Facilitation of calcium blocking and membrane effects by intrinsic sympathomimetic activity.

The interactions between ICI 118, 587 (Corwin) a beta 1-selective partial adrenergic agonist, and atenolol (Tenormin), propranolol (Inderal) and verapamil were examined first in anaesthetised dogs pretreated with syrosingopine and vagotomised. ICI 118, 587 was administered iv in cumulative doses of 0.1 to 1000 micrograms X kg-1. In four animals, heart rate increased from 102 +/- 4 to 188 +/- 12 beats X min-1 with a KA of 2.5 +/- 0.9 micrograms X kg-1. ICI 118, 587 was then administered to five groups each of four animals pretreated with atenolol (250 micrograms X kg-1 and 500 micrograms X kg-1iv), propranolol (250 micrograms X kg-1 and 500 micrograms X kg-1) or verapamil (200 micrograms X kg-1 plus 5 micrograms X kg-1 X min-1 iv). Both atenolol and propranolol shifted the dose response curve to the right but verapamil did not. Atenolol did not lower the maximal heart rate response to ICI 118,587. Both propranolol and verapamil slowed heart rate significantly (P less than 0.05) after, but not before, ICI 118,587. Further studies were then carried out in vitro. Cat papillary muscles were superfused with physiological saline at pH 7.4 and with either atenolol or ICI 118,587 at 5 X 10(-5) mol X litre-1. Tension was recorded at Lmax over a [Ca2+] range of 0.5 to 8 X 10(-3)mol X litre-1. The pA2 for verapamil against Ca2+ in the presence of atenolol and ICI 118,587 was 5.25 +/- 0.10 and 6.57 +/- 0.22 respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Beta-adrenoceptor stimulant properties of amidoalkylamino-substituted 1-aryl-2-ethanols and 1-(aryloxy)-2-propanols.

Parallel series of 2-[(2-amidoethyl)amino]-1-arylethanols and 1-[(2-amidoethyl)amino]-3-(aryloxy)-2-propanols have been prepared, and the compounds were tested as beta-adrenoceptor stimulants on the heart and circulation of the dog. The corresponding 2-(alkylamino)-1-arylethanols and 3-(alkylamino)-2-propanols have been tested for comparison and the structure-activity relationships (SAR) examined. The arylethanols are potent full agonists, showing selectivity for the heart relative to blood vessels, while the (aryloxy)propanols are even more cardioselective and are partial agonists. Within a narrow series of 1-[(amidoethyl)amino]-3-(4-hydroxyphenoxy)-2-propanols, careful examination of the SAR of the amide group showed that great variation in cardioselectivity and degree of agonism may be produce. From this study ICI 118587, N-[20[[2-hydroxy-3-(4-hydroxyphenoxy)propyl]amino]ethyl]-4-morpholinecarboxamide, was selected for its high cardioselectivity and 50% agonist properties. This compound in under clinical evaluation as a cardiac stimulant.

The cardiovascular effects of ICI 118,587: A beta 1-adrenoceptor partial agonist.

1 In a preparation in which cardiovascular reflexes were prevented from occurring, ICI 118,587 (1-(p-hydroxyphenoxy)-3-beta-(morpholinocarbonamido) ethylamino-2-propranol fumarate) caused dose-dependent positive chronotropic and inotropic effects upon the dog heart. 2 The increase in heart rate brought about by ICI 118,587 was about 43% of the maximum increase produced by isoprenaline. 3 For a given chronotropic effect produced by either ICI 118,587 or isoprenaline, each compound produced a similar inotropic effect as indicated by an increase in LV dp/dtmax. 4 In contrast to the direct stimulant action of ICI 118,587 on the heart no direct effects on vascular smooth muscle were observed. 5 ICI 118,587 was shown to be a competitive antagonist of the chronotropic and vasodilator effects of isoprenaline on the heart and blood vessels and of the chronotropic effects of noradrenaline on the heart. 6 It is concluded that ICI 118,587 is a selective beta 1-adrenoceptor partial agonist.

The effects of three beta-adrenoceptor blocking drugs on isolated preparations of skeletal and cardiac muscle.

1 The effects of propranolol, oxprenolol and practolol on the isometric twitch responses to electrical stimulation of isolated diaphragm muscles from the rat and of isolated papillary muscles from the rabbit are described.2 Depression of the twitch responses of the diaphragm muscle was produced by propranolol (20 mug/ml), by oxprenolol (100 mug/ml) and by practolol (500 mug/ml).3 Depression of the twitch responses of the papillary muscles was produced by propranolol (20 mug/ml) by oxprenolol (100 mug/ml) and by practolol (200 mug/ml).4 No increase of twitch tension was produced by oxprenolol or practolol on either tissue.5 It is concluded that propranolol, oxprenolol and practolol produce negative inotropic actions on isolated cardiac muscle by a mechanism unrelated to blockade of beta-adrenoceptors and which occurs at doses which are well in excess of those doses required to produce beta-blockade.

Interaction between the effects of 5-hydroxytryptamine and adrenaline on the growth of platelet thrombi in the coronary artery of the anaesthetized dog.

1. The interaction between adrenaline and 5-hydroxytryptamine (5-HT) has been quantitated on the rate of thrombus formation, in the stenosed coronary artery with damaged endothelium of the anaesthetized dog. 2. Changes in the plasma concentration of adrenaline were produced by varying the rate of an intravenous infusion of adrenaline and in the effects of 5-HT, by intravenous injections of the selective 5-HT2 receptor antagonist, ICI 170809. 3. Increases in the plasma concentration of adrenaline, which did not cause significant changes in blood pressure and heart rate, increased the rate of thrombus formation. 4. Antagonism of the 5-HT2 receptor by ICI 170809, in the absence of an infusion of adrenaline, abolished thrombus formation (mean ED50 0.41 microgram kg-1, i.v.). 5. The effects of adrenaline were non-competitively antagonized by ICI 170809; maximum effects were obtained in the dose-range 50-200 micrograms kg-1, i.v., when the mean dose-ratio increase in adrenaline required to restore equivalent rates of thrombus formation was 39 fold. 6. These results are consistent with a synergism between adrenaline and 5-HT and emphasize the importance of both on thrombus formation.

Redirection of arachidonic acid metabolism by ICI D1542: effects on thrombus formation in the coronary artery of the anaesthetized dog.

1. The effects of simultaneous redirection of arachidonic acid metabolism, by inhibition of thromboxane A2 (TXA2) synthase and blockade of the platelet thromboxane A2 receptor (TP-receptor), was examined on the rate of thrombus formation in a stenosed coronary artery with damaged endothelium in an anaesthetized dog. 2. Redirection of arachidonic acid metabolism was achieved by intravenous doses of ICI D1542, a selective and potent inhibitor of TXA2 synthase and the TP-receptor. 3. Redirection of arachidonic acid metabolism was demonstrated in whole blood, stimulated ex vivo by collagen. The ED50 for inhibition of TXB2 production was 7.1 micrograms kg-1, i.v.; there were corresponding increases in the production of the eicosanoids prostaglandin D2 (PGD2), PGE2 and PGF2 alpha. 4. Thrombus formation was inhibited by D1542 (ED50 0.55 micrograms kg-1, i.v.), but could be restarted by an intravenous infusion of adrenaline (0.2-38 micrograms kg-1 min-1, i.v.). In the presence of the maximum effective dose of D1542 (1 mg kg-1, i.v.) a 190 fold increase in the infusion rate of adrenaline was required to restore thrombus formation. 5. In the presence of D1542, removal of endoperoxide metabolites by inhibition of cyclo-oxygenase with aspirin (5 mg kg-1, i.v.) caused thrombus formation to restart, indicating the ability of the endoperoxide metabolites to inhibit thrombus formation in vivo. 6. These results indicate that, in the stenosed and damaged coronary artery of the dog, redirection of arachidonic acid metabolism by D1542 is more effective at preventing thrombus formation than inhibition of cyclo-oxygenase by aspirin.

The potentiation of sinus arrhythmia by vasoactive intestinal polypeptide (VIP) in the anaesthetized dog.

Vasoactive intestinal polypeptide (VIP) is a neuropeptide released from the vagus, which in contrast to acetylcholine has a long-acting positive chronotropic effect on the heart. The aim of this study, in the anaesthetized dog, was to examine the effects of VIP and a VIP antagonist when injected into the sinus node artery of a vagally intact heart in sinus arrhythmia. The response was compared to that produced by noradrenaline (NAD) infusion and stimulation of the sympathetic nerves to the heart. Mean +/- S.D. of 30 R-R intervals was used to describe mean heart rate interval and heart rate variability. VIP, a VIP antagonist, NAD and sympathetic nerve stimulation all caused increases in heart rate without significant increases in blood pressure. However, only VIP caused an increase in heart rate variability; VIP antagonism and NAD caused a decrease and sympathetic nerve stimulation had no effect. These results suggest that VIP and acetylcholine when released from the vagus act synergistically to increase sinus arrhythmia.

The effect of arterial wall shear stress on the incremental elasticity of a conduit artery.

AIMS: The purpose of this investigation was to determine the effects of flow mediated dilatation on arterial incremental elasticity (E(inc) ). METHODS: In four female anaesthetized pigs, the iliac artery and vein were connected by a shunt with a variable resistance which allowed blood flow and therefore shear stress to be regulated. E(inc) was calculated from simultaneous records of diameter and pressure throughout a minimum of four cardiac cycles. RESULTS: Passive increases in diameter (∼1-2%) throughout a cardiac cycle, brought about by pressure, resulted in a two- to threefold increase in E(inc) . In contrast, increases in shear stress caused active smooth muscle relaxation and a significant increase in diameter from 3.663 ± 0.215 mm to 4.488 ± 0.163 mm (mean ± SEM, P < 0.05) equivalent to a fractional increase in diameter (fD) of 1.5 with no significant change in mean arterial pressure, 108 ± 2 mmHg to 106 ± 1 mmHg (mean ± SEM). The average value of E(inc) per cardiac cycle at baseline was 2.17 ± 0.10 × 10(3) kPa and remained relatively constant until fD exceeded 1.3 thereafter increasing to a maximum of 9.23 ± 1.0 × 10(3) kPa. CONCLUSION: These results show that in a conduit artery during the dilatory response to shear stress, the interaction between smooth muscle and collagen operates so as to maintain E(inc) relatively constant over much of the working range of dilatation. This is consistent with a model of the arterial wall in which collagen is recruited both by passive stretch, in response to an increase in pressure and therefore wall stress, and also by active contraction of smooth muscle.

Dilatation in the femoral vascular bed does not cause retrograde relaxation of the iliac artery in the anaesthetized pig.

AIM: We tested the hypothesis that dilatation of a feeding artery may be elicited by transmission of a signal through the tissue of the arterial wall from a vasodilated peripheral vascular bed. METHODS: In eight pentobarbital anaesthetized pigs, acetylcholine (ACh, an endothelium-dependent vasodilator) was injected intra-arterially above (upstream) and below (downstream) a test segment of the left iliac artery, the diameter of which was measured continuously by sonomicrometry. RESULTS: Under control conditions, ACh injections upstream and downstream of the test segment caused dilatation. Downstream injection dilated the peripheral arterioles, resulting in increased blood flow and proximal dilatation. This is a shear stress, nitric oxide (NO)-dependent response. The experiment was then repeated after applying a stenosis to prevent the increased flow caused by downstream injection of ACh; the stenosis was placed either above the site of diameter measurement to allow retrograde conduction, or below that site to prevent distally injected ACh reaching the measurement site. Under these conditions, downstream injection of ACh had a minimal effect on the shear stress of the test segment with no increase in test segment diameter. This was not due to endothelial damage or dysfunction as injection of ACh upstream still caused a large increase in test segment diameter. CONCLUSIONS: Our results indicate that dilatation of the feeding artery of a vasodilated bed is caused by increased shear stress within the feeding artery and not via a signal transmitted through the arterial wall from below.

Characteristics of the response of the iliac artery to wall shear stress in the anaesthetized pig.

The functional significance of shear stress-induced vasodilatation in large conduit arteries is unclear since changes in the diameter have little effect on the resistance to blood flow. However, changes in diameter have a relatively large effect on wall shear stress which suggests that the function of flow-mediated dilatation is to reduce wall shear stress. The mean and pulsatile components of shear stress vary widely throughout the arterial system and areas of low mean and high amplitude of wall shear stress are prone to the development of atheroma. In this study, using an in vivo model with the ability to control flow rate and amplitude of flow independently, we investigated the characteristics of the response of the iliac artery to variations in both the mean and amplitude of wall shear stress. The results of this study confirm that increases in mean wall shear stress are an important stimulus for the release of nitric oxide by the endothelium as indicated by changes in arterial diameter and show for the first time, in vivo, that increases in the amplitude of the pulsatile component of shear stress have a small but significant inhibitory effect on this response. A negative feedback mechanism was identified whereby increases in shear stress brought about by increases in blood flow are reduced by the release of nitric oxide from the endothelium causing dilatation of the artery, thus decreasing the stimulus to cell adhesion and, through a direct action of nitric oxide, inhibiting the process of cell adhesion. The results also provide an explanation for the uneven distribution of atheroma throughout the arterial system, which is related to the ratio of pulsatile to mean shear stress and consequent variability in the production of NO.

An investigation into the physiological relevance of the vagal tachycardia in the anaesthetized dog.

AIM: Our aim was primarily to assess whether or not a vagal tachycardia can be elicited in vivo without administration of atropine, and secondly to evaluate whether the dose of atropine, a muscarinic antagonist, determines the magnitude of the tachycardia. METHODS: Experiments were carried out in the presence of atenolol (2 mg kg(-1)). The vagal tachycardia requires high vagal activity which was induced by noradrenaline infusion (20 microg min(-1)). Two techniques were then used to elicit a tachycardia, vagal section and atropine administration. RESULTS: The increase in blood pressure caused heart rate to fall to 60 +/- 7 beats min(-1) (mean +/- SEM). When the vagi were sectioned (n = 5) heart rate increased by 9 +/- 2 beats min(-1) above the intrinsic rate which was 108 beats min(-1), this increase was not significant. In contrast atropine given (9-20 microg kg(-1)) (n = 5) during high vagal activity increased heart rate by 81 +/- 22 beats min(-1) above the intrinsic rate (P < 0.05). To assess if the dose of atropine affects the magnitude of the vagal tachycardia, the right vagus was stimulated electrically at increasing frequencies (2, 4, 8, 16, 32 Hz) before and after increasing doses of atropine (0.02, 0.05, 1 mg kg(-1)). This reduced the magnitude of the bradycardia; however, the magnitude of the vagal tachycardia was unaffected. CONCLUSION: The vagal tachycardia cannot be elicited without atropine suggesting that it does not play a significant physiological role.