Direct Negative Chronotropic Effect Research Articles

Repeated complete atrioventricular block during remifentanil administration in a pediatric patient with brain tumor and acute hydrocephalus: a case report

BackgroundRemifentanil, an ultra-short-acting µ-opioid receptor agonist, is commonly used for anesthetic management due to excellent adjustability. Remifentanil is known to cause sinus bradycardia, however, because it has a direct negative chronotropic effect on the cardiac conduction system and there is an indirect negative chronotropic effect via the parasympathetic nervous system.Case presentationAn 8-year-old Japanese boy was diagnosed with acute hydrocephalus due to a brain tumor in the fourth ventricle and underwent emergency surgery. Imaging examination showed brainstem compression. Endoscopic third ventriculostomy and ventriculoperitoneal shunt surgery were scheduled. Remifentanil was started during induction of general anesthesia, but electrocardiogram showed sinus bradycardia, then Wenckebach-type atrioventricular block, and then complete atrioventricular block. Remifentanil was immediately discontinued, and we administered atropine sulfate. Complete atrioventricular block was restored to sinus rhythm. When remifentanil was restarted, however, the electrocardiogram again showed sinus bradycardia, Wenckebach-type atrioventricular block, and then complete atrioventricular block. Remifentanil was again immediately discontinued, we administered adrenaline, and then complete atrioventricular block was restored to sinus rhythm. Fentanyl was used instead of remifentanil with continuous infusion of dopamine. There has since been no further occurrence of complete atrioventricular block.ConclusionsThis is the first known case of complete atrioventricular block in a pediatric patient with increased intracranial pressure seemingly caused by administration of remifentanil.

REVERSAL OF PERIPHERAL AND CNS MEDIATED A1 ADENOSINE RECEPTOR HYPOTENSION

IntroductionA1 adenosine receptor (A1AR) agonists such as N6‐cyclohexyladenosine (CHA) are known for their neuroprotective and anti‐convulsant properties and for modulation of thermogenesis. We have demonstrated a neuroprotective, thermolytic effect following systemic administration of CHA combined with the peripherally acting adenosine receptor antagonist, 8‐(p‐sulfophenyl)theophylline (8‐SPT). However, A1AR‐mediated cardiovascular side effects limit the translation of this drug class, and clear understanding of the effects of this drug combination on hypotension and bradycardia are lacking. CHA delivered into the CNS increases para‐sympathetic influence on the heart to produce bradycardia similar to what is seen during onset of hibernation. Systemic administration of A1AR agonist produces bradycardia via direct negative chronotropic and inotropic effects. Evidence also supports other mechanisms of A1AR agonist modulation of blood pressure including indirect activation of peripheral β2 adrenergic receptors and central H1 receptors.HypothesisWe test the hypothesis that CHA lowers blood pressure via increased para‐sympathetic tone to the heart and direct effects on the heart.MethodsRats were implanted with telemetry transmitters to monitor Tb, heart rate (HR), mean arterial pressure (MAP) and administered drugs IP as follows, CHA (1.0mg/kg), 8‐SPT (25.0mg/kg), Atropine (1.0mg/kg), diphenhydramine (4.0mg/kg), or pro‐pranolol (4.0mg/kg), 15min prior to CHA. Cage surface temperature was initially cooled to 4°C and adjusted to maintain Tb at 32°C.Results8‐SPT with atropine reversed hypotension. 8‐SPT alone increased rate of resolution in MAP to baseline value. Pre‐treatment with propranolol, atropine, or diphenhydramine alone did not influence MAP. Diphenhydramine with 8‐SPT reduced the magnitude of hypotension (− 24% average one hour baseline change after CHA) compared to pre‐treatment with 8‐SPT (− 36%) alone.ConclusionsOur results suggest that A1AR induced hypotension is mediated through increased parasympathetic tone to the heart in addition to direct effect on the heart. Histamine receptor activation may also play a role, although the resolution of MAP seen may have been due to the anticholinergic effect of diphenhydramine instead of H1 receptor antagonism. Reversing hypotension necessitates addressing both mechanism with atropine and 8‐SPTSupport or Funding InformationNIH U54GM115371, NIH R15 NS070779, NIH: RL5GM118900, TL4 GM 18992, 1UL1GN118991This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.

Pulse wave analysis by digital photoplethysmography to record maternal hemodynamic effects of spinal anesthesia, delivery of the baby, and intravenous oxytocin during cesarean section

Objective: To investigate changes in maternal ECG ST index, blood pressure (BP), cardiac left ventricular (LV) ejection function and vascular tone/stiffness in large and small arteries occurring during elective cesarean section (CS) in spinal anesthesia.Material and methods: Twenty-six women were monitored with photoplethysmographic digital pulse wave (PW) analysis (DPA) before and after spinal anesthesia, after delivery of the baby, after 5 IU oxytocin bolus IV, and 5 min later. Statistics with Wilcoxon matched-pairs signed-rank and Friedman tests at a p < 0.05 were performed.Results: Spinal anesthesia resulted in significantly decreased BP, increased ST index and LV ejection time, and small-artery vasodilation. Delivery of the baby resulted in global vasoconstriction and increases in systolic BP and heart rate (HR). Oxytocin lowered BP, HR and ST index, increased LV ejection power and caused both large- and small-artery vasodilation. ST index and BP recovered after 5 min, but low HR and low vascular tone persisted.Conclusions: Spinal anesthesia and oxytocin caused arterial vasodilation and cardiac affection. Oxytocin caused a decrease in HR despite a fall in BP, indicating a direct negative chronotropic effect. Delivery of the baby caused momentous cardiovascular changes, possibly due to maternal emotions and auto-transfusion of blood from the uterus.

Synthesis of 1,2-benzisothiazolyloxypropanolamine derivatives and investigation of their activity at β-adrenoceptors

The synthesis of 3-methoxy-1,2-benzisothiazole derivatives, substituted in position 5- (compounds 1–7) or 7- (compounds 8–14), with oxypropanolaminic side chains and the pharmacological investigation on their activity at β-adrenoceptors are described. Compounds were prepared in an attempt to explore the ability of the benzisothiazole ring to interact with the β-adrenoceptor site and to establish whether oxypropanolaminic derivatives recognise the β 3-adrenoceptor subtype. All the products were tested on rat atria, bladder and small intestine, which preferentially (but not exclusively) express β 1-, β 2- and β 3-adrenoceptors, respectively. When compared with the reference, non-specific, β-adrenoceptor agonist isoprenaline, the products tested did not show any consistent β-adrenoceptor agonistic activity in the different models. Most compounds relaxed smooth muscle preparations, but such effect was resistant to the blockade by propranolol (1 μmol/l), ICI 118,551 (1 μmol/l) or bupranolol (1–10 μmol/l), thus excluding that the spasmolytic effect involves any β-adrenoceptors. When tested as antagonists, some of these products showed a concentration-dependent attenuation of the isoprenaline-induced effects in rat atria, without affecting β-adrenoceptor-mediated relaxation in smooth muscle. These data confirm the ability of the benzisothiazole ring to interact with β-adrenoceptors, but the substitution in 5- or 7-positions with oxypropanolaminic groups does not generate compounds endowed with specific activity at β 3-adrenoceptors. Conversely, most of these compounds behave as (specific) antagonists at β 1- (cardiac) adrenoceptors. At the maximum concentrations tested (1–100 μmol/l), these compounds also exert direct spasmolytic and negative chronotropic effects, which could be related to a blockade of Ca 2+-dependent mechanisms at an intracellular level and/or an anaesthetic-like activity at plasma membranes.

Effect of remifentanil with and without atropine on heart rate variability and RR interval in children

Remifentanil can cause bradycardia either by parasympathetic activation or by other negative chronotropic effects. The high frequency (HF) component of heart rate variability (HRV) is a marker of parasympathetic activity. This study aimed to evaluate the effect of remifentanil on RR interval and on HRV in children. Forty children ASA I or II were studied after approval by the human studies committee and informed parental consent was obtained. After stabilisation at sevoflurane 1 MAC, they were randomly divided into two groups: one received a 20 microg.kg(-1) atropine injection (AT + REMI) and the other ringer lactate solution (REMI). Three minutes later, a 1 microg.kg(-1) bolus of remifentanil was administered over 1 min, followed by a continual infusion at 0.25 microg.kg(-1).min(-1) for 10 min increased to 0.5 microg.kg(-1).min(-1) for a further 10 min. A time varying, autoregressive analysis of RR sequences was used to estimate classical spectral parameters: low (0.04-0.15 Hz; LF) and high (0.15-0.45 Hz; HF) frequency, whereas the root mean square of successive differences of RR intervals (rmssd) was derived directly from the temporal sequence. Statistical analyses were conducted by means of the multiple correspondence analysis and with non parametrical tests. Remifentanil induced an RR interval lengthening, i.e. bradycardia, in both groups compared to pretreatment values and was associated with an increase of HF and rmssd only for the REMI group. The parasympathetic inhibition by atropine did not totally prevent remifentanil's negative chronotropic effect. A direct negative chronotropic effect of remifentanil is proposed.

Direct Cardiac Effects in Isolated Perfused Rat Hearts of Fentanyl and Remifentanil

Opioids are widely used as analgesics to supplement general anaesthesia or as adjunct to anaesthetic agents and for long term analgesia and sedation in intensive care patients. Some clinical studies have suggested that opioids may have different and deleterious haemodynamic effects that remain incompletely examined. We compared the direct cardiac effects of fentanyl and remifentanil in isolated Wistar rat hearts. Twenty rats were randomly assigned to two groups. Hearts were perfused with modified Krebs Henseleit solution and were exposed to 1 x 10(-6) moles(M)/L fentanyl (n=10) in Group I and 1 x 10(-6) M/L remifentanil (n=10) in Group II. Heart rates, contractile force and coronary perfusion were recorded continuously during the study. There was a significant decrease in heart rate and increase in contractility and coronary perfusion in two groups (p<0.001). Fentanyl had less depressant effects on heart rate than remifentanil. We conclude that in isolated rat heart, fentanyl and remifentanil cause direct negative chronotropic and positive inotropic effect. Remifentanil had more depressant effects on heart rate than fentanyl in isolated rat heart.

The role of carotid chemoreceptors in the sympathetic activation by adenosine in humans.

The direct vasodilatory and negative chronotropic effects of adenosine in humans are counterbalanced by a reflex increase in sympathetic nerve traffic. A suggested mechanism for this reflex includes peripheral chemoreceptor activation. We, therefore, assessed the contribution of carotid chemoreceptors to sympatho-excitation by adenosine. Muscle sympathetic nerve activity was recorded during adenosine infusion (140 microg.kg(-1).min(-1) for 5 min) in five patients lacking carotid chemoreceptors after bilateral carotid body tumour resection (one male and four female, mean age 51 +/- 11 years) and in six healthy controls (two male and four female, mean age 50 +/- 7 years). Sympathetic responses to sodium nitroprusside injections were assessed to measure baroreceptor-mediated sympathetic activation. In response to adenosine, controls showed no change in blood pressure, an increase in heart rate (+48.2 +/- 13.2%; P<0.003) and an increase in sympathetic nerve activity (+195 +/- 103%; P<0.022). In contrast, patients showed a decrease in blood pressure (-14.6 +/- 4.9/-17.6 +/- 6.0%; P<0.05), an increase in heart rate (+25.3 +/- 8.4%; P<0.032) and no significant change in sympathetic activity. Adenosine-induced hypotension in individual patients elicited less sympathetic activation than equihypotensive sodium nitroprusside injections. In humans lacking carotid chemoreceptors, adenosine infusion elicits hypotension due to the absence of significant sympatho-excitation. Chemoreceptor activation is essential for counterbalancing the direct vasodilation by adenosine. In addition, blunting of the baroreflex sympathetic response to adenosine-induced hypotension may indicate a direct sympatho-inhibitory effect of adenosine.

The pharmacodynamic study of a potent new antimalarial (MC 1)

2,3-bis(Trifluoromethyl)-4-(3-hydroxyquinuclidinylquinoline) or MC 1 is a new synthetic compound with potent antimalarial activity in vitro and in vivo studies. The IC 50 values of MC 1 and chloroquine in in vitro culture of Plasmodium falciparum are 7.0×10 −8 and 6.06×10 −7 M, respectively. In an in vivo study using Plasmodium berghei infected mice as the test model, the survival time of the infected mice without drug treatment was 6.00+0.58 days. Chloroquine and MC 1 at an equal dose of 7.5 mg/kg, orally administered once daily for 4 days, prolonged the survival time of the infected mice from 6 to 14 days, and more than 28 days, respectively. At the doses that exhibit potent antimalarial activity in vivo, there are no observable toxic effects. Preliminary studies of the pharmacodynamic activity of this newly synthesized compound revealed that at the doses which exhibit potent antimalarial activity, there is no alteration in motor activity such as distance traveled, rotational behavior, and stereotypic activity. The blood glucose was not significantly altered. In the spontaneous beating, isolated right atria of mice, MC 1 exhibits direct negative chronotropism at high concentrations (10 −4 M). This effect is augmented in hyper-K + bathing solution. A direct negative chronotropic effect was also observed when mefloquine at 5×10 −5 M was used. Preliminary pharmacodynamic study suggested that MC 1 is a potential new antimalarial drug that should be studied further.

Pharmacologic Rationale for Trimetazidine in the Treatment of Ischemic Heart Disease

The classic approach to treating coronary heart disease involves interventions aimed at either increasing the oxygen supply to the heart muscle or decreasing the oxygen demand of the muscle. A new approach to treating coronary heart disease involves improving the efficiency of oxygen utilization by the tissue. Inhibiting fatty acid oxidation and stimulating glucose oxidation can significantly improve cardiac efficiency (cardiac work/oxygen consumed). This metabolic approach is not only beneficial as monotherapy in the treatment of angina pectoris, but is also beneficial in angina patients when used in combination with conventional therapy. Trimetazidine is a widely used metabolic agent that directly optimizes energy metabolism in the heart without causing any direct negative hemodynamic, inotropic or chronotropic effects. Trimetazidine acts by directly inhibiting fatty acid oxidation, resulting in an increase in glucose oxidation in the heart. The actions of trimetazidine occur as a result of inhibition of long-chain 3-ketoacyl CoA thiolase (3-KAT), an important enzyme involved in mitochondrial fatty acid oxidation. Because of this action, trimetazidine has been classified as a 3-KAT inhibitor, and is the first metabolic agent used clinically for treating coronary heart disease. Inhibition of fatty acid oxidation and stimulation of glucose oxidation with trimetazidine result in a decrease in acidosis in the ischemic muscle, thereby decreasing the requirement of energy for non-contractile purposes (i. e. increasing cardiac efficiency). This increase in glucose oxidation and decreased production of acidosis in the myocardium probably account for the cardioprotective effects of trimetazidine, which have been observed in many experimental and clinical studies. Both during and after ischemia, trimetazidine causes a significant improvement in cardiac efficiency, allowing the heart to perform a greater amount of work at a given level of oxygen. This therapeutic approach not only lessens the severity and symptoms of an angina attack in patients with coronary artery disease, but also decreases the incidence of angina attacks. As a result, using trimetazidine to optimize energy substrate preference is a novel and effective approach to treating ischemic heart disease.

Activated Cardiac Adenosine A1 Receptors Translocate Out of Caveolae

The cardiac affects of the purine nucleoside, adenosine, are well known. Adenosine increases coronary blood flow, exerts direct negative chronotropic and dromotropic effects, and exerts indirect anti-adrenergic effects. These effects of adenosine are mediated via the activation of specific G protein-coupled receptors. There is increasing evidence that caveolae play a role in the compartmentalization of receptors and second messengers in the vicinity of the plasma membrane. Several reports demonstrate that G protein-coupled receptors redistribute to caveolae in response to receptor occupation. In this study, we tested the hypothesis that adenosine A(1) receptors would translocate to caveolae in the presence of agonists. Surprisingly, in unstimulated rat cardiac ventricular myocytes, 67 +/- 5% of adenosine A(1) receptors were isolated with caveolae. However, incubation with the adenosine A(1) receptor agonist 2-chlorocyclopentyladenosine induced the rapid translocation of the A(1) receptors from caveolae into non-caveolae plasma membrane, an effect that was blocked by the adenosine A(1) receptor antagonist, 8-cyclopentyl-1,3-dipropylxanthine. An adenosine A(2a) receptor agonist did not alter the localization of A(1) receptors to caveolae. These data suggest that the translocation of A(1) receptors out of caveolae and away from compartmentalized signaling molecules may explain why activation of ventricular myocyte A(1) receptors are associated with few direct effects.

Comparison of the protective actions of Na+/H+ and Na+/Ca2+ exchange inhibitors in ischemic/reperfused rat hearts

The protective effects of the Na + /H + exchange inhibitors amiloride, EIPA (5-(N-ethyl-N-sopropyl)-amiloride), and HOE 694 (3-methylsulfonyl-4-(1-piperidino) benzoyl-guanidine) and the Na + / Ca 2+ exchange inhibitor, DCB (3,4-Dichlorobenzamil) on ischemia (30 min) / reperfusion (30 min) injury were studied using Langendorff perfused rat hearts. EIPA and HOE 694 given before ischemia protected the heart during reperfusion from mechanical and metabolic disturbances. A weak protective effect was observed with amiloride, but not with DCB. The cardioprotective efficacies of these compounds correlated with their potencies as Na + /H + exchange inhibitors as assessed by the NH 4 Cl prepulse method. None of the inhibitors was effective when given at reperfusion. EIPA and HOE 694 decreased myocardial rigidity as assessed by the resting tension (RT) which elevated during reperfusion. EIPA led to a more marked attenuation of RT elevation during reperfusion rather than ischemia, whereas diltiazem, a Ca 2+ channel blocker, suppressed RT elevation during ischemia but did not cause a further attenuation of RT during reperfusion. Treatment with EIPA as well as diltiazem before ischemia showed a direct negative chronotropic effect. Cardioprotective effects were also observed with diltiazem. These results suggest that Na + /H + exchange plays a more important role in ischemia-reperfusion-induced myocardial injury than does Na + /Ca 2+ exchange. The cardioprotective effects of EIPA appear to be produced by Ca 2+ channel blockade during ischemia and by Na + /H + exchange inhibition during reperfusion.

Comparison of the protective actions of Na/H and Na/Ca2 exchange inhibitors in ischemic/reperfused rat hearts

The protective effects of the Na+/H+ exchange inhibitors amiloride, EIPA (5-(N-ethyl-N-isopropyl)-amiloride), and HOE 694 (3-methylsulfonyl-4-(1-piperidino) benzoyl-guanidine) and the Na+/Ca2+ exchange inhibitor, DCB (3,4-Dichlorobenzamil) on ischemia (30 min) / reperfusion (30 min) injury were studied using Langendorff perfused rat hearts. EIPA and HOE 694 given before ischemia protected the heart during reperfusion from mechanical and metabolic disturbances. A weak protective effect was observed with amiloride, but not with DCB. The cardioprotective efficacies of these compounds correlated with their potencies as Na+/H+ exchange inhibitors as assessed by the NH4Cl prepulse method. None of the inhibitors was effective when given at reperfusion. EIPA and HOE 694 decreased myocardial rigidity as assessed by the resting tension (RT) which elevated during reperfusion. EIPA led to a more marked attenuation of RT elevation during reperfusion rather than ischemia, whereas diltiazem, a Ca2+ channel blocker, suppressed RT elevation during ischemia but did not cause a further attenuation of RT during reperfusion. Treatment with EIPA as well as diltiazem before ischemia showed a direct negative chronotropic effect. Cardioprotective effects were also observed with diltiazem. These results suggest that Na+/H+ exchange plays a more important role in ischemia-reperfusion-induced myocardial injury than does Na+/Ca2+ exchange. The cardioprotective effects of EIPA appear to be produced by Ca2+ channel blockade during ischemia and by Na+/H+ exchange inhibition during reperfusion. Drug Dev. Res. 48:160–170, 1999. © 1999 Wiley-Liss, Inc.

Muscarinic receptors in the failing human heart

In the human heart, as in the heart of several other species, muscarinic receptors are predominantly of the M 2-subtype that couple via a pertussis toxin-sensitive G i-protein to inhibit adenylyl cyclase. However, it is not clear whether an additional muscarinic receptor subtype exists in the human heart. In human right atrium, stimulation of muscarinic M 2 receptors causes direct negative inotropic and chronotropic effects; in human ventricular myocardium, however, the negative inotropic effect can be only achieved when basal force of contraction has been pre-stimulated by cyclic AMP-elevating agents such as β-adrenoceptor agonists, forskolin or phosphodiesterase inhibitors (indirect effect); this has been shown in various in vitro and in vivo studies. Evidence has accumulated that in chronic heart failure vagal activity is decreased. Cardiac muscarinic M 2 receptor density and functional responsiveness (inhibition of adenylyl cyclase activity and negative inotropic effects), however, are not considerably changed when compared with non-failing hearts although cardiac G i-activity is increased.

Effect of adenosine on heart rate variability in humans

By stimulating afferent nerve endings in skeletal muscle, heart, kidney and the carotid body, adenosine infusion evokes a receptor-specific sympatho-excitatory reflex in humans that overrides its direct negative chronotropic effect. We tested the hypothesis that adenosine increases heart rate by suppressing parasympathetic and augmenting sympathetic components of heart rate variability. High-frequency (PH; 0.15-0.50 Hz) and low-frequency (PL; 0.05-0.15 Hz) components of heart rate variability total power (PT) were determined by spectral analysis. The ratios PH/PT and PL/PH respectively were used to estimate parasympathetic and sympathetic input to the sino-atrial node. Heart rate was recorded before and during a 5 min intravenous infusion of adenosine (140 micrograms.min-1.kg-1) in seven healthy men. Adenosine did not affect blood pressure, but increased heart rate by 33+/-6 beats/min, and reduced PT, PH, PL and PH/PT. In contrast, there was an increase in PL/PH. In a second experiment in nine men, brachial artery infusion of adenosine (15 micrograms.min-1.100 ml-1 forearm tissue) increased heart rate by 3 beats/min, had no effect on PT, PH, PL or PH/PT, yet increased PL/PH. Intra-arterial adenosine exerts a modest effect on heart rate by modulating cardiac sympathetic indices, without affecting parasympathetic indices, of heart rate variability, whereas intravenous infusion of adenosine reduces heart rate variability and raises heart rate by decreasing parasympathetic and increasing cardiac sympathetic tone. These reflex effects may become clinically relevant during adenosine stress testing, or when endogenous adenosine is increased, such as during ischaemia, exercise or vasodepressor reactions, or in heart failure.

Inactivation of GiαProteins Increases Arrhythmogenic Effects ofβ-Adrenergic Stimulation in the Heart

Chronic treatment of rats with carbachol downregulates M-cholinoceptors and inhibitory, pertussis toxin (PTX)-sensitive G proteinalpha-subunits (Gialpha) and sensitizes the heart to arrhythmogenic effects of isoprenaline (ISO), suggesting a causal relationship. To test this hypothesis by a more direct and quantitative approach, nine groups of rats were treated for 24 h with increasing doses of PTX (1.25-200 microg/kg i.v.). Inactivation of cardiac Gialpha was determined biochemically by 32P-ADP-ribosylationin vitro and functionally by measuring contractile effects of carbachol. Effects of ISO were studied in spontaneously beating right atria (RA) and isolated papillary muscles (PM; paced at 1 Hz). PTX increased heart rate in conscious animals (ECG) with a bell-shaped dose-dependency (maximal increase 120 beats/min at 7.5 microg/kg). PTX dose-dependently inactivated 25-85% of total cardiac Gialpha, which linearly correlated with a loss of the direct negative chronotropic effect of carbachol in atria, but not with a loss of its indirect negative inotropic effect in PM. The latter was resistant up to PTX 20 microg/kg (=70% inactivation). The decrease in Gialpha closely correlated with an increased efficacy of ISO to induce spontaneous contractile activity (automaticity) in PM. At 3 micromol/l ISO, all PM from PTX 200 microg/kg beat spontaneously compared to 10% in control. In contrast, pretreatment with PTX only modestly and not clearly dose-dependently increased the inotropic potency of ISO (PTX 100 microg/kg: EC50 28v 81 nmol/l in control) and did not affect the chronotropic effect of ISO. The disparity of the functional consequences of PTX treatment suggest that under physiological conditions, Gialpha serve mainly to suppress arrhythmogenic, but not or to a minor extent, positive chronotropic or inotropic effects of beta-adrenoceptor activation.

In vivo B2-receptor-mediated negative chronotropic effect of bradykinin in canine sinus node

The chronotropic response to bradykinin (BK) injected into the sinus node artery was evaluated in anesthetized dogs. The animals (n = 14) were vagotomized and pretreated with propranolol (1 mg/kg i.v.) to prevent baroreceptor-mediated effects. Dose-dependent decreases in heart rate (from 2.4 +/- 1.3% for 1 microgram of BK to 13.1 +/- 3.7% for 10 micrograms of BK), as well as a significant fall in systemic systolic and diastolic blood pressures, were observed. Captopril (2 mg/kg i.v.) caused significant decreases in systolic (from 117 +/- 11 to 77 +/- 12 mmHg, P < 0.001) and diastolic (from 87 +/- 8 to 52 +/- 8 mmHg, P < 0.001) blood pressures but had no effect on heart rate. Converting-enzyme inhibition potentiated the BK-induced bradycardia. The new potent B2-receptor antagonist, HOE 140 (100 micrograms), significantly blocked the BK-induced chronotropic effect, whereas desArg9-BK, a B1-receptor agonist, was without effect. Prostaglandin involvement was excluded, since pretreatment with indomethacin did not prevent the bradycardia. In conclusion, in vivo BK induces a direct negative chronotropic effect, which is potentiated by converting-enzyme inhibition and is mediated by the B2-receptors independently of the prostaglandins.

Cardiac functional responses to adenosine by PD 81,723, an allosteric enhancer of the adenosine A1 receptor.

Adenosine, a locally released and rapidly metabolized nucleoside, protects the heart from damage during ischemia by reducing oxygen demand and increasing oxygen supply. The aminothiophene derivative (2-amino-4,5-dimethylthien-3-yl)[3-(trifluoromethyl)phenyl]-met hanone (PD 81,723) has been shown to act as an allosteric enhancer of the adenosine A1 receptor in brain membranes and thyroid cells. The present study investigates the effects of PD 81,723 in spontaneously contracting right atria and electrically stimulated left atria isolated from Sprague-Dawley rats. N6-cyclopentyladenosine (CPA), an adenosine A1 receptor agonist, produced concentration-dependent inhibition of heart rate in right atria and contractile parameters in left atria. In the right atrium, 5 microM of PD 81,723 significantly shifted the concentration-response curves for CPA to the left, both in the absence and presence of a nonselective adenosine receptor antagonist, 8-(p-sulfophenyl)theophylline (8-SPT, 10 microM). In the left atrium, PD 81,723 also shifted the concentration-response curves for CPA to the left, but only in the presence of 8-SPT. Potentiation of CPA-induced negative chronotropic and inotropic responses with PD 81,723, although not significant, was also observed in the presence of a selective adenosine A1 receptor antagonist, 1,3-dipropyl-8-cyclopentylxanthine (DPCPX, 1 nM). These results demonstrate that PD 81,723 enhances the direct negative chronotropic and inotropic effects of adenosine A1 receptor activation in rat atria.

Vagal stimulation and somatostatin potentiate cardiac vagal action in the toad, Bufo marinus

Cholinergic postganglionic neurones of the cardiac vagus in the toad. Bufo marinus, have been shown to contain the peptide somatostatin (SOM), which causes direct negative inotropic and chronotropic effects on the heart. In anaesthetised toads, high frequency stimulation (10 Hz) of cardiac vagus nerves results in prolonged cardiac slowing and potentiation of the cardiac slowing measured in response to a train of vagal stimuli at low frequency. Intravenous administration of the tetradecapeptide form of SOM also results in prolonged cardiac slowing and potentiation of cardiac vagal action. Effects on heart rate of small bolus doses of acetylcholine (ACh) were unaltered by administration of SOM, at the same time as cardiac vagal slowing was enhanced. It is suggested that SOM is released from vagal nerve endings by high frequency stimulation and enhances cardiac vagal action by a presynaptic mechanism.

Adenosine causes bradycardia in pacing-induced cardiac failure.

In normal, conscious dogs, systemic injection of adenosine causes arterial hypotension and a baroreceptor reflex tachycardia mediated in part by withdrawal of vagal tone from the sinoatrial node. After vagal section or muscarinic receptor blockade, however, adenosine injection causes bradycardia via a direct sinoatrial node inhibition. Because cardiac failure is marked by a loss of vagal tone, we hypothesized that adenosine injection in dogs with failing hearts would reduce heart rate. Mongrel dogs were instrumented with indwelling catheters, manometers, and ventricular pacing electrodes. After the dogs had recovered from the surgery, the ventricles were paced continuously at 210 beats per minute for 3 weeks, followed by pacing at 240 beats per minute for an additional week. This regimen caused mild ventricular and more striking atrial hypertrophy and a gradual onset of physiological and clinical signs of congestive heart failure. Adenosine injections that caused large tachycardias before the pacing regimen began caused progressively smaller increments in heart rate during the first 2 weeks of pacing. After 3 and 4 weeks, adenosine injections caused overt reductions in heart rate despite the concomitant arterial depressor response. We conclude that the loss of vagal tone associated with the development of cardiac failure unmasks the direct negative chronotropic effect of exogenous adenosine on the sinoatrial node.

Effects of Alfentanil on Isolated Cardiac Tissues of the Rabbit

Alfentanil causes cardiac stimulation or depression in intact animals and in clinical practice; there is no information concerning its direct effects on the heart. Therefore, we studied the effects of alfentanil on isolated cardiac tissues from young adult rabbits. The right atrium with sinoatrial node (SA node) was beating spontaneously, and the left atrium and papillary muscle were stimulated. Isometric contraction was monitored. Alfentanil, in concentrations of 0.05-0.5 mM, decreased by 6%-55% the frequency of contractions of the right atrial-SA node in a dose-related manner. In left atria and right atrial-SA node, but not in papillary muscle, alfentanil in concentrations greater than or equal to 0.01 mM increased the peak developed force and its maximum rate of increase. The time-to-peak developed force was prolonged in papillary muscle but not in right atrial-SA node and left atria. The maximum rate of fall of peak developed force was increased in left atria and decreased in papillary muscle by the administration of alfentanil. The time-to-50% relaxation of peak developed force was not consistently affected by alfentanil in all three muscle preparations. The same concentrations of alfentanil (greater than or equal to 0.01 mM) increased resting force in papillary muscle but not in left atria or right atrial-SA node. It is concluded that alfentanil has direct positive inotropic and negative chronotropic effects on the heart and that it causes contracture of ventricular myocardium.