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.

Antihypertensive treatment with verapamil and amlodipine. Their effect on the functional autonomic and cardiovascular stress responses.

Many biological and psychological factors induce haemodynamic and extra-cardiovascular functional changes mediated by the autonomic nervous system. Pharmacological blood pressure reduction, as a neurovegetative stimulus, can change the arousal of the sympathetic nervous system. We evaluated the effects of two calcium channel blockers, verapamil and amlodipine, both administered as monotherapies, upon the sympathetic stress response in 23 randomized mild-to-moderate essential hypertensives (161 +/- 2/98 +/- 1 mmHg). Patients performed four stress tests (mental arithmetic, colour word Stroop, cold pressor and handgrip) while extracardiovascular and haemodynamic functions were assessed non-invasively at every heart beat, during baseline, stress and recovery phases. The sympathetic response was evaluated by computing the 'area-under-the-curve' (value x time) measured during the psychophysiological session. The session was repeated at run-in, after placebo and during treatment. After one month's treatment, baseline blood pressure was significantly reduced in patients treated with amlodipine (139 +/- 1/84 +/- 1 mmHg; P < 0.001) and verapamil (140 +/- 2/85 +/- 1 mmHg; P < 0.001). The emotional arousal (frontalis muscular contraction, skin conductance) was unchanged, but the cutaneous vascular response was reduced (P < 0.05) in patients treated with verapamil. No changes in systolic or diastolic blood pressure were detectable, but amlodipine increased the heart rate response (P < 0.05). In contrast, verapamil reduced the heart rate (P < 0.05) without depressing the cardiac output response, which was increased with amlodipine (P < 0.05). Total vascular resistance was significantly (P < 0.001) reduced with both the treatments. Consequently, functional cardiac load, expressed by pressure-rate product and cardiac power, was significantly enhanced with amlodipine and reduced with verapamil. In conclusion, the abnormal sympathetic stress response, which characterizes the hypertensive patient, might be affected by the choice of medication. Verapamil in particular, moderated emotional arousal, the vasoconstrictive response and reduced cardiac load without lowering cardiac output demands. In contrast, in patients treated with amlodipine, in whom the cardiac output response was increased, the pattern was reversed and the functional cardiac load was also increased.

Stress reactivity in responder and non-responder hypertensives treated with verapamil and enalapril.

Hypertension was found to be associated with sympathetic overdrive but it is still debated if the antihypertensive agents can differently affect the stress response in hypertensive subjects. Through a psychophysiological study, we evaluated the effect of verapamil (V) and enalapril (E), both as monotherapy and association. Office BP was successfully reduced (< 145/90 mmHg) in 11 patients treated with V (V-Resp) and in 10 patients treated with E (E-Resp). Both the drugs were prescribed in 9 patients (V+E) who did not sufficiently lower their blood pressure (N-Resp) with monotherapy. Patients performed three stressors (color word stroop, cold pressor and handgrip). Extracardiovascular and hemodynamic functions were measured during baseline, stress and recovery periods. The response was evaluated adding the changes occurred in every phase of the psychophysiological session. This was performed before run-in and after any modification of the therapeutic intervention. The emotional arousal (phrontalis muscular contraction, skin conductance, peripheral temperature) was reduced when BP was normal. No change in BP reactivity was found. HR response decreased in V-Resp and cardiac output increased in E-Resp while the vascular reaction was restrained in E-Resp and V-Resp. This was reduced also in N-Resp when they assumed V+E and normalized their arterial pressure. The findings indicate that the sympathetic reactivity may be modified by the therapy. In particular, verapamil restrained the cardiac stress response without lowering the cardiac output and was advantageously associated with enalapril to control the psychophysiological response in more resistant hypertensive patients.

Diabetes modifies cardiovascular reactivity during hypertension.

Hypertension and diabetes often occur in the same patient, and this observation inspired the search for a new common pathogenetic hypothesis. The onset of diabetes during hypertension also could modify cardiovascular autonomic arousal. To identify a peculiar hemodynamic and psychophysiologic reactivity, a male population of mild essential hypertensive (166 +/- 6/102 +/- 8 mm Hg) patients (EH) and non-insulin-dependent hypertensive (169 +/- 10/101 +/- 7 mm Hg) diabetic subjects (HD) underwent a session of stress tests. Four tests, Mental Arithmetic, Incomplete Phrases, Cold Pressor, and Handgrip, were preceded and followed by a 10-minute recovery period. Functional tests were performed to identify any possible cardiac autonomic neuropathy. During the entire session, by means of a beat-to-beat noninvasive computerized device, hemodynamic and extracardiovascular functions were measured. The findings suggested the presence of a sympathetic hyperactivity in both HD and EH. In particular, HD showed a peculiar "tropism" for the peripheral vasculature. In these patients, in fact, total vascular resistance and peripheral temperature responses were 89.2% and -64.2%, respectively, versus 33.7% and -50.6%, which were found in EH. On the other hand, the ejection ventricular index was more depressed in HD (-27.9%) than in EH (-23.8%), although they did not seem to be affected by cardiac autonomic damage. The different profiles appear to confirm the increase of functional vascular damage in diabetic hypertensive patients, probably because of the insulin resistance or obsolete muscular cardiac damage.

Lipids and cardiovascular reactivity changes in hypertensive cigarette smokers: enalapril versus nifedipine treatment effects.

Cigarette smoking has many effects on the cardiovascular system, psyche, and serum lipids, which can create a vicious circle that is pejorative to the well-being of hypertensive patients, even if they are under pharmacologic treatment. To investigate the effect of two different antihypertensive agents, nifedipine and enalapril, on cardiovascular reactivity and lipoprotein patterns in cigarette smokers with hypertension, 92 essential hypertensive (175 +/- 11/103 +/- 8 mm Hg) subjects were studied, who had no sign of lipidosis, and subdivided into four groups in order of smoking habit and therapy. Over a 30-month follow-up period, the percentage changes in blood pressure (BP), heart rate (HR), triglycerides, total cholesterol, high density lipoprotein (HDL) and low density lipoprotein (LDL) cholesterol were evaluated while the patients underwent a session of psychophysiologic tests to assess sympathetic reactivity. The response was calculated through the difference in cumulative percentage changes (DC%) in systolic blood pressure (SBP), diastolic blood pressure (DBP), HR, muscular contraction (EMG), skin conductance (SCL), and peripheral temperature (TP). The office BP was reduced significantly in all groups. In the nonsmokers, enalapril reduced (p < 0.05) the SCL-, TP-, SBP-, and DBP-DC% reactivity, lowered (p < 0.05) TR, C-tot, and LDL, and increased (p < 0.05) the HDL. However, nifedipine magnified the sympathetic responses and the atherosclerotic lipoproteins and decreased (p < 0.05) the HDL.(ABSTRACT TRUNCATED AT 250 WORDS)

Stress response and antihypertensive treatment.

Results from many studies suggest that the central nervous system may play an important role in enhancing and maintaining sympathetic, metabolic and haemodynamic effects in patients with hypertension. Likewise, emotional and mental stresses may provoke phasic and sustained adrenergic responses in normotensive and untreated hypertensive patients. Because the various antihypertensive medications have different mechanisms of action, and elicit different neurovegetative responses, it is useful to distinguish between the effects of different treatments on sympathetic activity. To identify the effect of stress on sympathetic reactivity, we evaluated the extracardiovascular and haemodynamic responses to various stressor agents using noninvasive techniques. This psychophysiological approach allowed us to standardise stress, to identify individual cardioneurovegetative responses both before and during treatment, and to establish the effects of various treatments on the cardioneurovegetative response. The extracardiovascular psychophysiological response of patients with a family history of hypertension and of normotensive patients who later became hypertensive was characterised by an inability to recover after mental challenge. Therefore, prolonged sympathetic activity resulting from mental stimulation may contribute to the development of hypertension. Antihypertensive medications affected sympathetic reactivity differently. For example, nifedipine worsened sympathetic reactivity, while verapamil was able to correct abnormal neuroadrenergic responses. Furthermore, verapamil was successfully combined with enalapril in patients whose hypertension was resistant to monotherapy with the angiotensin converting enzyme (ACE) inhibitor. Therefore, the functional and structural consequences of sympathetic stimulation resulting from daily activation and pharmacological blood pressure adjustments are important in hypertensive patients, because they may have abnormal sympathetic reactivity to various stimuli.

Borderline hypertension: relationship between job and psychophysiological profile.

To identify relationships among hypertension, job and cardiovascular reactivity we studied 81 borderline hypertensives divided into labourers (L), white collars (W) and managers (M). After behavioral analysis, they underwent 4 tests: arithmetic, Sacks, acoustic, electric. Along the entire sitting, muscular contraction, skin conductance (SCL), peripheric temperature (THP), SBP, DBP and HR were taken, every 30". Depression, obsessive-compulsive, anxiety and neurotic traits were found in W. SBP, DBP and HR were not significantly different. Failed recovery curves of SCL were identified in M and W, but the presence of abnormal response profile, of both, SCL and THP, only in W. This autonomic dysreactivity, previously recognized as a possible characteristic of the prehypertensive condition, could uncover the role of certain work stressful condition to increase the sympathetic drive underlying hypertension.

[Left ventricular hypertrophy: physiopathological signs using a hemodynamic and cardio-autonomic approach]. / Ipertrofia ventricolare sinistra: indicazioni fisiopatologiche mediante approccio emodinamico e cardioneurovegetativo.

The presence of left ventricular hypertrophy (LVH) in either hypertensives -H- or in normotensives -N-, suggests that not only blood pressure is determining this anatomic change, but various factors, as neural or endocrine ones, could be involved in its genesis. In order to evaluate the role of sympathetic dys-reactivity on LVH, we studied three groups of subjects: a) 12 -H- (SBP 159+/-9; DBP 99.6+/-7; FC 80+/-7) with LVH, diagnosed by echocardiogram. b) 12 -N- (SBP 138.2+/-8; DBP 83+/-2; FC 75.6+/-4) with LVH. c) 12 -N- (SBP 136.6+/-11; DBP 81.8+/-5; FC 76.3+/-5) without LVH. Using computer interfaced equipment, we measured beat to beat, hemodynamic and extra-cardiovascular autonomic functions, during a session of stressors (Mental Arithmetic, Color Word Stroop, Cold Pressure and Handgrip Tests), preceded and followed by 10' of observation. Among the various considered indexes, we evaluated the Percentual Total Activity Index (PTAI), as percentual total activity change + percentual total recovery change. Our findings point out that the PTAI of N with LVH is significantly higher for SCL, PHT, HR, SV, CO, TPR than either in H with LVH or N without LVH. These data seem to demonstrate a prolonged reactivity in N without LVH and are according to the hypothesis that LVH could also be supported by a hyper-adrenergic state with sympathetic dys-reactivity, independently from high blood pressure values.

[Hemodynamic and psychophysiologic evaluation in hypertensive diabetic patients]. / Valutazione emodinamica e psicofisiologica in pazienti ipertesi-diabetici.

In order to evaluate a peculiar hemodynamic and psychophysiological reactivity in hypertensive-diabetics, a male population of mild essential hypertensives and mild NID hypertensive-diabetics underwent a session of tests:Arithmetic, Sacks', Cold Pressor, Hand-grip, preceded and followed by a 10' recovery period, Valsalva Manoeuver, Beat to beat, Tilt table. Along the entire session, by means of a beat to beat, non invasive computerized system, we measured some pressure, hemodynamic, and extra-cardiovascular variables. The obtained findings seem to suggest a sympathetic hyperreactivity both in HD and in H. In HD it has a particular "tropism" for peripheral vascular bed, as showed by vascular resistances and peripheral temperature responsivity; on the other hand the cardiac contractility index is more depressed than in H, suggesting that in HD, cardiac and pressor responses might be influenced by some mechanisms whose nature seem related to neither functional damage nor hemodynamic adjustments. The different profiles of the two populations seem to confirm the utility of this kind of hemodynamic, non invasive evaluation in all the pathologies where Autonomic Nervous System is involved, in order to obtain a better diagnosis approach and therapeutic treatment.

[Psychophysiologic markers of arterial hypertension]. / Markers psicofisiologici di ipertensione arteriosa.

Many studies, concerning cardiovascular reactivity in hypertensives, show contrasting data. The aim of the present study was to check, also measuring extracardiovascular variables, a procedure able to identify a peculiar characteristic of the prehypertensive phase. We studied 47 normotensives, who referred high blood pressure values, but that we did not find in our visit. The cardioneurovascular assessment was evaluated, by means of a non invasive, beat to beat technique, measuring SBP, DBP, HR, muscular contraction and skin conductance level (EMG, SCL), peripheric temperature (PT), during a psychophysiologic session. This was composed by 4 stressors (mental arithmetic and Sacks test, acoustic and electric stimulations), 5 minutes each, preceded and followed by an observation period of 10 minutes. After 18 month follow-up, we could distinguish 26 hypertensives (H), and 21 subjects maintained normal blood pressure values (N). The obtained findings showed, with statistical significance, 1) the hyperresponsiveness of SCL and PT; 2) the failed recovery, with consequent hyperdysreactivity, of SCL and PT; 3) the presence of both these phenomena in the H., while SBP, DBP and HR responses did not result a discriminative tool. These data seem 1) to reinforce the hypothesis that a hypersympathetic phase can characterize the prehypertensive stages of essential hypertension and 2) to suggest the psychophysiological approach as a useful method to diagnose prehypertension.

Efficacy of biofeedback treatment compared with drug therapy in hypertensive patients.

To assess the ability of biofeedback (BFB) in controlling hypertension a study was made of 40 hypertensive patients selected by means of the cardiovascular response to an arithmetic test. The patients were divided into four treatment groups: 10 patients were treated with diuretic therapy (D-T), 10 with beta-blocker therapy (Bb-T), 10 with BFB treatment, while 10 had no treatment at all (N-T). The BFB treatment consisted of 36 sittings where patients were requested to control muscular contraction, peripheric temperature and heart rate (HR) by means of a correlated acoustic signal. The results for blood pressure and HR reductions were compared during a 12-month follow-up period. The results for systolic blood pressure, diastolic blood pressure and HR indicate the efficacy of BFB for selected patients and suggest the possibility of using BFB treatment in the first stages of suspected neurogenic hypertension.