ANP but not BNP reflects early left diastolic dysfunction in type 1 diabetics with myocardial dysinnervation.

OBJECTIVE: We investigated whether plasma concentrations of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) reflect impaired diastolic relaxation or its improvement after ACE inhibition. METHODS: 7 long-term Type 1 diabetic patients with normal systolic but impaired diastolic function and with sympathetic myocardial dysinnervation and 10 controls were included. Exercise tolerance and maximal O 2 uptake were evaluated by bicycle exercise prior to the study. ANP, BNP and norepinephrine/epinephrine (NE/E) were determined at baseline and at 80 % .VO2 max workload and after recovery, before and following 12 weeks of treatment with fosinopril (10 mg/d). RESULTS: Isovolumetric relaxation time (IVRT) and A/E wave ratio were increased by 26.7 +/- 11.5 % and 54.4 +/- 26.1 % in diabetic patients as compared to controls, respectively (p < 0.02). After 12 weeks of fosinopril treatment, no differences in IVRT or A/E wave ratio were detectable between groups. ANP was enhanced in Type 1 diabetes as compared to controls (baseline: 9.2 +/- 3.0 vs. 4.5 +/- 1.1; exercise: 22.4 +/- 7.7 vs. 7.9 +/- 1.2; recovery: 20.3. +/- 4.6 vs. 9.5 +/- 2.0 fmol/ml, p < 0.02). Fosinopril treatment abolished any differences between groups. BNP plasma levels did not differ between groups and no exercise dependent changes were observed. NE- and E-increase was greater at 80 % .VO2 max work load in Type 1 diabetes than in controls (p < 0.05). Again, fosinopril abolished differences between groups. CONCLUSION: In Type 1 diabetes, impaired diastolic function is associated with elevated ANP and catecholamine plasma levels that are normalized after ACE inhibition. Thus, ANP but not BNP appears to be a sensitive biochemical marker for early diastolic dysfunction in Type 1 diabetes.

Exercise induces excessive normetanephrine responses in hypertensive diabetic patients.

BACKGROUND: Exaggerated sympathoadrenal function has been accused of contributing to hypertension in type-2 diabetes. Recently, plasma unconjugated (free) metanephrines were reported to be stable markers of catecholamine hypersecretion. Thus, we aimed to examine whether unconjugated metanephrines are reliable markers of stress response induced by standardized cycling exercise and to identify differences in such stress responses between hypertensive and/or diabetic patients. DESIGN: Type-2 diabetic patients with (DM/H; n= 8, 50 +/- 7 years, HbA1c: 7.7 +/- 0.6%) or without hypertension (DM/N; n = 6, 48 +/- 10 years, 7.5 +/- 1.8%) and nondiabetic hypertensive patients (H; n = 8, 56 +/- 4 years) were studied during incremental cycling exercise (15 min) to 75% of individual VO(2)max and during recovery (60 min). Plasma catecholamines and unconjugated metanephrines were measured by high-performance liquid chromatography with electrochemical detection. Hormone responses were quantified from the areas under the concentration-time curves and compared with those of age-, sex- and BMI-matched healthy volunteers (CON, n= 22). RESULTS: Blood pressure responses of DM/H and H, but not DM/N, were greater than those of CON (P < 0.01), whereas heart rates increased similarly in all groups. Unconjugated normetanephrine responses were only increased (P = 0.04) in DM/H (2156 vs. 1133 pg mL(-1) min(-1) but not in DM/N (1528 vs. 1300 pg mL(-1) min(-1) and H (1960 vs. 1425 pg mL(-1) min(-1) when compared with respective CON. Unconjugated metanephrines did not change from baseline, whereas catecholamine responses were comparable in all groups. CONCLUSIONS: The excessive response of plasma unconjugated normetanephrine to cycling may serve as a marker of exaggerated sympathoadrenal function in hypertensive type-2 diabetic patients.

Quantification of unconjugated metanephrines in human plasma without interference by acetaminophen.

BACKGROUND: Pheochromocytoma is a rare cause of hypertension resulting from increased catecholamine secretion. We aimed to develop a method to measure unconjugated plasma normetanephrine (NMN) and metanephrine (MN) without interference from acetaminophen, a widely prescribed drug for headaches. METHODS: Plasma samples were obtained from 48 subjects (23 males, 25 females; mean age, 49 +/- 14 years; hypertension, n = 37) under resting conditions. Following extraction on solid-phase cation-exchange columns, unconjugated metanephrines were analyzed by HPLC with electrochemical detection and with 4-hydroxy-3-methoxybenzylamine as an internal standard. Catecholamines were measured by HPLC. RESULTS: The assays were linear up to 2000 pg for NMN and for MN. Intraassay imprecisions (CVs) were 4.7% for NMN and 7.0% for MN, and the interassay CV was 12% for both NMN and MN. The limit of detection was 11 fmol for NMN and 17 fmol for MN. Ingestion of acetaminophen or its addition to plasma did not interfere with the MN peaks. Plasma NMN and MN were positively correlated (r = 0.52 and 0.49, respectively; P <0.01 for both) with the respective catecholamines. Plasma NMN (r = 0.27; P = 0.02) but not MN positively correlated with age, whereas only plasma catecholamines (and not metanephrines) were positively correlated (P <0.05) with diastolic blood pressure. CONCLUSIONS: This sensitive MN assay is not affected by simultaneous acetaminophen medication, and reveals a correlation of metanephrines with plasma and urinary catecholamines and age but not with blood pressure.

Diagnostic efficacy of unconjugated plasma metanephrines for the detection of pheochromocytoma.

BACKGROUND: Recently, measurement of plasma metanephrines was suggested to improve the detection of pheochromocytoma compared with the other common biochemical tests. OBJECTIVE: To examine the diagnostic precision of measurements of plasma metanephrines, plasma catecholamines, and urinary catecholamines and to assess their variability. METHODS: Plasma metanephrine as well as plasma and urinary catecholamine concentrations were measured by high-performance liquid chromatography with electrochemical detection. Before surgery, responses of plasma metanephrines and catecholamines to change of posture were determined. Intraoperatively, metanephrines and catecholamines were measured before skin incision, during maximal mechanical tumor manipulation, and repetitively after the tumor was separated from the circulation. Patients were reexamined 1 and 3 months after surgery. Patients with pheochromocytoma (n = 17) and with histologically proved other adrenal tumors (n = 14) were studied before, during, and after surgery. RESULTS: Measurement of plasma metanephrines and plasma and urinary catecholamines provided 100% and 82% sensitivity, respectively, for the detection of pheochromocytoma (P<.001). Levels of plasma catecholamines but not metanephrines increased in response to change of posture (norepinephrine, P =.03; epinephrine, P =.07) and intraoperative stress (norepinephrine, P =.002; epinephrine, P =.009). CONCLUSIONS: Plasma metanephrines offer improved efficacy for the diagnosis of pheochromocytoma. Less variability in response to external factors may favor plasma metanephrines in the screening for this disease. Arch Intern Med. 2000;160:2957-2963

Tyramine pressor effect in man: studies with moclobemide, a novel, reversible monoamine oxidase inhibitor.

The pressor effect of tyramine (TYR) administered i.v. and orally was measured in healthy volunteers during treatment with different therapeutic doses of moclobemide, a new, reversible, preferential type A monoamine oxidase inhibitor. With moclobemide 3 X 100 mg/day the systolic blood pressure (SBP) increase produced by TYR administered i.v. was potentiated 2.4-fold and that in response to TYR p.o. in the fasting state was increased 4.1-fold, as determined from equieffective TYR doses before and during moclobemide treatment. Peak concentrations of free TYR in plasma after oral doses of TYR were increased 2.6-fold, and a 2.5-fold smaller plasma TYR concentration produced the same SBP rise as before moclobemide treatment. No SBP increase was observed at plasma TYR concentrations below 20 ng/ml or after p.o. TYR does smaller than 80 mg. The potentiation of the pressor effect of i.v. TYR by single moclobemide doses up to 300 mg had disappeared 24 hrs after moclobemide administration. Peak TYR plasma concentration and concomitant SBP increments were considerably smaller when TYR was administered with a meal than when administered as a bolus with tap water, 2.1 times higher oral TYR doses being required to achieve similar peak TYR plasma concentration as in the fasting condition. The pressor effect of TYR was further, but only slightly, increased during treatment with moclobemide 3 x 200 mg/day, however SBP rises were again significantly smaller when TYR was given together with a meal. In contrast, tranylcypromine produced a 20 to 40-fold potentiation of the pressor effect of oral TYR and this potentiation was only slightly smaller when TYR was given with a meal. In conclusion the potentiation by moclobemide of the pressor response to oral TYR corresponds roughly to a fourfold left shift of the TYR dose-pressor response curve and is about 10 times less marked than after tranylcypromine. In real life situations, the ingestion of TYR in amounts less than 100 mg is highly unlikely to produce a clinically relevant blood pressure elevation.

Effect of moclobemide, a new reversible monoamine oxidase inhibitor, on absorption and pressor effect of tyramine.

We determined in healthy subjects the pressor effect and the plasma level of free tyramine in response to intravenous and oral tyramine doses before and after therapeutic doses (3 X 100 mg/day) of moclobemide, a new reversible, preferential type A monoamine oxidase (MAO) inhibitor. In fasting subjects moclobemide increased the pressor effect of intravenously and orally administered tyramine; the tyramine dose-pressor curve was shifted to the left by factors of 2.4 and 4.1, respectively. No increase in systolic blood pressure occurred at free plasma tyramine concentrations lower than 70 ng/ml before, and 20 ng/ml after, moclobemide. Peak plasma tyramine concentrations increased dose-dependently after oral tyramine; after moclobemide similar peak plasma concentrations of tyramine were obtained with 2.6 times smaller doses of tyramine. Thus, the potentiation by moclobemide of the pressor effect of oral tyramine appears to be due to inhibition of tyramine first-pass metabolism, as well as to inhibition of tyramine catabolism by MAO within adrenergic nerve terminals. The peak concentrations of free tyramine in plasma and the concomitant increase of systolic blood pressure were significantly (p less than 0.01) smaller when tyramine was administered with a meal (before or after moclobemide) than when given with tap water. We conclude that at doses of 3 X 100 mg/day moclobemide induces only a mild potentiation of the pressor effect of tyramine. This potentiation is virtually absent under natural conditions when tyramine is given with a meal.

Release of vitamin B12 from carrier erythrocytes in vitro.

Resealed erythrocyte ghosts (carrier erythrocytes) are potential in vivo carriers for exogenous enzymes or drugs, but data on carrier erythrocyte survival and clearance rate in humans are not available. We have measured the in vitro efflux of vitamin B12 encapsulated in human red cell by hypo-osmotic dialysis, as a preliminary for its use as a marker for in vivo human studies. Vitamin B12 was encapsulated into erythrocytes at a relative incorporation efficiency of 60%. In vitro hemolysis of carrier erythrocytes was minimal over 40 h, but vitamin B12 was rapidly lost from the cells, efflux t/2 was 5 h, presumably by diffusion through the intact cell membrane. Vitamin B12 (Vit B12) may, nevertheless, be a suitable marker for short-term human studies on carrier erythrocyte splanchnic clearance.