecular cloning of an adducin-like protein: evidence of a polymorphism in the normotensive and hypertensive rats of the Milan strain.  Biochem Bioph Res Co 1991; 177(3): 939-947
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  184. MANUNTA P, LAVERY G, LANZANI C, BRAUND PS, SIMONINI M, BODYCODE C, ZAGATO L, DELLI CARPINI S, TANTARDINI C, BRIONI E, BIANCHI G, SAMANI NJ. Physiological interaction between ADD1 and WNK1-NEDD4L pathways on sodium related blood pressure regulation. Hypertension 2008; 52: 366-372
  185. CAPASSO G, RIZZO M, GARAVAGLIA ML, TREPICCIONE F, ZACCHIA M, MUGIONE A, FERRARI P, PAULMICHL M, LANG F, LOFFING J, CARREL M, DAMIANO S, WAGNER CA, BIANCHI G, MEYER G. Upregulation of apical sodium-chloride cotransporter and basolateral chloride channels is responsible for the maintenance of salt-sensitive hypertension. Am J Physiol Renal Physiol 2008; 295 (2): F556-F567
  186. TORIELLI L, TIVODAR S, MONTELLA RC, IACONE R, PADOANI G, TARSINI P, RUSSO O, SARNATARO D, STRAZZULLO P, FERRARI P, BIANCHI G, ZURZOLO C. Alpha-adducin mutations increase Na/K pump activity in renal cells by affecting constitutive endocytosis: implications for tubular Na reabsorption. Am J Renal Physiol 2008; 295 (2): F478-F487
  187. KUZNETSOVA T, MANUNTA P, YU J, THJIS L, RICHART T, FAGARD RJ, MESSAGGIO E, CASAMASSIMA N, BIANCHI G, STAESSEN JA. Left ventricular geometry and endogenous ouabain in a Flemish population. J Hypertens 2009; 27(9):1884-1891
  188. STENSTROM K, TAKEMORI H, BIANCHI G, KATZ AI, BERTORELLO A. Blocking the SIK1 network prevents the increases in cell sodium transport caused by a hypertension-linked mutation in human alpha-adducin. J Hypertens 2009; 27: 2452-2457
  189. FERRANDI M, CUSI D, MOLINARI I, DEL VECCHIO L, BARLASSINA C, RASTALDI MP, SCHENA FP, MACCIARDI F, MARCANTONI C, ROCCATELLO D, PETERS LL, ARMELLONI S, MIN L, GIARDINO L, MATTINZOLI D, CAMISASCA C, PALAZZO F, MANUNTA P, FERRARI P, BIANCHI G. Alpha and beta-adducin polymorphisms affect podocyte proteins and proteinuria in rodents and decline of renal function in human IgA nephropathy. J Mol Medicine 2010; 88 (2); 203-217 suppl
  190. FERRANDI M, MOLINARI I, TORIELLI L, PADOANI G, SALARDI S, RASTALDI MP, FERRARI P, BIANCHI G. Adducin and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin. Part 1: Experimental Studies. Sci Transl Med 2010; 2: 59ra86 suppl
  191. LANZANI C, CITTERIO L, GLORIOSO N, MANUNTA P, TRIPODI G, SALVI E, DELLI CARPINI S, MESSAGGIO E, STAESSEN JA, CUSI D, MACCIARDI F, ARGIOLAS G, VALENTINI G, FERRARI P, BIANCHI G also on behalf of OASIS-HT Investigators. Adducin and ouabain-related gene variants predict the antihypertensive activity of rostafuroxin. Part 2: Clinical Studies. Sci Transl Med 2010; 59ra87 suppl
  192. BIGNAMI E, CASAMASSIMA N, FRATI E, LANZANI C, CORNO L, ALFIERI O, GOTTLIEB S, SIMONINI M, KEYUR BS, MIZZI A, MESSAGGIO E, ZANGRILLO A, FERRANDI M, FERRARI P, BIANCHI G, HAMLYN JM, MANUNTA P. Preoperative endogenous ouabain predicts acute kidney injury in cardiac surgery patients. Crit Care Med 2013; Jan 10.
  193. FERRANDI M, BARASSI P, TADINI-BUONINSEGNI F, BARTOLOMMEI G, MOLINARI I, TRIPODI MG, REINA C, MONCELLI MR, BIANCHI G, FERRARI P. Istaroxime stimulates SERCA2a and accelerates calcium cycling in heart failure by relieving phospholamban inhibition. Br J Pharmacol. 2013 Aug;169(8):1849-61. doi: 10.1111/bph.12278
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  197. CARUBELLI V, ZHANG Y, METRA M, LOMBARDI C, FELKER GM, FILIPPATOS G, O'CONNOR CM, TEERLINK JR, SIMMONS P, SEGAL R, MALFATTO G, LA ROVERE MT, LI D, HAN X, YUAN Z, YAO Y, LI B, LAU LF, BIANCHI G, ZHANG J; ISTAROXIME ADHF TRIAL GROUP. Treatment with 24 hour istaroxime infusion in patients hospitalised for acute heart failure: a randomised, placebo-controlled trial. Eur J Heart Fail. 2020 Sep;22(9):1684-1693
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