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Notes: Summary Pathogenetic mechanisms other than the quality of metabolic control may play a role in the development of diabetic nephropathy. Some cross-sectional studies have shown that elevated erythrocyte sodium-lithium countertransport (Na + /Li + CT) activity may be linked to incipient or overt nephropathy in insulin-dependent diabetic (IDDM) patients. The aim of the present work was to ascertain if high erythrocyte Na + /Li + CT activity anticipates the development of microalbuminuria in IDDM patients. Evaluation of this cation transport system was carried out in 159 normotensive, normoalbuminuric IDDM patients, who were divided into two groups: those with values above (Group A) and those with values below (Group B) the median level in the overall population (300 μmol/erythrocytes × h). A total of 79 patients in Group A and 80 in Group B underwent periodic examinations over a similar time period (5.2 years, range 3.3–7.4 years and 5.4 years, range 3.4–7.5 years, respectively). Median sodium-lithium countertransport activity was stable when evaluated after 2 and 4 years of follow-up. Only seven patients were excluded from the protocol because changes in their sodium-lithium countertransport activity placed them on the other side of the median value with respect to their baseline measurement. Thus, 152 patients completed the study (76 in Group A and 76 in Group B). Of the 76 patients in Group A, 17 developed persistent microalbuminuria (22.3 %). The number of patients in Group B showing persistent microalbuminuria was significantly lower (4 of 76; 5.2 %; p 〈 0.01). The sensitivity of erythrocyte Na + /Li + CT in predicting the development of microalbuminuria was 85 % and its specificity was 55 %. Seven patients of Group A and five of Group B developed arterial hypertension. Subjects in Group A had significantly higher mean HbA1 c values of twice yearly measurements than those in Group B (9.6 ± 1.7 vs 8.3 ± 1.7 %, p 〈 0.002, mean ± SD) despite similar daily insulin requirements. Systolic and diastolic blood pressure levels were also evaluated every 6 months and were significantly higher in the Group A than in the Group B patients, although on average within the normal range. The odds ratio for developing persistent microalbuminuria in IDDM with elevated baseline erythrocyte Na + /Li + CT activity after adjustment for gender and baseline albumin excretion rate, and mean 6 monthly plasma creatinine, HbA1 c and systolic and diastolic blood pressure levels was 4.2 (95 % confidence intervals 2.0–11.1). It was also found that the percentage of offspring having both parents with Na + /Li + CT activity above the median value was significantly higher in Group A than in Group B (Group A vs Group B: 35 vs 19 %; p 〈 0.01). On the contrary the percentage of offspring whose erythrocyte Na + /Li + CT was lower in both parents was lower in Group A than in Group B: 10 vs 38 %, p 〈 0.01). Parents of Group A offspring had arterial hypertension more frequently than those of Group B. These results indicate that erythrocyte Na + /Li + CT activity is a useful diagnostic tool in identifying normotensive, normoalbuminuric patients who may be predisposed to develop persistent microalbuminuria. This disorder in the cation transport system is associated with poor metabolic control, higher blood pressure, and male sex; it also appears to be, at least partly, genetically transmitted. [Diabetologia (1997) 40: 654–661]

Notes: 1. Aldosterone suppression is said to play a major role in the long term hypotensive efficacy of angiotensin converting enzyme inhibitors. However, in previous reports from other laboratories, plasma volume has been found mostly increased and sodium balance sometimes positive.2. The effects of the angiotensin converting enzyme inhibitor enalapril (10-40 mg/day, p.o., for 6 weeks) on blood pressure, body fluid volumes, renal function and plasma aldosterone were compared to those of hydrochlorothiazide (50 mg/day, p.o.) alone for 2 weeks and in association with propranolol (80-160 mg/day, p.o.) for 4 more weeks during a randomized double-blind parallel study in 14 essential hypertensives.3. Hydrochlorothiazide alone and in combination with propranolol induced slight and not significant change in either blood pressure and body fluids.4. The maximum hypotensive response to enalapril was achieved only after 2 weeks of continuous treatment possibly because after 1 week the hypotensive efficacy was lessened by a significant (P 〈 0.05) fluid retention secondary to a transient and not significant fall in renal perfusion. At this time aldosterone was not significantly changed compared to pretreatment values.5. After 6 weeks on enalapril, blood pressure was significantly reduced, plasma aldosterone further but not significantly decreased and extracellular fluid volume was normal.6. These findings indicate that aldosterone suppression contributes to the blood pressure lowering effect of enalapril by offsetting the salt and water retention observed on starting treatment and due to direct vasodilation.

Notes: 1. Prazosin (2 mg, p.o.) was administered to nine patients with essential hypertension while intra-arterial pressure was recorded by an Oxford portable apparatus. In all patients, 30 min-3 h after the administration, systolic and diastolic pressure fell on assuming the upright posture and four patients fainted. No correlation was found between the degree of fall in pressure and the plasma concentration of the drug. Acute expansion of the plasma volume by means of 6% Dextran infusion reduced the orthostatic blood pressure fall in all cases and a significant inverse correlation was found between plasma volume and orthostatic fall of pressure.2. After ten days of continuous treatment with prazosin, 2 mg daily, a significant decrease in blood pressure was observed while orthostatic hypotension disappeared, probably due to the plasma volume expansion induced by the drug.

Notes: Abstract Hypertension is a major side effect of cyclosporin (CsA). While the mechanism(s) responsible are unclear, CsA-induced endothelial dysfunction and CsA-induced hypertension have been attributed to the CsA effect on the endothelial-derived factors controlling vasomotor tone. Endothelial nitric oxide (NO) is crucial in the maintenance of a state of basal vasodilation, and recent studies have suggested an NO-mediated counterregulatory mechanism protective from CsA-induced vasoconstriction. Our study evaluates endothelial nitric oxide synthase (ecNOS) gene status (PCR analysis) and plasma levels of NO metabolites (ELISA) in kidney and heart transplant patients under chronic CsA treatment with CsA-induced hypertension. Since CsA increases superoxide production, which metabolises NO, plasma hydroperoxides from cholesterol esters and from triglycerides and peroxynitrite were also evaluated (HPLC) as an index of the presence of superoxides and of “oxidative stress”. Quantification of monocyte ecNOS mRNA and NO metabolites plasma levels from patients and controls (C) demonstrated NO system upregulation in patients notwithstanding the hypertension. The mean ecNOS to β-actin ratio was 1.80 ± 0.85 in patients vs 0.40 ± 0.09 in C (P 〈 0.04). NO metabolites were 34.03 ± 14.32 μM in patients vs 11.53 ± 5.64 μM in C (P 〈 0.001). Hydroperoxides from cholesterol esters and from triglycerides were also increased in patients, 3.4 ± 1.4 vs 1.3 ± 0.6 integrated area units (i. a. u.), P 〈 0.007 and 10.6 ± 6.4 vs 1.3 ± 0.8 i. a. u., P 〈 0.008, respectively, as well as the peroxynitrite plasma level, 0.32 ± 0.11 μM/l vs undetectable in C. This study confirms a CsA-induced NO system upregulation in transplanted patients. However, the NO-mediated counterregulatory system to CsA-induced vasoconstriction, present in normals, could be canceled in patients by CsA-induced superoxide (O2 –) and free radical production which, by increasing NO metabolism, could contribute to CsA-induced vasoconstriction and hypertension and predispose to atherosclerosis.