Insulin resistance in essential hypertension: a psychophysiological approach to the "chicken and egg" question.

AIMS: High levels of plasma insulin have frequently been found in patients with high blood pressure. The causal role of insulin resistance in essential hypertension, however, is still debated. Epidemiological and clinical studies have not provided complete responses to the original pathophysiological speculations, while the suggestion that enhanced sympathetic tone may induce both insulin resistance and hypertension is gaining ground. DATA SYNTHESIS: Many studies indicate that the high sympathetic drive in hypertensive patients originates within the brain, while other studies show that insulin resistance is associated with reduced vasodilatory capacity and increased vasoconstrictive functional responses ascribed to endothelial impairment. The sympathetic overdrive and enhanced cardiovascular reactivity, detectable since the earliest stages of hypertension lead to endothelial damage and, hence, impair the vasodilatory response, peripheral blood flow and flow-dependent metabolism. Thus, the link between hyperinsulinemia and high blood pressure might lie in the vascular abnormalities secondary to elevated sympathetic tone and exaggerated hemodynamic stress response. CONCLUSIONS: Examination of the literature and the results of recent pilot studies of the stress systemic and regional hemodynamic reactivity in the present paper suggests that behavioral characteristics and cardiovascular stress responses play a pivotal role in determining the hyperinsulinemic state in hypertensive patients. High sympathetic tone, with consequent vascular impairment and altered functional responses, may be the primary event causing hyperinsulinemia and start very early in patients with high blood pressure. In turn, hyperinsulinemia further contributes to vascular damage and aggravates the metabolic and hypertensive disease.

Distinct and combined vascular effects of ACE blockade and HMG-CoA reductase inhibition in hypertensive subjects.

Hypercholesterolemia and hypertension are frequently associated with elevated sympathetic activity. Both are independent cardiovascular risk factors and both affect endothelium-mediated vasodilation. To identify the effects of cholesterol-lowering and antihypertensive treatments on vascular reactivity and vasodilative capacity, we studied 30 hypercholesterolemic hypertensive subjects. They received placebo for 4 weeks, either enalapril or simvastatin for 14 weeks, and, finally, both medications for an additional 14 weeks. Postischemic forearm blood flow (MFBF) and minimal vascular resistance (mFVR) were used as indices of vasodilative capacity and structural vascular damage, respectively. Total (resting-stress-recovery phases) cardiovascular (blood pressure [BP] and heart rate [HR]) and regional hemodynamic (FBF and FVR) reactivity to stressful stimuli were calculated as area-under-the-curve (auc) (valuextime). Compared with baseline levels, simvastatin reduced total (TOT-C) and LDL cholesterol (LDL-C) (1.27 mmol/L, P<0.001 and 1.33 mmol/L, P<0.001, respectively). Enalapril also reduced TOT-C and LDL-C (0.6 mmol/L, P<0.001 and 0.58 mmol/L, P<0.05, respectively). MFBF was increased substantially by both treatments (P<0.001). Enalapril had a greater effect (-1.7 arbitrary units (AU), P<0.001) than simvastatin (-0.6 AU, P<0.05) on mFVR. During stress, FBF increased more with enalapril (4.4 FBFxminutes, P<0.001) than with simvastatin (1.8 FBFxminutes, P<0.01). Conversely, FVR stress response was reduced more with enalapril (9.1 FVRxminutes, P<0.001) than with simvastatin (2.9 FVRxminutes, P<0.01). During combination treatment, a significant (0.001>P<0.05) additive effect on hypercholesterolemia, structural vascular damage, BP, and FVR was shown. The findings suggest that angiotensin-converting enzyme (ACE) inhibition induces a larger reduction than HMG-CoA reductase blockade in vascular reactivity and structural damage in hypercholesterolemic hypertensive subjects.

Microvascular changes during laboratory stimuli and structural haemodynamic indices: the role of pulse pressure.

Office and ambulatory pulse pressure have been recognized as independent predictors of cardiovascular mortality and atherosclerosis in hypertensives as well as in normotensives. On the other hand, the vascular reactivity, in subjects with high pulsatile component of blood pressure, has not been studied yet. The purpose of our study was to identify the regional muscular hemodynamics and the cutaneous microvascular changes during laboratory stimuli in young adult very mild hypertensives with high pulse pressure. The cardiovascular (Finapres), the forearm vascular (plethysmography) and the microvascular cutaneous (laser-Doppler flowmetry and transcutaneous oximetry) responses to psychophysiological stimuli were measured. In addition, the hyperemic forearm vascular response to the ischaemic test was measured as haemodynamic index of vascular damage. We studied 15 very mild hypertensives with higher office pulse pressure and 15 patients with similar age, history of hypertension, metabolic parameters and systodiastolic blood pressure but lower pulse pressure values. Patients with high pulse pressure demonstrated reduced hyperemic response and increased residual vascular resistance at the forearm ischaemic test. They did not vary for all the parameters, except pulse pressure, during the baseline period but the total stress response, as residualized area-under-the-curve, was notably different. Patients with higher office pulse pressure demonstrated a significant increased heart rate, systolic and pulsatile blood pressure reactivity. On the contrary, they showed a reduced forearm and cutaneous blood flow response combined to a reduced transcutaneous tissutal oxygenation. The findings suggest that the increased pulsatile component of blood pressure might be associated to structural and functional vascular impairments since the very early stages of hypertension in young adults without metabolic disorders.

The synergistic effect of simultaneous addition of retinoic acid and vitamin D3 on the in-vitro differentiation of human promyelocytic leukemia cell lines could be efficiently transposed in vivo.

Both human cell lines HL-60 and AML-193 exhibit a myeloblastic and promyelocytic morphology, respectively, but may be regarded as bipotent leukemic precursors. They can be triggered to differentiate to either granulocytes or monocytes upon retinoic acid (RA) or 1,25-dihydroxyvitamin D (D3) addition, respectively. We have investigated the effect of combined addition of these chemical inducers on the in-vitro differentiation of both cell lines. RA and D3 added together exert synergistic effects on the in-vitro maturation of these myeloid cell lines. Interestingly, the additive effects were lost if the cells were incubated with the inducers added at sequential times. The synergistic effect could be transposed in vivo and could be clinically significant in the treatment of the promyelocytic leukemia. This clinical strategy may help to prevent retinoic acid resistance or to overcome it in patients relapsed after RA therapy and usually unresponsive to a reinduction therapy with RA alone.

Erythrocyte uroporphyrinogen decarboxylase activity: diagnostic value and relationship with clinical features in hereditary porphyria cutanea tarda.

A marked discrepancy between mild and late clinical features and a nearly complete absence of erythrocyte uroporphyrinogen decarboxylase activity (Ery-UROD activity) was observed in a case of inherited porphyria cutanea tarda. The entity and time of appearance of clinical features, the onset of clinical symptoms after exposure to contributing factors, the effectiveness of phlebotomies and heterozygosity of the mother alone for uroporphyrinogen decarboxylase (UROD) deficiency were typical for familial porphyria cutanea tarda (F-PCT), whereas the extremely low UROD activity was peculiar to hepatoerythropoietic porphyria (HEP). These observations indicate that: 1) Ery-UROD activity may not always be useful to discriminate between F-PCT and HEP; 2) Ery-UROD activity does not always correlate with clinical symptoms; 3) in inherited UROD deficiency, the genetic defect may be heterogeneous. Finally, the observed discrepancy may provide additional evidence for the existence of tissue-specific isozymes.