L-arginine inhibits noradrenaline release in sympathetically stimulated rabbit hearts.
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Animals↗
Biomedical subjects
A Wennmalm
Publications and source records attributed to A Wennmalm.
Role of the coronary endothelium in the regulation of sympathetic transmitter release in isolated rabbit hearts.
The roles of endothelium-derived relaxing factor (EDRF) and endothelin in the regulation of vascular tone are intensely studied at present. Since factors which directly affect vascular tone also frequently modulate sympathetic transmitter release, we found it of interest to study whether EDRF or endothelin displays such modulatory activity as well. Isolated rabbit hearts were perfused according to Langendorff, and the release of transmitter induced by sympathetic nerve stimulation was estimated by analysis of the effluent content of noradrenaline (NA) with liquid chromatography. The activity of EDRF spontaneously formed in the heart was counteracted by addition of haemoglobin (Hb, 2.4-15 g l-1) or facilitated by addition of superoxide dismutase (SOD, 14-140 U ml-1), to the perfusion solution. In other experiments authentic endothelin (0.1-10 nm) was given to the heart. Nerve stimulation (5 Hz for 30 s) elicited a release of NA into the cardiac effluent amounting to 319 +/- 28 pmol (n = 53). Hb lowered the coronary flow to 68 +/- 9% (P less than 0.01) and impaired the outflow of NA to 62 +/- 9% of control (P less than 0.01). SOD facilitated coronary flow by 11 +/- 4% (P less than 0.005), and augmented the outflow of NA by 15 +/- 6% (P less than 0.05). Endothelin dose-dependently inhibited the coronary flow, with an IC50 of about 1 nM, and in parallel decreased the efflux of NA. Mechanical obstruction of the coronary flow induced an attenuation of the efflux of NA that was quantitatively similar to the flow reduction.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Application of a new technique--blood pressure clamping--for analysis of prostaglandin interference with sympathetic neurotransmission in man.
To circumvent baroreceptor reflexes following drug-induced interference sympathetic neurotransmission, a new technique - blood pressure clamping--has developed. This implies that the sympathetic activity in an awake human is 'clamped' at a supranormal level by infusion of a vasodilator. In 11 healthy volunteers nitroprusside or saline was randomly infused in two consecutive 2-h periods. Plasma and urinary catecholamine levels were analysed by liquid chromatography. The experiments were repeated after random administration of the prostaglandin synthesis inhibitor, ibuprofen, or placebo. In the basal state (no ibuprofen, saline infusion) the mean arterial blood pressure was 81.4 +/- 2.3 mmHg, the heart rate was 60.9 +/- 0.3 beats min-1 and the plasma level of noradrenaline was 1.12 +/- 0.15 nM. Infusion of nitroprusside at a dose lowering the mean blood pressure by 11.6 +/- 1.6 mmHg and increasing the heart rate to 74.6 +/- 2.9 beats min-1 elevated plasma noradrenaline to 2.86 +/- 0.39 nM. After pretreatment with ibuprofen (saline infusion), the systemic blood pressure, the heart rate, and the plasma and urinary levels of noradrenaline were unaffected in comparison to before drug (80.1 +/- 2.3 mmHg, 58.4 +/- 0.3 beats min-1 and 1.13 +/- 0.12 nM respectively). Infusion of nitroprusside at a rate lowering the blood pressure by 11.2 +/- 2.4 mmHg and increasing the heart rate to 74.4 +/- 0.5 beats min-1, elevated the plasma level of noradrenaline to 2.46 +/- 0.38 ng ml-1, which is not different from before ibuprofen. The amount of nitroprusside required to lower the blood pressure was not different in the presence and absence of ibuprofen.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Effects of hydrodynamic forces on coronary production of prostacyclin and purines.
Prostacyclin and purine efflux rates from the isolated rabbit heart in response to variations of flow rate or perfusion pressure were investigated. Increases in coronary flow by 25, 50, and 100% augmented the effluxes of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) and purines equally, by up to four times. Increases in coronary pressure by 25, 50, and 100% augmented the outflow of 6-keto-PGF1 alpha by up to 20 times, whereas the outflow of purines increased no more than 6.5 times. Neither reduction of perfusate Ca2+ by 50% nor administration of quinacrine (1 microM) affected the basal efflux of 6-keto-PGF1 alpha or its response to an increase in coronary pressure. Both interventions did, however, reduce the pressure-induced purine efflux by approximately 50%. Pulsatile flow did not affect either the outflow of 6-keto-PGF1 alpha or that of purines, in comparison to steady flow at the same rate. The data demonstrate that an increase in coronary pressure activates a specific mechanism for prostacyclin production that appears independent of extracellular Ca2+ and of phospholipase activity.
6-Ketoprostaglandin F1 alpha↗
Excretion of thromboxane A2 and prostacyclin metabolites during treadmill exercise in patients with intermittent claudication.
Platelet activation, with subsequent formation of thromboxane A2 (TxA2), is thought to play a role in the development of arterial occlusion. In patients with severe atherosclerosis of the lower limbs, characterized by leg ulcers and rest pain, the basal formation of TxA2 and prostacyclin (PGI2) is increased. Corresponding data in patients with more moderate atherosclerosis of the lower limbs have not been reported. Since the capacity to physical exercise is not blunted in such patients proper evaluation of their TxA2-PGI2 synthesis should comprise not only assessment of the basal formation, but also TxA2/PGI2 biosynthesis during conditions of elevated cardiovascular activity. To address this, we analysed these eicosanoids in patients with a history of intermittent claudication. Urinary dinor-metabolites of TxB2 and PGI2 (Tx-M and PGI-M, respectively) were estimated by gas chromatography/negative ion-chemical ionization mass spectrometry in samples collected prior to, during and immediately after 20 min of severe treadmill exertion. The basal excretion of Tx-M was 105 +/- 26 pg/mg creatinine. It was not changed during exercise, but increased to 176 +/- 48 pg/mg creatinine (P less than 0.05) during the recovery. The basal excretion of PGI-M was 142 +/- 25 pg/mg creatinine. The PGI-M response to exercise varied from no change at all to a 30-fold increase, without any obvious correlation to experienced leg pain, walking distance or other recorded variables. During the recovery period the outflow of PGI-M was significantly higher than at rest (482 +/- 145 pg/mg creatinine; P less than 0.01). We conclude that in patients with intermittent claudication due to atherosclerosis (1) platelet activation does not occur during the course of the exercise, and (2) vascular prostacyclin formation can be dissociated from of TxA2 synthesis. The observed increase in PGI-M in some of the patients is suggested to reflect tissue ischaemia induced by the lack of adequate hyperaemia during exercise.
6-Ketoprostaglandin F1 alpha↗
Prostacyclin and regional coronary blood flow in experimental myocardial infarction.
Infusion of prostacyclin (PGI2) has been reported to affect infarct size and myocardial blood flow favourably in various animal models of myocardial ischaemia. Recent data suggest that a similar effect of PGI2 may occur also in humans with acute myocardial infarction. We addressed the hypothesis that PGI2 redistributes myocardial blood flow following coronary ligation, and that this effect favours perfusion of myocardium at risk and thereby limits infarct size. Following ligation of a distal branch of the left coronary artery in anaesthetized dogs, PGI2 (2-4 ng/kg/min) was infused for 72 h. Regional myocardial blood flow was assessed immediately after the coronary ligation and at the end of the drug infusion, by injection of 57Co- and 113Sn-labelled microspheres, respectively. Coronary ligation reduced regional coronary blood flow by 40-70%. During the subsequent 72 h the blood flow increased, being at the end of the period 50-70% of the flow in the non-ischaemic myocardium. PGI2 did not affect the spontaneous improvement of regional myocardial blood flow, as assessed at the end of the infusion. PGI2 also failed to affect infarct size, either when expressed in relation to total left ventricular mass, or in relation to area at risk. We conclude that PGI2, when infused immediately after coronary ligation in dogs in a clinically relevant dose, neither affects regional myocardial blood flow in the ischaemic regions, nor the size of the myocardial infarction.
Animals↗
Effect of adenosine on the formation of prostacyclin in the rabbit isolated heart.
1. The effect of adenosine on cardiac biosynthesis of prostacyclin (PGI2) was investigated. Rabbit hearts were perfused according to Langendorff at controlled pressure (with or without theophylline), or at controlled flow. The content of 6-keto-prostaglandin1 alpha (6-keto-PGF1 alpha, metabolite of PGI2) in the coronary effluent under basal conditions and during infusion of adenosine was determined using a highly specific radioimmunoassay. 2. In other experiments, rings of rabbit aorta were incubated with or without adenosine and the production of 6-keto-PGF1 alpha was analysed as above. 3. Administration of adenosine (10 micron) to hearts perfused at controlled pressure increased the coronary flow by up to 38%. The peak concentration of 6-keto-PGF1 alpha in the effluent exceeded the control by 177% (P less than 0.01), and the total efflux of 6-keto-PGF1 alpha exceeded the control by 179% (P less than 0.001). Theophylline (50 micron) reduced these effects of adenosine by 23%, 43% and 51%, respectively, without influencing the uptake of adenosine into the heart. 4. When adenosine (1-10 micron) was administered to hearts perfused at controlled flow, a dose-dependent decrease in the perfusion pressure, by 27% and 44% respectively, was observed. In parallel, the resulting increase in 6-keto-PGF1 alpha efflux was considerably lower (49% (P less than 0.05) and 43% (NS), respectively). A similar decrease in perfusion pressure induced in the absence of adenosine decreased the efflux of 6-keto-PGF1 alpha, by 15% (P less than 0.01) and 32% (P less than 0.001), respectively. 5. Addition of adenosine (1-10 microM) to incubates of rabbit aortic rings did not significantly affect the concentration of 6-keto-PGF1 alpha in the incubation medium in comparison with control. 6. We conclude that adenosine stimulates rabbit heart PGI2 formation, mainly by an action related to the vasodilator effect of the nucleoside.
6-Ketoprostaglandin F1 alpha↗
Excretion of prostacyclin and thromboxane A2 metabolites during leg exercise in humans.
Urinary levels of 2,3-dinorthromboxane B2 (Tx-M) and 2,3-dinor-6-ketoprostaglandin F1 alpha (PGI-M), measured by gas chromatography-negative ion-chemical ionization mass spectrometry, accurately reflect in vivo biosynthesis of thromboxane A2 (TxA2) and prostacyclin (PGI2), respectively. Although the basal excretion of Tx-M and PGI-M is adequately documented, no systemic data on the excretion during controlled exercise have been presented. We studied the effect of maximal tolerated exercise (2 h of bicycle ergometry) on the excretion of Tx-M and PGI-M in healthy humans. In addition, their urinary levels of epinephrine (E) and norepinephrine (NE) were analyzed. To address the impact of locally formed adenosine, all subjects were reinvestigated after administration of theophylline. Exercise did not affect the excretion of Tx-M (47 +/- 21 vs. 34 +/- 9 pg/mg creatinine) but increased the excretion of PGI-M (74 +/- 14 vs. 267 +/- 70 pg/mg creatinine; P less than 0.02). Theophylline augmented urinary NE and E but did not significantly change the PGI-M response to exercise. We suggest that the normal cardiovascular eicosanoid response to exercise is a platelet-independent increase in vascular PGI2 formation.
Adult↗
Myocardial ischaemia triggers formation of thromboxane.
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6-Ketoprostaglandin F1 alpha↗
Prostacyclin as neuromodulator in the sympathetically stimulated rabbit heart.
Prostaglandin E2 (PGE2) has previously been shown to inhibit sympathetic neurotransmission in different organs and species. Based on this inhibitory effect and on its reversal by cyclo-oxygenase inhibitors, PGE2 has been claimed to be a physiological modulator of in vivo release of norepinephrine (NE) from sympathetic nerves. It is now recognized that prostacyclin (PGI2) is the main cyclo-oxygenase product in the heart. We therefore addressed the question whether PGI2, within the same preparation, is formed in increased amounts during sympathetic nerve stimulation and has neuromodulatory activity. The effluent from isolated rabbit hearts subjected to sympathetic nerve stimulation or to infusion of NE or adenosine (ADO) was collected, and its content of PGE2 and 6-keto-PGF1 alpha (dehydration product of PGI2) was analyzed using gas chromatography/mass spectrometry, operated in the negative ion/chemical ionization mode. Other hearts were infused with PGI2 and nerve stimulation induced outflow of endogenous NE into the effluent was analyzed using HPLC with electrochemical detection. Nerve stimulation at 5 or 10 Hz (before but not after adrenergic receptor blockade), as well as infusion of NE (10(-6)-10(-5)M) or ADO (10(-4)M) increased the cardiac outflow of 6-keto-PGF1 alpha. Basal and nerve stimulation induced efflux of 6-keto-PGF1 alpha was approximately 5 times higher than the corresponding efflux of PGE2. PGI2 dose-dependently inhibited the outflow of NE from sympathetically stimulated hearts, the inhibition at 10(-6)M being approximately 40%. On the basis of these observations we propose that PGI2 is a more likely candidate than PGE2 as a potential modulator of neurotransmission in cardiac tissue in vivo.
6-Ketoprostaglandin F1 alpha↗
The role of myogenic relaxation, adenosine and prostaglandins in human forearm reactive hyperaemia.
1. Forearm blood flow was measured bilaterally in healthy young male and female volunteers, in the basal state and after upper-arm occlusion of arterial or venous blood flow for 1-20 min. The investigations were repeated after pre-treatment with drugs affecting vascular prostaglandins and/or adenosine. 2. Simultaneous arterial occlusion in one arm and venous occlusion in the contralateral arm for up to 20 min elicited a considerable reactive hyperaemia in the arm subjected to arterial occlusion, but completely failed to elevate the post-occlusive flow in the arm subjected to venous occlusion above the pre-occlusive level. 3. When the arterial occlusion was increased from 1 to 20 min there was a progressive increase in the subsequent reactive hyperaemia, up to 30 ml 100 ml tissue-1. The time dependence following 1-3 min of arterial occlusion was based on a facilitation of the peak post-occlusive flow, while prolongation of the arterial occlusion from 3 to 20 min augmented the reactive hyperaemia mainly by increasing its duration. 4. Inhibition of prostaglandin synthesis with ibuprofen reduced the total reactive hyperaemia following 3-5 min of arterial occlusion by up to 70%. This attenuation was due both to a reduction of peak post-occlusive flow and to a shortening of the duration of the post-occlusive hyperaemia. 5. The adenosine receptor antagonist theophylline reduced the reactive hyperaemia following 5 min of arterial occlusion by about 35%. Combined treatment with ibuprofen and theophylline did not reduce the reactive hyperaemia more than either drug alone. 6. Infusion of dipyridamole, a drug which inhibits the elimination of adenosine, reinforced the reactive hyperaemia by about 45%. This effect of dipyridamole was completely inhibited by administration of theophylline, and also by ibuprofen. 7. Plasma levels of adenosine, hypoxanthine and uric acid were maintained during the reactive hyperaemia, indicating increased production of purines during or immediately after the ischaemia. 8. It is concluded that the adequate stimulus for vascular relaxation in response to interruption of blood flow is omission of vessel wall distension. Local metabolic factors like endogenously formed prostaglandins and adenosine may act synergistically to this myogenic response but seem to be inactive alone. The lack of additive effects of ibuprofen and theophylline suggests a link between vascular relaxation induced by prostaglandins and by adenosine.
Adenosine↗
Vascular effects of infused adenosine are not mediated by prostacyclin release in humans.
Adenosine may contribute to the regulation of tissue blood flow directly and via release of vasoactive substances. For example, in the isolated, perfused heart, the nucleoside has been reported to release prostacyclin, a potent vasodilator. In humans, minor variations in prostacyclin release into the circulation result in readily detectable changes in the urinary excretion of its metabolite, 2,3-dinor-6-ketoprostaglandin (PG) F1 alpha, as measured by negative ion-chemical ionization gas chromatography-mass spectrometry. To test the hypothesis that prostacyclin participates in or mediates the vascular effects of adenosine, we administered adenosine (5.1 mg/min) or vehicle to healthy volunteers in random order as a 2-h infusion into the femoral artery under double-blind conditions. The plasma levels of adenosine, inosine, and hypoxanthine increased significantly during infusion of active drug, but the urinary excretion of adenosine and uric acid were unchanged, implying efficient tissue uptake of the infused nucleoside. Adenosine, but not vehicle, significantly (P less than 0.01) increased leg blood flow (from 2.7 +/- 0.3 to 8.7 +/- 2.5 ml X 100 ml tissue-1 X min-1), heart rate (from 66 +/- 3 to 80 +/- 4 beats/min), and urinary epinephrine excretion (from 2.8 +/- 0.4 to 5.4 +/- 0.8 ng/mg creatinine). In contrast, the excretion of 2,3-dinor-6-keto-PGF1 alpha was unaltered by infusion of adenosine. We confirmed that biologically significant alterations in prostacyclin release in the lower limb vascular bed would be reflected by the urinary metabolite in experiments involving local infusion of prostacyclin at a rate below the threshold necessary to alter limb blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)
6-Ketoprostaglandin F1 alpha↗
Prostacyclin offers protection against early extension of acute myocardial infarction.
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Clinical Trials as Topic↗
Leg exercise increases prostacyclin synthesis without activating platelets in both healthy and atherosclerotic humans.
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6-Ketoprostaglandin F1 alpha↗
Effect of prostacyclin on the severity of ischaemic injury in rabbit hearts subjected to coronary ligation.
The hypothesis that prostacyclin (PGI2) might have a direct cytoprotective action in ischaemic cardiac tissue was investigated. Myocardial ischaemia was induced in perfused rabbit hearts by ligating the left main coronary artery. Coronary flow, oxygen uptake, and turnover of lactate and purines were measured before and up to 120 min after coronary occlusion. After this, ischaemic tissue was separated from perfused myocardium, and levels of lactate, adenine nucleotides and creatine phosphate were determined in specimens from non ischaemic, ischaemic and border zones. PGI2 (final conc. 10(-7) M) was infused before or 30 min after ligation and the results were compared to those in control hearts. Coronary ligation reduced coronary flow and oxygen consumption by about 50%. The fractional extraction of lactate decreased from 20% to close to zero and purine release increased 5-fold. In the non-ischaemic area the tissue levels of ATP and creatine phosphate were high, with a low content of lactate, but in the ischaemic area the levels of ATP and creatine phosphate were considerably reduced and the content of lactate was high. Although coronary flow and oxygen uptake were elevated after treatment with PGI2, no change in lactate or purine turnover was observed. Neither the weight of the non-perfused myocardium nor the tissue levels of the adenine nucleotides, creatine phosphate and lactate were affected by PGI2 treatment. The data indicate that in this model, in which effects on cardiac work, collateral flow and platelets are eliminated, PGI2 does not limit ischaemic myocardial injury. Hence, the hypothesis of a direct cytoprotective action of PGI2 in ischaemic myocardial tissue was not supported.
Animals↗
Cardiovascular prostaglandins: some comments on their involvement in circulatory physiology and pathophysiology.
There is little, if any, good evidence in the literature to indicate a role for cardiovascular PG in congestive heart failure, either in its pathogenesis or as a consequence of and defense against its manifestations. Usually congestive heart failure is considered to develop as a vicious cycle in which impaired cardiac output, increased peripheral resistance, decreased renal blood flow, increased renin release and further increased peripheral resistance and decreased cardiac output are important constituents. Increased sympathetic activity may promote cardiovascular PG formation through the sympathetic neurotransmitter noradrenaline; such an action has, however, not been documented hitherto. Furthermore, increased plasma renin activity may promote PG formation via increased circulating levels of angiotensin; even such an action remains, however, to be demonstrated. If the heart failure leads to local tissue ischemia the hypoxia as such, or the subsequent increase in adenosine production, may also facilitate cardiovascular PG formation. All these mechanisms, if operative, would counteract the increased peripheral resistance, by promoting the formation of vasodilator PG. On the other hand PGI2 stimulates renal formation of renin, which would act to elevate the peripheral resistance. These contradictory effects of endogenously formed PG focus on the need for more careful studies on their involvement in the hemodynamic consequences of congestive heart failure: until more data are available it is impossible to know whether an activated synthesis of PG should be regarded as advantageous and worth therapeutical support, or negative and subject to inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)
6-Ketoprostaglandin F1 alpha↗
In vivo production of prostacyclin and thromboxane in patients with acute myocardial infarction.
The in vivo production of prostacyclin and thromboxane was monitored by measuring their major urinary metabolites 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha in ten patients with acute myocardial infarction, five on standard treatment and five receiving prostacyclin infusion. During acute myocardial infarction excretion of 2,3-dinor-thromboxane B2 and 2,3-dinor-6-keto-prostaglandin F1 alpha, measured by a gas chromatography-mass spectrometry method with deuterated internal standards, was significantly increased. This indicates that thromboxane and prostacyclin synthesis are increased during the development of acute myocardial infarction. The excretion data for 2,3-dinor-thromboxane B2 showed that after administration of aspirin there was less pronounced and more variable inhibition than expected. Prostacyclin infusion did not markedly affect the excretion of the thromboxane metabolite.
6-Ketoprostaglandin F1 alpha↗