Coronary Dilator Effect Research Articles

The coronary dilation effect of shen fu injection was mediated through NO.

ObjectivesShen Fu Injection (SF), which consisted of Red ginseng extraction injection (RG) and prepared aconite extraction injection (RA), is a traditional Chinese medicine mainly used for various cardiac diseases. This study is to analyse SF's effects on cardiac performance and coronary circulation. And the coronary dilating effect and mechanism of the above three injections were also explored.MethodsMature male guinea pigs were used as our animal model. We employed two types of perfusion methods (constant pressure and constant flow) in vitro, using Langendorff heart preparations to observe the cardiac function and coronary response to SF (1/200). The coronary dilation effects of the above three injections (1/800, 1/400 and 1/200) were recorded at basal coronary resting tone and when coronary vessels were pre-contracted with a thromboxane A2 analogue (U46619), in the presence or the absence of the inhibitor of nitric oxide synthesis (L-NAME, 10−4 M), the blocker of Ca2+-activated potassium channel(TEA, 10−3 M), or the blocker of adenosine triphosphate (ATP)-sensitive potassium channel (glybenclamide) (10−5 M).ResultsWhen perfused with constant pressure, SF significantly increased coronary flow, left ventricular developed pressure (LVDP) and the rate-pressure product (RPP). When perfused with constant flow, SF produced a significant reduction in the coronary perfusion pressure (CPP), LVDP and RPP. The coronary vasodilatation response of the above three injections can be reduced by L-NAME but was unaffected by TEA or glybenclamide when coronary vessels were pre-contracted with U46619 but not at resting tone. SF, RG and RA can all up-regulate eNOS expression in the human umbilical vein cells (EA.hy926).ConclusionWe demonstrated that SF does not contribute to the inotropic change of myocardium whose improvement is due to alternation of coronary flow. The coronary dilation effect of SF was mediated through RG and RA, via promoting NO release.

Dilation of Epicardial Coronary Arteries by the G Protein-Coupled Estrogen Receptor Agonists G-1 and ICI 182,780

Endogenous estrogens protect from coronary artery disease in premenopausal women, but the mechanisms involved are only partly understood. This study investigated whether activation of the novel G protein-coupled estrogen receptor (GPER, formerly known as GPR30) affects coronary artery tone, and whether this is affected by concomitant blockade of estrogen receptors (ER) α and β. Rings of epicardial porcine coronary arteries suspended in organ chambers were precontracted with prostaglandin F₂α, and direct effects of G-1 (GPER agonist) and ICI 182,780 (GPER agonist and ERα/ERβ antagonist) were determined. In addition, indirect effects on contractility to endothelin-1 and serotonin (a vasoconstrictor released from aggregating platelets during acute myocardial infarction) were assessed. ICI 182,780 and G-1 caused acute dilation of coronary arteries to a comparable degree (p < 0.05 vs. solvent control). Both GPER agonists attenuated contractions to endothelin-1 (p < 0.05 vs. ethanol), but not to serotonin (n.s.). In summary, these findings provide evidence for direct and indirect coronary artery dilator effects of GPER independent of ERα and ERβ, and are the first demonstration of arterial vasodilation in response to ICI 182,780.

Interspecies Differences and Extracellular Calcium Dependence in the Vasorelaxing Effect of Cromakalim in Isolated Human, Porcine, and Canine Coronary Arteries

Coronary arteries isolated from human, porcine, and canine hearts were depolarized with potassium chloride and relaxed by cromakalim (0.0125-10.0 micromol/L) at low (1.5 mmol/L) and high (7.5 mmol/L) extracellular calcium concentration ([Ca(2+)]( o)). At low [Ca(2+)](o), cromakalim (1 micromol/L) relaxed the coronary arteries with the order of porcine > canine > human. Fifty percent effective concentrations of cromakalim revealed the same order: 0.15 micromol/L in porcine, 0.36 micromol/L in canine, and 3.91 micromol/L in human coronary arteries. High [Ca(2+)](o) significantly enhanced the relaxing effect and decreased the potency of cromakalim in porcine and human but not in canine coronary arteries. In human coronary arteries, precontracted with the prostaglandin analogue (U46619), high [Ca(2+)]( o) enhanced the effect of 0.1 micromol/L cromakalim more efficiently in the presence than in the absence of endothelium. It appears that the coronary dilating effect of cromakalim largely depends on the species and is modulated by [Ca(2+)](o,) with a partly endothelium dependent manner.

Reactivity to endothelium-dependent and -independent vasoactive substances is maintained in coronary resistance vessels of the failing hamster heart.

Several studies suggest that regulation of coronary vasomotion is abnormal in heart failure, but controversies exist as to whether an altered endothelium-dependent dilation of the coronary vasculature contributes to these abnormalities. In the present study we evaluated the coronary reactivity to endothelium-dependent and -independent vasoactive substances in a model of chronic heart failure. Isolated hearts from > 200-day-old cardiomyopathic hamsters (UM-X7.1) and age-matched normal Syrian hamsters were mounted on a Langendorff apparatus and retrogradely perfused at constant pressure (100 mmHg). Heart rate, left ventricular developed pressure (LVP) and coronary flow (CF) were measured. A first group of normal and failing hearts were challenged with increasing doses of acetylcholine (Ach), 1-1000 nM, and sodium nitroprusside (SNP), 0.01-10 microM. A second group was challenged with Ach (100 nM) and SNP (1 microM) before and during infusion of the NO synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME). Finally, normal and failing hearts were challenged with Ach (100 nM) before and during infusion of indomethacin (10 microM) or tetraethylammonium (1 mM). Myocardial contractility and coronary flow were significantly impaired in failing hearts (LVP = 32 +/- 5 vs. 50 +/- 4 mmHg in normal hearts; CF = 4.7 +/- 0.6 vs. 6.7 +/- 0.6 ml/min in normal hearts). Coronary flow increases with increasing doses of Ach (EC50 = 84 +/- 15 nM for failing hearts and 100 +/- 3 nM for normal hearts, P = ns). At concentrations exceeding the EC50, failing hearts were more sensitive to the coronary dilator effects of Ach. The reduction in coronary flow elicited by L-NAME was similar in normal (-41 +/- 2%) and failing hearts (-40 +/- 3%); in both normal and failing hearts, the acetylcholine vasodilator response was not significantly affected by L-NAME. Indomethacin infusion resulted in a slight increase in coronary flow and significantly reduced the coronary dilator effects of acetylcholine. Tetraethylammonium had no significant effects on basal coronary perfusion of normal and failing hearts. However, in the latter group, acetylcholine vasodilator response was significantly attenuated. Results obtained in isolated failing hamster hearts allow us to conclude that (1) significant coronary dysfunctions are present in this model of chronic heart failure, (2) neither the NO-synthase nor the cyclo-oxygenase pathway contributes to these coronary dysfunctions, and (3) an adequate coronary vasodilator response appears to be present in this model of chronic heart failure.

Impaired coronary sensitivity to diltiazem in experimental heart failure: involvement of the cyclooxygenase but not the nitric oxide-synthase pathway.

Because controversies surround the increased negative inotropic effects of calcium antagonists in heart failure, other mechanisms may explain their lack of efficacy in this condition. We hypothesized that altered coronary sensitivity through endothelial dysfunctions may be involved. Our goal was to evaluate the effects of heart failure on coronary and cardiac sensitivity to the calcium antagonist diltiazem. Left ventricular developed pressure (LVP) and coronary flow (CF) were assessed in isovolumetrically beating, perfused, failing hearts from cardiomyopathic hamsters (UM-X7.1) and hearts from normal hamsters. Diltiazem concentration-response curves for both coronary dilation and its negative inotropic effects were charted under control conditions and in the presence of the specific nitric oxide (NO) synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 30 microM), and the cyclooxygenase inhibitor, indomethacin (10 microM). Diltiazem concentration-response curves for its negative inotropic action were similar in normal and failing hearts (IC50 1.2 and 2.3 microM, respectively). In contrast, the coronary dilator effects of diltiazem were impaired in failing hearts (EC50 for diltiazem-induced coronary dilation increased from 90 nM in normal hearts to 1.1 microM in failing hearts, p < 0.01). The involvement of endothelial dysfunctions in the observed coronary "desensitization" to diltiazem in heart failure was evaluated through the NO-synthase and cyclooxygenase pathways. Diltiazem concentration-response curves from failing hearts were not modified in the presence of L-NAME, whereas indomethacin normalized the coronary response to diltiazem in heart failure. These findings suggest that coronary "desensitization" to diltiazem occurs through parallel production and/or release of a vasoconstricting factor or factors originating from the cyclooxygenase pathway. Heart failure was not associated with increased cardiac sensitivity to diltiazem but rather with altered coronary sensitivity. These findings suggest that coronary desensitization may play a role in the lack of efficacy of diltiazem in heart failure and provide a better understanding of factors modulating the effects of calcium antagonists in heart failure.

Pharmacological Properties of KRN2391, a novel vasodilator of the nitrate-potassium channel opener hybrid type

1. The pharmacological properties of KRN2391 in animal experiments are reviewed. 2. The vasodilating mechanism of KRN2391 is based on both a nitrate action and a K channel opening action, and whether KRN2391 acts as a nitrate and/or a K channel opener depends on the type and the segment of blood vessels. 3. KRN2391 causes a preferential increase in coronary blood flow in anesthetized dogs. 4. KRN2391 produces an increase in oxygen supply to the heart and a decrease in myocardial oxygen consumption in anesthetized dogs. 5. KRN2391 shows antiangial effects in various anginal models of rats and cardioprotective effects in perfused rat hearts. 6. KRN2391 does not develop self-tolerance or cross-tolerance between KRN2391 and other nitrates in coronary dilating and vasodepressor effects. 7. The pharmacological properties of KRN2391 are thought to be beneficial for the treatment of patients with ischemic heart disease.

The effects of amrinone versus dobutamine on myocardial mechanics and energetics after hypothermic global ischemia

The effects on the postischemic myocardium of amrinone and dobutamine were studied in canine hearts that underwent 90 minutes of hypothermic (10 degrees C) arrested ischemia. In an isolated heart preparation cross-circulated by a support dog, left ventricular pressure-volume loops were collected under a constant afterload based on a mock circulatory system and a range of preload conditions controlled by a computerized servo volume pump. Dobutamine (0, 5, 10, 15 micrograms/kg per minute) and amrinone (0, 0.75, 1.5, 3.0 mg/kg) were tested in this order based on the weights of the support dogs in eight experiments. Changes in intrinsic myocardial contractility were analyzed as percent increases in the preload recruitable stroke work area from baselines. Dobutamine exhibited significant dose-related increases in the preload recruitable stroke work area. Amrinone did not produce significant increases in preload recruitable stroke work area at 0.75 mg/kg; amrinone's inotropic effect was equivalent to dobutamine, 5 micrograms/kg per minute at 1.5 mg/kg, and at the maximum dose (3.0 mg/kg) it was equivalent to dobutamine, 10 micrograms/kg per minute. The myocardial energetic efficiency was determined from the analysis of the myocardial oxygen consumption-pressure volume area relationship. The y intercept represents the basal metabolic oxygen requirement of the unloaded beating heart, and the slope is inversely proportional to the rate of energy conversion for increasing loading conditions. Dobutamine significantly increased the y intercepts, but it had no effects on the slopes. These changes demonstrate reduced myocardial efficiencies that are consistent with previous reports. Amrinone (0.75 and 1.50 mg/kg) did not result in change of the y intercepts and the slopes of myocardial oxygen consumption-pressure-volume area relationship from baseline conditions. The y intercept was increased with amrinone (3.0 mg/kg), although still not significantly higher than baseline and not to the extents of the dobutamine group. Dobutamine did not have any primary effect on coronary resistance, while amrinone significantly reduced coronary resistance in all loading conditions at 1.5 and 3.0 mg/kg. This study demonstrates that the inotropic effects of amrinone tested under this constant afterload preparation were lower than those of dobutamine. Amrinone has a superior profile of myocardial efficiency on the postischemic myocardium since it does not produce the oxygen-wasting effects of the traditional inotropic agents such as the beta agonists. This benefit, together with amrinone's coronary dilating effects, critically improves the supply/demand ratio that may be of importance in certain clinical situations.

Effects of neurotensin and neuropeptide Y on coronary circulation and myocardial function in dogs.

This study analyzed the effects of the neuropeptides, neurotensin, and human and porcine analogue, neuropeptide Y, in anesthetized open-chest dogs. The left anterior descending coronary artery was cannulated and perfused at constant pressure via a blood reservoir. Flow to the coronary cannula was measured by an electromagnetic flowmeter, and regional segment lengths were measured by sonomicrometer crystals. Neurotensin injected into the coronary cannula resulted in a dose-dependent increase of coronary flow; neuropeptide Y resulted in a decrease of coronary flow. Because these changes in flow were not explained by systemic hemodynamic effects or alterations in regional myocardial function, they were considered to be coronary dilatation or constriction. Coronary dilatation by neurotensin was not prevented by alpha- or beta-adrenoceptor blockade but was completely abolished by indomethacin or by lowering coronary perfusion pressure to 35 mmHg when depressed systolic segment shortening indicated myocardial ischemia. Coronary constriction by neuropeptides Y persisted at coronary perfusion pressure of 35 mmHg and was only attenuated by indomethacin. We conclude that in contrast to systemic effects, coronary vasodilatation by neurotensin is mediated by a prostanoid product of cyclooxygenase. Preactivation of the prostaglandin system may explain why neurotensin lost its coronary dilator effect during myocardial ischemia. Neuropeptide Y may elicit coronary constriction in addition to mechanic reduction of coronary flow resembling severe coronary stenosis.

Pharmacologic characteristics of a new calcium antagonist, manidipine: Beneficial effects on renal circulation and vascular changes

The calcium antagonist, manidipine, was developed on the basis of the hypothesis that antihypertensive drugs that act to improve renal hemodynamic alterations will be therapeutically beneficial in hypertensive patients. Manidipine shows long-lasting calcium channel-blocking action in vascular smooth muscle cells and antihypertensive actions in various types of hypertensive models. The drug has high selectivity for resistance vessels, dilates renal vasculature, and inhibits renal vascular constrictions induced by norepinephrine and angiotensin II in spontaneously hypertensive rats. It increases renal blood flow and has a prominent natriuretic action without changing glomerular filtration rate. The coronary dilating effect of the drug is similar to that of nifedipine, but its cardiodepressant effects are less potent than those of other dihydropyridines. Furthermore, manidipine prevents the development of cerebrovascular lesions and inhibits the progression of vascular damage in the brain and kidneys of stroke-prone spontaneously hypertensive rats. The drug also inhibits a proliferative response of the intima to balloon catheter-induced injury in the carotid arteries of spontaneously diabetic rats without affecting plasma lipids or blood pressure. These results suggest that manidipine may be useful for the treatment of hypertensive patients with or without vascular complications.

Mechanism of coronarydilator effects induced by bradykinin and phospholipase A2

Mechanism of coronarydilator effects induced by bradykinin and phospholipase A2

Nitric oxide and the cardiovascular actions of histamine

We had found that histamine (HA)-induced relaxation of cavian pulmonary artery is selectively inhibited by Nω-methyl-l-arginine (NMA) and thus depends on the synthesis ofl-arginine (ARG)-derived EDRF/nitric oxide (NO). We have now assessed whether ARG-derived NO also mediates the coronary-vasodilating effect of HA in the intact heart. Langendorff guinea pig hearts, vasoconstricted by the thromboxane agonist U46619 (86 nM), responded to HA (bolus intra-aortic injections of 1–30 μg) with dose-dependent increases in coronary flow (20–90%), heart rate and contractility. NMA (92 μM) markedly inhibited the HA-induced increase in coronary flow, but not its positive inotropic and chronotropic effects. A similar inhibition was obtained with the NO scavenging compound, Fe2+-myoglobin. ARG (1 mM) reestablished the coronary-dilating effects of HA in the presence of NMA. Thus, ARG-derived NO contributes significantly to HA-induced coronary-vasodilatation. Inasmuch as the ultimate HA effect on the coronaries depends on the balance between constriction and relaxation, mediated by smooth muscle and endothelial H1-receptors, respectively, as well as relaxation due to smooth muscle H2-receptors, dysfunction of the NO system is likely to precipitate HA-induced vasospasm.

Action of synthetic atrial natriuretic factor on contractility and coronary perfusion in isolated working rat hearts

The effects of atrial natriuretic factor were studied in isolated working rat hearts. Increasing concentrations, from 0.1 to 100 nM, of a synthetic rat-ANF (atrial natriuretic factor) were added to the perfusate. ANF had no effect on heart rate, contraction cycle or coronary resistance in concentrations up to 3 nM. At concentrations above 10 nM, peak dP/dt and oxygen consumption showed a slight dose-dependent increase. The greater decrease in coronary resistance, and the lowering of coronary oxygen extraction, suggest that ANF has a small coronary dilating effect. No arrhythmias were observed at any concentration of ANF.

Cardiac versus coronary dilator effects of SD-3211, a new nondihydropyridine calcium antagonist, in isolated, blood-perfused dog hearts

Coronary and cardiac effects of SD-3211 were compared in isolated, blood-perfused sinoatrial (SA) node, atrioventricular (AV) node, and papillary muscle preparations of dogs. SD-3211 was administered intraarterially. In all preparations SD-3211 produced an increase in coronary blood flow. In SA node preparations, the drug produced a decrease in sinus rate, and in high doses atrial standstill occurred. The dose that produced a 15% decrease in sinus rate was about 5.6 times the dose that doubled coronary blood flow. In AV node preparations, when injected into the artery supplying the AV node, the drug produced an increase in AV conduction time, and in high doses second- or third-degree AV block occurred. The dose that produced a 15% increase in AV conduction time was about 1.6 times the dose that doubled coronary blood flow. In the same preparations the drug slightly increased AV conduction time only at high doses when injected into the artery supplying the His-Purkinje-ventricular system. In paced papillary muscle preparations, the drug produced a decrease in the force of contraction. The dose that produced a 50% decrease in the force of contraction of the paced papillary muscle was about 50 times the dose that doubled coronary blood flow. The drug was virtually ineffective on ventricular automaticity. In short, in doses that doubled coronary blood flow, SD-3211 depressed only AV nodal conduction. This cardiovascular profile differs from those of diltiazem and verapamil, which do not discriminate between coronary vasculature and the SA and the AV node.

Coronary arteriolar vasoconstriction in myocardial ischaemia. Vasopressin, renin-angiotensin system and ANF

Vasopressin, the renin-angiotensin system and atrial natriuretic factor (ANF) interact in regulating blood pressure. While the vasoconstrictor effect of vasopressin and the renin-angiotensin system is well documented, the direct vascular effect of ANF is unclear. We studied in anaesthetized dogs the coronary vascular effects of agonists and antagonists of vasopressin and the renin-angiotensin system under control and ischaemic conditions, respectively. In addition, the action of ANF and its relationship to the renin-angiotensin system was analysed. A coronary artery was cannulated and perfused by a bypass system from the femoral arteries of the same animal. Coronary vasoconstriction by vasopressin was potentiated when myocardial ischaemia was induced by lowering coronary perfusion pressure while coronary constriction by angiotension I and II was mitigated. A vasopressin receptor blocker slightly reduced coronary blood flow at high doses (intrinsic activity) while the angiotensin II receptor blocker increased coronary flow in myocardial ischaemia. ANF effects were ambiguous at lower doses (1 ng (kg)-1 i.c.) with coronary constriction in 79% of dogs. At higher doses (1 microgram kg-1) ANF consistently induced coronary dilation. The angiotensin II receptor blocker saralasin significantly reduced this coronary dilator effect of ANF. Thus, in conclusion, a vasoconstrictor effect of endogenous vasopressin could not be shown by this study. In contrast, endogenous angiotensin II might participate in control of coronary blood flow during myocardial ischaemia. The coronary dilator effect of ANF at least in part appears to be due to interference with the renin-angiotensin system.

Epicardial coronary artery constriction with intravenous ethanol

Although in vitro studies have demonstrated ethanol-induced coronary artery constriction, in vivo reports suggest an ethanol-related coronary dilator effect with increases in coronary blood flow. The principal difference in these studies is the demonstration of epicardial coronary constriction with ethanol, while dilation is described only in resistance vessels. Clinical studies have noted evidence of myocardial ischemia following ethanol ingestion in patients with coronary artery disease, suggesting ethanol-related constriction of diseased epicardial coronary arteries. This study hypothesized that intravenous ethanol would constrict canine epicardial coronary arteries while producing arteriolar resistance vessel dilatation. Ten closed-chest mongrel dogs weighing 24 ± 1 kg (mean ± SEM) were given 8 g of ethanol intravenously over 30 min. Left anterior descending and circumflex proximal artery diameters were measured by quantitative coronary angiography; myocardial flow was measured by Xenon washout, and myocardial flow distribution was measured with radioactive microspheres. Baseline proximal left anterior descending and circumflex artery areas were 6.3 ± 0.5 and 5.8 ± 0.4 mm 2, respectively. Up to 30% left anterior descending and circumflex proximal artery narrowing was noted at 60 and 90 min following ethanol infusion. The constriction was reversed with nitroglycerin. There was a decrease in left anterior descending artery flow but no change in circumflex artery flow at 60 min. Blood ethanol level varied from 520 μg/ml initially to 205 μg/ml 90 min after the infusion terminated (intoxication = 1500 μg/ml). These data suggest that ethanol has significant vasoconstrictor action in vivo on epicardial coronary arteries.

Effects of the enantiomers of the dihydropyridine derivative 202–791 on contractility, coronary flow and ischemia-related arrhythmias in rat heart

The (+)-enantiomer of the dihydropydine 202–791 produced coronary constrictor and positive inotropic effects in Langendorff-perfused rat hearts whereas (-)-202-791 showed coronary dilator and negative inotropic effects. Both enantiomers showed the vascular effects at lower concentrations than the myocardial effects. Furthermore, the (+)-enantiomer significantly increased whilst the (-)-enantiomer reduced the number of ventricular ectopic beats occurring during coronary ligation. Arrhythmia-enhancing effects must therfore be considered when the potential therapeutic uses of calcium channel activators are discussed.

Effects of three histaminergic compounds on function and oxygen consumption of isolated guinea-pig hearts.

First experiences in man indicate, that even in catecholamine-insensitive congestive cardiomyopathy a considerable improvement of myocardial function can be attained by the H2-receptor agonist impromidine. In an isolated, pressure-volume work performing guinea-pig heart preparation cardiac effects of three histaminergic compounds (Na,5-dimethylhistamine (HC1)2, 5-ethyl-Na-methyl-histamine (HC1)2, Na,Na-dimethyl-histamine (HC1)2) were examined. Influences on function and myocardial oxygen consumption were compared to those obtained by impromidine. Dose-response curves for the histamine derivatives were 1.7-2.5 orders of magnitude right of the impromidine curves. Maximal inotropic stimulation was greater for Na,5-dimethyl-histamine (HC1)2 than for impromidine. All compounds exhibited a high chronotropic effect and, at high concentrations, a net coronary dilating effect.

Possible interactions of indomethacin and nitrates in angina pectoris

Intravenous indomethacin has been reported to diminish coronary flow in patients with angina. There is also evidence that indomethacin attenuates or abolishes the coronary dilator and venodilator effects of nitroglycerin. In 11 patients with stable angina of effort, prior administration of 100 mg of indomethacin appeared to increase (0.10 > p > 0.05), rather than reduce, the work load achieved compared with placebo on a double-blind basis. The increase in work load when patients were given nitroglycerin was not significantly changed after they were given indomethacin. Therefore, this study does not support the suggestion either that prostaglandins play a significant role in coronary vasoregulation on effort or that prostacyclin is an important mediator of the therapeutic action of nitroglycerin. From a practical therapeutic viewpoint, there is apparently no danger of aggravating stable, exercise-induced angina or of abolishing the benefit normally expected from nitroglycerin when patients with angina are given indomethacin in doses comparable to those used in this study.

Effects of tertiary and quaternary derivatives of aminomethylenedioxyindenes on some experimental arrhythmias.

The 2-n-propyl- and 2-n-butyl-3-dimethylamino-5,6-methylenedioxyindene hydrochlorides are intracellular calcium antagonists with coronary dilating and antiarrhythmic effects against ouabain- and calcium-induced arrhythmias. In the present study, pretreatment with these tertiary methylenedioxyindenes afforded significant protection against the calcium-dependent arrhythmias induced by chloroform in mice. On the other hand, their antiarrhythmic activity against aconitine- and methacholine-induced arrhythmias in rats (in which calcium does not play a primary etiological role) was suggestive but not impressive. The quaternary derivative, 2-n-butyl-5,6-methylenedioxy-3-trimethylammonium iodide, which was synthesized with the expectation of being devoid of antiarrhythmic activity owing to its exclusion from the intracellular compartment, unexpectedly demonstrated greater antiarrhythmic potency than the tertiary analogues against calcium-induced arrhythmias in rats and chloroform-induced arrhythmias in mice. Like the tertiary methylenedioxyindenes, the protective activity of the quaternary analogue against arrhythmias induced by aconitine or by methacholine in rats was suggestive but not impressive. Because of the relative inactivity of the quaternary methylenedioxyindene in vitro, it is proposed that its in vivo activity may be due either to metabolic activation or to concentration in cardiac tissue in sufficient quantity to allow diffusion into cardiac cells down a concentration gradient or to alter membrane electrophysiological properties to the extent of exerting antiarrhythmic activity.

Prostacyclin (PGI2) induces coronary vasodilatation in anaesthetised dogs

Prostacyclin (PGI2), the predominant metabolite of arachidonic acid in isolated hearts, relaxes strips of bovine coronary artery and is a potent vasodilator in isolated perfused hearts. We have examined the actions of prostacyclin on coronary blood flow in open chest dogs anaesthetised with chloralose. An electromagnetic flow probe was fitted to the left circumflex artery and phasic coronary flow, mean coronary flow (a measure of coronary volume flow over 4 s intervals), and coronary vascular resistance were recorded together with aortic pressure and heart rate. Intravenous infusion of prostacyclin (0.05 to 1.0 microgram.kg.1.min.1), reduced coronary vascular resistance and aortic pressure according to dose, but had only small effects on phasic coronary flow or mean coronary flow. Both tachycardia and bradycardia occurred during infusion of prostacyclin, but 6-oxo-prostaglandin F1alpha (infused at 10 micrograms.kg-1.min-1), the stable degradation produce of prostacyclin, had no cardiovascular effects. The coronary vasodilator effects of prostacyclin were clear when it was injected into the left circumflex artery via a fine catheter distal to the flow probe. Prostacyclin (0.05 to 0.5 microgram) increased phasic coronary flow and mean coronary flow up to 3 fold and reduced coronary vascular resistance without affecting aortic pressure or heart rate, although higher doses had systemic effects. Prostaglandin E1 (0.1 to 0.5 microgram), which also dilated the coronary vessels, had a longer lasting effect and was 1 to 4 times more potent than prostacyclin. Prostaglandin E2, (0.5 to 4 microgram) was less potent than prostacyclin. In four dogs prostacyclin (20 to 500 micrograms) applied epicardially to the left ventricle caused marked and prolonged coronary vasodilatation. Epicardial application of prostacyclin (10 to 25 micrograms) to the right ventricle increased coronary sinus oxygen content with minimal changes in blood pressure. The endoperoxide prostaglandin H2 was a coronary vasodilator of similar potency to prostacyclin, but its analogue U46619 is a vasoconstrictor. Inhibition of cyclo-oxygenase with indomethacin (5 mg.kg-1 i.v.) or sodium meclofenamate (2 mg.kg-1 i.v.) potentiated the coronary dilator effects of prostacyclin given intravenously or into the coronary artery. Cyclo-oxygenase inhibition did not alter the hypotensive effects and increased the coronary vasodilator potency of prostacyclin relative to prostaglandin E2. Thus the sensitivity of the coronary vascular bed to prostacyclin is enhanced when endogenous biosynthesis of prostaglandin-like substances is inhibited. Although the importance of arachidonic acid metabolites in the coronary circulation still requires validation in vivo, it is clear that prostacyclin, and not prostaglandin E2, is the prostaglandin most likely to be involved.