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Biomedical subjects

D Hasdai

Publications and source records attributed to D Hasdai.

At least 19 recordsLinked to original sources
PubMed1999

Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia.

BACKGROUND: Endothelin-1 (ET-1) is an endothelium-derived peptide that constricts coronary vessels through stimulation of the ET-A and ET-B receptors. Experimental porcine hypercholesterolemia is associated with impaired coronary endothelial function and elevated ET-1 concentrations. This study was designed to test the hypothesis that chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. METHODS AND RESULTS: Acetylcholine (10(-6) to 10(-4) mol/L) was serially infused into the left anterior descending coronary artery in pigs at baseline and after 12 weeks of a high-cholesterol diet. In the interim, the animals were randomized to 3 groups: Group 1 received no therapy, group 2 received 3 mg/kg per day RO 48-5695, a combined ET-A/ET-B receptor antagonist, and group 3 received 4 mg/kg per day ABT-627, a selective ET-A receptor antagonist. Percent change in coronary artery diameter, coronary blood flow, and coronary vascular resistance were calculated on the basis of quantitative coronary angiography and intracoronary Doppler. At 12 weeks, total cholesterol was significantly and similarly increased in all groups. Chronic endothelin receptor antagonism significantly increased coronary blood flow in response to acetylcholine at 12 weeks (group 1: -41.6%+/-10.7%, group 2: -4.7%+/-11.9%, group 3: 11.4%+/-7.4%). CONCLUSIONS: Chronic endothelin receptor antagonism preserves coronary endothelial function in experimental hypercholesterolemia. This study supports the role for ET-1 in the pathogenesis of endothelial function. Moreover, endothelin receptor antagonists may have a therapeutic role by maintaining coronary endothelial function in pathophysiological states.

Administration, Oral↗
PubMed1999

Safety and efficacy of ticlopidine for only 2 weeks after successful intracoronary stent placement.

BACKGROUND: In patients receiving intracoronary stents, stent thrombosis is reduced when ticlopidine therapy is combined with aspirin after the procedure. However, ticlopidine causes neutropenia in 1% of patients when administered for >2 weeks, and little is known about the duration that ticlopidine needs be administered to prevent stent thrombosis. METHODS AND RESULTS: We analyzed 827 patients undergoing successful stent placement in 1061 coronary segments at Mayo Clinic who were treated between May 1, 1996, and October 31, 1997. Chronic warfarin therapy, cardiogenic shock, and enrollment in research protocols requiring 4 weeks of ticlopidine were exclusion criteria; ticlopidine was discontinued after 14 days in all remaining patients. The mean age of the study population was 64+/-11 years; 49% had suffered a prior infarction, 20% had undergone coronary artery bypass surgery, and 65% had multivessel disease. The indication for stent placement was dissection or abrupt closure in 31% of patients and suboptimal results from balloon angioplasty in 18%. Placement was elective in 51% of patients, and 10.3% of patients were treated within 12 hours of an acute myocardial infarction. Mean nominal stent size was 3.3+/-0.5 mm. High-pressure inflations (>/=12 atm) were performed in all patients (mean, 17+/-4 atm). Intravascular ultrasound was used to facilitate stent placement in 8.8% of patients. Abciximab was administered to 38% of patients; 11% of patients who were at increased risk of stent thrombosis were treated with enoxaparin for 10 to 14 days. Adverse cardiovascular events in the 14 days after stent placement occurred in 11 patients (1.3%). Two patients died of nonischemic causes (sepsis and renal failure) in the 15th through 30th days after ticlopidine was stopped. However, there were no cardiovascular deaths, myocardial infarctions, coronary artery bypass operations, or repeat angioplasty procedures between the 15th and 30th days; stent thrombosis did not occur in any patient after ticlopidine had been stopped. No patient developed neutropenia, although 1.8% of the first 489 patients who were closely monitored for side effects from ticlopidine developed side effects requiring its discontinuation, and milder side effects occurred in 4.7%. CONCLUSIONS: In patients receiving intracoronary stents, the discontinuation of ticlopidine therapy 14 days after stent placement is associated with a very low frequency of stent thrombosis and other adverse events.

Abciximab↗
PubMed1999

Medical therapy after successful percutaneous coronary revascularization.

BACKGROUND: Percutaneous coronary revascularization frequently relieves angina in patients with ischemic heart disease and may obviate the need for antianginal medications. OBJECTIVE: To examine the use of antianginal medications after successful percutaneous coronary revascularization. DESIGN: Retrospective cohort study of the Mayo Clinic PTCA [percutaneous transluminal coronary angioplasty] Registry. SETTING: Tertiary care center. PATIENTS: 3831 patients who underwent successful percutaneous coronary revascularization from September 1979 through August 1997 and had not had myocardial infarction within the year before the intervention. MEASUREMENTS: Use of antianginal medications (beta-adrenergic blockers, nitrates, and calcium-channel blockers) before the intervention, at hospital discharge, and 6 months after the intervention. RESULTS: 99% of patients reported improvement in their symptoms at hospital discharge. At 6 months, 87% of patients were free of myocardial infarction, coronary bypass surgery, or additional percutaneous intervention. Compared with 66% of patients before the index intervention, only 12% of patients had severe angina at 6 months and 69% were completely free of angina. Nonetheless, at 6 months, 39% of patients were receiving beta-adrenergic blockers (preprocedure proportion, 43%; P < 0.001), 36% were receiving nitrates (preprocedure proportion, 41%; P < 0.001), and 57% were receiving calcium-channel blockers (preprocedure proportion, 50%; P < 0.001). These trends persisted for patients without hypertension and those who had complete revascularization. CONCLUSIONS: Successful percutaneous coronary revascularization did not substantially supplant the use of antianginal medications, which were commonly used despite the marked improvement in anginal status. This may reflect reluctance to alter therapy once symptoms of angina subside. Guidelines on continued medical therapy after percutaneous coronary revascularization are needed.

Adrenergic beta-Antagonists↗
PubMed1999

Smoking status and outcome after primary coronary angioplasty for acute myocardial infarction.

BACKGROUND: Because of the increased propensity of intracoronary thrombi to form in cigarette smokers, percutaneous transluminal angioplasty (PTCA) for acute myocardial infarction (AMI) may be less effective in smokers. We sought to determine the impact of smoking status on outcome after PTCA for AMI. METHODS: Patients enrolled in the GUSTO IIb Angioplasty Substudy were randomly assigned to receive PTCA or tissue-plasminogen activator (tPA) for AMI. The interaction of smoking status (nonsmokers = 344, former smokers = 294, current smokers = 490) and treatment strategy with the occurrence of death, nonfatal reinfarction, or nonfatal, disabling stroke at 30 days was analyzed. Procedural success (residual stenosis <50% and Thrombolysis in Myocardial Infarction [TIMI] flow grade 3) was also analyzed for patients who underwent PTCA (n = 444). RESULTS: Among patients who underwent PTCA, nonsmokers had worse percent stenosis of the culprit lesion before reperfusion (P =.03) and more often had TIMI flow grade 0 (P <.05). Procedural success was more common in smokers (65.6%) than in former smokers (53.3%) and nonsmokers (52. 4%; P =.02), reflecting a higher rate of postprocedure TIMI 3 flow. PTCA was associated with a better 30-day outcome than tPA for current smokers (odds ratio [95% confidence interval] = 0.41 [0.19 to 0.88]), with a similar trend for former smokers (0.73 [0.34 to 1. 58]) and nonsmokers (0.77 [0.42 to 1.40]). At 6 months, smokers randomly assigned to PTCA also had fewer deaths and reinfarction (0. 58 [0.31 to 1.07]). CONCLUSIONS: Although smoking status affects angiographic variables before and after PTCA for AMI, PTCA is associated with a better 30-day outcome than tPA regardless of smoking status and should be considered when readily available.

Angioplasty, Balloon, Coronary↗
PubMed1999

Cardiogenic shock complicating acute myocardial infarction: predictors of death. GUSTO Investigators. Global Utilization of Streptokinase and Tissue-Plasminogen Activator for Occluded Coronary Arteries.

BACKGROUND: Current knowledge of predictors of death among patients with cardiogenic shock complicating myocardial infarction is limited. We aimed to develop a risk assessment prognostic algorithm of 30-day mortality, including clinical and hemodynamic data prospectively collected among patients with cardiogenic shock in the 41,021-patient Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO-I) trial. METHODS: We used logistic regression modeling techniques to evaluate the relations between demographic, clinical, and hemodynamic characteristics and 30-day mortality rate for the entire shock population (n = 2968) and for patients who underwent right-heart catheterization (n = 995). RESULTS: The odds (95% confidence interval) of dying were 1.49 times higher (1.27-1.74) for patients 10 years older and 1.70 times higher (1.19-2.44) for patients with prior infarction. Findings derived from physical examination, such as altered sensorium and cold, clammy skin, were important independent predictors of prognosis (odds of dying 1.68 times higher for each [1.19-2.39 and 1.15-2.46]). The odds of dying were also 2.25 times higher (1.61-3.15) in patients with oliguria. Mortality rate was lowest for cardiac output and pulmonary capillary wedge measurements of 5.1 L/min and 20 mm Hg, respectively, and increased with either higher or lower values. Patients with shock had better outcomes than patients in whom shock developed later, although for the latter subgroup, prognosis was worse in patients who had heart failure (Killip class II to III). CONCLUSIONS: We devised a prognostic algorithm for patients with cardiogenic shock complicating acute myocardial infarction. In addition to demographic and easily derived physical examination features, data derived from right-heart catheterization added valuable information that increased the ability to predict outcome in this high-risk population.

Aged↗
PubMed1999

Coronary artery apoptosis in experimental hypercholesterolemia.

The altered coronary vasoactivity detected in experimental hypercholesterolemia before lesion formation is presumably due to an imbalance between vasodilating and vasoconstricting factors. Apoptosis, which has been previously described in advanced atherosclerosis, is modulated by vascular derived peptides with vasoactive properties. We hypothesized that coronary apoptosis occurs in experimental hypercholesterolemia prior to lesion formation. Pigs were sacrificed after being on either a high-cholesterol diet for 10-16 weeks (n = 17) or a normal diet (n = 9). Identification of apoptosis in each layer of coronary arteries and arterioles was performed by terminal deoxynucleotidyl transferase (TdT)-mediated dUTP-biotin nick end-labeling (TUNEL). In additional animals, ligation-mediated polymerase chain reaction (PCR) and transmission electron and confocal microscopy were done. Plasma cholesterol levels were higher in the cholesterol-fed animals (86+/-9 mg/dl versus 342+/-20 mg/dl, P < 0.001). Atheromatous plaques were not evident in the high-cholesterol group. TUNEL was positive in 11 of 17 hypercholesterolemic animals, primarily in the intima (1-2% of cells) and adventitia (3% of cells), but not in control vessels. A similar distribution was detected in arterioles. DNA bands were detected only in experimental animals, as were morphological features of apoptosis by transmission electron and confocal microscopy. In experimental hypercholesterolemia, apoptosis occurred in coronary arteries and arterioles before lesion formation. Apoptosis may be an integral process of early coronary atherosclerosis.

Animals↗
PubMed1999

Frequency and clinical outcome of cardiogenic shock during acute myocardial infarction among patients receiving reteplase or alteplase. Results from GUSTO-III. Global Use of Strategies to Open Occluded Coronary Arteries.

AIMS: Reteplase has been reported to achieve better patency of the infarct artery than alteplase. As infarct artery patency is strongly associated with survival among patients with cardiogenic shock, we postulated that treatment with reteplase would improve outcomes among shock patients. METHODS: We compared 30-day mortality rates among patients in GUSTO-III who either presented with shock or developed shock after enrollment; all patients received either front-loaded alteplase or reteplase (two bolus doses of 10 MU, 30 min apart). RESULTS: Shock occurred in 260 (5.3%) of 4921 patients randomized to alteplase and 560 (5.5%) of 10,138 patients randomized to reteplase. Of these patients, 28 (10.8%) and 55 (9.8%) randomized to alteplase and reteplase, respectively, presented with shock. In-hospital, 35% and 37% of shock patients assigned to alteplase or reteplase, respectively, underwent coronary angiography, with similar rates of percutaneous (approximately 11-13%) or surgical (approximately 2-3%) revascularization procedures subsequently performed. Death within 30 days occurred in 169 (65%) and 353 (63%) shock patients randomized to alteplase and reteplase, respectively (P = 0.59). Of patients presenting with shock, 64% and 58% of patients randomized to alteplase or reteplase died within 30 days (P = 0.59). CONCLUSION: Compared with alteplase, reteplase did not improve outcome among patients who presented with shock or developed shock after receiving thrombolytics. The newer-generation thrombolytic agents remain of limited efficacy in the treatment and prevention of shock.

Aged↗
PubMed1999

Apoptosis. Basic concepts and implications in coronary artery disease.

Apoptosis is an active form of cell death that is intricately regulated and distinct from necrosis. Data suggest that apoptosis may play a role in the pathophysiology of coronary atherosclerotic disease. Anatomic evidence of apoptosis has been observed in coronary atherosclerosis, restenosis, and transplant arteriopathy, accompanied by an increase in biochemical and genetic markers of apoptosis. Vasoactive substances such as nitric oxide and angiotensin II also regulate vascular smooth muscle cell apoptosis; vasodilating factors may induce apoptosis, whereas vasoconstricting factors may inhibit apoptosis. The aim of this article is to review key points regarding the detection of apoptosis, its regulation, and its possible role in the pathogenesis of coronary artery disease.

Apoptosis↗
PubMed1999

Attenuated in vitro coronary arteriolar vasorelaxation to insulin-like growth factor I in experimental hypercholesterolemia.

Insulin and insulin-like growth factor (IGF) 1 affect coronary vasoactivity. Experimental hypercholesterolemia is associated with coronary atherogenesis and altered vasomotor regulation. Because the IGF axis is altered during atherogenesis, we postulated that experimental hypercholesterolemia is associated with an altered coronary vasoactive response to IGF-1 in vitro. Coronary arteries and arterioles from pigs fed either a normal or high-cholesterol diet for 10 weeks were contracted with endothelin-1 and relaxed with cumulative concentrations of insulin or IGF-1 (10(-12) to 10(-7) mol/L). Control arterioles were also incubated with the nitric oxide synthase inhibitor 10(-4) mol/L N(G)-monomethyl-L-arginine (L-NMMA) or the potassium channel blocker 10(-2) mol/L tetraethylammonium (TEA), contracted with endothelin-1, and relaxed with insulin or IGF-1. Experimental hypercholesterolemia (1) increased serum cholesterol (9.5+/-1.0 versus 1.9+/-0.08 mmol/L; P<0.0001), (2) caused coronary arterial and arteriolar endothelial dysfunction in vitro (attenuated vasorelaxation to bradykinin), (3) did not alter the epicardial response to either insulin (P=0.80) or IGF-1 (P=0.12), and (4) significantly attenuated the arteriolar response to IGF-1 (maximal relaxation of 79+/-6% versus 42+/-8%; P=0.01) but not insulin (43+/-6% versus 53+/-7%; P=0.99). Control arteriolar vasorelaxation to IGF-1 was attenuated by both L-NMMA (P<0.001) and TEA (P=0.01), whereas only L-NMMA attenuated insulin (P<0.001). Staining for IGF-1 and IGF binding protein 2 was increased (P<0.05) in arterioles of cholesterol-fed pigs. IGF-1 and insulin are therefore coronary arteriolar vasorelaxants through different mechanisms. Experimental hypercholesterolemia is associated with resistance to the coronary arteriolar vasorelaxing effects of IGF-1 but not insulin, in conjunction with increased ligand and binding-protein expression. The IGF axis may contribute to the altered coronary vasoactivity in hypercholesterolemia.

Animals↗
PubMed1998

Usefulness of abciximab for treatment of early coronary artery stent thrombosis.

The clinical and angiographic outcomes of 10 patients who received abciximab as part of their therapy for early stent thrombosis was compared with 25 patients (using historical controls) who received conventional therapy. Although the angiographic outcome and the incidence of myocardial infarction in both groups was similar, there were no deaths or referral for emergency coronary bypass surgery in the abciximab-treated group versus 3 deaths and 10 referrals for emergency bypass surgery in the conventionally treated group.

Abciximab↗
PubMed1998

Abciximab administration and outcome after intracoronary stent implantation.

Although adjunctive abciximab therapy improves outcome after angioplasty or atherectomy, there are few data demonstrating its benefit for intracoronary stent implantation. We characterized patients receiving abciximab for stent placement in our practice and determined the impact of abciximab on outcome. Abciximab was introduced to our practice in April 1995 for percutaneous revascularization. Demographic, clinical, and angiographic variables that were independently associated with the use of abciximab for stent placement through 1996 (abciximab era) were examined. We then examined among all patients receiving stents from 1992 through 1996 (preabciximab and abciximab eras) whether the use of abciximab was independently associated with improved outcome (death, nonfatal Q-wave myocardial infarction, coronary bypass surgery, or target vessel percutaneous revascularization) in the hospital and at 30 days. The 30-day event rate was 7% for those who did or did not receive abciximab. The following characteristics were independently associated with the use of abciximab for stent placement in the abciximab era: thrombus before stent placement (chi-square 50.5), > or =2 stents implanted (chi-square 10.8), stent in venous graft (chi-square 7.4), calcific lesion (chi-square 5.8), and hypertension (chi-square 5.5). Among all patients receiving stents in the preabciximab and abciximab eras (n=1,859), the presence of these characteristics was independently associated with worse outcome. Abciximab, however, did not improve outcome in the hospital (odds ratio [95% confidence interval]=0.96 [0.58 to 1.58]) or at 30 days (0.87 [0.53 to 1.41]), even after adjusting for these characteristics. Abciximab for stent placement was used in high-risk patients in our practice but was not associated with improved outcome.

Abciximab↗
PubMed1998

Effect of basal epicardial tone on endothelium-independent coronary flow reserve measurement.

Increased basal epicardial tone may attenuate the coronary flow reserve (CFR) by causing vasodilatation of resistance vessels. We examined the effect of basal epicardial tone on the endothelium-independent CFR measurements in subjects with nonobstructive coronary disease. Patients underwent evaluation of endothelium-independent CFR using adenosine (18-36 microg) and endothelium-dependent CFR using acetylcholine (10(-6) M-10(-4) M), both administered intracoronary. CFR to adenosine, presented as the ratio of Doppler flow velocities post- and pre-adenosine, was measured at baseline and after intracoronary nitroglycerin (200 microg). Nitroglycerin increased the coronary artery diameter by 19.7 +/- 2.5%, and decreased the coronary vascular resistance from 3.0 +/- 0.2 mm Hg/ml/min to 1.8 +/- 0.1 mm Hg/ml/min (p < 0.0001). The response to adenosine at baseline and after nitroglycerin was similar (CFR ratio of 2.52 +/- 0.09 and 2.57 +/- 0.10, respectively, p = NS). The effect of nitroglycerin on the response to adenosine did not correlate with coronary endothelial function (r2 = 0.06, p = 0.13). The basal epicardial tone does not affect CFR measurements in patients with angina and nonobstructive coronary disease.

Acetylcholine↗
PubMed1998

Insulin and IGF-I attenuate the coronary vasoconstrictor effects of endothelin-1 but not of sarafotoxin 6c.

OBJECTIVE: To examine the hypothesis that insulin and insulin-like growth factor I (IGF-I) attenuate endothelin-induced contraction of porcine coronary epicardial arteries in vitro. BACKGROUND: Endothelin-induced coronary vasoconstriction is mediated by two types of receptors, A (ETA) and B (ETB), resulting in calcium influx. Both insulin and IGF-I attenuate endothelin-induced calcium influx into porcine coronary artery smooth muscle. METHODS: Epicardial arteries harvested from juvenile pigs were contracted with cumulative concentrations of endothelin-1 (ETA- and ETB-receptor agonist; 10(-10)-10(-6) M) or of sarafotoxin-6c (ETB-receptor agonist; 10(-11)-10(-7) M). In additional experiments, endothelin-1 or sarafotoxin-6c were added after incubation with 10(-8) M regular insulin or IGF-I. These experiments were repeated in vessels without endothelium. Contraction for each vessel was calculated relative to the response to 60 mM KCl. RESULTS: The maximal contractions to endothelin-1 in vessels with and without endothelium were 158 +/- 8 and 200 +/- 21%, respectively (p < 0.05 at 10(-8.5)-10(-6.5) M). Both insulin (at 10(-7)-10(-6) M) and IGF-I (at 10(-6.5)-10(-6) M) attenuated the contraction to endothelin-1 in vessels with intact endothelium, as well as in vessels without endothelium (at 10(-7) and 10(-6) M for insulin and 10(-7.5)-10(-6) M for IGF-I). The maximal contractions to sarafotoxin-6c in vessels with and without endothelium were 54 +/- 13 and 84 +/- 7%, respectively (p < 0.05 at 10(-9), 10(-8.5) and 10(-7) M). Insulin and IGF-I did not affect the response to sarafotoxin-6c in vessels with and without endothelium. CONCLUSION: Insulin and IGF-I attenuated ETA-receptor-mediated coronary contraction through an endothelium-independent mechanism. The IGF axis may serve as an endogenous modulator of endothelin-mediated vasoconstriction.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1998

Early development of high-degree atrioventricular block in inferior acute myocardial infarction is predicted by a J-point/R-wave ratio above 0.5 on admission.

This study assessed the ability of simple clinical and electrocardiographic (ECG) variables routinely obtained on admission to identify patients with inferior myocardial infarction who are at high risk of developing high-degree atrioventricular (AV) block within the first 24 h of hospitalization in 205 patients. The admission ECGs were classified into two patterns based on the J-point to R-wave amplitude ratio: pattern 1: those with J-point/R-wave ratio <0.5; pattern 2: patients with J-point/R-wave ratio >/=0.5 in >/=2 inferior leads (II, III and aVF). High-degree AV block was found in 10.2% of the patients (21 of 205 patients; 5 and 16% of the patients with initial patterns 1 and 2, respectively, p = 0.014). Multivariate logistic regression analysis revealed that the only variables independently associated with high-degree AV block were the initial ECG pattern 2 versus 1 (odds ratio, OR, 4.47, 95% confidence interval, CI, 1.18-16.9; p = 0.0276), age (OR 1.06, 95% CI 1.01-1.12; p = 0.0254); Killip class >1 (OR 2.33, CI 0.83-6. 54; p = 0.1065) and thrombolytic therapy (OR 0.32, 95% CI 0.11-0.93; p = 0.037).

Adult↗
PubMed1998

Acute endothelin-receptor inhibition does not attenuate acetylcholine-induced coronary vasoconstriction in experimental hypercholesterolemia.

Endothelin (ET) may mediate the enhanced coronary vasoconstriction associated with hypercholesterolemia. We hypothesized that short-term inhibition of ET receptors attenuates the coronary epicardial vasoconstrictor response to acetylcholine in experimental hypercholesterolemia. ET-1 (group I, n=5; 5 ng x kg[-1] x min[-1]) and acetylcholine (group III, n=7; 10[-6] to 10[-4] mol/L) were given by intracoronary infusion in pigs. ET-1 and acetylcholine were also infused with the specific ETA-receptor blocker FR-139317 (5 microg x kg[-1] x min[-1]; group II, n=6; group IV, n=6). Acetylcholine was also infused with the combined ET-receptor blocker, bosentan (0.5 mg/kg plus 1 mg x kg[-1] x h[-1], group V, n=5). The ETB-receptor agonist sarafotoxin 6c (5 ng x kg[-1] x min[-1]; n=4) was also infused. The percentage change in coronary artery diameter (%deltaCAD) to the infusions was measured at baseline and after 10 weeks of high-cholesterol diet in all animals. Sarafotoxin 6c mildly reduced %deltaCAD at baseline and 10 weeks (-10+/-2% and -12+/-3%, respectively). FR-139317 did not attenuate the epicardial vasoconstrictor response to ET-1 at baseline (%deltaCAD -18+/-8% for group I versus -12+/-6% for group II; P=NS) but did at 10 weeks (%deltaCAD -77+/-14% for group I versus -14+/-6% for group II; P<.05). FR-139317 did not affect the response to acetylcholine at baseline (%deltaCAD 5+/-2% for group III versus 7+/-3% for group IV, P=NS) or at 10 weeks (%deltaCAD -23+/-12% for group III versus -19+/-7% for group IV; P=NS). Bosentan did not affect the response to acetylcholine at baseline or 10 weeks. Short-term ET-receptor inhibition in experimental hypercholesterolemia attenuated the enhanced coronary epicardial vasoconstrictor effects of ET-1 but not acetylcholine-induced coronary epicardial vasoconstriction, suggesting that acetylcholine-induced coronary epicardial vasoconstriction may not be mediated by ET receptors.

Acetylcholine↗
PubMed1998

Insulin and insulin-like growth factor-I cause coronary vasorelaxation in vitro.

Insulin and insulin-like growth factor-I (IGF-I) may play a role in the modulation of coronary artery tone, yet there are few data regarding their vasoactive effects on the coronary vascular bed. We evaluated the vasorelaxation effects of insulin and IGF-I on porcine coronary epicardial vessels in vitro and elucidated possible mechanisms. Porcine epicardial arteries were contracted with 10(-7) mol/L endothelin-1 and relaxed with cumulative concentrations of either insulin or IGF-I (10(-12) to 10(-7) mol/L). The above experiments were repeated in vessels without endothelium. Vessels were also incubated with the nitric oxide synthase inhibitor NG-monomethyl-L-arginine (L-NMMA; 10(-4) mol/L) with and without 10(-3.5) mol/L L-arginine, the potassium channel blocker tetraethylammonium (TEA; 10(-2) mol/L), and the guanylyl cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3,-alpha]quinoxalin-1-one (ODQ; 10(-5.5) mol/L); vessels were then contracted with endothelin-1 and relaxed with insulin or IGF-I. Insulin and IGF-I were also added after contraction with 60 mmol/L KCl. Insulin and IGF-I caused a similar decrease in coronary epicardial tension after contraction with endothelin-1 (relaxation of 28+/-4% [n=7] and 25+/-3% [n=8] with insulin and IGF-I, respectively; P<0.0001 for both peptides). Removal of the endothelium did not affect these responses. Incubation with L-NMMA, but not ODQ, attenuated the vasorelaxation response to insulin and IGF in vessels without endothelium. L-Arginine did not reverse this effect of L-NMMA. KCl and TEA attenuated the vasorelaxation effect of both insulin and IGF-I. Thus, both insulin and IGF-I caused non-endothelium-dependent coronary vasorelaxation in vitro, probably through a mechanism involving the activation of potassium channels. These findings suggest that insulin and IGF-I participate in the regulation of coronary vasomotor tone.

Animals↗
PubMed1998

Prevalence of coronary blood flow reserve abnormalities among patients with nonobstructive coronary artery disease and chest pain.

OBJECTIVE: To determine the prevalence of abnormalities in endothelium-dependent and endothelium-independent coronary flow reserve among patients with non-obstructive coronary artery disease and chest pain. MATERIAL AND METHODS: We studied endothelium-dependent (after infusion of 10(-6) M to 10(-4) M of acetylcholine) and endothelium-independent (after administration of 18 to 36 micrograms of adenosine) coronary flow reserve among patients with nonobstructive coronary artery disease and chest pain who were undergoing assessment at Mayo Clinic Rochester. Coronary blood flow was derived from coronary artery diameter assessed by quantitative angiography and Doppler flow velocities. RESULTS: The cohort consisted of 203 patients (158 female and 45 male patients), who ranged in age from 17 to 78 years (mean, 51). Most patients (92%) had at least one risk factor for atherosclerosis; a substantial proportion had undergone extensive cardiac and noncardiac evaluation. Whereas 41.5% of the patients had normal coronary flow reserve, 58.5% had an abnormal response: 11.3% an impaired response to adenosine (flow velocity ratio of 2.5 or less), 29.2% an impaired response to acetylcholine (flow reserve ratio of 1.5 or less), and 18% a combined abnormality. No correlation (r2 = 0.03) was noted between endothelium-dependent and endothelium-independent flow reserve. CONCLUSION: Most study patients with chest pain and nonobstructive coronary artery disease undergoing coronary vasomotor evaluation had risk factors for coronary artery disease and diverse abnormalities in endothelium-dependent or endothelium-independent coronary flow reserve (or both). These findings underscore the need for a comprehensive assessment.

Acetylcholine↗