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Introduction Fifteen to thirty percent of patients with impaired cardiac function have ventricular dyssynchrony and warrant cardiac resynchronization therapy (CRT). While leadless pacemakers eliminate lead-related complications, their current form factor is limited to single-chamber pacing. In this study, we demonstrate the feasibility of multisite, simultaneous pacing using miniaturized pacing nodes powered through wireless power transfer (WPT). Methods A wireless energy transfer system was developed based on resonant coupling at approximately 200 MHz to power multiple pacing nodes. The pacing node comprises circuitry to efficiently convert the harvested energy to output stimuli. To validate the use of these pacing nodes, ex vivo studies were carried out on Langendorff rodent heart models (n = 4). To mimic biventricular pacing, two beating Langendorff rodent heart models, kept 10 cm apart, were paced using two distinct pacing nodes, each attached on the ventricular epicardial surface of a given heart. Results All ex vivo Langendorff heart models were successfully paced with a simple coil antenna at 2 to 3 cm from the pacing node. The coil was operated at 198 MHz and 0.3 W. Subsequently, simultaneous pacing of two Langendorff heart models 30 cm apart using an output power of 5 W was reliably demonstrated. Conclusion WPT provides a feasible option for multisite, wireless cardiac pacing. While the current system remains limited in design, it offers support and a conceptual framework for future iterations and eventual clinical utility.

Aim We studied whether available oxygen without induced mechanical stretch regulates the release of the biologically active B-type natriuretic peptide (BNP) from Langendorff heart. Methods Rat hearts were isolated and perfused with a physiological Krebs–Henseleit solution at a constant hydrostatic pressure in Langendorff set-up. The basal O2 level of perfusate (24.4 ± 0.04 mg L−1) was gradually lowered to 3.0 ± 0.01 mg L−1 over 20 min using N2 gas (n = 7). BNP and O2 level were measured from coronary flow. During control perfusions (n = 5), the O2 concentration was kept at 26.6 ± 0.3 mg L−1. Results A low oxygen concentration in the perfusate was associated with a significant increase in BNP release (F = 40.4, P

Background and purpose In drug research using the rat Langendorff heart preparation, it is possible to study left ventricular (LV) contractility using an intraventricular balloon (IVB), and arrhythmogenesis during coronary ligation-induced regional ischaemia. Assessing both concurrently would halve animal requirements. We aimed to test the validity of this approach. Experimental approach The electrocardiogram (ECG) and LV function (IVB) were recorded during regional ischaemia of different extents in a randomized and blinded study. Key results IVB-induced proarrhythmia was anticipated, but in hearts with an ischaemic zone (IZ) made deliberately small, an inflated IVB reduced ischaemia-induced ventricular fibrillation (VF) incidence as a trend. Repeating studies in hearts with large IZs revealed the effect to be significant. There were no changes in QT interval or other variables that might explain the effect. Insertion of an IVB that was minimally inflated had no effect on any variable compared with ‘no IVB’ controls. The antiarrhythmic effect of verapamil (a positive control drug) was unaffected by IVB inflation. Removal of an inflated (but not a non-inflated) IVB caused a release of lactate commensurate with reperfusion of an endocardial/subendocardial layer of IVB-induced ischaemia. This was confirmed by intracellular 31phosphorus (31P) nuclear magnetic resonance (NMR) spectroscopy. Conclusions and implications IVB inflation does not inhibit VF suppression by a standard drug, but it has profound antiarrhythmic effects of its own, likely to be due to inflation-induced localized ischaemia. This means rhythm and contractility cannot be assessed concurrently by this approach, with implications for drug discovery and safety assessment.

New Findings •What is the topic of this review? The topic of the review is the intrinsic cardiac nervous system in the rabbit. •What advances does it highlight? The anatomy of rabbit intrinsic ganglia is similar to that of other species, including humans. Immunohistochemistry confirms the presence of cholinergic and adrenergic neurones, with a striking arrangement of neuronal nitric oxide synthase-positive cell bodies. Activation of atrial ganglia produces effects on local and remote regions. Heart disease is a primary cause of mortality in the developed world, and it is well recognized that neural mechanisms play an important role in many cardiac pathologies. The role of extrinsic autonomic nerves has traditionally attracted the most attention. However, there is a rich intrinsic innervation of the heart, including numerous cardiac ganglia (ganglionic plexuses), that has the potential to affect cardiac function independently as well as to influence the actions of the extrinsic nerves. To investigate this, an isolated, perfused, innervated rabbit Langendorff heart preparation was considered the best option. Although ganglionic plexuses have been well described for several species, there was no full description of the anatomy and histochemistry of rabbit hearts. To this end, rabbit intrinsic ganglia were located using acetylcholinesterase histology (n = 33 hearts). This revealed six generalized ganglionic regions, defined as a left neuronal complex above the left pulmonary vein, a right neuronal complex around the base of right cranial vein, three scattered in the dorsal right atrium and a region containing numerous ventricular ganglia located on the conus arteriosus. Using immunohistochemistry, neurons were found to contain choline acetyltransferase or tyrosine hydroxylase and/or neuronal nitric oxide synthase in differing amounts (choline acetyltransferase > tyrosine hydroxylase > neuronal nitric oxide synthase). The function of rabbit intrinsic ganglia was investigated using a bolus application of nicotine or electrical stimulation at each of the above sites whilst measuring heart rate and atrioventricular conduction. Nicotine applied to different ganglionic plexuses caused a bradycardia, a tachycardia or a mixture of the two, with the right atrial plexus producing the largest chronotropic responses. Electrical stimulation at these sites induced only a bradycardia. Atrioventricular conduction was modestly changed by nicotine, the main response being a prolongation. Electrical stimulation produced significant prolongation of atrioventricular conduction, particularly when the right neuronal complex was stimulated. These studies show that the intrinsic plexuses of the heart are important and could be crucial for understanding impairments of cardiac function. Additionally, they provide a strong basis from which to progress using the isolated, innervated rabbit heart preparation.

Please cite this paper as: Tare M, Miller S, Wallace E, Sutherland A, Yawno T, Coleman H, Jenkin G, Parkington H. Glucocorticoid treatment does not alter early cardiac adaptations to growth restriction in preterm sheep fetuses. BJOG 2012;119:906–914. Objective To study the consequences of glucocorticoid treatment in fetal growth restriction (FGR) on cardiac function. Setting Laboratory. Sample Sheep. Methods Growth restriction was induced in sheep fetuses using single umbilical artery ligation (SUAL) on days 105–110 of gestation (term 147). Control fetuses were not ligated. Betamethasone (BM) (11.4 mg intramuscularly) or saline was administered to ewes on days 5 and 6 after surgery. Ewes were anaesthetised on day 7, the fetuses were removed, and their hearts were mounted on a Langendorff apparatus. Balloon catheters were inserted into the right and left ventricles. Outcome measures Ventricular contractile function and infarct area following ischaemia/reperfusion. Results The SUAL resulted in FGR (body weight 77% of control). The FGR was associated with increases in basal left ventricular pressure development and rates of contraction and relaxation. Right ventricular contraction was unaffected. Following brief ischaemia/reperfusion, the infarct area in FGR hearts was increased four-fold compared with controls. Antenatal BM resulted in a proportional increase in heart size and coronary flow, especially in FGR fetuses, and left ventricular pressure and heart rate responses to β-adrenoceptor activation were increased. Conclusions Fetal hearts rapidly adapt to FGR to maintain substrate delivery to the brain and heart. The FGR greatly enhanced the area of ischaemia, with implications for susceptibility in postnatal life. Antenatal BM treatment does not interfere with these cardiac changes but appears to increase left ventricle β-adrenoceptor responsiveness, which may render the offspring vulnerable to subsequent cardiac dysfunction.

BACKGROUND AND PURPOSE Rosiglitazone is an anti-diabetic drug improving insulin sensitivity and glucose uptake in skeletal muscle and adipose tissues. However, several recent clinical trials suggest that rosiglitazone can increase the risk of cardiovascular ischaemia, although other studies failed to show such risks. Therefore, the effects of rosiglitazone on the coronary circulation and any potential vascular targets need to be elucidated. Here, we show that the vascular isoform of the ATP-sensitive K+ (KATP) channel is inhibited by rosiglitazone, impairing physiological regulation of the coronary circulation. EXPERIMENTAL APPROACH The KIR6.1/SUR2B channel was expressed in HEK293 cells and studied in whole-cell and inside-out patch configurations. The Langendorff heart preparation was used to evaluate rosiglitazone in the coronary circulation of wild-type (WT) and KIR6.1-null (Kcnj8−/−) mice. KEY RESULTS KIR6.1/SUR2B channels in HEK cells were inhibited by rosiglitazone in a membrane-delimited manner. This effect was markedly enhanced by sub-micromolar concentrations of glibenclamide and the IC50 for rosiglitazone fell to 2µM, a therapeutically achievable concentration. In the Langendorff heart preparation rosiglitazone inhibited, concentration-dependently, the coronary vasodilation induced by isoprenaline, without affecting basal coronary tone. Effects of rosiglitazone on coronary perfusion were attenuated by more than 50% in the Kcnj8−/− mice, supporting the involvement of KATP channels in this effect of rosiglitazone on the coronary circulation. CONCLUSIONS AND IMPLICATIONS These results indicate that the vascular KATP channel is one of the targets of rosiglitazone action, through which this drug may compromise coronary responses to circulating vasodilators and perhaps also to metabolic stress.

Bradykinin is thought to play a major role among the endogenous cardioprotective candidates of ischaemic preconditioning (IPC). Little attention has been paid to the fact that in the tissue kallidin (KAL), rather than bradykinin might be the physiological mediator of the kallikrein–kinin system. In order to evaluate the importance of one or the other peptide the release and effect of both kinins has been investigated in isolated rat hearts following IPC. Bradykinin- and a KAL-like peptide were measured in the effluent of the rat isolated Langendorff heart with two different specific radioimmunoassays. The creatine kinase activity in the effluent was judged as degree of cardiac injury caused by ischaemia. During IPC, which consists of three 5 min no-flow and 5 min reperfusion cycles prior to the 30 min ischaemia, the bradykinin level in the effluent did not change significantly (15.4–19.4 pg ml−1). In the control group the bradykinin levels were 15.9–16.6 pg ml−1. During IPC KAL-like peptide (Arg1-, instead of Lys1-KAL), which has recently been verified by mass spectrometry, displays 5.8-fold higher levels in the effluent and significantly increases in the same time interval from 90.4 to 189 pg ml−1. After 30 min ischaemia the bradykinin levels in the IPC group were not significantly different to those of the control group (18.7 vs 14.4 pg ml−1). The KAL-like peptide levels in the IPC group vs the control group were 105 vs 86.1 pg ml−1. By the 30 min ischaemia the creatine kinase activity in the IPC group increased from 0.367 to 8.93 U l−1 (before and 10–30 min after ischaemia). In the control group during the same time period the creatine kinase levels increased from 0.277 to 34.9 U l−1. The low increase in creatine kinase activity following IPC was taken as equivalent of the cardioprotective action. A KAL antibody or HOE140 (kinin B2-receptor antagonist) completely abolished this beneficial effect of IPC (36.6 and 53.0 U l−1) when added to the perfusion medium during the reperfusion cycles of IPC prior to the 30 min ischaemia. Our data suggest that in rat hearts KAL-like peptide rather than bradykinin is the physiological compound activated by IPC and acting via the cardiac kinin B2-receptor. Thus, endogenously generated KAL-like peptide seems to play a major role in the cardioprotection of IPC. British Journal of Pharmacology (2005) 146, 952–957. doi:10.1038/sj.bjp.0706402

1. Mineralocorticoid receptor (MR) antagonism with spironolactone reduces mortality in heart failure on top of ACE inhibition. To investigate the underlying mechanism, we compared the actions of both aldosterone and spironolactone to those of angiotensin (Ang) II in the rat heart. 2. Hearts of male Wistar rats were perfused according to Langendorff. Ang II and aldosterone increased left ventricular pressure (LVP) by maximally 11+/-4 and 9+/-2%, and decreased coronary flow (CF) by maximally 36+/-7 and 20+/-4%, respectively. Spironolactone did not significantly affect LVP or CF. 3. In hearts that were exposed to a 45-min coronary artery occlusion and 3 h of reperfusion, a 15-min exposure to spironolactone prior to occlusion reduced infarct size (% of risk area) from 68+/-2 to 45+/-3%, similar to the reduction (34+/-2%) observed following 'preconditioning' (15 min occlusion followed by 10 min reperfusion) prior to the 45-min occlusion. Aldosterone exposure did not affect infarct size (71+/-5%). 4. In cardiomyocytes, aldosterone decreased [(3)H]thymidine incorporation maximally by 73+/-3%, whereas in cardiac fibroblasts it decreased [(3)H]proline incorporation by 33+/-7%. Spironolactone inhibited both effects. Ang II increased DNA and collagen synthesis, and these effects were reversed by aldosterone. 5. In conclusion, aldosterone induces positive inotropic and vasoconstrictor effects in a nongenomic manner, and these effects are comparable to those of Ang II. Aldosterone reduces DNA and collagen synthesis via MR activation, and counteracts the Ang II-induced increases in these parameters. MR blockade reduces infarct size and increases LVP recovery following coronary artery occlusion. The MR-related phenomena may underlie, at least in part, the beneficial actions of spironolactone in heart failure.

BAY 41-8543 is a novel, highly specific and so far the most potent NO-independent stimulator of sGC. Here we report the effects of BAY 41-8543 on the isolated enzyme, endothelial cells, platelets, isolated vessels and Langendorff heart preparation. BAY 41-8543 stimulates the recombinant sGC concentration-dependently from 0.0001 microM to 100 microM up to 92-fold. In combination, BAY 41-8543 and NO have synergistic effects over a wide range of concentrations. Similar results are shown in implying that BAY 41-8543 stimulates the sGC directly and furthermore makes the enzyme more sensitive to its endogenous activator NO. In vitro, BAY 41-8543 is a potent relaxing agent of aortas, saphenous arteries, coronary arteries and veins with IC(50)-values in the nM range. In the rat heart Langendorff preparation, BAY 41-8543 potently reduces coronary perfusion pressure from 10(-9) to 10(-6) g ml(-1) without any effect on left ventricular pressure and heart rate. BAY 41-8543 is effective even under nitrate tolerance conditions proved by the same vasorelaxing effect on aortic rings taken either from normal or nitrate-tolerant rats. BAY 41-8543 is a potent inhibitor of collagen-mediated aggregation in washed human platelets (IC(50)=0.09 microM). In plasma, BAY 41-8543 inhibits collagen-mediated aggregation better than ADP-induced aggregation, but has no effect on the thrombin pathway. BAY 41-8543 is also a potent direct stimulator of the cyclic GMP/PKG/VASP pathway in platelets and synergizes with NO over a wide range of concentrations. These results suggest that BAY 41-8543 is on the one hand an invaluable tool for studying sGC signaling in vitro and on the other hand its unique profile may offer a novel approach for treating cardiovascular diseases.

1. In the present study we investigated functional and binding characteristics of muscarinic receptors in experimental cardiac hypertrophy. 2. As models of cardiac hypertrophy we used hearts of spontaneously hypertensive rats (SHR) and Wistar rats with surgically induced abdominal aorta stenosis (ASR). Wistar Kyoto rats (WKY) and sham operated Wistar rats were used as respective controls. 3. The hypertrophy was more pronounced in hearts of ASR compared to SHR, although the mean arterial pressure was found to be lower. 4. Isolated, perfused Langendorff heart preparations (paced with 5 Hz) from both groups of hypertrophied hearts were less sensitive to the muscarinic agonists oxotremorin and methacholine (P < 0.05, all n = 6) when compared with control organs. The maximal reduction in contractile force induced by methacholine was 59.3 +/- 4.5% in SHR and 41.6 +/- 3.4% in ASR hearts versus 26.4 +/- 4.1% and 25.0 +/- 2.6% in control organs, respectively. 5. The density (fmol/mg protein-1) of muscarinic receptors in membrane homogenates of hearts from SHR (127.6 +/- 11.5) was unchanged, whereas in hearts from ASR (221.0 +/- 8.9) it was found to be reduced (P < 0.05) when compared to the respective controls (142.5 +/- 14.7 and 308.8 +/- 16.1, respectively, all n = 6). 6. From the present data we conclude that cardiac hypertrophy results in a loss of sensitivity towards muscarinic receptor stimulation. A corresponding reduction of left ventricular receptor density could only be demonstrated in massively hypertrophied hearts of ASR.

Terminal nerve fibres of the autonomic nervous system closely approach mast cells in peripheral organs, and mutual influences between release of neurotransmitters or mast cell mediators may cause neuro-immunological interactions. We have studied the influence of mast cell degranulation on the release of endogenous noradrenaline and newly incorporated acetylcholine (such as 14C-choline/acetylcholine overflow) evoked by stimulation of extrinsic postganglionic sympathetic or preganglionic vagal nerves in the rat Langendorff heart perfused with Tyrode solution. Compound 48/80 perfused in normal hearts, or ovalbumin infused into hearts from rats sensitized to ovalbumin, enhanced the overflow of endogenous histamine and serotonin. Both stimuli increased the release of mediators to a similar extent and with fast kinetics. Maximum average concentrations in the perfusate of histamine were about 800 nmol/l, and of serotonin 40 nmol/l, in a sample collected within 4 min after mast cell degranulation. Stimulation of autonomic nerves did not affect basal histamine or serotonin overflow. Whereas basal overflows were unaffected, the stimulation-evoked releases of both noradrenaline and acetylcholine, were facilitated when compound 48/80 was perfused before and during nerve stimulation. The facilitation of noradrenaline overflow was more pronounced (by 60%) when compound 48/80-induced mediator overflow started 4 min before nerve stimulation as compared to 30 s (15%), and was reduced by cocaine (by 50%), and, in the presence of cocaine, abolished by cimetidine (but was unaffected by mepyramine and thioperamide) and NG-nitro-(L)-(-)-arginine. In the presence of cimetidine and cocaine, when the facilitatory components were abolished, the evoked noradrenaline overflow observed 30 s after the start of infusion of compound 48/80 was inhibited, and the inhibition was partly reduced by methiotepin and ketanserin. Ovalbumin infusion in hearts from sensitized animals caused an inhibition of evoked noradrenaline overflow sensitive to methiotepin and also partly to ketanserin, and no facilitation was observed. The facilitation (> 100%) of evoked overflow of acetylcholine observed at 4 min after the start of perfusion with compound 48/80 was partly reduced by thioperamide (but not mepyramine or cimetidine) and to a comparable extent either by tropisetron (3 mumol/l) alone or by tropisetron plus methiotepin. In conclusion, degranulation of immunological cells is followed by histamine and serotonin release in the rat heart and may affect the release of autonomic neurotransmitters in rather unusual ways, by i) an uptake1-dependent and ii) an H2-mediated facilitation which probably involves nitric oxide as a permissive mediator, and iii) a serotonergic inhibition, of noradrenaline release, and iv) an H3- and serotonergic facilitation of acetylcholine release.

1. The role of K+ channels in the nitric oxide (NO)-independent coronary vasodilator effect of bradykinin was examined in the Langendorff heart preparation in which nitroarginine was used to inhibit NO synthesis and elevate perfusion pressure; cyclo-oxygenase was inhibited with indomethacin. 2. The K+ channel inhibitors, tetraethylammonium, procaine and charybdotoxin, but not glibenclamide, further increased perfusion pressure suggesting a role for K+ channels, other than ATP-sensitive K+ channels, in the regulation of coronary vascular tone under the experimental conditions adopted here. 3. The non-specific K+ channel inhibitors, tetraethylammonium and procaine, reduced vasodilator responses to bradykinin and cromakalim but not those to nitroprusside in the perfused heart treated with nitroarginine and indomethacin. 4. Glibenclamide, an inhibitor of ATP-sensitive K+ channels, reduced vasodilator responses to cromakalim but did not affect those to bradykinin or nitroprusside. 5. Charybdotoxin, an antagonist of Ca(2+)-activated K+ channels, inhibited responses to bradykinin but did not affect those to cromakalim or nitroprusside. 6. Nifedipine inhibited vasodilator responses to bradykinin and cromakalim without affecting those to nitroprusside. 7. Inhibition of cytochrome P450 with clotrimazole reduced responses to bradykinin but did not modify those to cromakalim or nitroprusside. 8. These results suggest that bradykinin utilizes a Ca(2+)-activated K+ channel to produce vasodilatation in the rat heart.

We investigated whether post-receptor alterations contribute to the diminished beta-adrenergic inotropic effects in the rat Langendorff heart following ischaemia (I) and reperfusion (R). We quantitated immunodetectable Gs and Gi protein alpha-subunit content, basal and stimulated adenylyl cyclase activity and cyclic AMP (cAMP) content in normoxic, ischaemic (30 min) and ischaemic reperfused (30 min) hearts. In addition, we measured the inotropic response of normoxic and reperfused Langendorff hearts to forskolin and dibutyryl cAMP (db-cAMP). Immunodetectable Gs and Gi alpha-subunits were unaltered by I or R. Basal adenylyl cyclase activity was decreased during I, but recovered during R. In membranes from normoxic hearts, isoprenaline, GTP, Gpp(NH)p, NaF, forskolin or Mn2+ enhanced adenylyl cyclase activity. This increase in activity was diminished in ischaemic hearts, but could be restored by R. cAMP content decreased time-dependently during I and did not recover by R, indicating ATP depletion. Forskolin and db-cAMP induced an inotropic response in normoxic hearts, which was virtually abolished after I and R. We conclude that adenylyl cyclase responsiveness is impaired during I. Since adenylyl cyclase responsiveness recovers during R, whereas inotropic responses to forskolin and db-cAMP are virtually absent in reperfused hearts, an additional mechanism downstream of cAMP formation appears to be defective during R, which prevents recovery of inotropic responses to hormonal stimulation.

The amiloride derivatives, 2',3'-benzobenzamil (BB), 3',4'-dichlorobenzamil (DCB), and 5-(N-4-chlorobenzyl)-2',4'-dimethylbenzamil (CBDB) are known as inhibitors of the Na+/Ca2+ exchange. This kind of drug action was recently suggested to be a new inotropic mechanism. In guinea-pig myocardium, we have studied the inotropic and the accompanying electrophysiological effects of the three compounds in order to assess their selectivity of action. In left atria and in papillary muscle, force of contraction increased with DCB and CBDB (atria only) at a high concentration (5 x 10(-5)-10(-4) mol/l) and after long exposure time, whereas BB produced a negative inotropic effect. In the isolated perfused Langendorff heart, the amiloride derivatives tested decreased spontaneous heart rate and force of contraction and prolonged the duration of contraction. In isolated cardiac myocytes, sodium current, calcium current and the delayed rectifier were reduced by concentrations of BB, DCB and CBDB similar to the IC50 values reported for the inhibition of the Na+/Ca2+ exchange. Our results demonstrate that the amiloride derivatives have multiple sites of action. It is concluded that more specific modulators of the Na+/Ca2+ exchange are required in order to define their contribution to the regulation of contractile activation of the heart.

The mechanism of the positive cardioactive effects induced by verbascoside in the Lagendorff rat heart has been investigated. Isolated rat hearts treated with alpha- or beta-adrenergic agents did not show significant reduction of the positive chronotropism, inotropism and increased coronary perfusion rate mediated by verbascoside. A significant increase in prostacyclin levels (142%) observed following the administration of verbascoside suggests that prostacyclin stimulates formation of cAMP which induces the cardioactivity associated with verbascoside.

Es wird uber die Synthese von N-(3′-Methoxybenzamidomethyl)-D-norephedrin (7) und analogen Verbindungen (1–6, 8–29) aus N-Chlormethyl-carbonamiden und Aminen und ihre Prufung am Langendorff-Herzen des Meerschweinchens berichtet. Einige Vertreter (3, 4, 7, 9, 13, 15) fuhren zu einer Erhohung von Coronardurchflus und Kontraktionsamplitude. Die N-Amidomethyl-β-phenolalkanolamine 24–26, 27 und 29, deren Synthese im Hinblick auf eine mogliche langanhaltende pressorische Wirkung erfolgte (chemische Retardpraparate), zeigen keine blutdrucksteigernden Effekte. Synthesis and Pharmacological Test of N-(3′-Methoxy-benzamidomethyl)-D-norephedrine and Analogous Compounds The synthesis of N-(3′-methoxybenzamidomethyl)-D-norephedrine (7) and of analogous compounds (1–6, 8–29) from N-chloromethyl-carbonamides and amines and their assay on the Langendorff heart of the guinea pig are described. Some compounds lead to a rise of the coronary flow and of the contraction amplitude. The N-amidomethyl-β-phenolalkanolamines 24–26, 27 and 29, which were synthesized with a view to a possible long acting blood pressure activity (chemical depot preparation), show no blood pressure-elevating effects.

1. A modified Langendorff heart preparation from the guinea-pig was used to analyse catecholamine responses. Contractile force, heart rate and coronary perfusion pressure were recorded. 2. Four components of the vascular response could be identified. (a) The initial phase was a vasoconstriction mediated by α-adrenoceptors which preceded any effects on heart rate and force. (b) A secondary constriction followed, which was due to the increased myocardial compression during positive inotropic and chronotropic responses. (c) The third, more predominant, effect was a prolonged dilatation probably associated with the increased metabolic activity of the heart. (d) A fourth component was a direct vasodilatation mediated by β-adrenoceptors which was evident when small doses of catecholamines were used but was usually masked by the more pronounced metabolically linked dilatation. 3. The actions of salbutamol were examined and since it caused direct vasodilatation by stimulation of β-adrenoceptors without other myocardial effects, these adrenoceptors were classified as the β2-type. 4. I.C.I. 50,172 was employed to block selectively the myocardial effects due to stimulation of β1-adrenoceptors and leave the vasodilator β2-adrenoceptors unaffected. 5. Adrenaline, noradrenaline and isoprenaline were compared at two dose levels, in the presence or absence of effects on heart rate and force. 6. Constrictor or dilator effects were found in the absence of other effects and were shown to depend to some extent on the rate of coronary perfusion.

The effect of replacing the basic aliphatic residue of orciprenaline [(A); R = isopropylamino] and salbutamol [(B); R = tert.butylamino] with: a) a heterocyclic amine; b) a basic residue containing a phenylcyclohexane radical had been studied. The synthesis of the compounds is outlined. They were tested in vitro for relaxation of histamine-induced spasm of tracheal chains and on the isolated Langendorff heart, and in vivo according to the Konzett and Rossler technique and for their action on the cardiovascular system. In all tests the new derivataives were less active than the reference substances; the only exception was (A) where R = 4-phenylpiperidine (M.G. 6604), which was almost as active as orciprenaline in the Konzett and Rossler test, had one third of its activity on isolated trachea and showed absolutely no influence on heart rate in vitro or in vivo. Its effect was not inhibited by beta-blocking agents; it therefore showed an antihistaminic profile.