Ginkgo biloba extract improves coronary blood flow in patients with coronary artery disease: role of endothelium-dependent vasodilation

Ginkgo biloba extract (GBE) has well-documented cardioprotective effects on coronary flow and positive effects on vasodilation through endothelium-derived nitric oxide in experimental animals, but these impacts in patients with coronary artery disease (CAD) have not yet been investigated. We designed this study to test the effects of GBE on distal left anterior descending coronary artery (LAD) blood flow and endothelium-dependent brachial artery flow-mediated dilation (FMD) in patients with CAD. Eighty CAD patients were randomly assigned to either GBE or saline (control) groups. LAD blood flow and brachial artery FMD were measured non-invasively using high-resolution ultrasound before and after intravenous administration of GBE or saline. GBE significantly increased LAD blood flow in maximal diastolic peak velocity (MDPV), maximal systolic peak velocity (MSPV) and diastolic time velocity integral (DTVI) compared with the control group (16.14 +/- 10.93 % vs. 0.28 +/- 2.14 %, 9.14 +/- 8.23 % vs. 0.79 +/- 2.56 %, and 15.23 +/- 7.28 % vs. 0.42 +/- 2.43 %, respectively, p < 0.01). Brachial artery FMD was also increased by 69.75 % (from 3.95 +/- 1.49 % to 6.55 +/- 2.51 %, p < 0.01). A linear correlation was found between the percentage changes in MDPV, MSPV, or DTVI of LAD blood flow and the percentage change in brachial artery FMD following treatment with GBE (r = 0.612, 0.486, or 0.521, respectively, p < 0.01). In summary, our data demonstrate that GBE treatment in CAD patients leads to an increase of LAD blood flow in MDPV, MSPV and DTVI, and the increase response might relate to the improved endothelium-dependent vasodilatory capacity. CAD: coronary artery disease DTVI: diastolic time velocity integral FMD: flow-mediated dilation GBE: GINKGO BILOBA extract LAD: distal left anterior descending coronary artery MDPV: maximal diastolic peak velocity MSPV: maximal systolic peak velocity NO: nitric oxide TTDE: transthoracic Doppler echocardiography.     

Pharmacologic inhomogeneity between the reactivity of intramural coronary arteries and arterioles

We hypothesized that because of their size, anatomic location, and hemodynamic function, coronary arteries and arterioles would respond differently to vasoactive substances. Intramural arteries (281.7 +/- 23.1 microm) and arterioles (77.3 +/- 6.6 microm) of the left anterior descending coronary of rats were isolated and cannulated. Spontaneous tone was lower in arteries than in arterioles (81.1 +/- 5.7 vs. 53.0 +/- 3.9% of passive diameter, p < 0.05 at 60 mm Hg intraluminal pressure). Arterial tone was adjusted by the thromboxane receptor agonist U46619 (5 x 10(-8) M ) to reach an active tone close to that of arterioles. Bradykinin elicited dilations in both types of vessels. Acetylcholine (10(-6) - 10(-5) M ) dilated arteries (by 42.6 +/- 11.5 microm) but constricted arterioles (by 16.4 +/- 9.3 microm). Sodium nitroprusside and adenosine elicited significantly greater dilations in arterioles than in arteries (by 7.9 and 11.9%, respectively, p < 0.05), whereas dilations to norepinephrine were similar. Inhibition of nitric oxide synthesis caused a significantly smaller constriction in arteries (10.2 +/- 3.31%) than in arterioles (31.6 +/- 6.9%) and completely blocked bradykinin-and acetylcholine-induced dilations, whereas it did not affect dilations to sodium nitroprusside, adenosine, and norepinephrine. Compared with arteries, arterioles have a greater spontaneous tone and enhanced nitric oxide modulation of basal tone and exhibit greater responsiveness to nitric oxide and adenosine. In addition, nitric oxide synthase is activated differently by pharmacologic stimuli in these segments. The qualitative and quantitative differences among vasoactive responses of coronary arteries and arterioles demonstrated in this study suggest segment-specific roles for endothelial and metabolic factors in regulation of coronary vascular resistance.     

Human urotensin-II is an endothelium-dependent vasodilator in rat small arteries

The possible role of the endothelium in modulating responses to human urotensin-II (U-II) was investigated using isolated segments of rat thoracic aorta, small mesenteric artery, left anterior descending coronary artery and basilar artery. Human U-II was a potent vasoconstrictor of endothelium-intact isolated rat thoracic aorta (EC(50)=3.5+/-1.1 nM, R(max)=103+/-10% of control contraction induced by 60 mM KCl and 1 microM noradrenaline). However the contractile response was not significantly altered by removal of the endothelium or inhibition of nitric oxide synthesis with L-NAME (100 microM). Human U-II did not cause relaxation of noradrenaline-precontracted, endothelium-intact rat aortae. Human U-II contracted endothelium-intact rat isolated left anterior descending coronary arteries (EC(50)=1.3+/-0.8 nM, R(max)=20.1+/-4.9% of control contraction induced by 10 microM 5-HT). The contractile response was significantly enhanced by removal of the endothelium (R(max)=55.4+/-16.1%). Moreover, human U-II caused concentration-dependent relaxation of 5-HT-precontracted arteries, which was abolished by L-NAME or removal of the endothelium. No contractile effects of human U-II were found in rat small mesenteric arteries. However the peptide caused potent, concentration- and endothelium-dependent relaxations of methoxamine-precontracted vessels. The relaxant responses were potentiated by L-NAME (300 microM) but abolished in the additional presence of 25 mM KCl (which inhibits the actions of endothelium-derived hyperpolarizing factor). The present study is the first to show that human U-II is a potent endothelium-dependent vasodilator in some rat resistance vessels, and acts through release of EDHF as well as nitric oxide. Our findings have also highlighted clear anatomical differences in the responses of different vascular beds to human U-II which are likely to be important in determining the overall cardiovascular activity of this peptide.     

Nitric oxide and prostaglandins modulate pressure-induced myogenic responses of intramural coronary arterioles

The myogenic response, an active constriction and dilation of vessels to changes in intravascular pressure, can play an important role in the regulation of coronary blood flow. The characteristics of the myogenic response and its modulation by endothelium-derived factors are organ and location specific and have not been studied extensively in intramural coronary arterioles. Thus, distal intramural branches (approximately 100 and approximately 170 microm active and passive diameter, respectively) of the left anterior descending coronary artery of rats were isolated and cannulated. Step increases in intraluminal pressure from 0 to 40 mm Hg elicited increases in diameter, whereas further increases in pressure from 50 to 150 mm Hg resulted in constrictions. In control, the pressure-induced myogenic tone of coronary arterioles was 67.3 +/- 2.7% of passive diameter (PD, obtained in Ca2+-free solution) at 60 mm Hg. Nomega-nitro-L-arginine (L-NNA, 10(-5) M), an inhibitor of nitric oxide synthase, reduced the initial arteriolar diameter (by 44.8 +/- 5.1 microm at 2 mm Hg, P < 0.05) and significantly mitigated increases in diameter to lower pressures and constrictions to higher pressures (41.1 +/- 5.6% of PD at 60 mm Hg). Administration of adenosine restored the initial diameter in the presence of l-NNA, but the increase in diameter to lower pressures and the decrease in diameter to higher pressures observed under control conditions remained greatly inhibited. Inhibition of prostaglandin synthesis, or PGH2/TxA2 receptors significantly reduced the constrictions to higher pressures as compared with control (indomethacin: from 57.9 +/- 4.8% of PD to 67.0 +/- 4.7% of PD at 150 mm Hg). Thus, because in isolated intramural coronary arterioles of rats a negative slope for the pressure-diameter curve develops only in the presence of nitric oxide and constrictor prostaglandins, they seem to be essential for the normal development of the myogenic response.     

内皮素—1促进猪冠状动脉再生内皮释放内皮衍生内过氧化物和血栓素A2

AIM: To determine the role of endothelium-derived contracting factor (EDCF) in the response to endothelin-1 in arteries with regenerated endothelium. METHODS: Rings of porcine coronary arteries, with and without endothelium of previously deendothelialized left anterior descending coronary arteries and native left circumflex coronary arteries, were suspended in conventional organ chambers for the measurement of isometric force. RESULTS: In quiescent rings of the previously deendothelialized left anterior descending coronary artery treated with the NO-synthase inhibitor nitro-L-arginine, endothelin-1 caused contractions which were larger in rings with than that in those without endothelium. Under the same experimental conditions, in the left circumflex coronary artery, the contractions to endothelin-1 were augmented markedly by the removal of the endothelium. In rings with endothelium of the previously deendothelialized left anterior descending coronary artery, indometacin (inhibitor of cyclooxygenase) and ridogrel (thromboxane A2 receptor antagonist and inhibitor of thromboxane synthase) inhibited contractions to endothelin-1. Dazoxiben (inhibitor of thromboxane synthase) inhibited, to the same extent as indometacin and ridogel, the response to higher concentrations of endothelin-1. The endothelium-dependent component of the response to lower concentrations of endothelin-1 was inhibited by indometacin and ridogrel, but not by dazoxiben. In rings without endothelium of both previously deendothelialized left anterior descending and native left circumflex coronary arteries, indometacin and ridogrel did not affect the contractions to endothelin-1. CONCLUSION: These findings suggest that in regenerated endothelium, high concentrations of endothelin-1 stimulate the release of thromboxane A2. Endoperoxides generated by activation of endothelial cyclooxygenase may be the endothelium-derived contracting factor(s) released in regenerated endothelium by lower concentrations of the peptide.     

内皮素-1促进猪冠状动脉再生内皮释放内皮衍生内过氧化物和血栓素A_2(英文)

AIM: To determine the role of endothelium-derivedcontracting factor (EDCF) in the response toendothelin-1 in arteries with regenerated endothelium.METHODS: Rings of porcine coronary arteries, withand without endothelium of previously deendothelializedleft anterior descending coronary arteries and native leftcircumflex coronary arteries, were suspended inconventional organ chambers for the measurement ofisometric force. RESULTS: In quiescent rings of thepreviously deendothelialized left anterior descending     

Prostaglandin E1 and nitroglycerin effects on canine epicardial conductance and distal coronary resistance vessels

Prostaglandin E1 (PGE1) has been reported to be a coronary vasodilator and has been considered clinically in the treatment of coronary vasospasm, but its mechanism of action is not known. To evaluate the vasomotor effect of PGE1, epicardial coronary and distal resistance vessel responses were compared by PGE1 and nitroglycerin infusion into the left anterior descending (LAD) artery of the closed-chest dog. Coronary angiography and 133Xe washout flow measurements were used to quantitate proximal and distal vessel responses, respectively. To evaluate potential inhibitory actions, vessels were contracted by continuous LAD infusion of prostaglandin F2 alpha (PGF2 alpha) or serotonin before dose-response testing with PGE1 or nitroglycerin. PGE1 alone produced a 20% dilation of the LAD in vivo but only with the highest dose (2.0 micrograms/min). PGE1, however, did not reverse epicardial vessel constriction induced by PGF2 alpha or serotonin. LAD flows (resistance vessel response) were increased comparably by PGE1 alone and with PGF2 alpha added (100 and 93% above control flow, respectively) but to a lesser extent with serotonin added (57% above control). In contrast, nitroglycerin completely reversed epicardial artery constrictions induced by PGF2 alpha and serotonin. Our findings indicate that although PGE1 is a vasodilator in vivo, it does not demonstrate a major effect in dilating epicardial conductance coronary arteries and therefore may not be beneficial in antagonizing endogenous contractile factors in treatment of coronary vasospasm. PGE1 does increase coronary blood flow by dilating distal resistance vessels. The beneficial effects of PGE1 in humans with unstable angina therefore are probably not due to vasorelaxing effects on epicardial coronary conductance arteries.     

Restoration of flow-dependent coronary dilation by ACE inhibition improves papaverine-induced maximal coronary blood flow in hypertensive patients: demonstration that large epicardial coronary arteries are more than conductance vessels

Restoration of flow-dependent coronary artery dilation by angiotensin-converting enzyme inhibition (ACEI) has been demonstrated in patients with hypertension. The aim of the present study was to evaluate whether dilation of conductance coronary arteries may alter maximal coronary blood flow (CBFmax) and minimal coronary resistance (CRmin) in hypertensive patients with reversible impairment of flow-dependent coronary artery dilation. Thirteen hypertensive patients with angiographically normal coronary arteries and no other risk factors were studied. Cross-sectional areas (CSAs) of proximal and distal left anterior descending (LAD) coronary arteries were determined by quantitative angiography. Coronary flow velocity was recorded in the distal LAD with an intracoronary Doppler catheter. Estimates of coronary blood flow and resistance were calculated at rest and during maximal increase in blood flow induced by papaverine injected in the midportion of the LAD, both before and after ACEI. Flow-dependent dilation of the proximal LAD, abolished before ACEI, was restored after (26.7 +/- 11.2%; p < 0.001). The increase in CSA of the distal LAD exposed to papaverine was significantly higher after ACEI than before (from 33.4 +/- 20.5% to 51.5 +/- 23.4%; p < 0.001). After restoration of proximal LAD flow-dependent dilation, CBFmax was increased by +21.0 +/- 10.3% (p < 0.001), and CRmin was reduced by 19.3 +/- 9.5% (p < 0.001). Thus, dilation of epicardial coronary arteries participates substantially in the coronary resistance in hypertensive patients. Restoration of flow-dependent coronary artery dilation by ACEI may improve the ability of coronary circulation to deliver its maximal myocardial blood flow in hypertensive patients.     

Flow-dependent, endothelium-mediated dilation of epicardial coronary arteries in conscious dogs: effects of cyclooxygenase inhibition

Endothelial damage or removal abolishes the dilation of epicardial coronary arteries induced by increments in flow through these arteries in vitro. Therefore, we tested whether or not the release of a cyclooxygenase product from endothelial cells in vivo is the mechanism of this flow-dependent dilation. In eight conscious dogs, instrumented to register the external diameter of two epicardial branches--anterior descending and circumflex--of the left coronary artery, increments in coronary flow increased and reductions in coronary flow decreased the diameter of the left circumflex epicardial artery by 182 +/- 11 micron/100% change in flow. When mean coronary flow in one epicardial branch was kept constant by a distal, flow-limiting stenosis during the application of flow-augmenting stimuli (temporal coronary occlusion or 80-400 micrograms/kg adenosine i.v.), no dilation of this artery was observed. Cyclooxygenase inhibition (suppressing the bradykinin-induced elevation of plasma 6-keto-PGF1 alpha) by indomethacin (5 mg/kg) or by diclofenac (10 mg/kg) increased smooth muscle tone in both epicardial arteries, but did not modify the flow-diameter relation (181 +/- 10 and 179 +/- 9 microns/100% change in flow, respectively). It is concluded that a tonic, instantaneous influence of coronary flow on the smooth muscle tone of the epicardial coronary arteries exists in vivo. It is unlikely that prostacyclin or another prostanoid is a mediator of this endothelium-mediated influence of flow on smooth muscle tone.     

Adrenoceptor subtypes involved in the baroreceptor reflex constriction of large coronary arteries in the anaesthetized dog

The baroreceptor reflex was invoked by bilateral occlusion of the carotid arteries in anaesthetized dogs. The effect of bilateral carotid occlusion on the diameter of the left circumflex coronary artery and late diastolic coronary resistance was examined after bilateral vagotomy and antagonism of beta-adrenoceptors and then compared to responses after selective antagonism of alpha 1- and alpha 2-adrenoceptors. In the absence of any change in heart rate, bilateral carotid occlusion decreased coronary artery diameter (-8 +/- 1%) and increased coronary resistance (59 +/- 14%). Prazosin (0.01 mg/kg i.a.), a selective antagonist of alpha 1-adrenoceptors, significantly attenuated the bilateral carotid occlusion-induced changes in coronary artery diameter (-2 +/- 2%) and late diastolic coronary resistance (20 +/- 11%). Selective antagonism of alpha 2-adrenoceptors by the intra-coronary injection of idazoxan (0.05 mg/kg) significantly reduced the bilateral carotid occlusion-induced increase in coronary resistance (14 +/- 12%) but did not affect the large artery constriction (-8 +/- 4%). When injected into the coronary circulation the alpha 1-adrenoceptor agonist phenylephrine constricted both the large artery and the resistance vessels. In contrast B-HT 920, a selective alpha 2-adrenoceptor agonist, constricted the resistance vessels but did not affect large coronary artery tone. The responses to phenylephrine and B-HT 920 were selectively antagonised by prazosin and idazoxan respectively. Reflex activation of the sympathetic nervous system results in constriction of both large coronary arteries and coronary resistance vessels when there is no change in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of pinacidil on myocardial blood flow and infarct size after acute left anterior descending coronary artery occlusion and reperfusion in awake dogs with and without a coexisting left circumflex coronary artery stenosis

To determine whether partial stenosis of a second major coronary artery promoted vasodilator-induced coronary steal and increased infarct size after acute coronary artery occlusion, we produced acute myocardial infarction by 4-h left anterior descending coronary artery occlusion and 20-h reperfusion in awake dogs with and without a mild to moderate stenosis (33-72%) of the proximal left circumflex coronary artery. Dogs were randomized to receive intravenous (i.v.) normal saline or pinacidil, a new antihypertensive agent with a marked coronary dilator property, beginning 40 min after onset of coronary artery occlusion and continuing throughout the occlusion and the first hour of reperfusion. Pinacidil was titrated to decrease mean aortic pressure 25 mm Hg, which resulted in an increase in heart rate (HR), cardiac output (CO), and left ventricular (LV) dP/dt and LVdP/dt/P. Saline infusion had no effects. Blood flows to ischemic and remote myocardium did not differ between dogs with and without coronary stenosis. Pinacidil increased blood flow threefold in normal myocardium, but had no effect on infarct zone myocardial blood flow or infarct size (58 +/- 4% of region at risk vs. 56 +/- 4% in animals receiving normal saline) in dogs without coronary stenosis. In contrast, similar administration of pinacidil in dogs with coronary stenosis reduced infarct size zone myocardial blood flow and increased infarct size (69 +/- 3% vs. 55 +/- 5% in the saline group, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

The effect of urocortin II administration on the coronary circulation and cardiac function in the anaesthetized pig is nitric-oxide-dependent

We planned to determine the primary effects and mechanisms of urocortin II, a member of the corticotrophin-releasing factor (CRF) family highly expressed in the cardiovascular system, on coronary blood flow and myocardial function in vivo. Urocortin II was infused into the left anterior descending coronary artery in 25 anaesthetized pigs whilst measuring haemodynamic variables, coronary blood flow, ventricular dP/dt(max) cardiac output and percentage of segmental shortening. This infusion was repeated after blockade of the autonomic nervous system, nitric-oxide synthase (NOS) or subtype 2 of the CRF receptors. In all experiments changes in heart rate and aortic blood pressure were prevented. Intra-coronary urocortin II increased, within 60 s, coronary blood flow (15+/-3.2%, P<0.05), dP/dt(max) (12.7+/-2.6%, P<0.05), cardiac output (16+/-2.3%, P<0.05) and percentage of segmental shortening (19.8+/-3.8%, P<0.05). Blockade of NOS abolished only the coronary effects whereas blockade of subtype 2 of the CRF receptors abolished all cardiac and coronary effects. It was shown for the first time that urocortin II administration primarily increases coronary blood flow and myocardial function through the release of nitric oxide and activation of subtype 2 of the CRF receptors in the anaesthetized pig. This provides a mechanism through which a local increase of urocortin II levels can help improve a compromised cardiovascular function.     

Enhanced response of pig coronary arteries to endothelin-1 after ischemia-reperfusion. Role of endothelin receptors, nitric oxide and prostanoids

To analyse the coronary effects of endothelin-1 after ischemia-reperfusion, the left anterior descending coronary artery of anesthetized pigs was subjected to 30-min occlusion followed by 60-min reperfusion. Then, rings distal (ischemic arteries) and proximal (control arteries) to the occlusion were taken from this artery and prepared for isometric tension recording. The sensitivity of the contraction in response to endothelin-1 (3 x 10(-10)-3 x 10(-7) M) and the endothelin ET(B) receptor agonist IRL-1620 (3 x 10(-10)-3 x 10(-7) M) was greater in ischemic vessels. The endothelin ET(A) receptor antagonist BQ-123 (10(-7)-3 x 10(-6) M) decreased the sensitivity of the response to endothelin-1 similarly in ischemic and control arteries. The endothelin ET(B) receptor antagonist BQ-788 (10(-6) M), endothelium removal or the inhibitor of nitric oxide synthesis N(omega)-nitro-L-arginine methyl ester (L-NAME 10(-4) M) potentiated the response to endothelin-1 and IRL-1620 in control arteries only. The cyclooxygenase inhibitor meclofenamate (10(-5) M) augmented the maximal response to endothelin-1 in control arteries, and reduced it in ischemic arteries. In precontracted arteries, IRL-1620 (3 x 10(-11)-3 x 10(-10) M) relaxed control but not ischemic arteries, and L-NAME or meclofenamate abolished this relaxation. Therefore, ischemia-reperfusion increases the coronary vasoconstriction in response to endothelin-1 probably due to impairment of endothelin ET(B) receptor-induced release of nitric oxide and prostacyclin, augmentation of the contractile response to activation of endothelin ET(B) receptors, and increased release of vasoconstrictor prostanoids.     

N-nitro L-arginine causes coronary vasoconstriction and inhibits endothelium-dependent vasodilatation in anaesthetized greyhounds.

1. The effect of N-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide biosynthesis, on large coronary artery diameter and coronary blood flow was examined in anaesthetized greyhounds. The effects of L-NNA on the coronary vascular responses to acetylcholine (ACh), glyceryl trinitrate (GTN) and 5-hydroxytryptamine (5-HT) were also assessed. 2. L-NNA (5 mg kg-1), infused into the left circumflex coronary artery, increased systemic mean arterial pressure and decreased the external diameter of the artery. Infusion of L-NNA decreased coronary blood flow in 5 of the 7 dogs tested and increased mean coronary resistance but neither of these effects was statistically significant. There was no change in heart rate. 3. Intra-arterial injection of both ACh (0.01-0.05 micrograms kg-1) and GTN (0.1-0.5 micrograms kg-1) increased large coronary artery diameter and coronary blood flow. Coronary vascular responses to the endothelium-dependent vasodilator ACh were significantly reduced by L-NNA, whereas the responses to the endothelium-independent vasodilator GTN were not significantly affected. 4. 5-HT (0.1 microgram kg-1, injected into the left circumflex coronary artery) decreased coronary artery diameter but increased coronary blood flow. After the administration of L-NNA the 5-HT-induced dilatation of the coronary resistance vessels was significantly attenuated whereas the constriction of the circumflex coronary artery was increased in 3 out of 3 dogs in which diameter could be measured, although the latter effect was not statistically significant. 5. These data indicate that L-NNA causes coronary and systemic vasoconstriction and selectively inhibits endothelium-dependent vasodilatation in the coronary circulation of the anaesthetized greyhound.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of cinepazide, a vasoactive substance, on canine coronary circulation after acute constriction of the left anterior descending coronary artery.

The left anterior descending coronary artery was variably constricted mechanically in nine dogs. Blood flow in the left anterior descending (LAD) and circumflex coronary arteries (CCA), aortic pressure and peripheral, i.e. post-stenotic coronary pressure were measured. Myocardial perfusion was determined from the clearance of radioactive xenon injected at a depth of 7 mm into the underperfused area supplied by the LAD artery. The vasoactive drug 1-(pyrrolidinyl-1-carbonyl)-methyl-4-(3,4,5-tri-methoxycinnamoyl)piperazine-maleate (cinepazide) was given at doses of 5-10 mg/kg by i.v. route. 1. Blood flow in the LAD was decreased stepwise to 50% of its initial value. There was practically no more coronary reserve. After drug injection, diastolic aortic pressure, that normally falls, was kept constant by clamping. Heart rate, perfusion pressure, post-stenotic pressure, and blood flow and resistance in the LAD showed practically no change. In the CCA, blood flow increased significantly (p less than 0.005) and flow resistance decreased (p less than 0.001). 133Xe clearance showed an increased myocardial perfusion (p less than 0.02) in the territory supplied by the LAD artery. 2. The lumen of the LAD was narrowed by 53%, i.e., coronary reserve was decreased. This constriction was followed by no haemodynamic reaction. After injection of cinepazide, mean and diastolic aortic pressure (p less than 0.02) and post-stenotic coronary pressure (p less than 0.005) decreased. Blood flow increased by 41% in the CCA and by 31% in the LAD. Coronary resistance in these vessels decreased (p less than 0.001 and 0.005, respectively). Here, too, the 133Xe clearance curve showed an increase in myocardial perfusion in the territory supplied by the LAD artery (+78%).     

Enhancement of constrictor response of spastic coronary arteries to acetylcholine but not to phenylephrine in patients with coronary spastic angina

This study examined the direct response of smooth muscle of coronary spasm sites to alpha1-adrenergic stimulation in patients with coronary spastic angina. Phenylephrine (1 microM in the coronary circulation, for 5 min), a stimulator of alpha1-adrenoreceptors, was directly infused into coronary arteries with spasm in 10 patients with coronary spastic angina and into normal coronary arteries in 10 control patients. The luminal diameter of epicardial coronary arteries was determined by computer-assisted quantitative angiography. The constrictor response to intracoronary injection of acetylcholine (ACh; 50 microg) was greater in spastic arteries than in control arteries (decrease from baseline, 48+/-2% vs. 12+/-2%, respectively; p<0.001). ACh (50 or 100 microg) induced coronary spasm associated with myocardial ischemia in all of patients with coronary spastic angina but not in any control patients. On the other hand, phenylephrine infusion did not induce coronary spasm in any of patients with coronary spastic angina or in control subjects. The constrictor response to phenylephrine infusion was comparable between spasm and control coronary arteries (decrease from baseline, 11+/-2% vs. 9+/-2%, respectively; p = NS). The results indicate that smooth muscle of spastic coronary arteries does not exhibit enhancement of constrictor response to direct stimulation of alpha1-adrenoreceptor on coronary smooth muscle. There may be receptor-specific enhancement of constrictor response to agonists in smooth muscle of spastic coronary arteries in patients with coronary spastic angina.     

Effect of ouabain on large coronary artery diameter

Cardiac glycosides have previously been shown to constrict small coronary resistance vessels. This study evaluated the effect of a bolus intravenous dose of ouabain (20 micrograms/kg) on large left circumflex coronary arterial diameter measured by sonomicrometry in nine awake chronically instrumented dogs. Between 5 and 10 min after ouabain administration external circumflex coronary diameter decreased (3.87 +/- 0.21 to 3.83 +/- 0.21 mm, p less than 0.05). Twenty minutes after ouabain administration, coronary diameter had returned to control. At the time of the peak decrease in coronary diameter, heart rate had decreased (104 +/- 7 to 82 +/- 7 beats/min, p less than 0.05), circumflex coronary blood flow had decreased (45 +/- 7 to 38 +/- 6 ml/min, p less than 0.05), total circumflex coronary resistance had increased (2.7 +/- 0.4 to 3.5 +/- 0.6 U, p less than 0.05) and aortic pressure was unchanged (108 +/- 4 to 113 +/- 4 mm Hg). Alpha-adrenergic blockade with phentolamine did not prevent the decrease in circumflex coronary arterial diameter in each of five dogs (3.67 +/- 0.28 to 3.60 +/- 0.28 mm, p less than 0.05). Therefore, intravenous ouabain caused vasoconstriction of large coronary arteries. These vasocontrictor effects were not mediated by alpha-adrenergic mechanisms. This constriction could have important consequences in the presence of coronary stenoses.     

Enhanced role for the opening of potassium channels in relaxant responses to acetylcholine after myocardial ischaemia and reperfusion in dog coronary arteries

1. Anaesthetized dogs were subjected to 1 h occlusion of the left circumflex coronary artery followed by 2 h of reperfusion. Relaxant responses were examined in coronary artery rings removed proximal (nonischaemic) or distal (ischaemic) to the site of occlusion. 2. Relaxant responses to acetylcholine (ACh) were similar in nonischaemic and ischaemic artery rings. In addition ACh-induced relaxation of nonischaemic and ischaemic artery rings was equally susceptible to inhibition of nitric oxide (NO) synthase using L-N(G)-nitroarginine (L-NOARG, 10(-4) M), or to inhibition of soluble guanylate cyclase using 1H-[1,2,4]oxadiazolo[4,3-a]quinoxaline-1-one (ODQ, 10(-5) M). 3. In nonischaemic arteries, the relaxation to ACh was unaffected by high K+ (67 mM) but in ischaemic arteries, the maximum relaxation to ACh was significantly reduced from 113+/-6 to 60+/-2% (ANOVA, P<0.05). Tetraethylammonium (TEA, 10(-3) M), an inhibitor of large conductance calcium activated potassium (BK(Ca)) channels did not inhibit the response to ACh in nonischaemic arteries but in ischaemic arteries TEA significantly shifted the concentration response curve to ACh to the right (pEC(50); nonischaemic, 7.07+/-0.25; ischaemic, 6.54+/-0.21, P<0.01, ANOVA) without decreasing the maximum relaxation. TEA did not affect the responses to sodium nitroprusside in either nonischaemic or ischaemic arteries. 4. In conclusion, ischaemia/reperfusion did not change the sensitivity of endothelium-dependent relaxation to L-NOARG or ODQ indicating that ischaemia did not affect the contribution of NO or cyclic GMP to ACh-induced relaxation. However, in ischaemic arteries the opening of the BK(Ca) channels contributed to relaxation caused by ACh whereas TEA had no effect in nonischaemic arteries. The factor responsible for the opening of this potassium channel was a factor other than NO and may be endothelium derived hyperpolarizing factor (EDHF).     

Celiprolol increases coronary blood flow and reduces severity of myocardial ischemia via nitric oxide release

Celiprolol is a selective beta(1)-adrenoceptor antagonist with antihypertensive actions, which causes renal vasodilation by increasing tissue nitric oxide (NO) levels. The authors tested whether celiprolol increases coronary blood flow (CBF) by increasing cardiac NO release in the ischemic heart in vivo. In open-chest dogs, coronary perfusion pressure of the left anterior descending coronary artery was reduced so that CBF decreased to 60% of control levels, and thereafter, coronary perfusion pressure was maintained constant. Ten minutes after the reduction of coronary perfusion pressure, we infused celiprolol into the left anterior descending coronary artery and measured fractional shortening and lactate extraction ratio as indices of regional myocardial contractility and metabolism. CBF significantly increased from 51.5 mL/100 g/min +/- 1.9 to 67.0 mL/100 g/min +/- 5.1 20 minutes after celiprolol infusion without changes in coronary perfusion pressure, while fractional shortening and lactate extraction ratio increased. Celiprolol also increased cardiac NO release. The L omega-nitroarginine methyl ester, the inhibitor of NO synthase, attenuated the increases in CBF, fractional shortening, lactate extraction ratio, and cardiac NO release due to celiprolol. ICI 118551, a beta(2)-adrenoceptor antagonist, did not blunt the effects of celiprolol and a nonselective beta-adrenoceptor antagonist, propranolol, increased neither CBF nor cardiac NO release, indicating that the effect of celiprolol is independent of beta-adrenoceptor blockade. It was concluded that celiprolol mediates coronary vasodilation and improves myocardial ischemia through NO-dependent mechanisms.     

Acetylcholine induces constriction of epicardial coronary arteries in anesthetized dogs after removal of endothelium

The acetylcholine-induced relaxation of isolated coronary arteries is reversed to contraction in the absence of endothelium. The importance of endothelium for the regulation of coronary blood flow remains unclear. We thus tested the effects of acetylcholine on epicardial arteries and on coronary resistance vessels in situ in 8 anesthetized dogs. The left circumflex coronary artery was perfused at constant pressure. Epicardial vasomotion was evaluated by sonomicrometry, the vasomotion of coronary resistance vessels by calculated end-diastolic resistance. Acetylcholine (1 microgram/kg/min i.c.) decreased epicardial resistance by 8.6 +/- 1.6% and end-diastolic resistance by 65.8 +/- 6.3%. The epicardial coronary segment was perfused with distilled water for 65 +/- 5 s to denude it of endothelium. After removal of epicardial endothelium, the decrease in end-diastolic resistance caused by acetylcholine was unchanged (59.6 +/- 1.2%); however, epicardial resistance was increased by 7.7 +/- 1.7%. Application of glyceryl trinitrate (5 micrograms/kg/min i.c.) induced a similar decrease of epicardial resistance before and after removal of endothelium:7.9 +/- 1.4 and 6.2 +/- 1.9%, respectively. We conclude that acetylcholine-induced dilation of epicardial coronary arteries is endothelium-dependent in vivo. However, the constriction of epicardial coronary arteries in the absence of endothelium is insufficient to reduce blood flow and to induce myocardial ischemia.