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Selective attenuation of endothelium-mediated vasodilation in atherosclerotic human coronary arteries
U Förstermann1, A Mügge, U Alheid
1Department of Clinical Pharmacology, Hannover Medical School, Federal Republic of Germany.
Insights
Atherosclerosis impairs endothelium-derived relaxing factor (EDRF) mediated relaxations in human coronary arteries, contributing to vasospasm and myocardial ischemia.
Area of Science:
- Cardiovascular Science
- Vascular Biology
- Pathophysiology
Background:
- Coronary artery disease (atherosclerosis) is a leading cause of mortality.
- Endothelium-derived relaxing factor (EDRF) plays a crucial role in regulating vascular tone.
- Impaired EDRF function is implicated in the pathogenesis of atherosclerosis.
Purpose of the Study:
- To investigate the impact of atherosclerosis on EDRF-mediated relaxations in human coronary arteries.
- To compare vascular responses in atherosclerotic versus non-atherosclerotic coronary arteries.
- To elucidate the role of EDRF in atherosclerosis-related vascular dysfunction.
Main Methods:
- Human epicardial coronary arteries from transplant patients (atherosclerotic vs. non-atherosclerotic) were used.
- Isometric tension recordings were performed in organ baths.
- Relaxation responses to EDRF-dependent (substance P, bradykinin, A23187) and independent (isoprenaline, glyceryl trinitrate) agonists were assessed.
Main Results:
- EDRF-mediated relaxations were significantly attenuated in atherosclerotic arteries compared to non-atherosclerotic arteries.
- Endothelium-independent relaxations to isoprenaline were unaffected by atherosclerosis.
- Atherosclerotic arteries showed altered responses to glyceryl trinitrate and inconsistent responses to acetylcholine.
Conclusions:
- Atherosclerosis impairs EDRF-mediated relaxations in human coronary arteries.
- This impairment contributes to vascular dysfunction, potentially leading to vasospasm and myocardial ischemia.
- Targeting EDRF pathways may offer therapeutic potential in managing atherosclerosis.
Abstract:
This study was undertaken to determine whether atherosclerosis impairs relaxations mediated by endothelium-derived relaxing factor (EDRF) in human coronary arteries. Epicardial coronary arteries were obtained from the hearts of cardiac transplantation patients with or without histologically documented coronary atherosclerosis (atherosclerotic arteries were from patients aged 42-55 years, nonatherosclerotic arteries were from patients aged 14-24 years). Transverse strip preparations were mounted in organ baths for isometric tension recording. Tension was induced with prostaglandins F2 alpha. Indomethacin (10(-5) M) was present to prevent possible interference from endogenously formed prostaglandins. The EDRF-mediated relaxations in response to substance P (10(-10) to 10(-8) M), bradykinin (10(-9) to 10(-7) M), and Ca2+-ionophore A23187 (10(-9) to 10(-7) M) were significantly attenuated in atherosclerotic arteries. In deendothelialized tissues these compounds had no effect. In contrast, endothelium-independent relaxations induced by isoprenaline (10(-7) to 10(-5) M) were not affected by atherosclerosis. Atherosclerotic arteries showed also normal relaxations with high concentrations of glyceryl trinitrate (10(-8) to 10(-7) M), but reduced relaxations with a lower concentration of the compound (10(-9) M). Acetylcholine (10(-7) to 10(-6) M) only produced endothelium-dependent relaxations in 8 of 60 arterial preparations (with or without atherosclerosis). In most of the arteries, it was a direct vasoconstrictor (which may have masked EDRF release in many cases). Omission of indomethacin from the bath solution increased the incidence of moderate acetylcholine-induced relaxations (9 of 16 preparations). It is concluded that atherosclerosis attenuates EDRF-mediated vasospasm and myocardial ischemia.