Maximum Tachycardia Research Articles

The brisk-standing-test for long QT syndrome in prepubertal school children: defining normal.

Long QT syndrome (LQTS) is associated with malignant arrhythmias and sudden death from birth to advanced age. Prolongation of the QT-interval, may however be concealed on standard electrocardiograms (ECG). The brisk-standing-test (BST) was developed to guide LQTS-diagnosis and treatment in adults. We hypothesized that the BST may be used in prepubertal children to identify LQTS subjects. Accordingly, reference values for the BST should be available to prevent incorrect diagnosis and treatment of LQTS. In this study, we aim to present reference values for prepubertal children. Healthy, prepubertal children, aged 7-13 years underwent a standard supine resting ECG and during continuous ECG recording performed a BST. The QT-interval and heart rate corrected QTc were measured during the different BST stages. Fifty-seven children, 29 boys (10.2 ± 1.1 years) and 28 girls (9.9 ± 1.1 years) were included. Baseline characteristics and response to standing were not statistically different for boys and girls: mean supine pre-standing heart rate 74 ± 9 vs. 77 ± 9 bpm, supine pre-standing QTc 406 ± 27 vs. 407 ± 17 ms, maximal heart rate upon standing 109 ± 11 vs. 112 ± 11 bpm, and QTc at maximal heart rate 484 ± 29 vs. 487 ± 35 ms. The QT interval corrected for heart rate-prolongation at maximal tachycardia after standing was 79 ± 26 (19-144) ms, which is significantly longer than previously published values in adults (50± 30 ms). The QT interval corrected for heart rate prolongation after brisk standing in healthy prepubertal children is more pronounced than in healthy adults. This finding advocates distinct prepubertal cut-off values because using adult values for prepubertal children would yield false positive results with the risk of incorrect LQTS-diagnosis and overtreatment.

Maximal tachycardia and high cardiac strain during night shifts of emergency physicians.

To compare tachycardia and cardiac strain between 24-hour shifts (24hS) and 14-hour night shifts (14hS) in emergency physicians (EPs), and to investigate key factors influencing tachycardia and cardiac strain. We monitored heart rate (HR) with Holter-ECG in a shift-randomized trial comparing a 24hS, a 14hS, and a control day, within a potential for 19 EPs. We also measured 24-h HR the third day (D3) after both shifts. We measured perceived stress by visual analog scale and the number of life-and-death emergencies. The 17 EPs completing the whole protocol reached maximal HR (180.9 ± 6.9bpm) during both shifts. Minutes of tachycardia >100bpm were higher in 24hS (208.3 ± 63.8) than in any other days (14hS: 142.3 ± 36.9; D3/14hS: 64.8 ± 31.4; D3/24hS: 57.6 ± 19.1; control day: 39.2 ± 11.6min, p < .05). Shifts induced a cardiac strain twice higher than in days not involving patients contact. Each life-and-death emergency enhanced 26min of tachycardia ≥100bpm (p < .001), 7min ≥ 110bpm (p < .001), 2min ≥ 120bpm (p < .001) and 19min of cardiac strain ≥30% (p = .014). Stress was associated with greater duration of tachycardia ≥100, 110 and 120bpm, and of cardiac strain ≥30% (p < .001). We demonstrated several incidences of maximal HR during shifts combined with a high cardiac strain. Duration of tachycardia were the highest in 24hS and lasted several hours. Such values are comparable to those of workers exposed to high physical demanding tasks or heat. Therefore, we suggest that EPs limit their exposure to 24hS. We, furthermore, demonstrated benefits of HR monitoring for identifying stressful events. ClinicalTrials.gov identifier: NCT01874704.

The effects of cocaine on heart rate and electrocardiogram in zebrafish (Danio rerio)

Zebrafish (Danio rerio) have been used as a model organism to explore the genetic basis for responsiveness to addictive drugs like cocaine. However, very little is known about how the physiological response to cocaine is mediated in zebrafish. In the present study electrocardiograms (ECGs) were recorded from adult zebrafish treated with cocaine. Treatment with cocaine resulted in a bell-shaped dose response curve with a maximal change in heart rate seen using 5mg/L cocaine. Higher doses resulted in a higher percentage of fish showing bradycardia. The cocaine-induced tachycardia was blocked by co-treatment with propranolol, a β-adrenergic antagonist, but potentiated by co-treatment with phentolamine, an α-adrenergic antagonist. Co-treatment with atropine, a classic cholinergic antagonist, had no effect on cocaine-induced tachycardia. Cocaine treatment of adult fish changed the ECG of treated fish, inducing a dose-dependent increase in QT interval after adjusting for heart rate (QTc), while not affecting the PR or QRS intervals. The acute effects of cocaine on heart rate were examined in 5-day old embryos to see if zebrafish might serve as a suitable model organism to study possible links of embryonic physiological response to subsequent adult behavioral response to the drug. Cocaine treatment of 5-day old zebrafish embryos also resulted in a bell-shaped dose response curve, with maximal tachycardia achieved with 10mg/L. The response in embryonic fish was thus comparable to that in adults and raises the possibility that the effects of embryonic exposure to cocaine on the developing cardiovascular system can be effectively modeled in zebrafish.

Abstract 9481: The Response of the Qt Interval and the T-wave Morphology to Sudden Tachycardia Provoked by Standing in Young Athletes

Background: the response of the QT interval to the sudden tachycardia provoked by standing can aid in the diagnosis of the long QT syndrome (LQTS). It is therefore important to know what is the normal response to this maneuver. The aim of this study was to characterise the response of the QT interval and the T-wave morphology following this provocation test in young healthy athletes. Methods: ECG was analysed as part of a prospective study about the impact of cardiovascular screening with ECG in young (14-35 years) athletes. ECG was performed after 5 minute of supine resting. Athletes without cardiac abnormalities, not taking drugs and with normal ECG (QTc for men &lt; 450 msec, for women &lt; 460 msec) were asked to stand up quickly with continuous ECG monitoring for 30”. Heart rate, QT, QTc (Bazett) and T-wave morphology [normal, biphasic, notched G1 (T2&gt;T1), notched G2 (T2&gt;&gt;T1)] were analysed at baseline and at maximal tachycardia. Results: ECG of 289 athletes was analysed (76 % men, mean age 18.4 ± 5.6 years). Baseline parameters were following: heart rate 69 ± 11/min, QT 378 ± 27 msec, QTc 401 ± 21 msec. After standing, the maximal heart rate was 101 ± 13/min. QT was 361 ± 28 msec (shortening by 17 ±11 msec). In 4 % of athletes QT increased by 10-20 msec. QTc was 466 ± 30 msec (lengthening of 65 ± 24 msec). In 12 % of athletes QTc was ≥ 500 msec. T-wave morphology during tachycardia were notched G2 in 6% of athletes. During tachycardia, 15 % of athletes displayed a QTc ≥ 500 msec or QT lengthening or notched G2 morphology of T waves. Conclusions: During sudden tachycardia, a significant proportion of healthy young athletes demonstrated QTc interval and changes of T-wave morphology in the magnitude observed in patients with the LQTS. Caution should be applied in interpreting these parameters in ECG tracing and Holter monitoring displaying sudden oscillations of heart rate in this population.

The Response of the QT Interval to the Brief Tachycardia Provoked by Standing: A Bedside Test for Diagnosing Long QT Syndrome

This study was undertaken to determine whether the short-lived sinus tachycardia that occurs during standing will expose changes in the QT interval that are of diagnostic value.The QT interval shortens during heart rate acceleration, but this response is not instantaneous. We tested whether the transient, sudden sinus tachycardia that occurs during standing would expose abnormal QT interval prolongation in patients with long QT syndrome (LQTS).Patients (68 with LQTS [LQT1 46%, LQT2 41%, LQT3 4%, not genotyped 9%] and 82 control subjects) underwent a baseline electrocardiogram (ECG) while resting in the supine position and were then asked to get up quickly and stand still during continuous ECG recording. The QT interval was studied at baseline and during maximal sinus tachycardia, maximal QT interval prolongation, and maximal QT interval stretching.In response to brisk standing, patients and control subjects responded with similar heart rate acceleration of 28 +/- 10 beats/min (p = 0.261). However, the response of the QT interval to this tachycardia differed: on average, the QT interval of controls shortened by 21 +/- 19 ms whereas the QT interval of LQTS patients increased by 4 +/- 34 ms (p < 0.001). Since the RR interval shortened more than the QT interval, during maximal tachycardia the corrected QT interval increased by 50 +/- 30 ms in the control group and by 89 +/- 47 ms in the LQTS group (p < 0.001). Receiver-operating characteristic curves showed that the test adds diagnostic value. The response of the QT interval to brisk standing was particularly impaired in patients with LQT2.Evaluation of the response of the QT interval to the brisk tachycardia induced by standing provides important information that aids in the diagnosis of LQTS.

Effects of exercise and β-blocker on blood pressure and baroreflexes in spontaneously hypertensive rats

Background Exercise training or β-blocker decreases high blood pressure (BP) and improves abnormal baroreflex function associated with hypertension. This study was undertaken to examine whether the effects of exercise training are additive to β-blocker in spontaneously hypertensive rats (SHR). Methods At 5 weeks of age, SHR were allocated to four groups: sedentary control, exercise training, treatment with moderate dose of bisoprolol, and their combination. Systolic BP was monitored by the tail-cuff method under restrained conditions. Sigmoidal mean arterial pressure (MAP)–heart rate (HR) reflex curves were obtained in rats at 17 weeks of age under quiet conditions before and after atenolol to ensure sympathetic blockade and to determine the vagal component of gain. After studying baroreflex function, intrinsic HR was obtained by additional administration of atropine. Results Before atenolol, both exercise training alone and bisoprolol alone lowered resting MAP and HR, and decreased upper plateau (maximal tachycardia) and lower plateau (maximal bradycardia), resulting in decreased sympathetic component of HR range (upper plateau − intrinsic HR) and increased vagal component of HR range (intrinsic HR − lower plateau). After atenolol, both exercise training alone and bisoprolol alone increased the gain of vagal component. Exercise training had no additive effect on any parameters to bisoprolol except for systolic BP and HR measured by the tail-cuff method. Conclusions Exercise training and bisoprolol have similar effects concerning resting hemodynamics and baroreflex function in SHR. Although additive effects of exercise training to bisoprolol are not evident under quiet, nonstressful conditions, some additive effects may be obtained under stress such as restrain.

Impaired atrial M(2)-cholinoceptor function in obesity-related hypertension.

The aim of this study was to investigate the activity of the parasympathetic limb of the baroreflex arch in a canine model of obesity-related hypertension. Twelve male beagle dogs were randomized into 2 groups. Six dogs were fed with normal canine food and 6 were submitted to a 10-week high-fat diet (HFD). We have evaluated the consequences of HFD on heart rate (HR) and blood pressure (BP) circadian cycles and methylscopolamine dose-response curves. Binding of [(3)H]-AF-DX 384 and adenylyl cyclase activity were investigated to determine the density and functionality of M(2)-cholinoceptors on right atrial membranes from control and HFD dogs. HFD induced a significant increase in body weight (15+/-1 vs 12+/-1 kg), systolic BP (161+/-5 vs 145+/-4 mm Hg), diastolic BP (92+/-3 vs 79+/-2 mm Hg), and HR (96+/-4 vs 81+/-3 bpm). Circadian rhythms of HR and BP observed in the baseline period were abolished after 9 weeks of HFD. After propranolol (1 mg/kg) pretreatment, the dose of methylscopolamine able to induce 50% maximum tachycardia was significantly increased after 9 weeks of HFD (7.4+/-0.3 vs 4.7+/-0.1 microg/kg). In the control group, the experimental period failed to modify these parameters. The numbers of M(2)-cholinoceptors measured in right atrial membranes were significantly lower in HFD than in control groups (54+/-6 vs 27+/-6 fmol/mg protein). The ability of carbachol to inhibit isoproterenol-stimulated adenylyl cyclase activity was significantly lower in HFD than in control groups (IC(50)=47+/-12 vs 6.4+/-1.4 micromol/L). However, the basal activity of adenylyl cyclase was unchanged by HFD. HFD decreases M(2)-cholinoceptor number and function in cardiomyocytes. This could explain the abolition of circadian rhythm of HR and the changes in chronotropic effect brought about by methylscopolamine.

Stimulation of the rat mesolimbic dopaminergic system produces a pressor response which is mediated by dopamine D-1 and D-2 receptor activation and the release of vasopressin

Treatment with dopamine receptor agonists has been shown to induce centrally mediated effects on cardiovascular regulation. We have investigated the effect on blood pressure and heart rate of stimulating the release of endogenous dopamine in the brain from the mesolimbic/mesocortical (A10) dopaminergic system of conscious Sprague-Dawley rats. Stimulation of the region of origin of the A10 dopaminergic system, the ventral tegmental area (VTA), with local micro-injection of the substance P analogue DiMe-C7, produced a dose-dependent increase in blood pressure and heart rate. The injection of 10 nmol of DiMe-C7 produced a maximum increase in blood pressure of 15–20 mmHg at 10 min following administration and a maximum tachycardia of 70–80 B/min. Intravenous pretreatment with the dopamine D-1 receptor antagonist SCH 23390 (0.1 mg/kg) or the dopamine D-2 receptor antagonist raclopride (0.5 mg/kg) markedly inhibited the pressor response and revealed a bradycardia. Furthermore, the pressor response and tachycardia were completely blocked by pretreatment with the vasopressin V-1 receptor antagonist, Pmp 1,O-Me-Tyr 2-[Arg 8]vasopressin (10 μg/kg). Pretreatment with the ganglion blocker, pentolinium (10 mg/kg), had little effect on the blood pressure response, however it attenuated the tachycardia. Micro-injection of 10 nmol of DiMe-C7 into a region 2 mm dorsal to the VTA had little effect on blood pressure yet produced a marked bradycardia. The administration of DiMe-C7 into the region of origin of the nigrostriatal A9 dopaminergic system, the substantia nigra, produced a slight but significant increase in blood pressure with little effect on heart rate. Intracerebroventricular administration of DiMe-C7 also produced a pressor response with a more pronounced tachycardia. The blood pressure responses produced by intranigral or i.c.v. injection of DiMe-C7 were not inhibited by pretreating the rats with raclopride. These results suggest an involvement of the mesolimbic A10 dopaminergic system in the regulation of blood pressure and heart rate through the activation of dopamine D-1 and D-2 receptors and vasopressin release.

Labelling with [125I]-SB 207710 of a small 5-HT4 receptor population in piglet right atrium: functional relevance.

1. We investigated the affinity of SB 207710 for sinoatrial 5-HT4 receptors and the density of right atrial 5-HT4 receptors with [125I]-SB 207710 in right atria of new-born piglets. 2. SB 207710 (1-100 nM) antagonized the 5-HT-evoked tachycardia surmountably with a pKB of 9.8. 3. [125I]-SB 207710 (5-1500 pM) labelled a small population of saturable binding sites with a pKD of 10.1 and with 5-HT4 receptor characteristics. The density of atrial binding sites with 5-HT4 receptor characteristics was 174 and 22 times lower respectively than those of atrial beta 1- and beta 2-adrenoceptors, labelled with (-)-[125I]-cyanopindolol. 4. We suggest that the small 5-HT4 receptor population may in part explain why the maximal tachycardia caused by 5-HT is smaller than that caused by catecholamines.

Autonomic neuropathy and prolongation of QT interval in human immunodeficiency virus infection.

Autonomic neuropathy has been reported in human immunodeficiency virus positive (HIV+) patients. Since alterations in cardiac innervation may determine QT interval prolongation, this interval was studied in a group of HIV+ subjects to evaluate if it is prolonged and to compare this measurement with other diagnostic tests for autonomic neuropathy. Fifty-seven HIV+ and 23 human immunodeficiency virus negative (HIV-) subjects were studied. Autonomic function was tested by noninvasive cardiovascular reflex tests, and the QT interval on the electrocardiogram was measured at rest, at maximum tachycardia during Valsalva manoeuvre, and afterwards at maximum bradycardia. QT intervals were corrected for heart rate according to Bazzett's formula (QTc). Autonomic neuropathy was found in 37 HIV+ subjects: 25 had moderate autonomic neuropathy (HIV+/mAN) and twelve had severe autonomic neuropathy (HIV+/sAN). The 23 HIV- and 20 HIV+ (HIV+/AN-) patients did not have autonomic neuropathy. QTc intervals were significantly longer in HIV+/sAN and HIV+/mAN than in HIV- at rest; in HIV+/sAN than in HIV- at maximum tachycardia; in HIV+/sAN and HIV+/mAN than in HIV+, in HIV+/sAN and HIV+/mAN than in HIV+/AN- and in HIV+/sAN than in HIV+/mAN at maximum bradycardia. QTc was > or = 440 ms in 24 out of 37 (64.8%) patients with autonomic neuropathy and in five out of 20 (25%) HIV+/AN- patients (sensitivity 65%, specificity 75%). A significant correlation was observed between scores of autonomic involvement and QTc interval prolongation. This study confirms that the QTc measurement is a reliable parameter indicating the presence of autonomic neuropathy. Since QT prolongation may determine ventricular arrhythmias, such patients must be followed because they may be at increased risk of sudden death.

Exercise training reduces the sympathetic component of the blood pressure-heart rate baroreflex in man

1. Exercise training reduces resting sympathetic activity, but the effects on sympathetic activation or withdrawal during baroreflex responses to blood pressure perturbations are controversial. The purpose of this study was to investigate the effects of training on both the vagal and sympathetic reflex heart rate responses to blood pressure changes. 2. Using 10 healthy males in a randomized cross-over design, we examined the effects of three 30 min cycling sessions at 70% of maximal capacity for 4 weeks on the steady-state reflex heart rate responses to perturbations in mean arterial pressure induced with injections of nitroprusside and phenylephrine. The method provides a sigmoidal relationship between changes in heart rate and blood pressure. The upper plateau (maximum tachycardia in response to blood pressure reduction) and lower plateau (maximum bradycardia in response to blood pressure elevation) are mainly mediated by the cardiac sympathetics and vagus, respectively. The slope of the relationship is a measure of reflex gain. 3. Training, which increased maximal oxygen consumption by 13 +/- 2% (mean +/- standard error of the difference), reduced supine and standing blood pressures by 3 +/- 1/3 +/- 1 mmHg (P less than 0.05) and 4 +/- 1/2 +/- 2 mmHg (P less than 0.05 for systolic), respectively, whereas resting heart rate was lowered by 6 +/- 1 beats/min (P less than 0.05). Reflex sensitivity in the presence of functioning vagus and sympathetics was not altered with training, but the vagal component of sensitivity, as assessed after sympathetic blockade with propranolol, was significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Piglet sinoatrial 5-HT receptors resemble human atrial 5-HT4-like receptors

5-Hydroxytryptamine (5-HT), 5-carboxamidotryptamine (5-CT) and the gastrointestinal kinetic benzamides renzapride and cisapride caused tachycardia in spontaneously beating right atria of piglet in the presence of 400 nmol/l (+/-)-propranolol and 6 mumol/l cocaine. The maximum tachycardia caused by agonists, compared to that evoked by 200 mumol/l (-)-isoprenaline, was 63% for 5-HT, 50% for 5-CT, 50% for renzapride and 28% for cisapride. The rank order of potency was 5-HT greater than renzapride greater than cisapride greater than 5-CT. The effects of the agonists, but not those of (-)-isoprenaline, were antagonised by 3 alpha-tropanyl-1H-indole-3-carboxylic acid (ICS 205930); the pKB of ICS 205930 (vs 5-HT) was 6.9. These characteristics suggest that piglet sinoatrial 5-HT receptors are similar to "so-called" 5-HT4 receptors previously described in mouse colliculi neurons. Piglet sinoatrial 5-HT4-like receptors resemble the human atrial 5-HT receptors that mediate positive inotropic effects of 5-HT.

QT interval prolongation in type 2 (non-insulin-dependent) diabetic patients with cardiac autonomic neuropathy

QT interval alterations were measured in 41 non-insulin-dependent (type 2) diabetic patients and 14 age- and sex-matched control subjects. Cardiac autonomic neuropathy (CAN) was assessed by noninvasive tests (deep breathing, Valsalva maneuver and lying-to-standing) and diabetics were divided into three groups according to the results of these tests: diabetics with definitive (n = 14), early (n = 13) and without (n = 14) CAN. The corrected values of QT intervals (QTc) at rest were significantly longer in diabetics with definitive (447 +/- 5 ms; p less than 0.001), early (426 +/- 5 ms; p less than 0.05) and without (424 +/- 5 ms; p less than 0.05) CAN than in controls (407 +/- 5 ms). Moreover, QTc intervals at rest were significantly (p less than 0.01) longer in diabetics with definitive CAN than in diabetics with early and without CAN. QTc intervals at maximum tachycardia, induced by Valsalva maneuver, were considerably longer in diabetics with definitive CAN (451 +/- 6 ms) than in controls (407 +/- 6 ms; p less than 0.001) and in diabetics with early (434 +/- 6 ms; p less than 0.05) or without (422 +/- 6 ms; p less than 0.01) CAN. Furthermore, QTc intervals at maximum tachycardia were significantly (p less than 0.01) longer in diabetics with early CAN than in controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Comparison of the effects of xamoterol and isoprenaline on rat cardiac β‐adrenoceptors: studies of function and regulation

1. The effects of the beta 1-selective partial agonist xamoterol and the full agonist isoprenaline on rat cardiac beta-adrenoceptors were compared in functional studies of heart rate response in vivo and in vitro. In addition, the ability of both agents to cause receptor down-regulation in the rat heart following chronic (6 days) subcutaneous infusions was assessed by radioligand binding with [125I]-pindolol. 2. In the functional studies, xamoterol produced a maximal effect equivalent to approximately 65% of that of isoprenaline and was overall less potent than the full agonist. 3. Compared to saline control, the density of beta-adrenoceptors was reduced approximately 39% in ventricular membranes prepared from animals after 6 days of isoprenaline infusion but was unaffected by xamoterol. The relative proportions of the beta-adrenoceptor subtypes were unchanged by either active treatment. 4. Plasma xamoterol level at the end of the infusion period was equivalent to that associated with maximum tachycardia in vivo and to the concentration producing maximal stimulation of the rat isolated atrium in vitro. Thus suggesting 100% beta-adrenoceptor occupancy during the period of xamoterol infusion. 5. These results indicate that in this animal model xamoterol does not induce cardiac beta-adrenoceptor down-regulation during chronic treatment, with doses that produce a maximal functional response both in vitro and in vivo.

Attenuation of the Baroreceptor Reflex by Propofol Anesthesia in the Rat

The effect of the intravenous (i.v.) short-acting anesthetic propofol on baroreflex control of heart rate (HR) was examined in normotensive rats. Propofol was infused at a fixed rate of 9 mg/kg.h immediately after a bolus dose of 10 mg/kg. Blood pressure (BP) was maintained with a plasma substitute. Conscious rats were used for comparisons. Reflex HR response were recorded after i.v. doses of the pressor agent phenylephrine and the depressor agent sodium nitroprusside. Baroreceptor reflex parameters were determined by sigmoidal computerized curve-fitting. Propofol produced tachycardia at rest and atropine increased HR only moderately. In addition, a limitation in the bradycardiac response to artificial BP increases (lower plateau) was shown. This set of data indicated a vagal depression. The sympathetic component of the baroreflex was equally affected, since the maximal tachycardia resulting from artificial BP decreases (higher plateau) was shifted toward lower values. A marked diminution of the baroreflex gain resulted from the reduced activity of both vagal and sympathetic components. The mechanism for this decrease in the baroreflex-dependent total autonomic effector output (HR range) probably reflects the interaction of propofol with the baroreceptor pathways.

Mechanism of the Tachycardia Following Systemic α-Methyldopa Administration in Conscious Rats

The mechanism of the tachycardia observed in conscious rats following systemic administration of alpha-methyldopa (alpha-MD) was investigated. Heart rate and mean arterial pressure were monitored following peripheral (i.p. and i.v.) and central (lateral and fourth ventricle and cisterna magna) administration of alpha-MD. As little as 25 mg/kg i.p. produced the maximum tachycardia observed: 136 +/- 30 beats/min within 30 min. However, after central administration of alpha-MD--producing similar reductions in blood pressure--only a gradually developing bradycardia occurred (maximum at 3-4 h), suggesting that the tachycardia was peripheral in origin. Tachycardia following administration of 25 mg/kg alpha-MD i.p. was prevented by pretreatment with propranolol, desmethylimipramine, and the dopa-decarboxylase inhibitor R04-4602, but not by pretreatment with pentolinium, guanethidine, the dopamine-beta-hydroxylase inhibitor FLA-63, or by adrenalectomy or depletion of endogenous catecholamines. In isolated spontaneously beating atria, alpha-MD produced a maximum increase in rate similar to that of isoprenaline. This effect of alpha-MD was blocked by propranolol and R04-4602 but not by FLA-63. These results suggest that the tachycardia observed in conscious rats following alpha-MD administration is caused by stimulation of cardiac beta-adrenoceptors following its conversion to alpha-methyldopamine in cardiac sympathetic neurons.

Transient bradycardia and subsequent sinus tachycardia produced by intravenous adenosine in healthy adult subjects.

Adenosine was administered in increasing intravenous bolus doses to nine healthy volunteers. A transient decrease in heart rate was observed which occurred about 20 s after injection. This was due to a reduction in sinus rate and/or transient block of conduction through the atrioventricular node, and lasted less than 10 s. An increase in sinus rate which followed any transient bradycardia was also observed. The maximum bradycardia and maximum tachycardia were each significantly related to the logarithm of adenosine dose.

The effect of enalapril (MK421), an angiotensin converting enzyme inhibitor, on the conscious pregnant ewe and her foetus.

The effects of enalapril, an angiotensin converting enzyme (ACE) inhibitor, on maternal and foetal blood pressure, heart rate and components of the renin-angiotensin-aldosterone system were studied in 9 chronically-cannulated pregnant ewes and their foetuses. Six ewes received 1 mg kg-1 enalapril i.v. while 3 were given 2 mg kg-1. Although the initial fall in blood pressure was slightly greater in the higher dose group, there was substantial overlap of data. The pressor response to angiotensin I, assessing ACE activity, was abolished within 10 min of administration, and did not recover during 3 h of observation. Maternal systolic and diastolic pressures reached a nadir 90 min after administration (P less than 0.001, P less than 0.002 respectively). The maximum tachycardia was seen at 60 min (P less than 0.05). The foetuses of the ewes given 1 mg kg-1 enalapril showed no change in systolic or diastolic blood pressure or heart rate. Those of the ewes given the higher dose showed late-onset hypotension, coincident with the lowest maternal blood pressures. Maternal plasma renin concentration (PRC) had risen significantly by 30 min (P less than 0.02), reaching a maximum at approximately 90 min. Maternal plasma angiotensin II and aldosterone concentrations both fell initially (P less than 0.05) but were almost at basal levels by the end of the experiment. Foetal plasma renin, angiotensin II and aldosterone concentrations were unchanged throughout the experiment. Peak values of enaprilic acid, the active principle, were recorded in maternal plasma 65-90 min after administration of 1 mg kg-1, and 25-30 min after the administration of 2 mg kg-1. A trace amount of the active principle was recorded in the foetal plasma of one lamb, whose mother had been given the higher dose. None was recorded in the plasma from three other lambs. Maternal plasma ACE concentrations fell by an average of 84%; in 4 of the 6 ewes in which concentrations were measured they were undetectable after treatment. Foetal plasma ACE concentrations were unchanged throughout. Enalapril at 1 mg kg-1 thus exerts a depressor effect on the pregnant ewe which is probably related to its blockade of the renin-angiotensin system. Both direct measurement of the drug and foetal observation suggest that it does not cross the sheep placenta at this dose. This is consistent with its failure to cross the blood-brain barrier. Foetal effects were noted at 2 mg kg-1, and there was an unexpected foetal death in this group.

Cardiac beta-adrenoceptor desensitization after sinoaortic baroreceptors denervation or isoproterenol-pretreatment

The chronotropic reactivity to beta-adrenergic stimulation was studied in isolated perfused hearts from sinoaortic baroreceptors denervated (SAD) rats in the phases of maximal tachycardia (5 h) and normalized heart rate (15 days) or after repeated injection of isoproterenol (1 mg/kg, 3 times daily for 10 days). The threshold doses of isoproterenol needed to cause a significant acceleration of heart rate were significantly higher in acute SAD (1.6 X 10(-7)M), chronic SAD (3.2 X 10(-7)M), and isoproterenol-pretreated (6.4 X 10(-7)M) rats than in control rats (0.8 X 10(-7)M). The maximal increment in basal heart rate was lower in acute (59%) and chronic (48%) SAD rats and in isoproterenol-pretreated rats (26%) than in control rats (78%). These results suggest that the increased efferent sympathetic outflow to the heart induced by SAD causes desensitization of cardiac beta-adrenoceptors and may explain the gradual tachycardia disappearance in this SAD hypertensive rats.

Effects of prenalterol and its N-homoveratryl derivative in the anaesthetized cat.

The in vivo activity of prenalterol (P), its N-homoveratryl derivative (Compound XI) and (−)-isoprenaline (ISO) have been assessed in vagotomized, chloralose anaesthetized cats. The three compounds produced the same maximal tachycardia, P and XI being 76 and 202 times less potent than ISO as agonists. P and XI had little effect on mean blood pressure. All doses used produced an atenolol-sensitive increase in systolic pressure. Reductions in diastolic pressure were obtained with doses that were supramaximal for cardiac effects. P and XI were inactive as vasodilators in the perfused hind-limb. Dilator responses to i. a. ISO in the hind-limb were antagonized by i. v. doses of P and XI which produced supramaximal effects on the heart. All three compounds produced a β-receptor mediated reduction in soleus muscle contractility. P and XI had intrinsic activities of approximately 0.8 and were 513 and 7956 times less potent than ISO respectively. Comparisons of results obtained in the heart and soleus muscle showed that P and XI had a 7 and 39-fold selectivity as cardiac stimulants respectively. Infusions of ISO, P and XI produced increases in heart rate, cardiac output and stroke volume and decreases in total peripheral resistance. None of the compounds displayed selective inotropic actions. ISO decreased mean blood pressure while small increases were obtained with P and XI. All the cardiovascular effects produced by P and XI were reversed following the injection of atenolol.