Increase In Peripheral Resistance Research Articles

Bedeutung des L-Arginin/NO-Systems für die Wirkung von Nebivolol

Beta-blockers exert their effects through blockade of beta-adrenoceptors. First-generation beta-blockers non-selectively block beta1- and beta2-adrenoceptors, while second-generation beta-blockers predominantly block beta1-adrenoceptors. Third-generation beta-blockers possess additional vasodilator properties. Nebivolol is a highly selective b1-blocker with additional vasodilator effects which are mediated by the endothelial L-arginine/nitric oxide system. The hemodynamic action of nebivolol differs from those of first and second-generation beta-blockers: it acutely decreases peripheral resistance (while first and second-generation beta-blockers cause an initial transient increase in peripheral resistance) and decreases in heart rate that are less pronounced than those evoked by first and second-generation beta-blockers. Beta-blockers are frequently used in the treatment of hypertension, coronary artery disease and chronic heart failure. Nebivolol should thus be a suitable drug for treating these diseases, especially since nitric oxide has vasodilator and anti-atherogenic effects. One long-term trial (the SENIORS study) has shown that nebivolol, compared with a placebo, reduced death and hospital admission in elderly patients with chronic heart failure. Additional studies are needed to investigate the clinical relevance of nitric oxide-mediated vasodilatation and to show if nebivolol is as efficacious as the other beta-blockers--metoprolol, bisoprolol and carvedilol--in the treatment of chronic heart failure.

The utility of the forced oscillation technique in assessing bronchodilator responsiveness in patients with asthma

To address the utility of the forced oscillation technique (FOT) in assessing bronchodilator responsiveness compared with forced expiratory volume in 1s (FEV(1)). This is a retrospective analysis of consecutive 126 patients with a clinical history of asthma without any other lung diseases at a pulmonary function testing laboratory. The following measurements were obtained three times each, before and after two doses of pirbuterol 0.2mg inhalation: the respiratory resistance at 5Hz (Rrs5), the mean respiratory resistance between 5 and 20Hz (Rrs5-20), and the mean respiratory conductance (Grs5-20) by FOT and the FEV(1) by spirometer. These measurements were transformed into dimensionless subject-specific effect-size "d-scores" by dividing them by the estimated pooled within-subject standard deviation. Descriptive statistics for each value were the following [mean baseline value (+/-sd), Delta value (pre- minus post value), and d-score (P value compared to FEV(1))]: Grs5-20 (Ls(-1)kPa(-1)) [1.79+/-0.53, Delta=+0.39, d=2.64 (P<0.001)], Rrs5-20 (kPaL(-1)s) [0.60+/-0.16L, Delta=-0.10, d=2.56 (P=0.001)], Rrs5 (kPaL(-1)s) [0.78+/-0.25, Delta=-0.16, d=2.52 (P<0.001)], and FEV(1) (L) [1.90+/-0.64, Delta=-0.20, d=1.83]. The higher d-score of Grs5-20, Rrs5-20 and Rrs5 compared to FEV(1) indicates that these are better indicators for bronchodilator response than FEV(1). The percentages of subjects exhibiting change in the expected direction after bronchodilator were not significantly different between each value: Rrs5 (85.7%), Rrs5-20 (83.3%), Grs5-20 (83.3%), and FEV(1) (83.3%) [P>0.05]. Several forced oscillation measures, namely Grs5-20, Rrs5-20 and Rrs5, are more accurate and sensitive for detecting bronchodilator response than FEV(1) in patients with asthma.

Flow-Dependent Remodeling of Small Arteries

See related article, pages 86–92 From the embryonic state to the end of life, the elements of the circulatory system are exposed to hemodynamic forces associated with the circulation of blood. Various levels of intraluminal (transmural) pressure and wall shear stress represent the natural environment for the tissues of the vascular wall. Physiological or pathological changes in the level of these forces elicit active responses in the cellular and noncellular elements of the vascular wall. In the short-term, vessels may change their functional diameter, whereas, if the hemodynamic forces are altered chronically, this results in morphological changes of the wall, indicated by changes in vessel diameter and wall thickness, frequently termed remodeling, aimed at minimizing the effect of altered hemodynamic forces on the vascular wall. A change in intraluminal pressure was the first to be recognized widely as a potential stimulus for functional or morphological changes in vessel diameter.1–3 Indeed, vascular remodeling was recognized as an important factor in the stable increase in peripheral resistance in hypertension, a disease in which the intraluminal pressure is elevated.1–4 There are ample original publications and reviews on this subject.1–4 The present editorial focuses on the remodeling of vessels that are initiated by a change in blood flow. ### Early Findings on the Effects of Chronic Alterations of Blood Flow In 1893, Thoma summarized, with great insight, his own and other investigators’ ideas describing the relationship between blood flow and vascular dimensions. He posited that growth of the “cross-diameter” of vessels was dependent on the velocity of blood flow. Recklinghausen (1883) and Nothnagel (1889) drew similar conclusions, namely, that it is not an increase in pressure, but rather an increase in flow velocity, which brings about the development of widened or new collateral blood vessels. Later Kamiya and Togawa demonstrated in carotid arteries that flow/wall shear stress elicits remodeling,5 whereas in …

Defect baroreceptor function in females prone to vaso‐vagal reactions

Objective There seems to be increased ortostatic susceptibility in females when compared to males. The mechanism behind this gender difference is unclear. The present study was designed to compare vagal females (VF) with non vagal females (NF) during hypovolemic circulatory stress. Design ands Methods: Lower body negative pressure (LBNP) up to 60 H2O was used on healthy females (22.8±0, 4 years, n=17), to create graded hypovolemic circulatory stress. Venous compliance, capacitance in the leg and arm as well as forearm blood flow (FBF) were measured with volumetric technique. Blood pressure and heart rate was monitored. Five females developed vagal reactions and were compared with the other twelve. Results The VF had lower resting pulse pressure. There were no significant differences in venous capacitance, venous compliance or net capillary filtration in the calf during LBNP. Pulse pressure decreased more in VF during higher LBNP levels, p<0.01. Despite this, the increase in peripheral resistance was attenuated in VF, p<0.05. The compensatory arm capacitance response to LBNP was decreased in VF, p<0.05. Conclusions The hypovolemic stress seemed to be of similar magnitude in both non-vagal and vagal females. However, pulse pressure during hypovolemic stress was more markedly reduced in the VF. Despite the increased baroreceptor stimulus, they responded with less increase in peripheral resistance and mobilised less blood from the peripheral circulation during the hypovolemic stimulus. This suggests a less effective baroreceptor activation-sympathetic discharge-effector response in vagal females.

Doxazosin Gastrointestinal Therapeutic System: A Clinical Perspective

Doxazosin Gastrointestinal Therapeutic System: A Clinical Perspective

The thermoregulatory-vascular remodeling hypothesis: An explanation for essential hypertension

The supposition that temperature homeostasis has precedence over blood pressure homeostasis, that vascular remodeling ensues, that hypertension is the consequence and that sodium chloride ingestion sets the sequence in motion, constitutes the thermoregulatory-vascular remodeling hypothesis. Because the cardiovascular system plays a role in both temperature and blood pressure regulation, the ingestion of sodium chloride creates conflict between temperature homeostasis and blood pressure homeostasis. Vasodilatation would lower the blood pressure following the ingestion of sodium chloride, but increased blood flow to the cutaneous circulation would increase heat loss and decrease core body temperature. Regional vasodilatation that does not involve the cutaneous circulation could lower the blood pressure without lowering the core temperature, but if temperature homeostasis has precedence over blood pressure homeostasis, and if regional vasodilatation incompletely restores blood pressure homeostasis, then elevations in blood pressure may persist following the ingestion of sodium chloride. The kidneys gradually excrete the excess sodium chloride, thereby normalizing the blood pressure, but prolonged elevations in blood pressure lead to vascular remodeling, sustained increases in peripheral resistance, and a higher baseline blood pressure. Following countless sodium chloride ingestions, essential hypertension develops. The thermoregulatory-vascular remodeling hypothesis predicts that antihypertensive medications that are vasodilators will accelerate heat loss due to increased blood flow to the cutaneous circulation. As a result, either core body temperature will decrease or there will be a compensatory increase in the metabolic rate. This prediction could be tested experimentally. The main clinical implication of the thermoregulatory-vascular remodeling hypothesis is that avoiding the ingestion of sodium chloride is the key to preventing essential hypertension.

Oral treatment and in vitro incubation with fructose modify vascular prostanoid production in the rat

1.-- In the rat, a fructose-enriched diet induces hyperglycaemia, hypertriglyceridaemia, insulin resistance and hypertension; a model which resembles the human metabolic syndrome. 2.-- Prostanoids, metabolites of arachidonic acid, include vasoactive substances synthesized and released from the vascular wall that have been implicated in the increase of peripheral resistance, one of the mechanisms involved in the fructose-induced hypertension. 3.-- The aim of the present study was to: (i) analyse the effects of the in vitro incubation with fructose on the production and release of prostanoids in rat thoracic aorta and in rat mesenteric bed and (ii) compare the effects of incubation with those of the in vivo acute and chronic treatment of rats with fructose and with the combination of both in vivo and in vitro procedures. 4.-- Blood pressure, glycaemia and triglyceridaemia were significantly elevated in both 4- and 22-week fructose-treated groups. Meanwhile, body and heart weight as well as insulinaemia were similar between experimental animals and controls. 5.-- In aortae, 4 weeks of Fructose treatment did not modify the prostanoid pattern release, but in vitro incubation decreased prostacyclin (PGI(2)) production. However, after 22 weeks, fructose treatment and incubation exerted the same effect. 6.-- In mesenteric bed, after 4 weeks, the incubation and the combination of both procedures reduced the release of the vasodilators PGI(2) and PGE(2), while fructose treatment only diminished the PGE(2) release. On the contrary, the production of the vasoconstrictor thromboxane A(2) (TXA(2)) was enhanced by incubation and both the procedures. After 22 weeks, fructose treatment increased PGI(2) release, while it was reduced by incubation. The combination of both did not modify this peripheral resistance when compared with controls. Finally, incubation of tissues from treated rats increased the release of the vasoconstrictors, PGF(2alpha) and TXA(2). 7.-- In conclusion, the mesenteric bed, a resistance vascular bed, seems to be more sensitive than the aorta, a conductance vessel, to the effects of fructose on prostanoid production. This difference could be related to a more relevant role of resistance vessels in the regulation of peripheral resistance and consequently of blood pressure. The observed effects should contribute to a shift in the balance of the release of prostanoid in favour of vasoconstrictor metabolites. This phenomenon could be related to an increase in the peripheral resistance and the mild hypertension observed in the fructose-treated rats.

Remodeling of Blood Vessels

Vascular functions, including tissue perfusion and peripheral resistance, reflect continuous structural adaptation (remodeling) of blood vessels in response to several stimuli. Here, a theoretical model is presented that relates the structural and functional properties of microvascular networks to the adaptive responses of individual segments to hemodynamic and metabolic stimuli. All vessels are assumed to respond, according to a common set of adaptation rules, to changes in wall shear stress, circumferential wall stress, and tissue metabolic status (indicated by partial pressure of oxygen). An increase in vessel diameter with increasing wall shear stress and an increase in wall mass with increased circumferential stress are needed to ensure stable vascular adaptation. The model allows quantitative predictions of the effects of changes in systemic hemodynamic conditions or local adaptation characteristics on vessel structure and on peripheral resistance. Predicted effects of driving pressure on the ratio of wall thickness to vessel diameter are consistent with experimental observations. In addition, peripheral resistance increases by approximately 65% for an increase in driving pressure from 50 to 150 mm Hg. Peripheral resistance is predicted to be markedly increased in response to a decrease in vascular sensitivity to wall shear stress, and to be decreased in response to increased tissue metabolic demand. This theoretical approach provides a framework for integrating available information on structural remodeling in the vascular system and predicting responses to changing conditions or altered vascular reactivity, as may occur in hypertension.

Psychosocial stress-induced hypertension results from in vivo expression of long-term potentiation in rat sympathetic ganglia

Long-term potentiation in sympathetic ganglia (gLTP) is an activity-dependent unique form of synaptic plasticity in that it is serotonin-dependent and can be completely inhibited by 5-HT3 receptor antagonists. Long lasting enhancement of the basal tone of ganglionic transmission seen with gLTP results in a sustained increase in peripheral resistance that leads to elevated blood pressure. We examined the possibility that, in sympathetic ganglia, stress-induced gLTP may be responsible for the expression of stress hypertension. Chronic treatment of male and female Wistar rats with a 5-HT3 receptor antagonist, tropisetron (ICS; 5 mg/kg/day) or ondansetron (0.5 mg/kg/day), prevented or reversed psychosocial stress-induced increases in blood pressure in stressed rats with no significant effect on blood pressure of unstressed control rats. Pharmacological and electrophysiological evidence that supports the presence of gLTP in ganglia isolated from stressed hypertensive rats includes inhibition of basal synaptic transmission by 5-HT3 antagonists, failure to induce gLTP with repetitive stimulation indicating occlusion of gLTP due to saturation and a left hand shift of the input/output curve. We suggest that a sustained stress-induced increase in central sympathetic efferent impulses to ganglia may provide the repeated high frequency presynaptic activity required to induce gLTP in sympathetic ganglia, thereby enhancing sympathetic tone to blood vessels resulting in hypertension.

Simulation of Lung Function Evolution After Heart-Lung Transplantation Using a Numerical Model

A morphometry-based computational model for expiratory flow in humans was used to study the unusual configuration of the maximum expiratory flow-volume (MEFV) curve associated with alterations in lung function after heart-lung transplantation (HLT). The postoperative MEFV curve showed a peak, followed by a gently sloping plateau over the midvolume range, ending in a knee where the flow suddenly fell, instead of the usual observed uniform decrease in expiratory flow. We have tested several hypotheses about the relationship between the pattern of changes in the configuration of the MEFV curve and pathological changes in the airway mechanics through computer simulations. Principally, effects of lung denervation and airway obstruction, associated with the development of bronchiolitis obliterans in the lung periphery, have been investigated. The calculated curves are similar in appearance to the measured postoperative flow-volume curves and confirm reliability of the earlier hypotheses. We conclude that the plateau-knee configuration of the MEFV curve can result from flow limitation in one of the first airway generations, that this flow limitation coupled with an increase in peripheral airway resistance results in plateau shortening, and that flows exceeding predicted values during the second part of expiration may be produced by lung denervation. Additionally our results demonstrate that airways larger than the transitional and respiratory bronchioles can be involved in pulmonary function deterioration observed in patients affected with obliterative bronchiolitis. Our findings indicate that the computational model, based on a symmetrical dichotomous branching structure of the bronchial tree, along with pathological data, can be employed to evaluate the effects of heterogeneous changes in the lung periphery. Index Terms-Airway mechanics, forced expiration, lung transplantation, mathematical modeling, maximal expiratory flow-volume curve.

Type 2 Diabetic Mice Have Increased Arteriolar Tone and Blood Pressure

Type 2 diabetes mellitus (T2-DM) is frequently associated with vascular dysfunction and elevated blood pressure, yet the underlying mechanisms are not completely understood. We hypothesized that in T2-DM, the regulation of peripheral vascular resistance is altered because of changes in local vasomotor mechanisms. In mice with T2-DM (C57BL/KsJ-(db-)/db-), systolic and mean arterial pressures measured by the tail cuff method were significantly elevated compared with those of control (db+/db-) animals (db/db, 146+/-5 and 106+/-2 mm Hg versus control, 133+/-4 and 98+/-4 mm Hg, respectively; P<0.05). Total peripheral resistance, calculated from cardiac output values (measured by echocardiography) and mean arterial pressure were significantly elevated in db/db mice (db/db, 25+/-6 versus control, 15+/-1 mm Hg[middot]mL(-1)[middot]min(-1)). In isolated, pressurized gracilis muscle arterioles (diameter approximately 80 microm) from db/db mice, stepwise increases in intraluminal pressure (from 20 to 120 mm Hg) elicited a greater reduction in diameter than in control vessels at each pressure step (at 80 mm Hg, db/db, 66+/-4% versus control, 79+/-3%). The passive diameters of arterioles (obtained in Ca2+-free solution) and the calculated myogenic index were not significantly different in the 2 groups. The presence of the prostaglandin H2/thromboxane A2 receptor antagonist SQ29548 did not affect arteriolar diameters of control mice but reduced the enhanced arteriolar tone of db/db mice back to control levels (at 80 mm Hg, 80+/-4%). The inhibitor of cyclooxygenase-1 (COX-1), SC-560, did not affect the basal tone of arterioles, whereas NS-398, an inhibitor of COX-2, caused a significant shift in the arteriolar pressure-diameter curve of vessels from db/db mice (at 80 mm Hg, 76+/-3%) but not in those of control mice. Also, in aortas of db/db mice, expression of COX-2 was enhanced compared with controls. Collectively, these findings suggest that in mice with T2-DM, the basal tone of skeletal muscle arterioles is increased because of an enhanced COX-2-dependent production of constrictor prostaglandins. These alterations in microvascular prostaglandin synthesis may contribute to the increase in peripheral resistance and blood pressure in T2-DM.

Cannabinoids and Endotoxemia

Endocannabinoids and CB1 receptors have been implicated in endotoxin (LPS)-induced hypotension: LPS stimulates the synthesis of anandamide in macrophages, and the CB1 antagonist SR-141716 inhibits the hypotension induced by treatment of rats with LPS or LPS-treated macrophages. Recent evidence indicates the existence of cannabinoid receptors distinct from CB1 or CB2 that are inhibited by SR-141716 but not by other CB1 antagonists such as AM251. In pentobarbital-anesthetized rats, intravenous injection of 10 mg/kg LPS elicited hypotension associated with profound decreases in cardiac contractility, moderate tachycardia, and an increase in lower body vascular resistance. Pretreatment with 3 mg/kg SR-141716 prevented the hypotension and decrease in cardiac contractility, slightly attenuated the increase in peripheral resistance, and had no effect on the tachycardia caused by LPS, whereas pretreatment with 3 mg/kg AM251 did not affect any of these responses. SR-141716 also elicited an acute reversal of the hypotension and decreased contractility when administered after the response to LPS had fully developed. The LPS-induced hypotension and its inhibition by SR-141716 were similar in pentobarbital-anesthetized wild-type, CB1−/−, and CB1−/−/CB2−/− mice. We conclude that SR-141716 inhibits the acute hemodynamic effects of LPS by interacting with a cardiac receptor distinct from CB1 or CB2 that mediates negative inotropy and may be activated by anandamide or a related endocannabinoid released during endotoxemia.

A comparison between haemodynamic effects of vasopressin analogues

Some analogues of arginine vasopressin (AVP) reportedly possess hypotensive properties, and two such peptides are Cys(1)-Tyr(2)-Phe(3)-Val(4)-Asn(5)-Cys(6)-Pro(7)- d-Arg(8)-Gly(9)-NH(2) (VD-AVP) and d(CH(2))(5)-Cys(1)- d-Tyr(Et)(2)-Arg(3)-Val(4)-Asn(5)-Cys(6)-Lys(7)-Lys(8)-ethylenediamine(9) (TA-LVP). In the present investigation we examined the effects of TA-LVP (0.3, 1.0 and 3.0 microg/kg/min), VD-AVP (0.3, 1.0 and 3.0 microg/kg/min) and AVP (1.0, 3.0, 10 ng/kg/min) on haemodynamics, blood volume (BV) and plasma troponin levels in anaesthetised rats. Infusion of TA-LVP significantly ( P<0.05) reduced blood pressure (-45+/-3%; n=8; mean +/- SEM), mean circulatory filling pressure ( P(mcf); -41+/-3%), and cardiac output (CO; -59+/-4%). The reduction in CO at a lower dose of TA-LVP was due to reduced venous tone, while at higher doses the reduction was predominantly the result of reduced BV (-35+/-4%). The large decrease in BV during the infusion of TA-LVP, substantially increased resistance to venous return (50+/-11%), which was the main contributor in reducing CO. Administration of AVP significantly increased blood pressure (41+/-4%) and arterial resistance (98+/-16%) without any impact on P(mcf) and BV, while significantly reducing CO (-26+/-5%). Infusion of VD-AVP did not produce hypotension, but produced a modest but significant reduction in CO (-18+/-5%) and insignificant but moderate increases in peripheral resistance (30+/-12%) and resistance to venous return (28+/-8%). Plasma troponin levels were not affected by any of the peptides. The hypotensive action of TA-LVP was due to a reduction in CO as a result of a reduced pre-load, while the pressor effect of AVP increased after-load sufficiently to impede flow, reducing CO. VD-AVP was devoid of any hypotensive effects, suggesting that V(2)-vasopressin receptors are most likely to play a limited role in the control of cardiac and vascular function in these animals.

Effects of intralipid infusion on blood viscosity and other haemorheological parameters in neonates and children

To study acute haemorheological effects of intralipid in preterm and full-term neonates and children. Circulatory complications of intralipid infusion, such as increases in pulmonary and peripheral flow resistance, have been associated with impaired blood rheology. During total parenteral nutrition, 10 preterm infants, 10 full-term neonates and 10 children received an initial dose of intralipid as continuous infusion (0.6 g/kg) over 4 h. Additionally, blood of 10 healthy preterm infants, 10 full-term neonates and 10 adults was incubated with intralipid. Whole blood and plasma viscosity (capillary viscometer), red blood cell (RBC) deformability (rheoscope) and RBC aggregation (Myrenne aggregometer) were measured before and after intralipid infusion and before and after in vitro incubation of blood with intralipid. During intralipid infusion, plasma triglyceride levels increased from 0.13 +/- 0.27 to 2.16 +/- 0.68 g/l in the preterm infants, from 0.14 +/- 0.21 to 1.64 +/- 0.54 g/l in the full-term neonates and from 0.65 +/- 0.31 to 2.26 +/- 0.60 g/l in the children. Whole blood viscosity decreased by about 10% after intralipid in all three groups due to similar decreases in haematocrit. RBC aggregation decreased by about 20% after intralipid infusion. Plasma proteins, plasma viscosity and RBC deformation were not affected by intralipid. In vitro incubation of blood with intralipid resulted in a marked reduction of RBC aggregation that was related to the intralipid concentration. At intralipid concentrations of 4 and 8 mg/ml, no RBC aggregation was noted in preterm and full-term neonates. In adults, RBC aggregation decreased by 50%. Previously described deleterious effects of intralipid on circulation can not be explained by changes in haemorheological properties.

Cannabinoid antagonist SR-141716 inhibits endotoxic hypotension by a cardiac mechanism not involving CB1 or CB2 receptors.

Endocannabinoids and CB1 receptors have been implicated in endotoxin (LPS)-induced hypotension: LPS stimulates the synthesis of anandamide in macrophages, and the CB1 antagonist SR-141716 inhibits the hypotension induced by treatment of rats with LPS or LPS-treated macrophages. Recent evidence indicates the existence of cannabinoid receptors distinct from CB1 or CB2 that are inhibited by SR-141716 but not by other CB1 antagonists such as AM251. In pentobarbital-anesthetized rats, intravenous injection of 10 mg/kg LPS elicited hypotension associated with profound decreases in cardiac contractility, moderate tachycardia, and an increase in lower body vascular resistance. Pretreatment with 3 mg/kg SR-141716 prevented the hypotension and decrease in cardiac contractility, slightly attenuated the increase in peripheral resistance, and had no effect on the tachycardia caused by LPS, whereas pretreatment with 3 mg/kg AM251 did not affect any of these responses. SR-141716 also elicited an acute reversal of the hypotension and decreased contractility when administered after the response to LPS had fully developed. The LPS-induced hypotension and its inhibition by SR-141716 were similar in pentobarbital-anesthetized wild-type, CB1(-/-), and CB1(-/-)/CB2(-/-) mice. We conclude that SR-141716 inhibits the acute hemodynamic effects of LPS by interacting with a cardiac receptor distinct from CB1 or CB2 that mediates negative inotropy and may be activated by anandamide or a related endocannabinoid released during endotoxemia.

Age dependency of cardiovascular autonomic responses to head-up tilt in healthy subjects.

In elderly subjects, heart rate responses to postural change are attenuated, whereas their vascular responses are augmented. Altered strategy in maintaining blood pressure homeostasis during upright position may result from various cardiovascular changes, including age-related cardiovascular autonomic dysfunction. This exploratory study was conducted to evaluate impact of age on cardiovascular autonomic responses to head-up tilt (HUT) in healthy subjects covering a wide age range. The study population consisted of 63 healthy, normal-weight, nonsmoking subjects aged 23-77 yr. Five-minute electrocardiogram and finger blood pressure recordings were performed in the supine position and in the upright position 5 min after 70 degrees HUT. Stroke volume was assessed from noninvasive blood pressure signals by the arterial pulse contour method. Heart rate variability (HRV) and systolic blood pressure variability (SBPV) were analyzed by using spectral analysis, and baroreflex sensitivity (BRS) was assessed by using sequence and cross-spectral methods. Cardiovascular autonomic activation during HUT consisted of decreases in HRV and BRS and an increase in SBPV. These changes became attenuated with aging. Age correlated significantly with amplitude of HUT-stimulated response of the high-frequency component (r = -0.61, P < 0.001) and the ratio of low-frequency to high-frequency power of HRV (r = -0.31, P < 0.05) and indexes of BRS (local BRS: r = -0.62, P < 0.001; cross-spectral baroreflex sensitivity in the low-frequency range: r = -0.38, P < 0.01). Blood pressure in the upright position was maintained well irrespective of age. However, the HUT-induced increase in heart rate was more pronounced in the younger subjects, whereas the increase in peripheral resistance was predominantly observed in the older subjects. Thus it is likely that whereas the dynamic capacity of cardiac autonomic regulation decreases, vascular responses related to vasoactive mechanisms and vascular sympathetic regulation become augmented with increasing age.

A simple method for E(max) evaluation: in vitro results.

E(max) is an important parameter to evaluate the state of the heart and of its contractile capability. Its determination is not easy and rather inaccurate: However, it can be clinically relevant during mechanical and/or pharmacological heart assistance as it can suggest how to modify pharmacological therapy or the control strategy of the device. Aim of this study is to develop a method based on ventricular energetics to evaluate E(max). If arterial elastance line slope is modified, for example by a slight peripheral resistance increase, E(max) (assuming that it is constant) can be evaluated computing the energy transferred to the arterial elastance before and after the change. The corresponding equation contains known or easily computable variables and the difference delta between end diastolic volume and ventricular rest volume. If the ratio of deltas before and after the disturbance is near to 1, the equation returns a fair estimation of E(max). The method was tested in vitro, in different circulatory conditions, using an open loop numerical model of the circulation built out of a variable elastance model of the ventricle connected to a modified windkessel representing the systemic arterial tree. The results obtained in in vitro experiments suggest clinically testing this method.

Effect of interleukin 8 and ICAM-1 on calcium-dependent outflow of K+ in erythrocytes from subjects with essential hypertension

SUMMARYIntroduction: The pathogenic mechanisms underlying the increase in peripheral resistance and the contraction of smooth muscular fibre cells in essential hypertension are not yet clearly understood. However, it is now known that immune system activation plays a role in the pathogenesis of some forms of arterial hypertension, and recent data show that the Ca2+ influx in some cells (i.e. red blood cells, leukocytes, platelets, smooth muscular fibre cells) is increased in subjects with essential hypertension, thus revealing a possible alteration in cellular membrane. The end-points of this study were therefore to ascertain whether red blood cells used as a cellular membrane model have a greater Ca2+ dependent K+ flow (Gardos effect) in hypertensive patients than in normotensive controls, to point out a different regulation of ionic channels, and whether IL-8 and the adhesion molecule ICAM-1 influence the membranous outflow.Material and methods: The study was conducted on 87 Caucasian subjects. Of these, 50 (25 men, 25 women; mean age 43 ± 3 years, mean body mass index (BMI) 27 ± 0.5 and 22.3 ± 0.3 kg m2, respectively) had mild-to-moderate hypertension (mean arterial blood pressure 120±8mmHg).The other 37 (18 men, 19 women; mean age 39 ± 3 years; BMI 23.8 ± 0.5 kg m2 and 22.8 ± 0.5 kg m2, respectively were normotensive healthy volunteers (mean arterial blood pressure 89 ± 2 mm Hg).All the patients and subjects were untreated for at least 4 weeks before blood sampling.Results: Ca2+-dependent K+ outflow was found to be greater in samples from patients with essential hypertension than in those from normotensive controls. lL-8 and ICAM-1 significantly enhanced the Ca2+-dependent K+ outflow in red blood cells from hypertensive subjects but had an inhibitory effect on cells from controls. In the experimental model, the presenceof TMB-8, a membrane calcium antagonist, significantly reduced the Ca2+-dependent K+ efflux.Conclusion: Vasoconstriction in subjects with essential hypertension may therefore depend on a different regulation of ionic flow that probably supports an increased Ca2+ inflow in smoothmuscle fibre cells. Under certain pathological conditions, some immune system components (i.e. interleukins, adhesion molecules) may directly enhance membrane permeability to Ca2+, thus inducing vasoconstriction in the smooth muscle cells.

The Effect of Flax Seed Cultivars with Differing Content of α-Linolenic Acid and Lignans on Responses to Mental Stress

Background: Phytoestrogens offer a possible alternative to hormone replacement therapy. Flax seed contains large quantities of a phytoestrogen precursor, secoisolariciresinol diglucoside (SDG), as well as large quantities of α-linolenic acid; these factors may be protective against vascular disease. We have previously shown that the rise in blood pressure during mental stress is a strong predictor of atherosclerosis progression.Methods: 35 postmenopausal women with vascular disease, 62 ± 8 years of age, were treated in a random-sequence double-blind Latin square crossover study comparing three strains of flax seed: Flanders (low in lignan and high in α-linolenic acid), Linola 989 (high in lignan and low in α-linolenic acid) and AC Linora (intermediate in both lignan and α-linolenic acid).Results: Compared to the pre-treatment baseline diet, all three strains of flax significantly reduced blood pressure during mental stress induced by a frustrating cognitive task (Stroop color-word interference task) (p = 0.004). Linola 989, the strain highest in lignan and lowest in α-linolenic acid, was associated with the least increase in peripheral resistance during stress, the greatest reduction in plasma cortisol during stress and the smallest increase in plasma fibrinogen during mental stress.Conclusion: Flax phytoestrogens ameliorate certain responses to stress and thus may afford protection against atherosclerosis; this hypothesis should be tested in clinical trials.

C-peptide levels and the duration of lactational amenorrhea

Changes in insulin sensitivity play an important role in directing metabolic energy toward milk production in lactating mammals. In rats, prolactin causes upregulation of insulin receptors in mammary tissue together with an increase in peripheral insulin resistance, leading to a preferential allocation of energy to support milk production (1, 2). In humans, the shift in energy allocation during lactation away from peripheral tissues and toward milk production is correlated with lower insulin levels (2–4).