Post-absorptive and insulin-mediated muscle protein metabolism in liver-transplanted patients.

Cirrhotic patients after liver transplantation show a near-normal glucose homeostasis when in stable condition. In contrast, the basal and insulin-mediated whole-body protein metabolism remain altered several years after the graft. To examine whether the persisting defect of protein metabolism was due to the muscle, 7 non-diabetic liver-transplanted patients in stable condition were studied by means of the catheterization of the brachial artery and the deep forearm vein (to measure the balance across the forearm) and the infusion of labelled leucine and phenylalanine associated with indirect calorimetry. Whole-body proteolysis (as determined by endogenous leucine flux, ELF), protein synthesis (from non-oxidative leucine disposal, NOLD) and leucine oxidation (LO) were reduced in comparison to previously obtained values in a normal population. Insulin infusion (while maintaining euglycemia) induced a not significant variation of forearm phenylalanine Ra (24.4-->16.5 micromol/100 ml forearm min(-1); proteolysis) and Rd (18.5-->19.7; protein synthesis). In contrast, the whole-body insulin-dependent inhibitions of ELF (31.5-->21.8 micromol/m(2) min) and NOLD (27.3-->18.4) were impaired with respect to a normal population. On the basis of the present results, we conclude that skeletal muscle is not responsible for the alterations of leucine metabolism persisting after liver transplantation. By exclusion, this points to the liver as the major determinant of the leucine metabolism defect.

Postabsorptive muscle protein metabolism in type 1 diabetic patients after pancreas transplantation.

Insulin was shown to induce protein anabolism in vivo mainly by inhibiting proteolysis. Heterotopic pancreas transplantation in type 1 diabetes mellitus is characterized by peripheral hyperinsulinemia due to systemic rather than portal insulin delivery. Therefore, we studied the postabsorptive muscle protein metabolism in type 1 diabetic patients with or without pancreas transplantation. The forearm balance technique was performed in 9 type 1 diabetic patients on exogenous insulin treatment, in 4 type 1 diabetic patients following successful pancreas transplantation and in 6 healthy volunteers. Labelled leucine and phenylalanine were infused to quantify whole-body and muscle protein synthesis, respectively. In the postabsorptive state, whole-body protein synthesis (leucine kinetics) was similar in pancreas-transplanted patients and controls. In contrast, muscle protein synthesis tended to be less negative in pancreas-transplanted patients with respect to type 1 diabetic patients and healthy volunteers. The present data suggest that recipients with peripheral insulin delivery and chronic hyperinsulinemia are characterized by a preferential stimulation of protein synthesis in muscle rather than in the splanchnic district. When insulin was infused acutely, while maintaining euglycemia, the whole-body and muscle protein synthesis rates were approximately halved in type 1 diabetic patients with and without pancreas transplantation. We conclude that pancreas transplantation is able to normalize basal and insulin-stimulated protein metabolism. Chronic hyperinsulinemia counteract steroid-induced protein degradation by means of a mild, but persistent stimulation of muscle protein synthesis.

The interference by nicardipine and diltiazem on alpha-adrenergic receptor-mediated vasoconstriction in isolated human subcutaneous arterioles.

The effects of nicardipine and diltiazem on alpha-adrenergic receptor-mediated vasoconstriction in isolated human subcutaneous arterioles was studied. Arterioles were mounted in a myograph and stimulated at 50% of maximal contraction with norepinephrine. The vasoconstrictor responses to an unrelated agonist, endothelin, was used for comparison. The percentage of decrement in tension produced by nicardipine or diltiazem was the parameter evaluated. Both calcium channel blockers caused an equipotent and dose-dependent relaxation of the vasoconstrictor responses to norepinephrine and endothelin I. The equipotent alpha-adrenolytic effect exerted by nicardipine and diltiazem in subcutaneous arterioles contrasts with the preferential antagonism by local nicardipine in the forearm. This suggests that the interaction between alpha-adrenergic receptor activation and structurally unrelated calcium channel blockers is affected by the regional and functional characteristics of the vessels under study.

Evidence for a systemic defect of resistance-sized arterioles in hypertrophic cardiomyopathy.

BACKGROUND: To investigate whether the abnormalities of coronary arterioles observed in association with hypertrophic cardiomyopathy represent a generalized phenomenon, both forearm and coronary vasodilator reserve were measured in 12 patients with hypertrophic cardiomyopathy. METHODS: Forearm vasodilator reserve was evaluated by measuring minimal forearm vascular resistance (Rmin, the ratio of mean intra-arterial pressure to peak forearm blood flow measured by venous plethysmography) under conditions of maximal postocclusive reactive hyperemia. RESULTS: In a subgroup (n = 5) of patients, the intra-arterial infusion of sodium nitroprusside combined with arterial occlusion did not produce additional vasodilation, indicating that the ischemic stimulus was indeed maximal. Coronary reserve was quantitated by measuring left ventricular blood flow (13N-ammonia and positron emission tomography) and coronary resistance at baseline and after intravenous dipyridamole (0.56 mg/kg). Rmin was significantly greater in patients than in a group of age- and sex-matched controls. The percentage change in coronary resistance after dipyridamole was significantly related to Rmin, whereas no correlation was found between change in coronary resistance and individual septal thickness values. CONCLUSIONS: Independent of cardiac hypertrophy, systemic and coronary arterioles of patients with hypertrophic cardiomyopathy are affected by an abnormality that may contribute to the clinical evolution of this syndrome.

Lack of correlation between cardiac mass and arteriolar structural changes in mild-to-moderate hypertension.

A morphological restructuring of cardiac and arteriolar tissue is common in hypertension. The parallel evolution of these two processes as a compensatory response to pressure overload is a frequently assumed but unsubstantiated hypothesis. To evaluate this possibility, we have concomitantly measured left ventricular mass (LVM; two-dimensional echo) and minimal forearm vascular resistance (FVR; derived from the ratio of intra-arterial blood pressure: forearm blood flow by venous plethysmography) at maximal postischemic (13 min ischemia + 1 min hand exercise) reactive hyperemia. The study was performed on 29 essential hypertensive patients (15 males, 14 females, aged 50 +/- 10 years) who had not been undergoing treatment for hypertension for at least 15 days at the time of study. Minimum FVR was taken as a hemodynamic index of the integrated arteriolar lumen at the forearm level. LVM index and minimum FVR ranged from normal to clearly altered values. In spite of a wide spread of values, no correlation existed between the individual values of the two variables. Systemic mean blood pressure correlated with minimum FVR and tended to correlate with LVMI. Thus, morphological restructing of cardiac and arteriolar tissue does not seem to evolve in parallel in human hypertension. Pressure overload may contribute to cardiovascular hypertrophy, but other unrelated mechanisms may also underlie the development of cardiac and arteriolar abnormalities of human hypertension.

Does a digoxin-like substance participate in vascular and pressure control during dietary sodium changes in patients with primary aldosteronism?

To evaluate the importance of an endogenous sodium pump inhibitor in the pathogenesis of low renin human hypertension, the urinary excretion of a digoxin-like immunoreactive substance (DLIS) was measured in eight patients with primary aldosteronism (n = 5, with adenomas) during two sequential 1-week periods of low- (20 mmol/l NaCl) and high- (200 mmol/l NaCl) sodium intake. DLIS excretion increased consistently during high-sodium intake while urinary aldosterone, plasma renin activity, cortisol and adrenocorticotropic hormone did not change. Although blood pressure showed a time-course parallel to that of the urinary DLIS, the blood pressure increments were not accompanied by evidence of vasoconstriction since forearm blood flow (plethysmographic technique) increased and forearm vascular resistances were reduced. Moreover, the reactivity of forearm arterioles to local norepinephrine was unchanged during the period of low- and high-salt intake, despite the fact that an endogenous sodium pump inhibitor should, supposedly, sensitize the responses to an adrenergic agonist. Finally, forearm vasoconstrictor responses to ouabain, a pharmacological Na+,K(+)-ATPase antagonist, were potentiated during the high-salt diet, a result not expected if an increased number of sodium pumps were occupied by an endogenous inhibitor. These results provide unequivocal evidence for a modulation by salt intake of the urinary excretion of a DLIS in patients with primary aldosteronism. This substance might participate in the regulation of body fluid volume in this syndrome and possibly in other physiological conditions. However, no evidence could be found for a cause--effect relationship between blood pressure and DLIS increments during high-salt intake, at least during the short-term course of the study.

An atrial natriuretic factor analogue at low doses attenuates forearm reflex vasoconstriction to cardiopulmonary receptor deactivation in patients with hypertension.

Contrasting data exist about a possible modulation of the autonomic function by atrial natriuretic factor (ANF) in human beings, particularly at low, biologically, significant concentrations. We have evaluated that possibility by increasing plasma ANF levels through the infusion of a synthetic analogue (WY-47,663, anaritide) in five male patients with mild to moderate uncomplicated hypertension. Nonhypotensive lower body negative pressure (-10 mm Hg x 5 min) was used to selectively deactivate cardiopulmonary receptors and to stimulate sympathetic efferent tone reflexogenically. ANF was given at either a low rate (0.005 micrograms/kg/min x 60 min, which was previously shown to increase plasma ANF in a range compatible with physiologic stimuli) or at a high rate (0.05 micrograms/kg/min x 60 min, each). Administration of ANF was preceded and followed by vehicle infusion (Haemacell x 30 min). Forearm blood flow (venous plethysmography), intraarterial blood pressure, and heart rate were monitored continuously, and venous immunoreactive ANF, plasma renin activity, aldosterone level, and venous hematocrit were measured at the end of both control and infusion periods. Arterial norepinephrine values, an indirect index of sympathetic discharge, were measured at rest and during lower body negative pressure conditions. Graded systemic ANF infusion increased immunoreactive ANF and venous hematocrit, decreased aldosterone level and plasma renin activity, whereas resting norepinephrine levels, blood pressure, and heart rate did not change. Lower body negative pressure decreased forearm blood flow during vehicle infusion, but it lost its vasoconstrictor effect during infusion of ANF. To identify the site of that inhibitory action, ANF was also infused into the brachial artery at rates that raised local but not systemic levels of immunoreactive ANF.(ABSTRACT TRUNCATED AT 250 WORDS)

Calcium entry blockade and agonist-mediated forearm vasoconstriction in hypertensive patients. Difference between nicardipine and verapamil.

The interference by nicardipine and verapamil with the response to vasoactive stimuli, such as lower body negative pressure and angiotensin II, has been evaluated in the forearm of hypertensive patients. Forearm blood flow was monitored during the intraarterial infusion of either drug at rates equieffective on basal flow. Nicardipine blunted the peak forearm vasoconstrictor action of lower body negative pressure and a comparable result was obtained when angiotensin II was administered intraarterially. In spite of a comparable increase in forearm flow, nicardipine was more potent than verapamil in inhibiting vasoconstriction following both stimuli. Thus, nicardipine suppressed regional vascular reactivity, probably by blockade of the influx of extracellular calcium, in response to receptor activation, since both alpha-adrenergic and angiotensin II receptor-mediated vasoconstrictor responses were attenuated. However, the results of the comparison with an unrelated calcium entry blocker, such as verapamil, may suggest that nicardipine, and possibly other dihydropiridine derivatives, preferentially antagonize agonist-mediated vasoconstriction in the human forearm.

Atrial natriuretic factor as a vasodilator agent in hypertensive patients.

To investigate the role of Atrial Natriuretic Factor (ANF) in modulating arteriolar tone in hypertension, a synthetic 25 AA human ANF-analogue (anaritide) was infused intraarterially in the forearm vascular bed of five patients with mild hypertension. A dose-dependent increase in blood flow (plethysmographic technique) was seen at rates covering a thousand-fold range (0.008, 0.08, 0.8, 8.0 micrograms/dl tissue/min x 15 minutes each). At the lowest infusion rate, the forearm blood flow increment was associated with changes in local venous ANF concentrations comparable with those reported during biological stimuli in hypertensive man and consistent with an ANF physiologic role in forearm arterioles of hypertensive patients. However, at local venous concentrations greater than 1000 pg/ml, ANF did not relax forearm vessels by more than about one-fourth of the total forearm vasodilator capacity (as assessed through a maximally active ischemic stimulus). These data confirm the low potency of ANF as an endogenous vasodilator, although vasodilator potency is not a necessary requirement for physiologic systems involved in the regulation of muscular vascular tone. Systemic arterial pressure, heart rate, and contralateral flow did not change during the study in spite of the markedly increased peripheral ANF levels recirculating from the local forearm administration. This behavior indicates that arteriolar vasodilation is apparently not the main mechanism of action of ANF on systemic hemodynamics in hypertensive patients.

Reactive hyperemia during short-term blood flow and pressure changes in the hypertensive forearm.

The aim of the present study was to further validate our method for the determination of minimal forearm vascular resistance after ischemia (13 min arterial occlusion and 1 min hand exercise) in patients with hypertension. This parameter, calculated as the ratio of mean blood pressure (intra-arterial recordings on the experimental side) to forearm blood flow (strain-gauge venous plethysmography), was measured basally and after either increasing (through unrelated vasodilators such as sodium nitroprusside or the calcium antagonist nicardipine in six mild-to-moderate uncomplicated hypertensives) or decreasing (norepinephrine, n = 4) flow without changes in systemic pressure. In spite of the divergent starting flow values, minimal postischemic forearm vascular resistance was unchanged, indicating a lack of relationship with functional arteriolar tone and the achievement of maximal dilatation. In two additional groups of patients, systemic arterial pressure was decreased by approximately equipotent oral doses of either nifedipine, a calcium antagonist (n = 6), or captopril, an angiotension converting enzyme inhibitor (n = 5). Under these conditions, minimal forearm vascular resistance was unchanged from pretreatment values, suggesting that local autoregulatory mechanisms were overridden during the reactive hyperemia, and that the vessel lumen was dependent on the distending pressure. Overall, the data show that our experimental conditions are suitable for measuring minimal forearm vascular resistance as a functional correlate of the morphological status of systemic arterioles in arterial hypertension.

Calcium entry blockade and agonist-mediated vasoconstriction in hypertensive patients.

The effects of two chemically unrelated calcium channel blockers--nicardipine and verapamil--on vascular responses to exogenous norepinephrine were evaluated in uncomplicated hypertensive patients. Each drug was infused into the brachial artery at rates that did not affect systemic blood pressure or heart rate, and forearm blood flow was measured using strain gauge venous plethysmography. Nicardipine 1 microgram/100 ml forearm tissue/min dilated the forearm arterioles and antagonized the vasoconstrictor effect of norepinephrine, whereas verapamil 1 microgram/100 ml tissue/min was ineffective, even though both drugs relaxed basal tone to the same extent. The difference between nicardipine and verapamil was also evident when reflex forearm vasoconstriction was elicited by the application of a lower body negative pressure and the drugs were infused intra-arterially at 1 and 3 micrograms/100 ml tissue/min, respectively. To evaluate whether a comparable behavior might also hold for nonsympathomimetic agents, increasing doses of angiotensin II were administered to the forearm vascular bed after pretreatment with either nicardipine or verapamil. Both drugs increased forearm blood flow, but only nicardipine antagonized the effect of angiotensin II in the forearm, showing that the impairment of vasoconstrictor mechanisms was not dependent on a specific receptor. Important differences seem to exist between nicardipine and verapamil with regard to agonist-mediated vasoconstriction in hypertensive patients, which is consistent with the heterogeneity of calcium channel blockers as a pharmacological class. Preferential antagonism of a series of vasoconstrictor stimuli may characterize the vasodilatory and, possibly, the antihypertensive effect of nicardipine.

Forearm vasodilatory capacity in patients with syndrome X: a comparison with normal and hypertensive subjects.

Minimal forearm vascular resistances during maximal postischaemic vasodilation were measured in normotensive subjects with syndrome X, a condition characterized by angina and normal coronary arteries, in which a reduced coronary and systemic vasodilatory capacity has been reported. Age- and sex-matched normals and essential hypertensives constituted the control groups. The syndrome X patients had a significantly higher minimal forearm vascular resistance than the normals, indicating that arteriolar alterations may occur in the normotensive state and therefore cannot be considered solely as a consequence of hypertension.

Low dose atrial natriuretic factor in primary aldosteronism: renal, hemodynamic, and vascular effects.

Whether atrial natriuretic factor (ANF) plays a physiological role in primary aldosteronism has yet to be determined. In the present study, the renal, hemodynamic, humoral, and vascular effects of a synthetic (WY-47663) human analogue were studied in five water-loaded (15 ml H2O/kg) patients with adenomatous primary aldosteronism, a salt-sensitive, low renin, volume-expanded syndrome. ANF was infused for 3 hours at a low rate (0.005 micrograms/kg/min), which approximately doubled circulating immunoreactive ANF. Glomerular filtration rate and renal blood flow (inulin and para-aminohippurate clearance) remained stable, but sodium excretion increased significantly suggesting a dissociation between renal hemodynamics and natriuresis as well as a direct inhibitory effect on tubular sodium reabsorption by ANF. Intra-arterial diastolic blood pressure, heart rate, forearm blood flow (plethysmographic method), and arterial plasma norepinephrine did not change, but systolic blood pressure declined and hematocrit rose suggesting plasma volume contraction by ANF. Plasma aldosterone levels were unchanged indicating a loss of ANF-mediated aldosterone inhibition, possibly related to qualitative or quantitative alterations of ANF receptors in tumoral adrenal tissue. Infusion of the analogue into the brachial artery was at a rate of 0.005 micrograms/dl forearm tissue/min x 30 minutes, which also doubled local immunoreactive venous ANF concentrations and vasodilated forearm arterioles. These data suggest a physiological role for ANF in modulating body fluid volume even in human primary aldosteronism.