Cinzia Simoni

Hypertension-related hypoalgesia, autonomic function and spontaneous baroreflex sensitivity

OBJECTIVE The mechanisms involved in the relationship between pain perception and hypertension are poorly understood. This study has sought to investigate whether the spontaneous baroreflex sensitivity and the autonomic nervous system balance are related to hypertension-associated hypoalgesia. METHODS In the morning, 73 untreated male subjects (45 hypertensives, 28 normotensives) were submitted to a simultaneous recording of electrocardiographic and blood pressure signals in resting condition. The tracings were analysed off-line to evaluate the spectral components of the low frequency (LF) and high frequency (HF) powers (autoregressive algorithm; LF/HF ratio used in subsequent analysis as an index of sympathovagal balance), and the alphaLF (alphaLF), an index of baroreflex sensitivity. After the rest period, the subjects underwent dental pain perception evaluation (pulpar tester: test current increasing from 0 to 0.03 mA, expressed in relative Units) to determine the dental pain threshold and tolerance. Afterwards, a 24-h ambulatory blood pressure monitoring was performed. RESULTS A significant relationship was observed between alphaLF and pain threshold (r = -0.34; p = 0.003). When a multivariate analysis was computed to control for age, 24-h systolic pressure and LF/HF ratio, alphaLF was a predictive independent factor associated with pain threshold (model p = 0.019; r = -0.31; p = 0.025). Moreover, the 24-h systolic pressure was independently associated with pain threshold (model p = 0.019; r = 0.30, p = 0.031). The relationship between alphaLF and relative tolerance was not statistically significant. When the association between the LF/HF ratio and pain sensitivity was assessed as a secondary endpoint, no significant relationship was observed. Since no significant interaction was found, the effect of alphaLF and LF/HF ratio on pain perception was assumed to be similar in normotensive and hypertensive subjects. CONCLUSIONS The relationship found between unstimulated baroreflex sensitivity and pain threshold suggests a modulation of pain perception by baroreflex pathways in hypertension-associated hypoalgesia. In a baseline condition, the autonomic nervous system balance does not seem to influence pain sensitivity.

Simvastatin treatment modifies polymorphonuclear leukocyte function in high-risk individuals: a longitudinal study.

Background Although extensive experimental evidence supports a primary role of polymorphonuclear leukocytes (PMNs) in atherosclerosis, few data exist concerning the functional properties of these cells and their pharmacological modulation in high-risk individuals. Objective The production of the proinflammatory chemokine interleukin-8 (IL-8), migration and chemotaxis, and reactive oxygen species (ROS) generation were investigated in a longitudinal study in PMNs obtained from high-risk individuals during statin treatment. As a secondary endpoint we compared PMN function of high-risk patients with that of controls. Methods and results PMNs were isolated from 21 high-risk individuals before treatment and 3 and 30 days after the beginning of simvastatin treatment, and from healthy controls. During treatment a significant reduction was observed both in resting (P = 0.009) and N-formyl-Met-Leu-Phe (fMLP)-stimulated (P = 0.008) IL-8 production, and in the chemotactic index (P = 0.038), whereas ROS generation did not significantly change. In comparison with cells from controls, PMNs obtained from patients before starting simvastatin treatment showed higher resting and fMLP-stimulated IL-8 release (P = 0.007 and P = 0.002, respectively) and ROS generation (resting, P = 0.009; and fMLP-stimulated, P = 0.046), whereas migration and the chemotactic index did not significantly differ. Conclusions An activation of neutrophils is present in high-risk individuals, shown by the enhanced production of IL-8, and increased ROS generation. The 4-week statin treatment is able to reduce the cell capability to produce IL-8, and to decrease chemotaxis, thus affecting the proinflammatory properties of PMNs.

Angiotensin II type 1 receptor expression in polymorphonuclear leukocytes from high-risk subjects: changes after treatment with simvastatin.

Statins may directly interfere with the effects of angiotensin (Ang) II, which is a key player in the pathogenesis of atherosclerosis (ATH). Ang II promotes a wide array of detrimental processes including a prominent proinflammatory effect, increasingly regarded as a target for therapeutic intervention. Because the proinflammatory effects of Ang II are exerted mainly through the activation of Ang II type 1 receptors (AT1Rs) the present study was devised to investigate by means of real-time polymerase chain reaction (PCR) and flow cytometry techniques the expression of such receptors on circulating polymorphonuclear leukocytes (PMNs) from subjects at high risk for vascular events before and during treatment with simvastatin and in sex- and age-matched healthy controls. In vitro experiments were also performed to assess the ability of simvastatin to interfere with Ang II signaling in human PMNs. In comparison to controls, high-risk subjects had similar AT1R expression on the cell membranes but significantly higher AT1R messenger ribonucleic acid (mRNA) levels. Treatment of high-risk subjects with simvastatin for 30 days resulted in a reduction of AT1R mRNA down to the levels of cells from healthy subjects. In vitro, Ang II-induced activation of the guanosine triphosphate (GTP)-binding protein Rac 1 in human PMNs was inhibited by simvastatin. In conclusion, simvastatin induces downregulation of AT1R expression, interferes with Ang II activity in PMNs, and contributes to the antiinflammatory profile of statins that can explain the therapeutic effects of these drugs.

Changes in pain perception during treatment with angiotensin converting enzyme-inhibitors and angiotensin II type 1 receptor blockade.

Objectives Besides the well-known role of the angiotensin system in blood pressure control, an interaction of angiotensin and pain perception has been suggested. This study sought to investigate whether an angiotensin converting enzyme inhibitor, which facilitates bradykinins, algesic peptides, and/or an AT1 receptor antagonist may modify hypertension-related hypoalgesia in humans. The study was approved by the ethical committee of our Department. Methods A total of 22 hypertensive patients were submitted to dental pulp stimulation to obtain the dental pain threshold and tolerance, and to 24 h blood pressure monitoring together with a control group of 55 normotensives. Then the hypertensives were randomized to enalapril or losartan treatment and were re-evaluated (dental pain perception and ambulatory monitoring) after 8 weeks of the first treatment and after an additional 8 weeks of the second treatment. Results Untreated hypertensives showed a reduced perception to painful stimuli when compared with normotensives. A significant reduction of both pain threshold and tolerance was observed during the anti-hypertensive treatments (Friedman test:P = 0.007 and P = 0.006, respectively). Pain sensitivity was similar during the two treatments and it did not differ from pain sensitivity values of normotensive controls. ANCOVAs were computed to evaluate the relationship between anti-hypertensive agents and pain sensitivity, after controlling for blood pressure. A 24 h mean pressure served as covariate, removing any effect of blood pressure; a significant difference was observed entering both pain threshold and tolerance as dependent variables (F = 5.28, P = 0.0076;F = 8.16, P = 0.0007, respectively). Conclusions Both the angiotensin converting enzyme inhibitor enalapril and the AT1 receptor blocking agent losartan acted similarly on pain threshold and tolerance, pain sensitivity being increased during the two anti-hypertensive treatments. The blood pressure reduction during drug assumption could not account for the pain sensitivity changes observed. The latter may be due to a specific pharmacodynamic mechanism mediated through angiotensin II AT1 receptors.

Thyroid hormone and thyrotropin regulate intracellular free calcium concentrations in human polymorphonuclear leukocytes: In vivo and in vitro studies

Intracellular free calcium concentrations (Ca++i) were studied in polymorphonuclear leukocytes (PMNs) from 13 athyreotic patients who had been previously treated by total thyroidectomy and radioiodine therapy for differentiated thyroid carcinoma, and from age- and sex-matched euthyroid healthy controls. Patients were studied twice, when hypothyroid (visit 1) and after restoration of euthyroidism by L-T4 TSH-suppressive therapy (visit 2). PMNs from patients at visit 1 had significantly lower resting (Ca++)i levels compared to both visit 2 and controls. Values at visit 2 did not differ from those of the controls. Stimulus-induced (Ca++)i rise was also significantly blunted at visit 1 and normalized at visit 2, possibly through a differential contribution of distinct intracellular Ca++ stores, as suggested by the response pattern to the chemotactic agent, N-formyl-Met-Leu-Phe (fMLP), to the selective SERCA pump inhibitor, thapsigargine, and to the mitochondrial uncoupler, carbonyl cyanide p-trifluoromethoxyphenyl-hydrazone (FCCP). In vitro treatment of PMNs from healthy subjects with high TSH concentrations impaired intracellular Ca++ store function. Both resting (Ca++)i levels and fMLP-induced (Ca++)i rise increased in the presence either of low-concentration TSH or of T4, but effects of TSH and T4 were not additive. T3, rT3, and TRIAC had no effect. In conclusion, this study provides evidence for a direct relationship between thyroid status and (Ca++)i homeostasis in human PMNs, mainly related to direct actions of TSH and T4 on these cells.

Global link between heart rate and blood pressure oscillations at rest and during mental arousal in normotensive and hypertensive subjects.

UNLABELLED Complex phenomena modulate the interplay between heart rate and blood pressure variability, in particular after adjustments induced by stimuli or in pathophysiological conditions. This study sought to investigate in 25 hypertensive and 16 normotensive male subjects whether relationships operating at rest may be preserved after a central nervous system arousal induced by a mental stress test. As a secondary endpoint, we evaluated the potential changes of the components of heart rate and blood pressure variability during stress. RESULTS A significant correlation was observed between components of RR and systolic blood pressure (SBP) variability (p<0.0001), after controlling for the subjects status (normotensive vs. hypertensive) and for stress-steps (baseline condition, during stress test and recovery). Moreover, the multiple regression model accounted for the potential effects of the baseline alpha(LF) value and for the baseline heart rate and systolic blood pressure. The relationship operating between the LF/HF(RR) ratio and LF/HF(SBP) ratio was not different either at the different steps of stress test (interaction: p=0.87) or in the two groups of normotensive and hypertensive subjects (interaction: p=0.76). The variables of RR and SBP variabilities were modified during stress and recovery. In particular, the LF/HF(RR) ratio and LF/HF(SBP) ratio increased during stress and decreased during recovery. CONCLUSIONS The association between heart rate and blood pressure oscillations was preserved during central nervous system arousal by mental stress both in normotensives and hypertensives. A central integration may account for this constant relationship, the correlation being independent from baseline heart rate, blood pressure and baroreflex sensitivity.

Changes in plasma lipids during renin-angiotensin system blockade by combination therapy (enalapril plus valsartan) in patients with diabetes and hypertension.

There is experimental evidence of an interaction between the angiotensin system and lipid metabolism. The aim of this study was to evaluate whether a block of the angiotensin system achieved both by ACE inhibition and angiotensin II-AT1 receptor blockade could affect the plasma lipid profile and, if so, what relationship exists between these possible changes and glucose metabolism and blood pressure. In 50 patients with type 2 diabetes and hypertension, treated with diabetes drugs and enalapril, we evaluated the glycemic and lipid profile together with the HOMA insulin-resistance index, blood pressure and microalbuminuria at baseline and 3 months after the addition of valsartan. At the second evaluation, blood pressure was reduced as expected, whereas the glycemic profile, the HOMA index, and the body mass index were unchanged. Total cholesterol, LDL-c, and apoprotein B were reduced during combination therapy (P = 0.003, P = 0.001, and P = 0.004, respectively), plasma HDL-c was slightly though significantly increased (P = 0.024), whereas apoprotein A and triglyceride levels did not change. After adjustment for the insulin resistance index and for blood pressure, the reduction of LDL-c and apoprotein B and the increase in HDL-c remained significant. The variation in lipid profile was not related to the changes in blood pressure. Moreover, the addition of valsartan to enalapril was associated with a reduction in microalbuminuria, which remained significant after adjustment for LDL-c or blood pressure changes. Thus, the greater degree of renin-angiotensin system blockade or specific pharmacodynamic effects of valsartan could account for the changes in plasma lipid profile observed in this study.

Circadian blood pressure variability is associated with autonomic and baroreflex-mediated modulation of the sinoatrial node.

Objective — The day-night variability of blood pressure (BP) is of interest in the analysis of ambulatory blood pressure monitoring (ABPM). The aim of this study was to investigate whether the nocturnal BP reduction was associated with the autonomic and baroreflex-mediated modulation of the sinoatrial node in normotensive and hypertensive subjects. Methods and results — 63 consecutive untreated male subjects (40 hypertensive and 23 normotensive) were studied. Spectral parameters of RR interval variability and the alphaLF index (a measure of baroreflex gain) were calculated at rest.Then all the subjects performed a 24-h ABPM. Results — As regards the relationships involving 24-h BP and resting heart rate (HR) and HR variability parameters, a significant correlation was found between mean RR and both systolic and diastolic nocturnal BP falls (r = 0.40, p < 0.001, r = 0.32, p < 0.01, respectively); moreover, a significant correlation was found between the nocturnal fall of systolic BP and both the LF/HF ratio and absolute power of HF (r = –0.25, p < 0.05 and r = 0.29, p < 0.05, respectively). The alphaLF index was significantly associated with the nocturnal diastolic BP fall (r = 0.26, p < 0.05) whereas the association with the systolic fall did not reach statistical significance (r = 0.23, p = 0.07). Conclusions — The relationship found between the nocturnal reduction of BP and both the LF/HF ratio and HF power of RR variability suggests that factors influencing the sympatho-vagal modulation to the heart are associated with the day-night variability of blood pressure. Moreover, the relationship between BP fall and the spontaneous baroreflex sensitivity index alphaLF, may indicate a role of the baroreflex-mediated arc function in the BP adjustments occurring during the night.

Autonomic function and baroreflex sensitivity during angiotensin-converting enzyme inhibition or angiotensin II AT-1 receptor blockade in essential hypertensive patients.

Objective — The influence of ACE-inhibition and angiotensin II AT1 receptor blockade on the autonomic function and baroreflex sensitivity was investigated in hypertension. Methods and results — Heart rate variability was assessed in a resting condition by power spectrum analysis to evaluate the low frequency (LF) power, high frequency (HF) power and LF/HF ratio in 19 hypertensive patients and 23 normotensive controls. Moreover, the coherence between the tachogram and the systogram was evaluated, and the baroreflex gain (αLF -index), describing the transfer function of variability in the systolic pressure signal to variability in the RR interval, was obtained. Then a 24-h ambulatory blood pressure monitoring was performed.The 19 hypertensive patients were randomized to either enalapril or losartan treatment, and after 2 months were resubmitted to the RR variability and baroreflex study and to blood pressure monitoring.The subjects then crossed to the other antihypertensive treatment and were re-evaluated after an additional two months. No significant difference was found either in LF power and HF power and LF/HF ratio between normotensive and hypertensive subjects whereas a slight though significant difference was observed in the αLF -index. In hypertensive patients, both the treatments with enalapril and losartan reduced blood pressure and had no effect on heart rate. No significant change was observed in autonomic balance or in baroreflex sensitivity during the two antihypertensive treatments. Conclusions — In hypertensive patients, the angiotensin system or bradykinins do not seem to have any modulatory effect on the sympathetic/parasympathetic control of blood pressure and baroreflex sensitivity, in a resting condition. Since heart rates were unchanged by the two antihypertensive treatments despite a significant reduction of blood pressure, a resetting of baroreflex function was observed during both ACE-inhibition and angiotensin II AT1 receptor blockade.

Changes in autonomic modulation to the heart and intracellular catecholamines. A longitudinal study in differentiated thyroid carcinoma during short-term hypothyroidism and thyroid hormone replacement.

Background: The effects of thyroid deprivation on the autonomic modulation to the heart remain controversial. Methods: In this study in patients followed for thyroid carcinoma, we investigated (1) heart rate variability parameters and the baroreflex gain and (2) intracellular catecholamine levels in circulating lymphocytes during short-term hypothyroidism (phase 1) and after reinstitution of TSH-suppressive thyroid hormone replacement (phase 2). Results: The RR interval value (p < 0.01) and systolic blood pressure (p < 0.05) were higher in phase 1 than in phase 2. The low-frequency/high-frequency (LF/HF) ratio was significantly lower in the hypothyroid state (p < 0.05), with a higher HF component (p < 0.05). After adjusting for mean RR interval in the regression model, the difference between the power of RR interval oscillations calculated in the two states was greater for the LF band (p = 0.005) and it was borderline significant for the HF band (p = 0.052). The baroreflex gain αLF index was similar in the two phases. The stimulus-induced cellular production of norepinephrine and epinephrine in peripheral blood mononuclear cells was significantly higher in phase 2. Conclusion: The neurally-mediated influences on the sinus node and the study of intracellular catecholamine production suggest a reduced sympathoexcitation in hypothyroidism compared with the treatment phase. The early increase in blood pressure observed after thyroid hormone withdrawal is not due to impaired sensitivity of the baroreflex arc.