Nitric oxide synthases in vagal neurons are crucial for the regulation of heart rate in awake dogs.

Nitric oxide synthase (NOS) inhibitors elicit bradycardias independent of the endothelium (e-NOS) or increases in blood pressure. Therefore, this bradycardia could be mediated by other NOS isoforms, most likely that of the nervous system (n-NOS). If so, heart rate variability (HRV) as a measure of vagal activity should be an indicator of the activity of n-NOS in vagal neurons. To test this, we studied the dose-effect relations of L-NAME (0.3 - 50 mg x kg(-1)) on heart rate (HR), HRV and systemic vascular resistance (SVR) in seven awake dogs. HRV was analyzed in the time domain as standard deviation of the RR-intervals (SDNN) and in the frequency domain as power in the high (0.15 - 0.5 Hz) and low (0.04 - 0.15 Hz) frequency range. The effects of HR and SDNN reached their maxima at a dose of 3 mg x kg(-1) and had their ED50 at 0.27 +/- 0.03 mg x kg(-1) and 0.43 +/- 0.1 mg x kg(-1), respectively, whereas SVR had its maximum at 10 mg x kg(-1) and ED50 at 0.86 +/- 0.11 mg x kg(-1) (p < 0.05). HF-power (vagal activity) predominated compared to LF-power (mainly sympathetic activity) during baseline as well as after L-NAME. The effects on HR and HRV were absent after ganglionic blockade (hexamethonium), whereas the effects on SVR remained unchanged. Thus, NO exerts a powerful restraining activity on vagal neurons and plays a key role in the adjustment of heart rate in awake resting animals with prevailing vagal activity.

Determination of total blood volume by indicator dilution: a comparison of mean transit time and mass conservation principle.

OBJECTIVE: Using indocyanine green (ICG), blood volume can be determined within minutes according to the mass conservation principle by back-extrapolation of the concentration/time curve to the time of injection (BVTinj) or by the transit time approach (BVMTT) as the product of cardiac output and mean transit time (MTT) of ICG through the circulation. To see which factor accounts for the difference between the two methods we measured cardiac output and MTT independently and compared the volumes with those obtained by dilution of Evans blue (BVEB). DESIGN: Prospective animal study. SETTINGS: University department of experimental anaesthesiology. ANIMALS: Six anaesthetised, spontaneously breathing dogs with chronically implanted ultrasound flow probes around the pulmonary artery. MEASUREMENTS AND RESULTS: BVMTT and BVTinj agreed closely (48 +/- 2 ml.kg-1 and 49 +/- 2 ml.kg-1), but underestimated blood volume by about 40% compared with BVEB (75 +/- 1 ml.kg-1). Transit times measured were 33 +/- 1 s and should be about 50 s as calculated from the quotient of BVEB and cardiac output. CONCLUSIONS: Both methods underestimate blood volume by about the same extent compared with BVEB, probably because slowly perfused compartments are not detected during the short measurement period of 4 min. In the case of the transit time approach, rather short transit times result and in the case of the mass conservation principle, back-extra-polation yields rather high plasma concentrations of ICG at the time of injection. Accordingly, the two methods seem to be equivalent for measuring blood volume rapidly, although the absolute volume is underestimated by about 40%.

Subjective ratings of pain correlate with subcortical-limbic blood flow: an fMRI study.

Studies investigating the cerebral representations of pain using functional imaging techniques failed to elucidate the affective aspects of pain. This investigation used functional magnetic resonance imaging to measure pain-related changes in cerebral activity during painful stimulation with a strong affective component. Vascular pain was induced via balloon dilatation of a dorsal foot vein of healthy volunteers. The subjects rated their perceived pain uninterruptedly during imaging, allowing cerebral activity to be correlated with both stimulus function (boxcar) and, more importantly, subjective ratings reflecting individual pain experience. The findings indicated signal increases in subcortical-limbic regions, particularly in the amygdala. This region is suggested to be involved in the affective dimension of pain.

Inhalation anaesthetics increase heart rate by decreasing cardiac vagal activity in dogs.

Inhalation anaesthetics decrease heart rate in isolated hearts but mostly increase heart rate in the intact organism, although most inhibit sympathetic drive. Differences in the degree of increase in heart rate between agents may be related to differences in their vagolytic action. To test this hypothesis, we studied the effects of halothane (H), isoflurane (I), enflurane (E), sevoflurane (S) and desflurane (D) [1-3 MAC (minimum alveolar concentration)] on heart rate and heart rate variability (HRV) as a measure of cardiac vagal activity in seven dogs. HRV was analysed in the time domain as the standard deviation of the RR interval (SDNN) and in the frequency domain as power in the high-frequency (HF, 0.15-0.5 Hz) and low-frequency (LF, 0.04-0.15 Hz) ranges. Heart rate increased with anaesthetic concentration and there were corresponding decreases in SDNN, HF power and LF power. Heart rate increased most with D (+40 beats min(-1)), least with H (+8 beats min(-1)) and to an intermediate extent with S, I and E. SDNN and HF power, as measures of vagal activity, changed in the opposite direction and decreased in the same order as heart rate increased. However, SDNN and HF power correlated significantly with heart rate [r=-0.81 (0.04) and -0.81 (0.03) respectively] and were independent of the anaesthetic and its concentration (P<0.05). Consistent with our hypothesis, these results suggest that differences between agents in the degree of increase in heart rate are explained by differences in their vagolytic action.

Different response of oxygen consumption and cardiac output to various endogenous and synthetic catecholamines in awake dogs.

OBJECTIVE: To determine whether catecholamines with different adrenergic receptor affinities are characterized by individual relationships between cardiac output (Q) and oxygen consumption (VO2). DESIGN: Comparison of the dose-effect relationships and Q/VO2 relationships of four different catecholamines in the same awake dogs. SETTING: University research department of experimental anesthesiology. SUBJECTS: Ten trained, healthy dogs in the basal metabolic state with chronically implanted ultrasonic flow transducers around the pulmonary artery for the continuous measurement of cardiac output. INTERVENTIONS: Increasing doses of norepinephrine, epinephrine, dobutamine, or dopexamine were infused in a randomly varied sequence on separate days until VO2 and Q reached a maximum. MEASUREMENTS AND MAIN RESULTS: VO2 was measured by indirect calorimetry, and Q was measured via the pulmonary artery by ultrasonic flowmetry. In healthy dogs, catecholamines increased both VO2 and Q in a dose-dependent manner until a plateau was reached when VO2 had doubled and Q had quadrupled compared with baseline conditions. Regardless of the catecholamine, the resulting Q/VO2 relationships were linear up to the maximal effects, but their slopes (s) differed significantly between agents (p < .05, paired sign test) and increased approximately three-fold in the order norepinephrine (s = 34), epinephrine (s = 54), dobutamine (s = 86), and dopexamine (s = 105). Except for norepinephrine, the catecholamines also increased oxygen delivery more than VO2, so that O2 extraction decreased to 40% below baseline. CONCLUSIONS: Catecholamines are characterized by linear Q/VO2 relationships with drug-specific slopes. All agents (except norepinephrine) increased oxygen delivery more than oxygen demand. For the practice of catecholamine therapy, our experiments imply that synthetic agents such as dobutamine and particularly dopexamine may be preferred in the treatment of low cardiac output states because they increase Q with the least metabolic effects.

Metabolic regulation of cardiac output during inhalation anaesthesia in dogs.

BACKGROUND: The metabolic regulation of tissue blood flow manifests itself in a linear relation between blood flow and oxygen consumption, the latter being the independent variable. It is unknown, however, if this fundamental physiological principle operates also during inhalation anaesthesia known to be associated with decreases in both cardiac output (Q) and oxygen consumption (VO2). METHODS: Seven dogs (23-32 kg) with chronically implanted flow probes around the pulmonary artery were repeatedly anaesthetized with halothane, enflurane, isoflurane, sevoflurane, and desflurane at increasing minimum alveolar concentrations (1-3 MAC). Cardiac output (ultrasound transit-time flowmeter) and VO2 (indirect calorimetry) were measured continuously. We also imposed selective changes in Q, and thus of O2 supply, to see if and to what extent this would alter VO2 during anaesthesia (1.5 MAC). RESULTS: In awake dogs under basal metabolic conditions, VO2 was 4.6 +/- 0.1 ml.kg-1.min-1 and Q 105 +/- 3 ml.kg-1.min-1 (mean +/- SEM). During inhalation anaesthesia, VO2 and Q decreased by approximately 30% and 60%, respectively. The concentration-effect relations of both variables did not differ between anaesthetics, yielding a uniform Q/VO2 relation, which was nearly linear in the range (0-2 MAC) with an average slope of 39 +/- 1 (range 30-55). Above 2 MAC, Q decreased more for a given change in VO2, and O2 extraction increased by 50%, indicating compromised oxygen delivery (DO2). Imposed changes in Q, both in awake and anaesthetized dogs, yielded Q/VO2 relations which were notably steeper (slopes 114 to 187) than those observed during inhalation anaesthesia. More important, imposed increases in Q and thus DO2 during anaesthesia (1.5 MAC) to rates comparable to that in the awake state produced a much less than proportional increase in VO2 without restoring it to baseline. CONCLUSIONS: Inhalation anaesthesia is characterized by a uniform Q/VO2 relation with an almost linear course at an anaesthetic concentration up to 2 MAC, regardless of the anaesthetic. Metabolic regulation of blood flow apparently operates also during inhalation anaesthesia up to 2 MAC so that the decrease in VO2 determines Q. This implies that cardiac output alone provides little information on the function of the circulation during inhalation anaesthesia unless related to metabolic demands, i.e. to VO2.

Effects of pulmonary blood volume on vascular reactivity in the lung.

OBJECTIVE: Pulmonary flow resistance is mainly determined by vessel calibres, resulting from the interaction of volume-passive distension and active vasomotion. However, quantitative information on the interplay between these counteracting forces in the lung is lacking. Therefore, we aimed at quantifying (1) the effects of vasomotor tone on pulmonary blood volume (Qp) and (2) the influence of Qp on vascular reactivity. DESIGN: Experimental study in isolated zone III rabbit lungs perfused with autologous blood. SETTING: Research department of experimental anaesthesiology. INTERVENTIONS: Stepwise changes of pulmonary blood flow (Q = 0-200 ml.min-1) and Qp (10-30 ml) were applied independently of each other during normoxia (control), hypoxic vasoconstriction (3% O2) and vasodilation by papaverine (10(-4) M). MEASUREMENTS: The arteriovenous pressure gradient (delta P) was calculated as the difference between the pressures in the pulmonary artery and the left atrium. Qp was continuously measured as reciprocal volume changes in the blood reservoir. RESULTS: Vasomotor interventions did not alter Qp despite substantial changes in pulmonary artery pressure. Vasoconstriction and decreasing Qp shifted the pressure/flow curves to greater delta P, whereas vasodilation, as well as increasing Qp, had the opposite effect. Analysis of the pressure/flow relations by the equation delta P = K.Qm revealed that both parameters (K and m) were functions of Qp but only K was affected by vasoconstriction and vasodilation. K, an indicator of flow resistance, decreased hyperbolically to one-sixth and approached each other as Qp was tripled, whereas m increased only 1.5-fold (0.5-0.8). The factorial changes of K from constricted to dilated states varied from 2 to 2.9 and attained a maximum at Qp = 20 ml. CONCLUSIONS: Pulmonary blood volume, although not affected by vasomotor interventions, attenuates vascular reactivity in the lung.

Incidence and time course of cardiovascular side effects during spinal anesthesia after prophylactic administration of intravenous fluids or vasoconstrictors.

UNLABELLED: We studied the time course of arterial hypotension and/or bradycardia requiring treatment during spinal anesthesia and compared the efficacy of i.v. fluid or vasoconstrictor administration for the prevention of these side effects. Patients (n = 1066) were randomly allocated to either a volume group (lactated Ringer's solution 15 mL/kg within 15 min before spinal anesthesia), a dihydroergotamine group (10 microg/kg i.m. 15 min before anesthesia), or a placebo group. All patients breathed O2-enriched air during spinal anesthesia (4 mL of plain 0.5% bupivacaine). With the placebo, there were side effects (mean incidence 22.9%) for up to 45 min after the start of anesthesia. Dihydroergotamine reduced the incidence of side effects, preferentially the late ones, more (mean incidence 11.8%) than fluid administration (mean incidence 16.9%), which was effective only during the first 15 min of anesthesia. Both heart rate and arterial pressure decreased within 15 min before the manifestation of symptoms. In a subgroup of patients, the incidence of side effects (8%) was greatly reduced by the intraoperative application of both sedatives and opioids. We conclude that cardiovascular side effects may occur at any time during spinal anesthesia. Fluid administration reduced the incidence of early events, but dihydroergotamine the late events. IMPLICATIONS: Cardiovascular side effects requiring treatment occurred at any time during spinal anesthesia in our placebo-controlled study, regardless of the prophylactic regimen (fluid infusions versus dihydroergotamine).

Error in measurement of oxygen and carbon dioxide concentrations by the DeltatracII metabolic monitor in the presence of desflurane.

In experiments in dogs on the metabolic effects of inhalation anaesthetics, we noticed that in the presence of desflurane, oxygen uptake (VO2) measured with the Deltatracll metabolic monitor seemingly increased whereas it decreased when determined independently by the Fick principle. This difference remained even after correction for changes in gas concentration on addition of an inhalation anaesthetic. Therefore, we suspected that desflurane interferes with the measurement of gas concentrations. Using different precision gases, we found that desflurane disturbed both the paramagnetic oxygen sensor and the infrared carbon dioxide detector so that the measured oxygen (when FIO2 was > 0.21) and carbon dioxide concentrations were greater than expected. These errors multiply in the computing process of oxygen uptake by the DeltatracII. When the DeltatracII is to be used during inhalation anaesthesia, its results should be corrected for the presence of an anaesthetic gas. More importantly, corrections must also be made for measurement errors of the oxygen and carbon dioxide sensors, unless the device has been equipped with a modified (nickel membrane) oxygen sensor insensitive to the presence of volatile agents.

Bronchial temperature reflects transcapillary heat transport of isolated blood-perfused rabbit lungs.

The pulmonary capillaries are in such close proximity to the terminal airways that changes in capillary blood temperature should also cause changes in bronchial wall temperature. Therefore, we hypothesized that injection of cold solutions into the pulmonary artery would yield bronchial temperature-time curves similar to those in the pulmonary artery and left atrium. These bronchial curves should mainly represent the capillary bed. Isolated rabbit lungs (n=8) were ventilated (5% CO2 in air) and perfused (autologous blood, 37 degrees C) at various flow rates (50-200 mL x min[-1]). Thermistor probes (diameter 0.46 mm) registered temperature changes in the pulmonary artery, at the bronchial wall (wedge position) and in the left atrium after injection of 0.8 mL Ringer's lactate (0 degrees C) into the pulmonary artery. Bronchial temperature-time curves were found to resemble "dilution" curves located between pulmonary arterial and left atrial curves. Independent of flow rate, their appearance times, peaks and calculated mean transit times were between those from the pulmonary artery and the left atrium. We conclude that bronchial temperature-time curves reflect transcapillary heat transport and that this approach might be useful in gaining further information about vascular transport processes in the interior of the lung.

Pulmonary blood volume and its effects on pressure/flow relations and flow resistance in isolated lungs of rabbits.

Quantitative information about the effects of pulmonary blood volume (Qp) on pulmonary haemodynamics is lacking since Qp changes inevitably with flow. To separate flow-dependent from volume-dependent changes in intravascular pressures we imposed changes in Qp (measured continuously) by altering outflow pressure in seven isolated, blood-perfused rabbit lungs and studied the effects of Qp on the relations between arteriovenous pressure gradient (DeltaP) and blood flow (Q.) under two conditions: flow-dependent volume changes were either permitted or compensated. In the latter circumstances, DeltaP changed more for a given change in Q.. The DeltaP/Q. relations were shifted to smaller DeltaP when Qp was increased. Hence, the calculated flow resistance (R = DeltaP/Q.) decreased with increasing Qp at a given Q.. Assuming constant viscosity, changes in R can be predicted from changes in vessel geometry and thus Qp. We found that R increased less than expected (by a factor of 3-7.5 instead of 9) when Qp was reduced to one-third. This discrepancy may be explained by a change in blood distribution within the lung despite constant Qp and by a change in apparent blood viscosity with Q.. Regardless of these speculations we have shown that Qp determines DeltaP at each flow and thus flow resistance.

Bronchial temperature as a key to the interior pulmonary capillary bed of anaesthetized dogs.

The terminal airways are separated from the surrounding pulmonary capillaries by a tissue layer of a few micrometers in thickness only. Therefore, it should be possible to gain information about in vivo transcapillary heat transport of the interior pulmonary vascular bed by recording the terminal bronchial temperature. For this purpose, we studied temperature-time curves in the pulmonary artery, bronchial system and the aorta of six anaesthetized dogs permanently instrumented for measuring pulmonary blood flow. Thermistors recorded temperature changes at the three locations after injection of 5 ml cold solution into the right atrium. From the observed temperature-time curves mean transit times between the three recording sites were calculated for various pulmonary blood flows (integral of delta Ttdt/integral of delta Tdt) (range 1.1-3.5 1/ min). We found that the temperature-time curves of the bronchial system resemble typical "dilution" curves and are interspaced between those in the pulmonary artery and those in the aorta. Regardless of pulmonary blood flow, mean transit times from the pulmonary artery to the distal bronchial system and from there to the aorta were about equal. We conclude that transcapillary heat transfer generates bronchial temperature-time curves which permit an estimation of the relation of precapillary to postcapillary mean transit times in the interior of the lung.

The role of pain from veins for the formation of perivenous edema in humans.

To test the hypothesis that nociception from veins plays a role in the formation of perivenous edema, we looked at edema along hand veins of humans during painful noxious stimulation in the presence and absence of nerve conduction block. Pain from vascularly isolated hand vein segments was evoked by perfusion with hyperosmolar saline and rated with the help of an electronically controlled visual analogue scale. Perivenous edema measured as changes in skin altitude was continuously recorded by means of infrared reflection. To alternately block the innervation of skin and vein segment we used a perivenous block (vein but not skin numbed), a distal ulnar nerve block (skin but not vein numbed), and a proximal ulnar nerve block (both vein and skin numbed). Without nerve block, hyperosmolar saline always evoked both pain and a continuous increase in perivenous edema to a maximum of 2.0-3.2 mm after 30 min. On painless control perfusions with isoosmolar saline, edema increased slightly (0.2-0.8 mm) to a plateau which was maintained until the end of perfusion. When the vein was denervated by perivenous or proximal ulnar nerve block, hyperosmolar saline evoked a slight increase in edema which resembled that of control perfusions in both extent and time course. On distal ulnar nerve block, which numbed the skin but not the vein, both pain and substantial edema were evoked. These observations show that nociception from veins is a prerequisite for perivenous edema to occur.

Nitric oxide as a chemical link in the generation of pain from veins in humans.

In humans, both nitric oxide (NO) and bradykinin, a naturally occurring algetic and a potent NO liberator, evoke pain from hand veins. The afferent innervation of these veins consists solely of polymodal nociceptors which are located close to the endothelium, a well-known source of NO, thus suggesting NO as a chemical link in nociception. Consistent with this hypothesis, our observations show that neither bradykinin, nor hyperosmolar solutions (a noxious physicochemical stimulus) evoke pain from hand vein segments that have been exposed to the NO-synthase (NOS) inhibitor NG-mono-methyl-L-arginine. An intact NOS pathway is therefore a prerequisite for pain to be evoked by bradykinin and hyperosmolar solutions from veins, indicating for the first time in humans that vascular pain is mediated by NO. Thus, new directions for research on analgesics may be opened.

Nitric oxide evokes pain at nociceptors of the paravascular tissue and veins in humans.

1. Nitric oxide (NO) evokes pain on intracutaneous application, apparently by exciting cutaneous nociceptors. To look for similarities in the responsiveness and sensitivity of other nociceptive systems to NO we determined pain intensity-concentration relations for NO applied to paravascular tissue and veins in humans. 2. NO solutions (0.4-2.0 mM) were either injected paravascularly or perfused through a vascularly isolated hand vein segment. The subjects rated pain continuously with the help of an electronically controlled visual analog scale, which made it possible to determine both the time course (latency, duration) and the intensity of NO-evoked pain. 3. Regardless of where it was applied, at concentrations above 0.7 mM NO always evoked pain of similar time course and concentration dependence. Pain increased proportionally to the concentration of applied NO, reaching subjects' tolerance maximum at four to five times the threshold concentration. 4. Pain intensity-NO concentration relations were congruent, indicating that the respective nociceptive systems are equally sensitive to NO. 5. Our observations are consistent with the hypothesis that NO is a chemical link in peripheral nociception.

The nociceptive systems of skin, paravascular tissue and hand veins of humans and their sensitivity to bradykinin.

To study the pain-evoking properties of bradykinn on the nociceptive systems of skin, paravascular tissue and hand veins of humans, bradykinin was injected intracutaneously, retrogradially into occluded finger veins for reaching the paravascular tissue or into vascularly isolated hand vein segments of seven subjects. Regardless of the injection site, bradykinin always evoked pain of concentration-related intensity within nearly similar concentration ranges of 0.1-10.0 microM, yielding congruent pain intensity-concentration relations. Thus, in humans, the nociceptive systems of skin, deep tissue and hand veins are equally sensitive to the endogenous algetic bradykinin.

Atrial natriuretic peptide alters neither capillary filtration nor vascular compliance of both skin and skeletal muscle of humans.

We studied the effects of hANP 99-126 on capillary filtration and venous compliance in both the calf (mainly skeletal muscle) and foot (mainly skin) of humans. Six healthy mean received ANP (intravenous injection of 25 micrograms followed by continuous infusion of 0.1 microgram.kg-1.min-1) for 30 min. Another six men served as time controls. Capillary filtration coefficient, venous compliance, and also volume and blood flow of both calf and foot were measured repeatedly by occlusion plethysmography before, during, and after ANP. Additionally, we determined hematocrit, central venous pressure, venous pressure in the foot, arterial pressure, and heart rate. Filtration coefficients, venous compliance, blood flow of both calf and foot as well as arterial blood pressure did not change systematically during the infusion of ANP, and yet leg volume and central venous pressure (3.1 +/- 0.8 cm H2O) decreased while both hematocrit (3.1 +/- 1.0%) and heart rate (17 +/- 11 min-1) increased. Thus, the ANP-evoked decrease in central venous pressure and increase in hematocrit are unrelated to blood pooling or increases in capillary filtration in skeletal muscle and skin of healthy humans.

Nitric oxide evokes pain in humans on intracutaneous injection.

To test the hypothesis that nitric oxide (NO) acts algetically in humans, we determined pain intensity/dose relations for intracutaneously applied NO solutions. NO, dissolved in isoosmolar phosphate buffer, was injected in the forearm of six volunteers and the subjects rated NO-evoked pain continuously with the help of an electronically controlled visual analogue scale. Pain always occurred at a NO dose of 12 nmol, increased with dose and reached the tolerance maximum at 50 nmol. This shows for the first time the genuine pain evoking properties of NO.

[The circulatory effect of conduction anesthesia near the spinal cord. Pathogenesis, prophylaxis and therapy of heart circulation complications]. / Kreislaufeffekte rückenmarknaher Leitungsanästhesien. Pathogenese, Prophylaxe und Therapie von Herz-Kreislaufkomplikationen.

Major conduction anaesthesia is not harmless. Based on new findings about sympathetic blockade, it was analysed whether circulatory side effects after spinal or epidural anaesthesia, in particular cardiocirculatory arrest, correlate with the level of segmental spread and whether prophylactic or therapeutic measures are effective. With spinal or epidural anaesthesia in healthy, unpremedicated patients, blood pressure, heart rate, and cardiac output remain within +/- 20% of normal independent of the height of segmental spread. However, in patients with circulatory diseases and/or premedication blood pressure often drops more than 20%, especially when cranial spread exceeds T4. Cardiocirculatory arrest during major conduction anaesthesia: (1) is preceded by an interval of 10-20 min recognisable by narrowing of the pulse pressure and continuous decreases in blood pressure and heart rate; (2) does not correlate with the level of segmental spread; and (3) is possibly caused by reduced filling of the heart and/or vagal activity. Infusion of crystalloid or colloid solutions may diminish the drop in blood pressure, whereas vasopressors reduce the frequency and extent of cardiocirculatory side effects. As yet, however, there is no safe prophylaxis to prevent cardiocirculatory arrest. Cardiopulmonary resuscitation after circulatory arrest must be combined with early administration of catecholamines.