Conducted vasoreactivity: the dynamical point of view.

Conducted vasodilation is part of the physiological response to increasing metabolic demand of the tissue. Similar responses can be elicited by focal electrical or chemical stimulation. Some evidence suggests an endothelial pathway for nondecremental transmission of hyperpolarizing pulses. However, the underlying mechanisms are debated. Here, we focus on dynamical aspects of the problem hypothesizing the existence of a bistability-powered mechanism for regenerative pulse transmission along the endothelium. Bistability implies that the cell can have two different stable resting potentials and can switch between those states following an appropriate stimulus. Bistability is possible if the current-voltage curve is N shaped instead of monotonically increasing. Specifically, the presence of an inwardly rectifying potassium current may provide the endothelial cell with such properties. We provide a theoretical analysis as well as numerical simulations of both single- and multiunit bistable systems mimicking endothelial cells to investigate the self-consistence and stability of the proposed mechanism. We find that the individual cell may switch readily between two stable potentials. An array of coupled cells, however, as found in the vascular wall, requires a certain adaptation of the membrane currents after a switch, in order to switch back. Although the formulation is generic, we suggest a combination of specific membrane currents that could underlie the phenomenon.

Endothelial nitric oxide synthase phosphorylation at Threonine 495 and mitochondrial reactive oxygen species formation in response to a high H2O2 concentration.

BACKGROUND: Hydrogen peroxide (H2O2) is produced in vessels during ischemia/reperfusion and during inflammation, both leading to vascular dysfunction. We investigated cellular pathways involved in endothelial nitric oxide synthase (eNOS) phosphorylation at Threonine 495 (Thr(495)) in human umbilical vein endothelial cells (HUVECs) exposed to H2O2. METHODS: HUVECs were exposed to 400 µM H2O2 for 30 min. Phosphorylation at Thr(495) was assessed by Western blotting and reactive oxygen species (ROS) monitored by flow cytometry. Protein kinase C (PKC) pathways were investigated by pretreatment with PKC-ß inhibitor ruboxistaurin or pan-PKC inhibitor GF109203X. In addition, we investigated ROCK and ERK pathways by MEKK1/2 inhibitor U0126 and ROCK inhibitor Y27632. RESULTS: H2O2 increased eNOS phosphorylation at Thr(495) (to 176% vs. control (100%), p < 0.001) along with increased mitochondrial ROS formation (from 19.7 to 45.3%, p < 0.01). This rise in phosphorylation could be prevented by U0126 and Y27632 in a dose-dependent manner, but did not result in lowered mitochondrial ROS formation. Conversely, addition of the antioxidant N-acetyl-L-cysteine only prevented mitochondrial ROS formation but did not prevent phosphorylation of eNOS Thr(495). CONCLUSION: H2O2-mediated phosphorylation of eNOS Thr(495) is mediated by ROCK and ERK activity, but not by PKC, and is uncoupled from mitochondrial ROS signaling. Furthermore, ERK inhibition increased mitochondrial ROS formation.

Dynamic changes in renal sodium handling during sympathetic stimulation in healthy human males.

The temporal response of changes in renal sodium reabsorption during increased renal sympathetic nerve activity has not been investigated. Central hypovolemia by application of lower-body negative-pressure (LBNP) elicits baroreceptor mediated sympathetic reflexes to maintain arterial blood pressure. We hypothesized, that during 90 min LBNP, the renal sodium retention would increase rapidly, remain increased during intervention, and return to baseline immediately after end of intervention. METHODS: 30 young, healthy, sodium loaded, non-obese males were exposed to -15 mmHg LBNP, -30 mmHg LBNP, -15 mmHg LBNP + renin blockade or time-control (0 mmHg LBNP) for 90 min. Urine was collected every 15 min during 90 min of intervention and 60 min of recovery to identify a possible relation between time of intervention and renal response. RESULTS: All intervention groups exhibited a comparable reduction in distal sodium excretion at the end of the intervention (P = 0.46 between groups; -15 mmHg: -3.1 ± 0.9 %, -30 mmHg: -2.9 ± 0.6 %, -15 mmHg + aslikiren: -1.8 ± 0.6 %). -15 mmHg+Aliskiren resulted in a slower onset, but all groups exhibited a continued reduction in sodium excretion after 1 h of recovery despite return to baseline of renin, aldosterone, diuresis and cardiovascular parameters. CONCLUSION: Sympathetic stimulation for 90 min via LBNP at -30 mmHg LBNP compared to -15 mmHg did not result in a greater response in fractional Na+ excretion, suggesting that additional baroreceptor unloading did not cause further increases in renal sodium reabsorption. Changes in distal Na+ excretion were linear with respect to time (dose) of intervention, but seem to exhibit a saturation-like effect at a level around 4 %. The lack of recovery after 1 h is also a new finding that warrants further investigation.

Dynamics of nephron-vascular network.

The paper presents a modeling study of the spatial dynamics of a nephro-vascular network consisting of individual nephrons connected via a tree-like vascular branching structure. We focus on the effects of nonlinear mechanisms that are responsible for the formation of synchronous patterns in order to learn about processes not directly amenable to experimentation. We demonstrate that: (i) the nearest nephrons are synchronized in-phase due to a vascular propagated electrical coupling, (ii) the next few branching levels display a formation of phase-shifted patterns due to hemodynamic coupling and mode elimination, and (iii) distantly located areas show asynchronous behavior or, if all nephrons and branches are perfectly identical, an infinitely long transient behavior. These results contribute to the understanding of mechanisms responsible for the highly dynamic and limited synchronization observed among groups of nephrons despite of the fairly strong interaction between the individual units.

Functional modeling of the shift in cellular calcium dynamics at the onset of synchronization in smooth muscle cells.

In the present paper we address the nature of synchronization properties found in populations of mesenteric artery smooth muscle cells. We present a minimal model of the onset of synchronization in the individual smooth muscle cell that is manifested as a transition from calcium waves to whole-cell calcium oscillations. We discuss how different types of ion currents may influence both amplitude and frequency in the regime of whole-cell oscillations. The model may also explain the occurrence of mixed-mode oscillations and chaotic oscillations frequently observed in the experimental system.

Synchronization of period-doubling oscillations in vascular coupled nephrons.

The mechanisms by which the individual functional unit (nephron) of the kidney regulates the incoming blood flow give rise to a number of nonlinear dynamic phenomena, including period-doubling bifurcations and intra-nephron synchronization between two different oscillatory modes. Interaction between the nephrons produces complicated and time-dependent inter-nephron synchronization patterns. In order to understand the processes by which a pair of vascular coupled nephrons synchronize, the paper presents a detailed analysis of the bifurcations that occur at the threshold of synchronization. We show that, besides infinite cascades of saddle-node bifurcations, these transitions involve mutually connected cascades of torus and homoclinic bifurcations. To illustrate the broader range of occurrence of this bifurcation structure for coupled period-doubling systems, we show that a similar structure arises in a system of two coupled, non-identical Rössler oscillators.

Characterizing multimode interaction in renal autoregulation.

The purpose of this paper is to demonstrate how modern statistical techniques of non-stationary time-series analysis can be used to characterize the mutual interaction among three coexisting rhythms in nephron pressure and flow regulation. Besides a relatively fast vasomotoric rhythm with a period of 5-8 s and a somewhat slower mode arising from an instability in the tubuloglomerular feedback mechanism, we also observe a very slow mode with a period of 100-200 s. Double-wavelet techniques are used to study how the very slow rhythm influences the two faster modes. In a broader perspective, the paper emphasizes the significance of complex dynamic phenomena in the normal and pathological function of physiological systems and discusses how simulation methods can help to understand the underlying biological mechanisms. At the present there is no causal explanation of the very slow mode. However, vascular oscillations with similar frequencies have been observed in other tissues.

A method for assessment of the dynamic response of the arterial baroreflex.

AIM: The baroreflex is a key mechanism in cardiovascular regulation, and alterations in baroreceptor function are seen in many diseases, including heart failure, obesity and hypertension. We propose a new method for analysing baroreceptor function from continuous blood pressure (BP) and heart rate (HR) in both health and disease. METHODS: Forty-eight-hour data series of BP and HR were collected with telemetry. Sprague Dawley rats on standard chow (n = 11) served as controls, while rats on a high-fat, high-fructose (HFHC) diet (n = 6) constituted the obese-hypertensive model. A third group of rats underwent autonomic blockade (n = 6). An autoregressive-moving-average with exogenous inputs (ARMAX) model was applied to the data and compared with the α-coefficient. RESULTS: Autonomic blockade caused a significant reduction in the strength of the baroreflex as estimated by ARMAX [ARMAX- baroreflex sensitivity (BRS)] -0.03 ± 0.01 vs. -0.19 ± 0.04 bpm heartbeat-1) . Both methods showed a ~50% reduction in BRS in the obese-hypertensive group compared with control (body weight 531 ± 27 vs. 458 ± 19 g, P < 0.05; mean arterial pressure 119 ± 3 vs. 102 ± 1 mmHg, P < 0.05; ARMAX-BRS -0.08 ± 0.01 vs. -0.15 ± 0.01 bpm heartbeat-1 , P < 0.05; α-coefficient BRS 0.51 ± 0.07 vs. 0.89 ± 0.07 ms mmHg-1 , P < 0.05). The ARMAX method additionally showed the open-loop gain of the baroreflex to be reduced by ~50% in the obese-hypertensive group (-2.3 ± 0.3 vs. -4.1 ± 0.3 bpm, P < 0.05), while the rate constant was similar between groups. CONCLUSION: The ARMAX model represents an efficient method for estimating several aspects of the baroreflex. The open-loop gain of the baroreflex was attenuated in obese-hypertensive rats compared with control, while the time response was similar. The algorithm can be applied to other species including humans.

Double-wavelet approach to studying the modulation properties of nonstationary multimode dynamics.

On the basis of double-wavelet analysis, the paper proposes a method to study interactions in the form of frequency and amplitude modulation in nonstationary multimode data series. Special emphasis is given to the problem of quantifying the strength of modulation for a fast signal by a coexisting slower dynamics and to its physiological interpretation. Application of the approach is demonstrated for a number of model systems, including a model that generates chaotic dynamics. The approach is then applied to proximal tubular pressure data from rat nephrons in order to estimate the degree to which the myogenic dynamics of the afferent arteriole is modulated by the slower tubulo-glomerular dynamics. Our analysis reveals a significantly stronger interaction between the two mechanisms in spontaneously hypertensive rats than in normotensive rats.

Angiotensin II modulates conducted vasoconstriction to norepinephrine and local electrical stimulation in rat mesenteric arterioles.

OBJECTIVE: Localized application of a vasoconstricting agent onto the wall of an arteriole results not only in a local constriction of the vessel, but also in a conducted vasoconstriction which is detectable more than a millimeter upstream and downstream from the application site. We investigated the effect of intravenous infusion of angiotensin II (ANG II), losartan or methoxamine on conducted vasoconstriction to local application of norepinephrine (NE) or local electrical stimulation onto the surface of rat mesenteric arterioles in vivo. METHODS: In anesthetized male Wistar rats (n = 43) NE (0.1 mM) or a local depolarizing current was continuously applied onto mesenteric arterioles using micropipettes. Local and conducted vasoconstriction was measured using videomicroscopy. Conducted responses were measured 200-1000 microns upstream from the application site. RESULTS: Systemic infusion of ANG II (4 ng/min) raised mean arterial blood pressure by 6 +/- 2 mm Hg and increased the conducted but not the local vasoconstrictor response to NE (P < 0.02). Infusion of the alpha 1-agonist methoxamine raised blood pressure to the same extent, but did not change conducted vasoconstriction significantly. Blockade of endogenous ANG II by infusion of the AT1-receptor blocker losartan decreased conducted vasoconstriction to NE (P < 0.03). In parallel with the findings using NE, ANG II increased (P < 0.05) and losartan decreased (P < 0.01) conducted vasoconstriction when local electrical stimulation was used to initiate the conducted vascular response. CONCLUSION: The findings suggest that conducted vasoconstriction to NE and local electrical stimulation in rat mesenteric arterioles are modulated by ANG II, an increase in the plasma levels of ANG II increasing conducted vasoconstriction.

Chaos and non-linear phenomena in renal vascular control.

Renal autoregulation of blood flow depends on the functions of the tubuloglomerular feedback (TGF) system and the myogenic response of the afferent arteriole. Studies of the dynamic aspects of these control mechanisms at the level of both the single nephron and the whole kidney have revealed a variety of non-linear phenomena. In halothane-anesthetized, normotensive rats the TGF system oscillates regularly at 2-3 cycles/min because of the non-linearities and the time delays within the feedback system. Oscillations are present in single nephron blood flow, tubular pressure and flow, and in the tubular solute concentrations. Nephrons deriving their afferent arteriole from the same cortical radial artery are entrained, and consequently oscillate at the same frequency. Experimental studies have shown that the synchronization is due to an interaction of the TGF between nephrons. A necessary condition for the interaction is that the nephrons derive their blood supply from the same cortical radial artery. Development of hypertension is associated with a shift from periodic oscillations of tubular pressure to random-like fluctuations. Numerical analyses indicate that these fluctuations are an example of deterministic chaos. Experimental studies show that the development of hypertension is associated with an increase in strength of the interaction between nephrons. Mathematical models suggest that an increased nephron-nephron interaction could cause a bifurcation in the dynamics of TGF from periodic oscillations to deterministic chaos. In addition to the TGF mediated oscillation, experimental studies have also demonstrated the presence of a faster oscillation, this having a frequency of 120-160 mHz. This is caused by a mechanism intrinsic to the vascular wall, and presumably represents the well-known phenomenon of vasomotion. Using newly developed non-linear analytical methods non-linear interactions between vasomotion and the TGF mediated oscillation were detected both in single nephron and in whole kidney blood flow. The physiological significance of these non-linear phenomena in renal vascular control is discussed.

Short- and long-term variations in non-linear dynamics of heart rate variability.

OBJECTIVES: The purpose of the study was to investigate the short- and long-term variations in the non-linear dynamics of heart rate variability, and to determine the relationships between conventional time and frequency domain methods and the newer non-linear methods of characterizing heart rate variability. METHODS: Twelve healthy subjects were investigated by 3-h ambulatory ECG recordings repeated on 3 separate days. Correlation dimension, non-linear predictability, mean heart rate, and heart rate variability in the time and frequency domains were measured and compared with the results from corresponding surrogate time series. RESULTS: A small significant amount of non-linear dynamics exists in heart rate variability. Correlation dimensions and non-linear predictability are relatively specific parameters for each individual examined. The correlation dimension is inversely correlated to the heart rate and describes mainly linear correlations. Non-linear predictability is correlated with heart rate variability measured as the standard deviation of the R-R intervals and the respiratory activity expressed as power of the high-frequency band. The dynamics of heart rate variability changes suddenly even during resting, supine conditions. The abrupt changes are highly reproducible within the individual subjects. CONCLUSIONS: The study confirms that the correlation dimension of the R-R intervals is mostly due to linear correlations in the R-R intervals. A small but significant part is due to non-linear correlations between the R-R intervals. The different measures of heart rate variability (correlation dimension, average prediction error, and the standard deviation of the R-R intervals) characterize different properties of the signal, and are therefore not redundant measures. Heart rate variability cannot be described as a single chaotic system. Instead heart rate variability consists of intertwined periods with different non-linear dynamics. It is hypothesized that the heart rate is governed by a system with multiple "strange" attractors.

K(V)7.4 channels participate in the control of rodent renal vascular resting tone.

AIM: We tested the hypothesis that K(V)7 channels contribute to basal renal vascular tone and that they participate in agonist-induced renal vasoconstriction or vasodilation. METHODS: KV 7 channel subtypes in renal arterioles were characterized by immunofluorescence. Renal blood flow (RBF) was measured using an ultrasonic flow probe. The isometric tension of rat interlobar arteries was examined in a wire myograph. Mice afferent arteriolar diameter was assessed utilizing the perfused juxtamedullary nephron technique. RESULTS: Immunofluorescence revealed that K(V)7.4 channels were expressed in rat afferent arterioles. The K(V)7 blocker XE991 dose-dependently increased the isometric tension of rat interlobar arteries and caused a small (approx. 4.5%) RBF reduction in vivo. Nifedipine abolished these effects. Likewise, XE991 reduced mouse afferent arteriolar diameter by approx. 5%. The K(V)7.2-5 stimulator flupirtine dose-dependently relaxed isolated rat interlobar arteries and increased (approx. 5%) RBF in vivo. The RBF responses to NE or Ang II administration were not affected by pre-treatment with XE991 or flupirtine. XE991 pre-treatment caused a minor augmentation of the acetylcholine-induced increase in RBF, while flupirtine pre-treatment did not affect this response. CONCLUSION: It is concluded that K(V)7 channels, via nifedipine sensitive channels, have a role in the regulation of basal renal vascular tone. There is no indication that K(V)7 channels have an effect on agonist-induced renal vasoconstriction while there is a small effect on acetylcholine-induced vasodilation.

Dynamic autoregulation and renal injury in Dahl rats.

The Dahl salt-sensitive (Dahl S) rat develops hypertension and renal injuries when challenged with a high salt diet and has been considered to be a model of chronic renal failure. Renal injuries appear very early in life compared with the spontaneously hypertensive rat (SHR). During the course of hypertension, a gradual impairment of autoregulatory control of renal blood flow might expose the glomerular circulation to periods of elevated pressure, resulting in renal injuries in Dahl S rats. Dynamic autoregulatory capacity was assessed in Dahl S and Dahl salt-resistant (Dahl R) rats, SHR, and Sprague-Dawley rats by inducing broad-band fluctuations in the arterial blood pressure and simultaneously measuring renal blood flow. Dynamic autoregulation was estimated by the transfer function using blood pressure as the input and renal blood flow as the output. Renal morphological injuries were evaluated in Dahl S rats and SHR and were scored semiquantitatively. Dynamic autoregulation was efficient and comparable in the low-frequency range (<0.015 Hz) in Dahl R rats, SHR, and Sprague-Dawley rats. The response in Dahl S rats depended strongly on the initiation time of the high salt diet. Autoregulation was preserved during a low salt diet and in rats exposed to a late-onset hypertension of short duration, only partly preserved if the late-onset hypertension was of a longer duration, and abolished in early-onset hypertension. All Dahl S rats on a high salt diet showed severe morphological changes in the kidney. In conclusion, autoregulatory capacity in the kidney of Dahl S rats is gradually impaired when rats are rendered hypertensive with a high salt diet. Renal morphological injuries develop before loss of dynamic autoregulation. Impaired autoregulation appears to be the result, not the cause, of the process that ultimately leads to renal failure in the Dahl S rat.

Renal tubular function in patients treated with high-dose cisplatin.

The effect of three cycles of high-dose cisplatin (40 mg/m2 day for 5 days) on renal tubular function was evaluated in 30 patients. A significant impairment of proximal tubular salt and water reabsorption rates was observed, but also distal tubular function seemed to be affected. These changes were also present 6 months after termination of treatment. Sodium and magnesium clearance increased significantly during treatment. Magnesium clearance normalized shortly after treatment but sodium clearance was significantly elevated 6 months after treatment. Proteinuria, albuminuria, and amino aciduria, together with an increase of beta 2-microglobulin and N-acetyl-beta-D-glucosaminidase (NAG) excretion rates, were observed during each treatment cycle. A good correlation was registered between the increase in urinary excretion rates of protein, NAG, and magnesium and the decrease in proximal tubular salt and water reabsorption during cisplatin administration.

Exaggerated natriuresis and lithium clearance in spontaneously hypertensive rats.

Since hypertension is associated with changes in the handling of various cations (including sodium and lithium) across the cell membrane, the present study investigated the validity of the lithium clearance method in hypertension by comparing two measures of proximal reabsorption. Thus, fractional lithium excretion and transit time (TT)-occlusion time (OT; e-TT/T) were determined successively in the same spontaneously hypertensive rat (SHR, Okamoto strain). The rats were examined both before and after an acute saline load. The results show that the lithium clearance method can be used for the determination of proximal reabsorption in SHR. Utilizing the lithium clearance method, the changes in renal sodium handling underlying the exaggerated natriuresis were investigated in unanaesthetized catheterized rats. It was found that the exaggerated natriuresis was associated with an increased output from the proximal tubule, whereas no difference in distal sodium handling could be detected between SHR and normotensive Wistar-Kyoto rats (WKY).

Effects of acute volume loading on kidney function in patients with essential hypertension, as estimated by the lithium clearance method.

This study investigated the mechanism underlying the exaggerated natriuresis seen in patients with essential hypertension. The study used the lithium clearance method, which permits accurate determination of both proximal and distal sodium reabsorption in man. One litre of isotonic sodium chloride, intravenously (i.v.), produced a significant increase in sodium excretion in patients with essential hypertension, both during and after the infusion. This increase in sodium excretion was accompanied by a significant increase in the clearance of lithium, indicating an increased output of isotonic fluid from the proximal tubules. The calculated distal reabsorption of sodium increased during the natriuresis. In the normotensive controls, sodium excretion increased only after the infusion of 1 l isotonic saline. This was accompanied by a modest increase in absolute distal sodium reabsorption. However, when the amount of saline was increased to 2 l, similar changes to those seen in hypertensives given 1 l of saline occurred in normotensive subjects. Furthermore, chronic antihypertensive treatment abolished the phenomenon of exaggerated natriuresis. It is concluded that the exaggerated natriuresis represents the normal response to sodium loading being reset to a lower level. This resetting may be a secondary consequence of the high blood pressure, since lowering the pressure abolishes the phenomenon.

Structural evidence for counter-current flow in proximal tubules versus pertitubular capillaries in the rat kidney. Evaluation of the counter-current mechanism between the proximal convoluted tubules and the peritubular capillaries in the rat nephron.

BACKGROUND: In spite of the very high exchange of water and solutes between the proximal tubules and the peritubular capillaries, very little is known about flow directions in these two interrelated structures. We therefore developed a morphological technique suitable for the quantitative evaluation of a counter-current system between the proximal convoluted tubules and the peritubular capillaries in rat renal cortex. METHODS: In male pentothal-anesthetized Wistar rats (body weight 200-250 g), India ink was injected into the aorta above the renal arteries, followed by instant freezing of the right kidney in isopentane at -165 degrees C, and subsequent freeze-substitution in alcohol. In microscopic slides from kidneys in which only 20-55% of the cortical peritubular capillary loops was filled with ink--representing the arterial end of the capillaries--and in which the proximal tubular segmentation could be identified in PAS-stained sections, the segments of the convoluted proximal tubules were quantitatively compared with regard to the presence of ink-stained and unstained peritubular capillaries in nephrons from the whole renal cortex. RESULTS: In the microscopic specimens of the five animals used both the loops from the first segment (P1) of the proximal convoluted tubule and those of the second segment (P2) were systematically packed closely together, the transitional segment (P1-2) being interposed between the groups. Around the loops of P1, 8%+/-2% of the capillaries was stained with India ink. In contrast, surrounding the P2 loops 67%+/-5% of the capillaries contained ink, significantly exceeding that for P1 (p<0.01). CONCLUSION: Throughout the rat renal cortex, the most proximal fraction of the peritubular capillaries surrounds the second segments of the proximal convoluted tubules, while the first tubular segments are surrounded by the more distal fraction of the peritubular capillaries. Consequently, the flows in the peritubular capillaries and in the proximal convoluted tubules in the rat renal cortex are systematically arranged as a counter-current system. This feature was previously identified only in superficial nephrons.

Intracerebroventricular metformin attenuates salt-induced hypertension in spontaneously hypertensive rats.

The aim of this study was to examine the effects of long-term continuous intracerebroventricular (icv) infusion of metformin on blood pressure (BP) in spontaneously hypertensive rats (SHR). To accelerate the development of hypertension, SHR were fed a 8% NaCl diet during the 3-week study period. Metformin was given in the following doses: 0 (isotonic saline; n = 7), 25 (n = 8), 50 (n = 6), 100 (n = 6), and 200 microg/day icv (n = 5). Mean arterial pressure (MAP) and heart rate (HR) were measured by radiotelemetry, and as a measure of the contribution of sympathetic nerve activity to BP, the decrease in MAP in response to ganglionic blockade with hexamethonium, 30 mg/kg iv, was determined once weekly. In vehicle treated rats, MAP increased by 27+/-4 mm Hg, whereas in rats treated with a low dose of metformin (25 microg/day), MAP increased only by 7+/-3 mm Hg (P < .01). The hypotensive response to hexamethonium was attenuated by all doses of metformin suggesting that chronic icv metformin decreased central sympathetic outflow. The highest doses of metformin (100 and 200 microg/day) also prevented development of hypertension, but these doses were highly neurotoxic as demonstrated by histologic evaluation post mortem. Fast-Fourier transformation of MAP revealed increased variability within the 0.15 to 0.6 Hz frequency range in rats treated with neurotoxic doses of metformin, suggesting impaired sympathetic control of BP in these animals. In conclusion, long-term icv infusion with apparently nontoxic doses of metformin attenuates hypertension and decreases the hypotensive responses to ganglionic blockade in SHR, suggesting a centrally elicited sympathoinhibitory action.

Long-range correlations of serial FEV1 measurements in emphysematous patients and normal subjects.

In obstructive lung disease the annual change in lung function is usually estimated from serial measurements of forced expiratory volume in 1 s (FEV1). Frequent measurements in each patient may not improve this estimate because data are not statistically independent; i.e., the measurements are autocorrelated. The purpose of this study was to describe the correlation structure in time series of FEV1 measurements. Nineteen patients with severe alpha1-antitrypsin deficiency (phenotype PiZ) and moderate to severe emphysema and two subjects with normal lungs were followed for several years with daily self-administered spirometry. FEV1 measurements fulfilling standard criteria were detrended, and the autocorrelation profile and the power spectrum were calculated. On average the subjects were followed for >3 yr and performed >1,000 acceptable spirometries. The autocorrelation of FEV1 measurements in the emphysematous patients was approximately 0.35 for short intervals and decreased almost exponentially with a half time of 38 days. Between 3 and 4 mo, the autocorrelation function became negative. It reached a minimum of -0.1 at approximately 8 mo and then increased toward zero over the following 12 mo. The autocorrelation function in the two normal subjects showed a similar pattern, but with a faster decay toward zero. In the patients, the power spectrum had a peak at 1 cycle/wk and showed a 1/f pattern, where f is frequency, with a slope of -0.88 at lower frequencies. We conclude that serial spirometric measurements show long-range correlations. The practical implication is that FEV1 need not be measured more often than once every 3 mo in studies of the long-term trends in lung function.