GPER modulates tone and coronary vascular reactivity in male and female rats

Compared with age-matched men, premenopausal women are largely protected from coronary artery disease, a difference that is lost after menopause. The effects of oestrogens are mediated by the activation of nuclear receptors (ERα and ERβ) and by the G protein-coupled oestrogen receptor (GPER). This study aims to evaluate the potential role of GPER in coronary circulation in female and male rats. The baseline coronary perfusion pressure (CPP) and the concentration–response curve with a GPER agonist (G-1) were evaluated in isolated hearts before and after the blockade of GPER. GPER, superoxide dismutase (SOD-2), catalase and gp91phox protein expression were assessed by Western blotting. Superoxide production was evaluated ‘in situ’ via dihydroethidium fluorescence (DHE). GPER blockade significantly increased the CPP in both groups, demonstrating the modulation of coronary tone by GPER. G-1 causes relaxation of the coronary bed in a concentration-dependent manner and was significantly higher in female rats. No differences were detected in GPER, SOD-2 and catalase protein expression. However, gp91phox expression and DHE fluorescence were higher in male rats, indicating elevated superoxide production. Therefore, GPER plays an important role in modulating coronary tone and reactivity in female and male rats. The observed differences in vascular reactivity may be related to the higher superoxide production in male rats. These findings help to elucidate the role of GPER-modulating coronary circulation, providing new information to develop a potential therapeutic target for the treatment of coronary heart disease.

Sufentanil attenuates impairment of the endothelium-dependent vasodilation induced by hypoxia–reoxygenation in the rat coronary artery

Sufentanil has been used broadly in cardiac surgery, but the mechanisms by which it modulates coronary vascular tone after ischemia–reperfusion injury are largely unknown. Effects of sufentanil on coronary tone and on the relaxation of rat coronary arteries (CAs) in response to endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) relaxing agents in the presence of hypoxia–reoxygenation (H/R) was studied in an in vitro organ chamber setup. Sufentanil (10−7–10−4 mol/L) relaxed rat CA rings in endothelium-dependent and endothelium-independent manners. In endothelium-intact rings, preincubation of H/R-treated CAs with sufentanil (10−5 mol/L) significantly increased the acetylcholine response, but did not augment sodium nitroprusside-induced relaxation. Sufentanil-mediated potentiation of acetylcholine-induced relaxation was not affected by a nitric oxide synthase inhibitor or by intermediate- or small-conductance Ca2+-activated K+ channel blockers. However, potentiation was abolished by iberiotoxin (100 nmol/L), a selective inhibitor of large-conductance Ca2+-activated K+ channels, as well as Rp-cAMPS (30 μmol/L), a cyclic AMP-dependent protein kinase (PKA) inhibitor. Sufentanil induced endothelium-dependent and endothelium-independent relaxation and attenuated H/R-induced impairment of endothelium-dependent vasodilation in the rat CAs. The potentiating effect of sufentanil may involve activation of large-conductance Ca2+-activated K+ channels via cAMP-dependent mechanisms.

Quantitative analysis of exercise-induced enhancement of early- and late-systolic retrograde coronary blood flow

Coronary blood flow (CBF) is reduced and transiently reversed during systole via cardiac contraction. Cardiac contractility, coronary tone, and arterial pressure each influence systolic CBF (CBFSYS), particularly by modulating the retrograde component of CBFSYS. The effect of concurrent changes in these factors on CBFSYS during dynamic exercise has not been examined. Using chronically instrumented swine, we hypothesized that dynamic exercise enhances retrograde CBFSYS. Phasic CBF was examined at rest and during treadmill exercise [2–5 miles/h (mph)]. Absolute values of mean CBF over the cardiac cycle (CBFCYCLE) as well as mean CBF in diastole (CBFDIAS) and mean CBFSYS were increased by exercise, while relative CBFDIAS and CBFSYS expressed as percentage of mean CBFCYCLE were principally unchanged. Early retrograde CBFSYS was present at rest and increased in magnitude (−33 ± 4 ml/min) and as a percent of CBFCYCLE (−0.6 ± 0.1%) at 5 mph. This reversal was transient, comprising 3.7 ± 0.3% of cardiac cycle duration at 5 mph. Our results also reveal that moderately intense exercise (>3 mph) induced a second CBF reversal in late systole before aortic valve closure. At 5 mph, late retrograde CBFSYS amounted to −53 ± 11 ml/min (−3.1 ± 0.7% of CBFCYCLE) while occupying 11.1 ± 0.3% of cardiac cycle duration. Wave-intensity analysis revealed that the second flow reversal coincided with an enhanced aortic forward-going decompression wave (vs. rest). Therefore, our data demonstrate a predictable increase in early-systolic CBF reversal during exercise and additionally that exercise induces a late-systolic CBF reversal related to the hemodynamic effects of left ventricular relaxation that is not predictable using current models of phasic CBF.

Effect of hyperoxia and vitamin C on coronary blood flow in patients with ischemic heart disease

Pathological formation of reactive oxygen species within the coronary circulation has been hypothesized to mediate some clinical manifestations of ischemic heart disease (IHD) by interfering with physiological regulation of coronary tone. To determine the degree to which coronary tone responds to acute changes in ambient levels of oxidants and antioxidants in vivo in a clinical setting, we measured the effect of an acute oxidative stress (breathing 100% oxygen) on coronary capacitance artery diameter (quantitative angiography) and blood flow velocity through the coronary microcirculation (intracoronary Doppler ultrasonography) before and after treatment with the antioxidant vitamin C (3-g intravenous infusion) in 12 IHD patients undergoing a clinical coronary interventional procedure. Relative to room air breathing, 100% oxygen breathing promptly reduced coronary blood flow velocity by 20% and increased coronary resistance by 23%, without significantly changing the diameter of capacitance arteries. Vitamin C administration promptly restored coronary flow velocity and resistance to a slightly suprabasal level, and it prevented the reinduction of coronary constriction with rechallenge with 100% oxygen. This suggests that acute oxidative stress produces prompt and substantial changes in coronary resistance and blood flow in a clinical setting in patients with IHD, and it suggests that these changes are mediated by vitamin C-quenchable substances acting on the coronary microcirculation. This observation may have relevance for clinical practice.

KCa+ channels contribute to exercise-induced coronary vasodilation in swine

Coronary blood flow is controlled via several vasoactive mediators that exert their effect on coronary resistance vessel tone through activation of K+ channels in vascular smooth muscle. Because Ca2+-activated K+ (KCa+) channels are the predominant K+ channels in the coronary vasculature, we hypothesized that KCa+ channel activation contributes to exercise-induced coronary vasodilation. In view of previous observations that ATP-sensitive K+ (KATP+) channels contribute, in particular, to resting coronary resistance vessel tone, we additionally investigated the integrated control of coronary tone by KCa+ and KATP+ channels. For this purpose, the effect of KCa+ blockade with tetraethylammonium (TEA, 20 mg/kg iv) on coronary vasomotor tone was assessed in the absence and presence of KATP+ channel blockade with glibenclamide (3 mg/kg iv) in chronically instrumented swine at rest and during treadmill exercise. During exercise, myocardial O2 delivery increased commensurately with the increase in myocardial O2 consumption, so that myocardial O2 extraction and coronary venous Po2 ([Formula: see text]) were maintained constant. TEA (in a dose that had no effect on KATP+ channels) had a small effect on the myocardial O2 balance at rest and blunted the exercise-induced increase in myocardial O2 delivery, resulting in a progressive decrease of [Formula: see text] with increasing exercise intensity. Conversely, at rest glibenclamide caused a marked decrease in [Formula: see text] that waned at higher exercise levels. Combined KCa+ and KATP+ channel blockade resulted in coronary vasoconstriction at rest that was similar to that caused by glibenclamide alone and that was maintained during exercise, suggesting that KCa+ and KATP+ channels act in a linear additive fashion. In conclusion, KCa+ channel activation contributes to the metabolic coronary vasodilation that occurs during exercise. Furthermore, in swine KCa+ and KATP+ channels contribute to coronary resistance vessel control in a linear additive fashion.