Permissive role of prostanoids in acetylcholine-induced cerebral vasoconstriction

The present study was designed to test the hypothesis that prostanoids play a permissive role in acetylcholine-induced cerebral constriction. Pial arterioles of newborn pigs were observed using a closed cranial window. Pial arteriolar constriction induced by topical acetylcholine (10(-5) M) was blocked by indomethacin (5 mg/kg i.v.), but was restored when acetylcholine was coadministered with topical prostaglandin (PG) F2 alpha (1 ng/ml), U46619 (1 ng/ml) or PGH2 (100 ng/ml). The restored acetylcholine response was blocked by topical pirenzepine (10(-3) M), a muscarinic-1 antagonist. Constriction and ability of all three prostanoids to restore acetylcholine-induced constriction was blocked by SQ 29,548 (10(-4) M), a purported thromboxane A2/PGH2 receptor antagonist. Subthreshold concentrations of U46619 and PGF2 alpha (0.1 ng/ml) restored acetylcholine-induced constriction, whereas threshold and subthreshold concentrations of PGE2, platelet-activating factor and norepinephrine had no effect. Therefore, activation of the thromboxane A2/PGH2 receptor appears to be necessary for acetylcholine-induced constriction to occur. Thus, prostanoids appear to play a permissive role in acetylcholine-induced pial arteriolar constriction in newborn pigs.     

Elevated glucose promotes generation of endothelium-derived vasoconstrictor prostanoids in rabbit aorta

The effects of glucose on endothelium-dependent responses and vasoactive prostanoid production were determined by incubating isolated rabbit aortae in control (5.5 or 11 mM) or elevated (44 mM) glucose for 6 h to mimic euglycemic and hyperglycemic conditions. Rings of aortae incubated in elevated glucose, contracted submaximally by phenylephrine, showed significantly decreased endothelium-dependent relaxations induced by acetylcholine compared with the aortae incubated in control glucose. Treatment with indomethacin, a cyclooxygenase inhibitor, or SQ29548, a prostaglandin H2/thromboxane A2 receptor antagonist, restored acetylcholine relaxations of rings in elevated glucose to normal, while these agents had no effect on the relaxation of rings incubated in control glucose. Aortae incubated with mannose (44 mM) as a hyperosmotic control relaxed to acetylcholine normally. The relaxations in response to A23187 and sodium nitroprusside were not different between rings exposed to control and elevated glucose. Radioimmunoassay measurements showed a significant increase in acetylcholine-stimulated release of thromboxane A2 and prostaglandin F2 alpha in aortae with, but not without endothelium incubated with elevated, but not with control glucose. Thus a possible mechanism for endothelium dysfunction in diabetes mellitus is the hyperglycemia-induced increased generation of endothelium-derived vasoconstrictor prostanoids.     

Oestrogen attenuates coronary vasoconstriction after angioplasty: role of endothelin-1

BACKGROUND AND AIMS: There were controversies as to whether endothelin-1 is released after coronary angioplasty. We sought to determine whether endothelin-1 is released after coronary angioplasty and whether oestrogen administration can affect coronary vasomotor tone by reducing endothelin-1 concentrations. METHODS: The study was designed to prospectively investigate 24 consecutive patients scheduled for elective coronary angioplasty. Patients were randomized into two groups according to whether they did not (group 1, n = 12) or did (group 2, n = 12) have intracoronary treatment with oestrogen. Quantitative coronary angiography was monitored at baseline, immediately after successful angioplasty, and 15 min after the last deflation. Blood samples for measuring the levels of endothelin-1 were drawn from the ascending aorta and the coronary sinus simultaneously before angioplasty and 15 min after balloon dilatation. RESULTS: The diameters of the coronary artery at the dilated segments were significantly reduced 15 min after dilation compared with those immediately after dilation in group 1 from 3.20 +/- 0.22 to 2.30 +/- 0.23 mm (P < 0.001), respectively. The vasoconstriction was significantly blunted in group 2. The endothelin-1 levels from the coronary sinus rose significantly, by 29%, 15 min after angioplasty in group 1, which was attenuated after administering oestrogen. Significant correlation was found between the changes of coronary vasomotion of the dilated segment and endothelin-1 levels (r = 0.70, P = 0.01). CONCLUSION: Endothelin-1 is released into the coronary circulation after angioplasty, and this vasoactive substance may contribute to the occurrence of vasoconstriction. The vasoconstriction is attenuated by oestrogen by reducing the endothelin-1 levels. This finding provided a new strategy to treat coronary vasoconstriction after angioplasty.     

alpha 2-Adrenoceptors potentiate angiotensin II- and vasopressin-induced renal vasoconstriction in spontaneously hypertensive rats

Hypertension in spontaneously hypertensive rats (SHRs) is due in part to enhanced effects of vasoactive peptides on the renal vasculature. We hypothesize that the G(i) signal transduction pathway enhances renovascular responses to vasoactive peptides in SHRs more so than in normotensive Wistar-Kyoto (WKY) rats. To test this hypothesis, we examined in isolated perfused kidneys from SHRs and WKY rats the renovascular responses (assessed as changes in renal perfusion pressure in mm Hg) to angiotensin II (10 nM) and vasopressin (3 nM) in the presence and absence of UK-14,304 [5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine; an agonist that selectively activates the G(i) pathway by stimulating alpha(2)-adrenoceptors]. In SHR, but not WKY, kidneys, UK-14,304 (10 nM) enhanced (P < 0.05) renovascular responses to angiotensin II (control WKY, 43 +/- 6; UK-14,304-treated WKY, 52 +/- 19; control SHR, 66 +/- 17; UK-14,304-treated SHR, 125 +/- 16) and vasopressin (control WKY, 42 +/- 17; UK-14,304-treated WKY, 36 +/- 11; control SHR, 16 +/- 8; UK-14,304-treated SHR, 83 +/- 17). Pretreatment of SHRs with pertussis toxin (30 microg/kg, intravenously, 3-4 days before study) to inactivate G(i) blocked the effects of UK-14,304. Western blot analysis of receptor expression in whole kidney and preglomerular microvessels revealed similar levels of expression of AT(1), V(1a), and alpha(2A) receptors in SHRs compared with WKY rats. We conclude that activation of alpha(2)-adrenoceptors selectively enhances renovascular responses to angiotensin II and vasopressin in SHRs via an enhanced cross talk between the G(i) signal transduction pathway and signal transduction pathways activated by angiotensin II and vasopressin.     

Evidence against serotonin as a vasoconstrictor neurotransmitter in the rabbit basilar artery

It has been suggested recently that serotonergic nerves distinct from the known adrenergic innervation are present in cerebral blood vessels. We have confirmed that serotonin is present in the wall of rabbit cerebral arteries using a high-performance liquid chromatography technique, with levels in the basilar artery of 0.27 +/- 0.04 microgram/g wet wt. Furthermore, adrenergic denervation in vitro with 6-hydroxydopamine, while substantially reducing norepinephrine content, did not alter serotonin levels in the basilar artery. However, it was not possible to demonstrate specific accumulation of [3H]serotonin into distinct serotonergic nerves. Both the basilar artery and ear artery (which has been shown not to be innervated with serotonergic nerves) accumulated [3H]serotonin when incubated with a low concentration (10(-8) M). However, [3H]serotonin accumulation was reduced markedly in 6-hydroxydopamine-treated vessels as well as in the presence of the norepinephrine uptake blocker, desmethylimipramine. Furthermore, pretreatment with the serotonin uptake blocker, fluoxetine, did not inhibit selectively [3H]serotonin accumulation in the basilar artery. Thus, the majority of [3H]serotonin accumulation can be attributed to adrenergic nerves. The possibility that serotonergic nerves contribute to the neurogenic constrictor response of the rabbit basilar artery was also tested. Adrenergic denervation with 6-hydroxydopamine in vitro abolished the constrictor response to transmural nerve stimulation completely, but levels of endogenous serotonin were not affected. Thus, although the presence of endogenous serotonin in cerebral arteries has been confirmed, this substance does not appear to contribute to the neurogenic vasoconstriction seen in this vessel.     

Effects of SR 49059, a non-peptide antagonist of vasopressin V1a receptors, on vasopressin-induced coronary vasoconstriction in conscious rabbits

Summary— The effect of SR 49059, a new potent non-peptide vasopressin (AVP) V_1a receptor antagonist, was investigated on AVP-induced electrocardiogram modifications. A high intravenous dose of AVP (0.5 IU or 1.23 μg/animal) produced an important transient t -wave elevation (from 4.7 ± 0.2 to 8.9 ± 0.7 mm) and heart rate decrease (from 199 ± 5 to 99 ± 6 bpm) in conscious rabbits. The t -wave increase was a significant index of coronary vasoconstriction-induced cardiac ischemia. SR 49059 had potent protective effects in this model both by intravenous (0.125 to 0.5 mg/kg) and oral (2.5 to 10 mg/kg) routes. After a 30-min pre-treatment, SR 49059 showed dose-dependent protection on t -wave elevation and heart rate decrease with ED₅₀'s of 95 (95% CL: 168-22) and 30 (95% CL:54-6) μg/kg iv, respectively. Complete blockade occurred with doses of 2 mg/kg iv and upwards. By the oral route, SR 49059 was rapidly absorbed and a dose of 10 mg/kg displayed a protective effect lasting more than 6 hours on both electrocardiogram parameters. Moreover, SR 49059 exerted a high stereospecific inhibitory effect since its enantiomer was totally inactive at 0.5 mg/kg iv, suggesting that protection occurred by interaction with vascular AVP V_1a receptors. Thus, SR 49059 is the first specific non-peptide V_1a antagonist with long-lasting oral activity on AVP-induced coronary vasoconstriction and bradycardia. With this original profile, SR 49059 could be a promising therapeutical antivasospastic agent for preventing AVP- induced cardiac damage.     

Triptans and chest symptoms: the role of pulmonary vasoconstriction

Triptans are effective and well tolerated in the treatment of acute migraine. Chest symptoms are a common adverse effect unrelated to coronary vasoconstriction in most patients. Although the aetiology of chest symptoms remains to be fully defined, pulmonary vasoconstriction is a possible underlying mechanism. Pre-clinical studies of isolated human blood vessels were used to identify the cerebral selectivity of triptans and ascertain if selectivity vs the pulmonary vasculature predicts a lower rate of chest symptoms. Controlled clinical trials and post-marketing surveillance studies were reviewed to document the incidence of chest symptoms after triptan therapy. In clinical trials, the incidence of chest symptoms at usual therapeutic doses ranged from 1 to 4% depending on the triptan and study design, whereas in post-marketing surveillance studies, up to 41% of patients specifically asked about chest symptoms reported them. A comparative clinical trial showed that almotriptan was associated with lower incidence of chest symptoms than sumatriptan (0.3 vs 2.2%). The intrinsic activity of almotriptan, a second-generation triptan, on human pulmonary arteries and veins was lower than that of sumatriptan. Pre-clinical studies of isolated pulmonary blood vessels may predict the clinical likelihood of chest symptoms; however, additional comparisons are needed.     

Endogenous angiotensin II in the regulation of hypoxic pulmonary vasoconstriction in anaesthetized dogs

Introduction

The role played by several vasoactive mediators that are synthesized and released by the pulmonary vascular endothelium in the regulation of hypoxic pulmonary vasoconstriction (HPV) remains unclear. As a potent vasoconstrictor, angiotensin II could be involved. We tested the hypothesis that angiotensin-converting enzyme inhibition by enalaprilat and type 1 angiotensin II receptor blockade by candesartan would inhibit HPV.

Methods

HPV was evaluated in anaesthetized dogs, with an intact pulmonary circulation, by examining the increase in the Ppa–Ppao gradient (mean pulmonary artery pressure minus occluded pulmonary artery pressure) that occurred in response to hypoxia (inspiratory oxygen fraction of 0.1) at constant pulmonary blood flow. Plasma renin activity and angiotensin II immunoreactivity were measured to determine whether activation or inhibition of the renin–angiotensin system was present.

Results

Administration of enalaprilat and candesartan did not affect the Ppa–Ppao gradient at baseline or during hypoxia. Plasma renin activity and angiotensin II immunoreactivity increased during hypoxia, and subsequent measurements were consistent with effective angiotensin-converting enzyme inhibition after administration of enalaprilat, and with angiotensin receptor blockade after administration of candesartan.

Conclusion

These results suggest that, although the renin–angiotensin system was activated in hypoxia, angiotensin II is not normally involved in mediating acute HPV.

     

Platelet-activating factor: evidence against a role in hypoxic pulmonary vasoconstriction

The mechanism of hypoxic pulmonary vasoconstriction (HPV) remains unknown. The platelet-activating factor (PAF) antagonist WEB 2086 attenuated HPV in the isolated lung model of the rat. We evaluated the effect of WEB 2086 on HPV in an intact animal. Pigs were anesthetized, mechanically ventilated, and had their hemodynamic variables monitored with a pulmonary artery catheter and arterial line. Cardiac output was measured by thermodilution. Initial studies determined that PAF (0.03 to 1.0 micrograms) injected iv dose-dependently increased pulmonary vascular resistance (PVR) with a 262 +/- 58% increase in PVR 5 min after a dose of 1.0 microgram. WEB 2086 (25 mg/kg iv) completely blocked the increase in PVR caused by iv PAF. Additionally, indomethacin (2 mg/kg followed by 2 mg/kg.h iv) treatment of the animals attenuated the PAF-induced increase in PVR. To evaluate the effect of WEB 2086 on HPV, animals were alternately ventilated with 21% oxygen and 10-min periods of 10% oxygen to induce HPV. After three initial control episodes of hypoxic ventilation, WEB 2086 (25 mg/kg) was injected iv and two more episodes of ventilation with 10% oxygen were given. During the three control HPV episodes the increases in PVR were 80 +/- 10%, 108 +/- 10%, and 107 +/- 22% (n = 5). After WEB 2086, the increase in PVR during two episodes of hypoxia were 96 +/- 28% and 99 +/- 19%, respectively, which was not significantly different from the control response to hypoxia. We conclude that iv PAF dose dependently increases PVR in pigs, and can be blocked by WEB 2086, that its effect is partially mediated through cyclooxygenase products, and that PAF does not appear to mediate HPV in this species.     

The role of vasoconstriction in the local Shwartzman reaction

The local Shwartzman reaction was provoked in the skin of the ear, hind leg, and costovertebral angle of the rabbit, as well as in the ventral abdominal skin. Certain adrenergic blocking drugs reduced the incidence of positive reactions when given prior to the provocative dose of bacterial polysaccharide. Epinephrine and other vasoconstrictor drugs administered intradermally into the prepared skin site produced typical hemorrhagic-necrotic lesions when the usual intravenous injection of polysaccharide was omitted. This reaction could be blocked by adrenergic blocking drugs, but appeared to be augmented by heparin or nitrogen mustard. A hypothesis has been developed to help explain the mechanism of the local Shwartzman reaction. Following the preparatory dose, tissue metabolic changes occur which lead to increased lactic acid production and render the area particularly susceptible to anoxia. Following the provocative dose, adrenergic vasoconstriction occurs. It is suggested that this vasoconstriction may be intensified at the prepared site by small residual amounts of the preparatory dose of polysaccharide which might potentiate the action of the epinephrine. The anoxia initiated by the vasoconstriction is prolonged and intensified by the formation of intravascular thrombi around clumps of leucocytes and platelets. This anoxia, superimposed on the local metabolic changes, leads to the characteristic lesion of hemorrhage and necrosis. Thus a combination of factors, all of causal importance and largely due to known pharmacologic properties of bacterial lipopolysaccharide, occur in specific sequence to lead to the classic local Shwartzman reaction.     

The role of serotonin and dopamine in schizophrenia

For many years schizophrenia was attributed to an overabundance of dopamine in the brain, and until recently conventional neuroleptics (dopamine-D₂ receptor antagonists) have been the mainstay of pharmacologic treatment for patients with this illness. The dopaminergic mechanism of action makes conventional neuroleptics effective for the positive symptoms of schizophrenia but not for the negative symptoms. It is now recognized that serotonin also plays an important role in the pathogenesis of schizophrenia. By blocking both dopamine and serotonin receptors, the newer antipsychotic agents such as clozapine, risperidone, and olanzapine are effective for both the positive and negative symptoms of schizophrenia and are less likely than conventional neuroleptics to cause extrapyramidal symptoms at prescribed doses. Although the newer antipsychotics are tolerated better than conventional neuroleptics, each of these newer drugs is associated with some adverse effects, such as hypotension and sedation. Further research into the neurobiology of schizophrenia may lead to the development of even more effective and safe antipsychotic medications for schizophrenia.     

The role of low pressure baroreceptors in reflex vasoconstrictor responses in man

Studies were performed on 11 healthy men to evaluate the role of low pressure baroreceptors in the reflex forearm vasoconstrictor responses (plethysmography) to venous pooling produced by lower body negative pressure. Lower body negative pressure (LBNP) at - 5, - 10, - 20, and - 40 mm Hg lowered central venous pressure by 42, 59, 74, and 93%, respectively, and decreased forearm vascular conductance by 24, 29, 34, and 40%, respectively. The decreases in forearm blood flow and conductance during the low levels of venous pooling (LBNP - 5 and - 10 mm Hg) occurred without significant changes in arterial pressure, arterial dP/dt. and heart rate. These results with the low levels indicate that maneuvers which decrease venous return and central venous pressure in man can influence forearm vascular tone without significant changes in the determinants of carotid and aortic baroreceptor activity. During high levels of venous pooling (LBNP - 20 and - 40 mm Hg), significant decreases in arterial pressure and dP/dt and significant increases in heart rate accompanied the further reductions in central venous pressure, forearm blood flow, and forearm vascular conductance. About 73% of the decrease in conductance during venous pooling at LBNP - 40 mm Hg, which was sufficient to decrease arterial pressure and activate high pressure baroreceptor reflexes, occurred during low levels of venous pooling at LBNP - 10 mm Hg without changes in arterial pressure. This suggests that much of the forearm vasoconstriction with the high levels of venous pooling, which were sufficient to decrease arterial pressure, may be accounted for by reflexes originating in areas other than high pressure baroreceptors. The results of these studies suggest that low pressure baroreceptors exert an important influence on forearm vascular tone during decreases in venous return and central venous pressure in man.     

Oestradiol-induced hypotension in spontaneously hypertensive rats: putative role for intracellular cations, sodium-potassium flux and prostanoids.

1. The effect of oestradiol alone and in combination with indomethacin on blood pressure, erythrocyte cation concentration and Na(+)-K+ flux has been studied in adult female normotensive and spontaneously hypertensive rats. 2. Oestradiol alone resulted in a significant decrease in blood pressure in spontaneously hypertensive rats (from 165.3 +/- 3.9 to 146.4 +/- 2.7 mmHg, P less than 0.001), whereas it induced a significant increase in normotensive rats (from 111.8 +/- 1.8 to 124.1 +/- 3.6 mmHg, P less than 0.001). When indomethacin and oestradiol were administered simultaneously or when indomethacin was given alone, no change in blood pressure occurred in spontaneously hypertensive rats (158.6 +/- 6.9 and 159.8 +/- 6.2 mmHg, respectively). 3. The fall in blood pressure induced by oestradiol in spontaneously hypertensive rats was associated with significant reductions in erythrocyte K+ concentration (from 127.4 +/- 1.2 to 116.9 +/- 1.7 mmol/l of cells, P less than 0.001), in erythrocyte Na+ concentration (from 14.3 +/- 0.8 to 13.0 +/- 0.6 mmol/l of cells, P less than 0.02), in ouabain-sensitive erythrocyte Na+ flux (from 17.8 +/- 0.3 to 16.0 +/- 0.4 mmol h-1 (l of cells)-1, P less than 0.01) and in ouabain-sensitive erythrocyte K+ flux (from 11.4 +/- 0.2 to 10.4 +/- 0.2 mmol h-1 (l of cells)-1, P less than 0.01). No change in blood pressure, erythrocyte cation concentration or Na(+)-K+ flux occurred when oestradiol and indomethacin were given together or when indomethacin was administered alone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Thrombosis in one coronary artery causes generalized coronary vasoconstriction in a dog model of unstable angina

We investigated the effect of thrombosis in one coronary artery upon the vascular resistance of another coronary artery. In previous investigations, using an animal model of unstable angina, we have observed increased resistance downstream from thrombus within a left circumflex coronary artery (LCx) stenosis and vasoconstriction of collateral vessels from the left anterior descending artery (LAD) supplying the distal LCx vascular bed. In the present paper, we induced thrombosis within a stenosis of the LCx of 16 beagle dogs, and observed the changes in blood flow to the myocardium supplied by the LAD using the radioactive microsphere technique. This blood flow decreased with thrombosis (P = 0.005) in these animals, whereas it did not do so in three time-control experiments. The pressures across the coronary vascular bed, i.e. arterial pressure to coronary venous pressure (coronary sinus catheter), did not change. Thus the vascular resistance of the LAD bed increased significantly from 147 +/- ll.5 mmHg/ml/sec/g of tissue to 172 +/- 13.4 mmHg/ml/sec/g of tissue (P = 0.02). As the LAD territory is not perfused with blood from the artery containing thrombus, we conclude that the effect observed is caused either by release of vasoconstrictors from the thrombus into the general circulation, or by activation of a neural reflex vasoconstriction. The study suggests that unstable angina involving thrombosis in one coronary artery is a global coronary vascular disease.     

Signaling mechanisms for muscarinic receptor-mediated coronary vasoconstriction in isolated rat hearts

Signaling mechanisms for muscarinic receptor-mediated vasoconstriction in coronary resistance arteries were studied in potassium-arrested isolated rat hearts perfused at a constant flow rate. The cholinergic agonist bethanechol was given by bolus injection or constant infusion. Perfusion pressure was monitored as an indicator of coronary vascular resistance. Bolus injection of bethanechol evoked a phasic vasoconstriction in a dose-dependent manner, whereas infusion of bethanechol evoked a tonic vasoconstriction without producing tachyphylaxis. Bethanechol-induced phasic vasoconstriction was eliminated by perfusion with a Ca(2+)-free buffer. The L-type voltage-operated Ca(2+) channel blocker nifedipine decreased the maximal constrictor response to bethanechol by 59 +/- 2% (n = 4, P <.001), whereas the putative receptor-operated Ca(2+) channel blocker SK&F 96365 converted this vasoconstriction into vasodilation that was not mediated by nitric oxide. The protein kinase C inhibitor chelerythrine reduced the maximal phasic vasoconstrictor response to bethanechol by 78 +/- 2% (n = 6, P <.001) Bethanechol-induced tonic vasoconstriction was rapidly converted to a sustained vasodilation during infusion of SK&F 96365 or nifedipine, whereas infusion of chelerythrine gradually attenuated the tonic response to bethanechol. Results from other experiments do not support a role for phospholipase A(2)-dependent mediators in generating coronary vasoconstrictor responses to bethanechol. It is concluded that voltage-independent receptor-operated Ca(2+) channels, voltage-operated Ca(2+) channels, and protein kinase C are major signaling components for muscarinic receptor-mediated contraction of rat coronary resistance arteries.     

Neurogenic coronary vasoconstrictor effects of digitalis during acute global ischemia in dogs.

The rapid i.v. administration of digitalis has recently been shown to cause a substantial increase in coronary vascular resistance in the normal heart. This neurogenically mediated decrease in coronary blood flow would be potentially detrimental if it occurred during ischemia. The present study evaluates the effects of i.v. acetylstrophanthidin and digoxin on coronary vascular resistance during acute global ischemia in 29 dogs anesthetized with chloralose and urethane. Under these conditions, 0.5 mg of i.v. acetylstrophanthidin in 15 dogs resulted in erratic increases in coronary vascular resistance. The peak rise was 12+/-5% above control (P less than 0.01). In 7 of the 15 dogs, the initial erratic rise in coronary vascular resistance culminated in a steep rise associated with acute elevation in left ventricular end-diastolic pressure, which in four dogs terminated in ventricular fibrillation. During the nonischemic control periods, the peak rise in coronary vascular resistance with acetylstrophanthidin was 16+/-1% above control (P less than 0.01). In five dogs, prior alpha adrenergic receptor blockade with phenoxybenzamine prevented the rise in coronary vascular resistance with acetylstrophanthidin during ischemia. Similar erratic increases in coronary vascular resistance were observed with i.v. digoxin (1 mg) during ischemia in three dogs. In two of these dogs, there was a progressive rise in coronary vascular resistance associated with elevation of left ventricular end-diastolic pressure and ventricular fibrillation. The increase in coronary vascular resistance with digoxin during ischemia was abolished with phenoxybenzamine in two additional dogs. Thus, i.v. digitalis in the ischemic heart results in potentially detrimental increases in coronary vascular resistance mediated through alpha adrenergic receptor stimulation.     

Increased coronary vasoconstrictor response to acetylcholine in women with chest pain and normal coronary arteriograms (cardiac syndrome X)

Aims

Cardiac syndrome X (CSX) is characterized by exercise-induced angina, positive exercise stress-test responses and angiographically normal coronary arteries. The condition characteristically affects more women than men and is often associated with coronary microvascular dysfunction, i.e., abnormal vasodilatory responses. Recent clinical observations suggest that increased coronary vasoconstriction may have a pathogenic role in CSX. We therefore sought to assess the prevalence of increased epicardial and microvascular coronary vasoconstriction in women with CSX.

Methods and results

Among 1,120 consecutive women with angina undergoing diagnostic coronary angiography 39 fulfilled criteria for CSX (mean age 63?±?9?years) and were included in the study (27 also complained about rest angina). Five women without angina (mean age 64?±?24?years) and normal coronary arteriograms served as controls. Patients and controls underwent intracoronary acetylcholine testing with a standardized protocol. Severe (≥75?% diameter reduction) epicardial constriction developed in 12 CSX patients (31?%) with reproduction of their angina in 10. All 12 patients showed diffuse epicardial constriction affecting mainly the distal coronary segments. Twenty-two CSX patients (56?%) experienced their usual angina without epicardial constriction of which 21 had ischemic ECG shifts. The remaining five CSX patients (13?%) had no angina or constriction in response to acetylcholine. None of the control patients had angina or constriction during ACH testing.

Conclusion

Increased epicardial as well as microvascular coronary constriction in response to acetylcholine are frequent findings in women with CSX. The results indicate that inappropriate coronary constriction is likely to contribute to the anginal symptoms of these patients. The ACH-test may be useful in the clinical setting to unmask this vasomotor disorder.