Intravenous treatment with rimiterol and salbutamol in asthma.

The bronchodilating efficacies and beta2-adrenoceptor selectivities of rimiterol (0.2, 0.1, and 0.05 mug kg-minus1 min-minus1) and sal-utamol (0.1, 0.5, and 0.025 mug kg-minus1 min-minus1), intravenously infused for one hour, were determined in five patients with chronic asthma. Each drug infusion produced and maintained a dose-related improvement in forced expiratory volune in one second (FEV1). A further increase in FEV1 was produced by inhalation of the same drug by pressurized aerosol at the end of each infusion, which suggested that no resistance had occurred. Similar dose-related increases in heart rate, pulse pressure, and skeletal muscular tremor were produced by each drug. Peak heart rate increases varied greatly between individuals, ranging from 12 to 30 beats/min with the high doses but always less than 10 beats/min with the low doses of each drug. On rimiterol the heart rate reached equilibrium earlier during the infusions and declined more rapidly after they had stopped, thus providing an accurate means for monitoring dosage. Rimeterol with its short half life-a desirable property for an intravenous drug with respect to safety-may prove to be a valuable bronchodilator in severe asthma when intravenous infusions are indicated.     

Interaction between depressor and pressor reflexes arising from the aorta in dogs

In 18 dogs anesthetized with morphine-chloralose the interaction between the aortic nerve (AN) pressor and depressor reflexes was studied. Low-intensity, high-frequency electrical stimulation of the AN causes large decreases in heart rate and systemic pressure characteristic of baroreflex responses. High-intensity, low-frequency stimulation of the AN causes modest increases in heart rate and systemic pressure similar to the responses observed to intraaortic nicotine. Simultaneous electrical stimulation of these antagonistic reflexes results in much smaller (P less than 0.001) reductions in heart rate and systemic pressure that can be explained on the basis of simple addition of the individual responses. Similarly the AN depressor reflexes are suppressed during intraaortic infusions of nicotine (40 micrograms/min). The results suggest that the inhibitory effects of the AN baroreflexes are suppressed by the aortic chemoreflexes . This interaction occurs in the CNS rather than at the level of the heart or vascular smooth muscle.     

Improvement of the isoprenaline infusion test by plasma concentration measurements

A simple and sensitive method for the determination of isoprenaline (ISO) in plasma by high performance liquid chromatography (HPLC) with electrochemical detection is presented. Blood pressure and heart rate responses to i.v. infusion of ISO (15, 38 and 76 ng/kg/min) were studied in 15 subjects. Blood samples for ISO analyses were drawn after 7.5 min infusions on each dose level. A four- to six-fold interindividual variation in the venous plasma concentrations of ISO was found. Comparisons were made between estimates of the sensitivity to ISO from concentration-effect and dose-effect curves for both heart rate and diastolic blood pressure responses. Despite an overall correlation between the two methods of estimating ISO sensitivity, individual estimates of sensitivity differed markedly due to the differences in the plasma concentrations attained during infusions of standardized doses of ISO. The venous plasma concentration of ISO required to elevate heart rate by 25 beats/min (CC25) varied between 0.3 and 1.7 nM, whereas the corresponding dose of ISO (CD25) varied between 10 and 27 ng/kg/min.     

Effect of central naloxone on hormone and blood pressure responses to hemorrhage in conscious sheep

The role of the brain opioid system in the control of hypothalamic-pituitary-adrenal activity was studied in 10 conscious sheep with an indwelling cannula in a cerebral lateral ventricle. On separate days, sheep received infusions of artificial CSF (control) and the opiate antagonist, naloxone (100 micrograms/hr) before and during acute moderate hemorrhage (15 ml/kg over 10 min). Infusion of naloxone before hemorrhage raised plasma ACTH and resulted in a significant increase in cortisol compared to the control infusion. In contrast, ACTH and cortisol responses to hemorrhage tended to be blunted by central naloxone infusion. The responses of vasopressin, aldosterone and the catecholamines remained unaffected by naloxone. The fall in blood pressure and the rise in heart rate accompanying hemorrhage were likewise unaltered. These results suggest that brain opioid peptides have an inhibitory effect on basal ACTH secretion but do not play a major role in modulating the hemodynamic or pituitary-adrenal responses to acute moderate hemorrhage in conscious sheep.     

Vagal blockade does not prevent adrenocorticotropin, cortisol, and cardiopulmonary responses to thromboxane A2.

Previously, we reported that thromboxane A2 (TxA2) mediates heart rate, adrenocorticotropin (ACTH), cortisol, and blood gas responses, although the specific site of action was not identified. In the present study, we interrupted vagal nervous transmission in chronically instrumented conscious sheep and infused the TxA2 mimetic U46619 or saline into the carotid artery or U46619 into the vena cava to determine whether TxA2 acts at vagal afferent nerves. Heart rate increased in all three groups during vagal blockade, and responses were not different between groups. Carotid artery and intravenous infusions of U46619 resulted in an increase in blood pressure, but responses were not different between groups. PaO2 decreased in response to vagal blockade in all groups, and responses were not different among groups. Arterial pH increased and PaCO2 decreased during vagal blockade in response to carotid artery U46619 infusions but not in response to vagal blockade alone or combined with carotid artery saline or intravenous U46619. ACTH, cortisol, and hematocrit increased significantly in response to carotid artery infusions of U46619 during vagal blockade but not in response to carotid artery saline or intravenous U46619 infusions. In summary, carotid artery infusions of TxA2 mimetic result in ACTH, cortisol, PaCO2, pHa, and hematocrit responses that are not prevented by vagal blockade. We conclude that these responses are mediated at a site perfused by the carotid vasculature and not at a site innervated by the vagal nerves, findings consistent with the hypothesis that TxA2 acts on the brain to mediate cardiopulmonary and pituitary-adrenal responses.     

Role of the area postrema in angiotensin II modulation of baroreflex control of heart rate in conscious mice

This study reports the effects of angiotensin II (ANG II), arginine vasopression (AVP), phenylephrine (PE), and sodium nitroprusside (SNP) on baroreflex control of heart rate in the presence and absence of the area postrema (AP) in conscious mice. In intact, sham-lesioned mice, baroreflex-induced decreases in heart rate due to increases in arterial pressure with intravenous infusions of ANG II were significantly less than those observed with similar increases in arterial pressure with PE (slope: -3.0 +/- 0.9 vs. -8.1 +/- 1.5 beats x min(-1) x mmHg(-1)). Baroreflex-induced decreases in heart rate due to increases in arterial pressure with intravenous infusions of AVP were the same as those observed with PE in sham animals (slope: -5.8 +/- 0.7 vs. -8.1 +/- 1.5 beats x min(-1) x mmHg(-1)). After the AP was lesioned, the slope of baroreflex inhibition of heart rate was the same whether pressure was increased with ANG II, AVP, or PE. The slope of the baroreflex-induced increases in heart rate due to decreases in arterial blood pressure with SNP were the same in sham- and AP-lesioned animals. These results indicate that, similar to other species, in mice the ability of ANG II to acutely reset baroreflex control of heart rate is dependent on an intact AP.     

Simultaneous biofeedback of heart rate and frontal EMG as a pretraining for the control of EEG theta activity

Following one base-line session, 20 normal subjects received four half hour sessions consisting of simultaneous feedback of heart rate and frontalis muscle (pretraining). Ten subjects received contingent (CF), the other ten noncontingent feedback (NCF). Subjects were asked to lower heart rate and frontal muscle tension (EMG). Heart rate within sessions decreased up to 19 bpm, with a mean of 4 bpm for the CF group. There was only a weak decrease over sessions, however, because of the strong habituation effect. The following events accompanied the heart rate decrease: (1) an increase of the variability of the heart rate, (2) a decrease of the variance of the EMG, (3) an increased correlation between heart rate slowing and EMG decrease, and (4) an increasing subjective experience of control of heart rate and EMG. After pretraining, subjects received eight sessions of auditory feedback of their frontal EEG theta activity (four sessions with CF and four sessions with NCF in balanced order). There was a weak increase of theta for the CF condition over sessions, but a decrease within the sessions. Pretraining on heart rate and frontal EMG control had no influence on the performance during theta training. It was hypothesized that control of heart rate slowing and theta control involve different mechanisms.     

The role of behavioral conditioning in the cardiovascular adjustment to exercise

The purpose of this study was to determine if normal subjects could be trained to attenuate their cardiovascular responses while exercising on a bicycle ergometer. Ten young, untrained subjects exercised on a bicycle ergometer for five sessions. Half of the group was asked to slow their heart rate while exercising with heart rate feedback during exercise. Their average heart rate increase was 20% less than that of the control subjects, who exercised without feedback. The control subjects subsequently also received feedback during exercise and they were able to attenuate their heart rate responses comparably. Systolic blood pressure was not affected by feedback training. Changes in rate-pressure product paralleled changes in heart rate. These data show that autonomically mediated adjustments to exercise can be brought under experimental control through the use of appropriate behavioral techniques.     

Cardiovascular effects of prostaglandin D3 and D2 in anesthetized dogs

Prostaglandin (PG) D₃ has been identified as an inhibitor of human platelet aggregation, but little is known of the hemodynamic activity of this material. In morphine pretreated, chloralose-urethan anesthetized dogs, bolus intravenous injections (1, 3.2 and 10 μg/kg) of PGD₃ and also PGD₂ were associated with marked, dose-related increases in pulmonary arterial pressure. Cardiac index and rate increased, while peripheral vascular resistance decreased in response to injections of PGD₃. A biphasic (depressor followed by a pressor phase) effect on systemic arterial pressure was observed after PGD₂, while PGD₃ was associated with dose-related depressor responses. Graded intravenous infusions (0.25, 0.50 and 1.0 μg/kg/min) of PGD₃ and PGD₂ were associated with qualitatively similar cardiovascular responses. Quantitatively, PGD₃ infusions were associated with greater decreases in peripheral vascular resistance and greater increases in cardiac output, heart rate, and peak left ventricular dp/dt than were infusions of PGD₂. In contrast, PGD₃ was less potent than PGD₂ as a pulmonary pressor material. Systemic arterial pressure responses to infusions of the prostaglandins were variable. In these experiments, PGD₃ and PGD₂ were associated with qualitatively similar cardiovascular responses characterized by peripheral vasodilatation.     

Postvagal potentiation of the chronotropic effect of norepinephrine

Following termination of vagal stimulation, heart rate increases above control (postvagal tachycardia). This phenomenon has been attributed to vagally mediated release of norepinephrine in the sinus node region, although other contributory factors may be important. The possibility that, during the postvagal period, the chronotropic efficacy of norepinephrine is enhanced was investigated. Mongrel dogs (N = 6) were pretreated with reserpine in order to minimize postvagal tachycardia and hence allow reliable detection of enhanced responsiveness to norepinephrine. The dogs were then anesthetized with chloralose, autonomically decentralized, and instrumented to record electrocardiogram, aortic blood pressure, and electrograms from right atrium and right ventricle. Thirty-, forty-, or sixty-second infusions of norepinephrine were administered via the sinus node artery. The mean cycle length decrease produced by norepinephrine alone was 95 msec (which corresponds to a heart rate increase of + 19.6 bpm). After a 30-sec period of vagal stimulation, norepinephrine infusions produced a cycle length decrease of 139 msec (+32.5 bpm). These results are significant at the P less than 0.05 level. It is concluded that norepinephrine infusions produce a significantly greater magnitude of tachycardia when administered postvagally. It is proposed that this postvagal potentiation of the chronotropic effect of norepinephrine may contribute to postvagal tachycardia. Indeed, there may be a synergistic relationship between this phenomenon and vagally mediated release of norepinephrine in the mediation of postvagal tachycardia.     

Vasodilative and anti-adrenergic effects of adenosine in diabetic rat hearts.

To determine the vasodilative and negative inotropic effects of adenosine in hearts of diabetic rats, isolated hearts, perfused at constant perfusion pressure (Langendorff technique), were prepared from age-matched control Wistar rats and rats made diabetic 10 weeks prior to study by a single injection of streptozotocin (65 mg.kg-1, i.p.). Adenosine and nitroprusside each increased coronary inflow when administered either as bolus injections or as infusions. Coronary flow responses to nitroprusside were unchanged in diabetic hearts. Coronary flow responses of diabetic hearts to adenosine injections were unchanged, but responses to adenosine infusions tended to be larger than in normal hearts. Diabetes had no significant effect on the EC50 for either vasodilator. Adenosine inhibited the inotropic effect of isoproterenol (enhanced left ventricular (LV) pressure (P) and LV dP/dtmax) in normal hearts, independently of its vasodilative action. This negative inotropic action of adenosine appeared equally strong in diabetic hearts. We conclude that adenosine's coronary vasodilative and anti-beta-adrenergic, negative inotropic effects in the rat heart were not diminished after 10 weeks of streptozotocin-induced diabetes mellitus. Thus, earlier reports of diminished adenosine dilative efficacy in experimental diabetes may have been unique to those particular models.     

5-Hydroxytryptamine inhibits the tachycardia induced by selective preganglionic sympathetic stimulation in pithed rats.

It has been shown in several species that serotonin (5-hydroxytryptamine; 5-HT) is able to inhibit the responses produced by sympathetic stimulation in a wide variety of blood vessels and other organs, including the heart. However, in pithed rats, the analysis of potential sympatho-inhibitory actions of 5-HT is hampered by the fact that 5-HT (given as i.v. bolus injections) produces tachycardia per se. Moreover, most studies have investigated 5-HT-induced sympatho-inhibition at only one frequency of stimulation. Thus, the present study set out to find the experimental conditions to overcome these problems. In this regard, we analyzed the potential ability of 5-HT, administered as i.v. continuous infusions, to inhibit the tachycardia caused by stimulation of the preganglionic (C7-T1) sympathetic outflow in pithed rats. Sympathetic cardiostimulation (0.01-3 Hz) resulted in frequency-dependent increases in heart rate; these responses were potentiated after desipramine (50 microg/kg, i.v.). During continuous infusions of 5-HT (3.1-10 microg/kg.min, i.v.), but not saline, the sympathetically-induced tachycardia was dose-dependently inhibited in both control and desipramine-pretreated rats. This inhibitory effect of 5-HT was significantly more pronounced at lower frequencies of stimulation. In contrast, the above infusions of 5-HT did not inhibit the tachycardia induced by i.v. bolus injections of noradrenaline in both control and desipramine-pretreated rats. Taken together, the above findings confirm that 5-HT induces inhibition of the sympathetic chronotropic outflow in the rat by acting at receptors located prejunctionally, without evoking tachycardia, over a wide range of stimulation frequencies.     

Automated drug delivery system to control systemic arterial pressure, cardiac output, and left heart filling pressure in acute decompensated heart failure.

Pharmacological support with inotropes and vasodilators to control decompensated hemodynamics requires strict monitoring of patient condition and frequent adjustments of drug infusion rates, which is difficult and time-consuming, especially in hemodynamically unstable patients. To overcome this difficulty, we have developed a novel automated drug delivery system for simultaneous control of systemic arterial pressure (AP), cardiac output (CO), and left atrial pressure (Pla). Previous systems attempted to directly control AP and CO by estimating their responses to drug infusions. This approach is inapplicable because of the difficulties to estimate simultaneous AP, CO, and Pla responses to the infusion of multiple drugs. The circulatory equilibrium framework developed previously (Uemura K, Sugimachi M, Kawada T, Kamiya A, Jin Y, Kashihara K, and Sunagawa K. Am J Physiol Heart Circ Physiol 286: H2376-H2385, 2004) indicates that AP, CO, and Pla are determined by an equilibrium of the pumping ability of the left heart (SL), stressed blood volume (V), and systemic arterial resistance (R). Our system directly controls SL with dobutamine, V with dextran/furosemide, and R with nitroprusside, thereby controlling the three variables. We evaluated the efficacy of our system in 12 anesthetized dogs with acute decompensated heart failure. Once activated, the system restored SL, V, and R within 30 min, resulting in the restoration of normal AP, CO, and Pla. Steady-state deviations from target values were small for AP [4.4 mmHg (SD 2.6)], CO [5.4 ml x min(-1) x kg(-1) (SD 2.4)] and Pla [0.8 mmHg (SD 0.6)]. In conclusion, by directly controlling the mechanical determinants of circulation, our system has enabled simultaneous control of AP, CO, and Pla with good accuracy and stability.     

Effect of human atrial natriuretic peptide on blood pressure after sodium depletion in essential hypertension.

Human atrial natriuretic peptide was infused over four hours in three patients with essential hypertension. When the patients had a sodium intake of 200 mmol (mEq) daily an infusion of 0.5 micrograms atrial natriuretic peptide/min caused no significant change in blood pressure, whereas an infusion of 1.0 micrograms/min caused a gradual decrease in blood pressure and an increase in heart rate. After two to three hours of infusion with the higher dose two patients showed a sudden decrease in heart rate, with symptomatic hypotension. When the same patients had an intake of 50 mmol sodium daily their blood pressure was more sensitive to infusion of atrial natriuretic peptide; one patient again developed symptomatic hypotension, this time during an infusion of 0.5 micrograms/min. During all infusions distinct natriuresis occurred irrespective of whether blood pressure was affected. Prolonged, relatively low dose infusions of atrial natriuretic peptide can cause unwanted symptomatic hypotension. The effect on blood pressure is enhanced after sodium depletion, and blood pressure should be monitored carefully during longer infusions of atrial natriuretic peptide in patients with essential hypertension.     

Increased cardiac sympathetic nerve activity in heart failure is not due to desensitization of the arterial baroreflex

Increased sympathetic drive to the heart worsens prognosis in heart failure, but the level of cardiac sympathetic nerve activity (CSNA) has been assessed only by indirect methods, which do not permit testing of whether its control by arterial baroreceptors is defective. To do this, CSNA was measured directly in 16 female sheep, 8 of which had been ventricularly paced at 200-220 beats/min for 4-6 wk, until their ejection fraction fell to between 35 and 40%. Recording electrodes were surgically implanted in the cardiac sympathetic nerves, and after 3 days' recovery the responses to intravenous phenylephrine and nitroprusside infusions were measured in conscious sheep. Electrophysiological recordings showed that resting CSNA (bursts/100 heartbeats) was significantly elevated in heart-failure sheep (89 +/- 3) compared with normal animals (46 +/- 6; P < 0.001). This increased CSNA was not accompanied by any increase in the low-frequency power of heart-rate variability. The baroreceptor-heart rate reflex was significantly depressed in heart failure (maximum gain -3.29 +/- 0.56 vs. -5.34 +/- 0.66 beats.min(-1).mmHg(-1) in normal animals), confirming published findings. In contrast, the baroreflex control of CSNA was undiminished (maximum gain in heart failure -6.33 +/- 1.06 vs. -6.03 +/- 0.95%max/mmHg in normal sheep). Direct recordings in a sheep model of heart failure thus show that resting CSNA is strikingly increased, but this is not due to defective control by arterial baroreceptors.     

Baroreflex modulation of muscle sympathetic nerve activity during cold pressor test in humans

The purpose of this project was to test the hypothesis that baroreceptor modulation of muscle sympathetic nerve activity (MSNA) and heart rate is altered during the cold pressor test. Ten subjects were exposed to a cold pressor test by immersing a hand in ice water for 3 min while arterial blood pressure, heart rate, and MSNA were recorded. During the second and third minute of the cold pressor test, blood pressure was lowered and then raised by intravenous bolus infusions of sodium nitroprusside and phenylephrine HCl, respectively. The slope of the relationship between MSNA and diastolic blood pressure was more negative (P < 0.005) during the cold pressor test (-244.9 +/- 26.3 units x beat(-1) x mmHg(-1)) when compared with control conditions (-138.8 +/- 18.6 units x beat(-1) x mmHg(-1)), whereas no significant change in the slope of the relationship between heart rate and systolic blood pressure was observed. These data suggest that baroreceptors remain capable of modulating MSNA and heart rate during a cold pressor test; however, the sensitivity of baroreflex modulation of MSNA is elevated without altering the sensitivity of baroreflex control of heart rate.     

Parameters of the circadian rhythm of pineal melatonin secretion affecting reproductive responses in Siberian hamsters

The major function of the mammalian pineal gland appears to be its central role in photoperiodism. The pineal hormone, melatonin, is synthesized and secreted primarily at night, under the control of a circadian oscillator that is entrained to the light-dark cycle. Both the circadian phase and the duration of the nocturnal peak of melatonin secretion are established primarily by interactions between the endogenous circadian oscillator and the daily photic cycle. The duration of the melatonin peak varies inversely with day length, and this relationship between day length and the duration of each circadian melatonin peak appears to be an integral part of the photoperiodic mechanism. When pinealectomized animals are given daily melatonin infusions of long duration, they exhibit physiologic responses that normally are observed during exposure to short day photoperiods; when administered short-duration melatonin infusions, the animals display long photoperiod-type responses. In addition to the importance of the duration of each melatonin peak, certain other parameters appear to be significant. If a long-duration infusion of melatonin is interrupted by a period of 2 hours or more without melatonin (i.e., to produce two short duration infusions), the responses are those typical for long day-exposed animals. Thus, to elicit short day-type responses, each long-duration melatonin peak must be relatively continuous; responses are not determined simply by the total time of exposure to melatonin in each circadian cycle. Also, long-duration melatonin peaks may not be effective to elicit photoperiod-type responses unless they are present at frequencies of nearly once every 24 hours or more.     

Contingency in ecosystem but not plant community response to multiple global change factors

Community and ecosystem responses to global environmental change are contingent on the magnitude of change and interacting global change factors. To reveal whether responses are also contingent on the magnitude of each interacting factor, multifactor, multilevel experiments are required, but are rarely conducted. We exposed model grassland ecosystems to six levels of atmospheric CO(2) and six levels of nitrogen enrichment, applying the latter both chronically (simulating deposition) and acutely (simulating fertilization). The 66 treatments were maintained for 6?months under controlled growing conditions, with biomass harvested every 28?d and sorted to species. Aboveground plant productivity responses to CO(2) were contingent on nitrogen amount, and the responses to nitrogen amount were dependent on whether applications were chronic or acute. Specifically, productivity responses to increasing CO(2) concentrations were accentuated with higher nitrogen enrichments, and productivity was greater when higher nitrogen enrichments were applied acutely. Plant community composition was influenced only by nitrogen enrichment, where the co-dominant grass species with the greatest leaf trait plasticity increasingly dominated with higher nitrogen amounts. Community processes are considered to be unpredictable, but our data suggest that the prediction of the impacts of simultaneous global changes is more complex for ecosystem processes, given that their responses are contingent on the levels of interacting factors.     

Vascular responses to plasma hypoosmolality in man.

To study limb vascular responses to plasma hypoosmolality in man, we infused test solutions of hypoosmolar NaCl (145 mOsm/kg) and control solutions of isosmolar NaCl (290 mOsm/kg) into the brachial arteries of 14 mornotensive and 13 essential hypertensive patients. Limb blood pressures were monitored, limb blood flow was measured by indicator-dilution, and limb vascular resistance was calculated as mmHg/ml flow/min/100 cm3 limb volume. The infusions did not significantly change systemic plasma osmolality, sodium concentration, or blood pressure. Compared to control infusions, the hypoosmolar infusions decreased limb venous plasma osmolality and serum sodium concentrations by an average of 12 mOsm/kg and 7 mEq/1, respectively. Compared to control infusions, limb venous serum concentrations of potassium, calcium, magnesium, or blood hematocrit were not altered by the hypoosmolar infusions. In response to the hypoosmolar infusions, limb resistance increased by 28% in normotensives and by 26% in hypertensives. We conclude that the acute local vascular response to a small reduction in plasma osmolality in the limb of man is a large increase in vascular resistance. We found no evidence for abnormal responses to plasma hypoosmolality in essential hypertensives.     

Effect of intravenous infusion of salbutamol on ventilatory response to carbon dioxide and hypoxia and on heart rate and plasma potassium in normal men.

Intravenous infusion of salbutamol 10 mug/min in seven healthy subjects significantly increased their ventilatory responses to inhaled CO2 in both hypoxia and hyperoxia. These changes in chemical control of breathing are unlikely to be significant when the drug is used in severe asthma but may benefit patients with acute exacerbations of chronic ventilatory failure. The infusion also increased heart rate, which was most pronounced when hypoxia was combined with hypercapnia. The infusion produced an average fall in plasma potassium from 3-99 to 3-10 mmol/l, which was associated with an increase in plasma glucose and serum insulin, suggesting that this arose from a shift of potassium from the extracellular to the intracellular space. Routine monitoring of plasma potassium and the electrocardiogram is indicated when an intravenous salbutamol infusion is used to treat severe asthma as the drug may predispose to cardiac dysrhythmias.