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.     

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.     

Effects of nicorandil on large epicardial coronary artery in conscious dogs

The effect of 2-nicotinamidoethyl nitrate (nicorandil, SG-75, Sigmart) on coronary circulation was studied in conscious dogs, instrumented previously under sterile condition with sonomicrometers for the external coronary diameter measurement, and an electromagnetic flow plobe on the left circumflex coronary artery and a catheter into the thoracic aorta. Intravenous administration of nicorandil in doses of 10, 30, 100 and 300 micrograms/kg increased coronary blood flow dose-relatedly by 13 +/- 2, 24 +/- 3, 144 +/- 18 and 309 +/- 36%, respectively. Nicorandil also increased the diameter of the large epicardial coronary artery by 38 +/- 6, 71 +/- 11, 150 +/- 24 and 173 +/- 26 microns in doses of 10, 30, 100 and 300 micrograms/kg, respectively. To eliminate flow-dependent dilation of the coronary artery, the external diameter of the large epicardial coronary artery was measured during fixing the amount of coronary blood flow constant by a cuff occluder after intravenous administration of nicorandil, however, the degree of coronary diameter increase was not attenuated. Thus, nicorandil dilates both large and small coronary arteries in conscious dogs, the former dilation being independent from changes in coronary blood flow.     

Effects of intravenous nicorandil on coronary circulation in humans: plasma concentration and action mechanism

We investigated the cardiovascular profile of nicorandil, an antianginal agent, in humans. Pharmacologically, nicorandil acts as both an adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channel opener and a nitrate. We examined which of these mechanistic components has a predominant vasodilatory effect at clinical doses. Fourteen patients underwent cardiac catheterization. The effects of the continuous intravenous infusion of nicorandil (12 mg/45 min) were examined in angiographically normal coronary arteries. Coronary vascular resistance was calculated from coronary artery diameter and coronary blood flow velocity measured using an intravascular Doppler catheter. We compared the hemodynamic responses to nicorandil with those to the intracoronary injection of nitroglycerin (250 microg) and papaverine (12 mg). The epicardial coronary arteries responded to nicorandil at the lowest plasma concentration examined (dilation of +14.0 +/- 3.3% at approximately 170 ng/ml), whereas dilation of the coronary resistance arteries (i.e., a decrease in coronary vascular resistance) took place only at higher concentrations (>200 ng/ml). Nitroglycerin caused no further changes in coronary artery diameter or coronary vascular resistance. Papaverine caused no further increase in coronary artery diameter, but markedly decreased coronary vascular resistance (1.6 +/- 0.3 to 0.4 +/- 0.1 mm Hg/ml/min; p < 0.05). Nicorandil significantly decreased pulmonary capillary wedge pressure (i.e., reduced cardiac preload) at a plasma level of >200 ng/ml, but did not change either systemic or pulmonary vascular resistance. Thus nicorandil preferentially dilated epicardial coronary arteries rather than coronary resistance arteries, and had a stronger effect on preload than on afterload. These changes in human coronary hemodynamics suggest that the nitrate actions of nicorandil as a coronary vasodilator predominate over those as a K(ATP) opener.     

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.     

Intracoronary collagen: effects on coronary collateral circulation and the role of thromboxane

This study investigated the effects of intravascular collagen on coronary collateral blood flow. Collateral vessel growth was stimulated in 11 dogs by embolizing the left anterior descending (LAD) coronary artery with a hollow stainless steel plug. Experiments were performed 41 +/- 7 days after coronary embolization when collateral vessels were moderately well developed. Under alpha-chloralose anesthesia, the LAD was cannulated, and retrograde blood flow was used as a measure of collateral flow. Collagen (10-100 microg/kg) injected into the left main coronary artery caused a decrease of coronary collateral blood flow that became maximal at 3 min after injection and subsided within 9 min. At peak effect intracoronary collagen decreased retrograde flow by 53 +/- 6% from 32.7 +/- 8.2 to 16.8 +/- 3.7 ml/min (p < 0.05) with no change in systemic hemodynamics. Selective thromboxane A2 (TxA2)-receptor blockade with SQ30,741 had no effect on collateral blood flow during basal conditions but attenuated the collateral constriction in response to collagen. Thus, after SQ30,741, collagen caused only a nonsignificant decrease retrograde flow from 35.9 +/- 9.0 to 31.7 +/- 9.62 ml/min. The findings indicate that intravascular collagen exerts a potent vasoconstrictor effect on coronary collateral vessels. Attenuation of this response by TxA2-receptor blockade suggests that thromboxane released by activated platelets is the principal mediator of this response.     

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%).     

5-Hydroxytryptamine does not release endothelium-derived relaxing factor in rat isolated coronary arteries

Removal of the endothelium from isolated rat proximal and distal coronary artery segments shifted the 5-HT concentration-response curve to the left without affecting, the maximal contractile response. 5-HT had no relaxing effect in 10(-5) M prostaglandin F2 alpha-precontracted vessels with an intact endothelium in the presence of 10(-5) M ketanserin. The spontaneous myogenic tone increased in both proximal and distal coronary artery segments after the endothelium had been removed. Indomethacin (10(-5) M) reduced the response of the proximal coronary artery segments to 5-HT by 35% but indomethacin had no effect on the 5-HT concentration-response curve of the distal coronary artery segments. Indomethacin relaxed precontracted (40 mM potassium) proximal coronary artery segments independently of the presence of the endothelium, suggesting a non-specific relaxing effect of indomethacin in these arteries. It is concluded that rat coronary artery endothelium is unresponsive to 5-HT because it lacks 5-HT1 receptors. The increased 5-HT sensitivity and spontaneous myogenic tone of endothelium-denuded rat coronary arteries is probably due to the elimination of the relaxing stimulus mediated by spontaneously released endothelium-derived relaxing factor.     

Endothelin-A receptor antagonism promotes decreased vasodilation but has no differential effect on coronary artery compliance in hypertensive patients

The importance of endothelin-1 in the pathophysiology of essential hypertension is unclear. We therefore examined whether there is a differential effect of endothelin-A antagonism on vasodilation and coronary artery compliance in hypertensive compared to normotensive patients. We examined atherosclerotic non-stenotic arteries from 18 non-diabetic, 10 normotensive patients and eight hypertensive patients, before and after intracoronary infusion of BQ-123 (6 mumol), an endothelin-A receptor antagonist. The systolic and diastolic artery lumen area in the proximal segment was measured using an intravascular ultrasound catheter. Systolic blood pressure decreased only in hypertensive patients (F = 5.44, P = 0.03), after BQ-123 administration. The diastolic artery lumen increased from 8.9 +/- 2.9 mm at baseline to 10.8 +/- 3.0 mm after BQ-123 administration (P < 0.05) in normotensive patients and from 10.6 +/- 4.6 mm to 10.8 +/- 4.0 mm (P = NS) in the hypertensive patients (F = 3.98, P = 0.01). The respective values for the systolic artery lumen, in the two groups, before and after BQ-123 were: 10.2 +/- 3.4 mm and 12.7 +/- 3.2 mm (P < 0.01) in the normotensive group and 12.0 +/- 5.5 mm and 12.8 +/- 5.0 mm (P = NS) in the hypertensive group (F = 3.37, P = 0.08). Artery compliance did not have a differential response to BQ-123. In conclusion, endothelin-A antagonism causes decreased vasodilation but does not have a differential effect on coronary artery compliance in hypertensive patients.     

Vasomotor function of pig coronary arteries after chronic coronary occlusion

Placement of an ameroid constrictor in large-conduit pig coronary arteries causes progressive stenosis and distal myocardial ischemia. Blood perfusion in the ischemic region is partly dependent on vasomotor responses to neural and humoral factors distal to the occlusion site. To ascertain the degree of impairment of vascular function in pigs, the authors induced myocardial ischemia by placing an ameroid constrictor in the left circumflex coronary artery and examined vascular reactivity and histopathology distal to the constriction site. The sensitivity of the distal left circumflex coronary and nonoccluded control left anterior descending arteries to PGF(2alpha) was similar. After nitric oxide blockade using Nw-nitro-l-arginine methylester (l-NAME), the sensitivity and maximal contraction to PGF(2alpha) were significantly increased in both the left circumflex coronary (EC50: 5.86 +/- 0.74 vs. 3.28 +/- 0.84 microM; C(max): 4.63 +/- 0.28 vs. 6.25 +/- 0.30 g, P < 0.01) and left anterior descending (EC50: 6.57 +/- 0.73 vs. 2.78 +/- 0.16 microM; C(max): 5.09 +/- 0.37 vs. 6.95 +/- 0.39 g, P < 0.01) arteries. Substance P-induced relaxation (100 pM) was blocked to a larger degree in the distal left circumflex coronary artery when compared with the left anterior descending artery (76.9 +/- 4.2% vs. 56.4 +/- 3.1%, P < 0.05). Endothelium-independent relaxation to sodium nitroprusside was similar in the left circumflex coronary and left anterior descending arteries before and after nitric oxide blockade. Histopathologic examination showed no major differences between distal left circumflex coronary artery segments and left anterior descending artery controls. However, scanning electron microscopy showed endothelial hypertrophy and activation in specimens from the left circumflex coronary arteries. In summary, as a result of the major hemodynamic changes induced by a chronic constriction and eventual occlusion of a large coronary artery, distal segments underwent adaptive compensatory changes. Such compensation may be related to an increased nitric oxide production by the hypertrophic endothelium in response to alterations in coronary hemodynamics.     

Enhanced release of endothelium-derived hyperpolarizing factor in small coronary arteries from rats with congestive heart failure

1. Previous studies have suggested that the production of nitric oxide (NO) is reduced in coronary vessels of animals with congestive heart failure (CHF). However, the response to endothelium-derived hyperpolarizing factor (EDHF) in small coronary resistance arteries from CHF rats has not been investigated. The aim of the present study was to determine whether flow-induced dilation (FID) is altered in small coronary arteries from CHF rats and to characterize the role of EDHF in this process. 2. Small coronary arteries (97 +/- 6 microm) were isolated from control rats and from rats in which CHF was induced by left coronary artery ligation. The arteries were cannulated at 60 mmHg with flow. Changes in internal diameter were examined using videomicroscopy. 3. There was no significant difference in FID in small coronary arteries between control and CHF rats (68 +/- 6 vs 61 +/- 4% (expressed as a percentage of maximal dilation induced by nitroprusside (%MaxD(NP))), respectively). Flow-induced dilation in control rat vessels showed greater attenuation by N(G)-monomethyl-L-arginine (L-NMMA) than vessels from CHF rats (%NO-mediated FID 32 +/- 5 vs 16 +/- 3% (%MaxD(NP)), respectively). Pretreatment with indomethacin had no significant effect on FID in vessels from either rat group. Flow-induced dilation was attenuated by KCl (40 mmol/L) to a greater degree in vessels from CHF rats in the presence of L-NMMA and indomethacin compared with vessels from control rats (%EDHF-mediated FID: 36 +/- 4 vs 25 +/- 5% (%MaxD(NP)), respectively). Flow-induced dilation was abolished by removal of the endothelium and was significantly decreased in vessels from CHF rats in response to charybdotoxin plus apamin or tetrabutylammonium compared with control rat vessels. 17-Octadecynoic acid had no significant effect on FID in vessels from either control or CHF rats. 4. In conclusion, the FID of small coronary arteries is mediated by K+ channels, including the K(Ca) channels. Endothelium-derived hyperpolarizing factor-mediated dilation may compensate for the loss of NO-mediated dilation in CHF.     

Role of arterial smooth muscle tone and geometry in the regulation of peripheral conduit artery mechanics by shear stress

1. Although arterial blood flow is recognized as an important modulator of vascular tone and geometry, the effect of acute changes in shear-stress on conduit artery mechanics has not been fully investigated in humans because of technical limitations. 2. To assess, respectively, the effects of decreases and increases in flow and shear stress on radial artery tone and mechanics, arterial pressure (photoplethysmography), total blood viscosity, radial artery internal diameter, wall thickness (echotracking) and blood flow (Doppler) were measured in healthy volunteers (mean (+/-SEM) age 25 +/- 1 years) during a distal flow arrest (n=12) and hand skin heating (n=18). 3. Radial artery flow decreased from 31 +/- 4 to 7 +/- 1 10(-3) L/min during distal flow arrest (P < 0.001) and increased from 10 +/- 2 to 22 +/- 4 and 69 +/- 6 10(-3) L/min during heating (P < 0.001). At mean arterial pressure, these changes in flow were respectively associated with a parallel flow-dependent reduction and increase in diameter and midwall stress. There was no significant modification in mean elastic modulus. Compliance did not change when flow decreased and only increased at the highest level of flow. Finally, the cross-sectional compliance and incremental modulus were fitted as functions of midwall stress. The decrease in flow was associated with an upward shift of the modulus-midwall stress curve and a downward shift of the compliance-midwall stress curve. The increase in flow was associated with a downward shift of the modulus-midwall stress curve and an upward shift of the compliance-midwall stress curve at each level of wall shear stress. 4. By using two different procedures, we obtained similar results concerning the direct effects of increases and decreases in flow on stiffness of the arterial wall and on arterial compliance and demonstrated the presence of a flow-dependent regulation of arterial smooth muscle tone of peripheral conduit arteries in humans.     

Effect of antiischemic therapy on coronary flow reserve and the pressure-maximal coronary flow relationship in anesthetized swine.

The effect of nifedipine (0.5, 1.0, and 2.0 micrograms/kg/min), metoprolol (0.1, 0.5, and 1.0 mg/kg), the beta 1-selective adrenoceptor partial agonist epanolol (10, 50, and 200 micrograms/kg), or equivalent volumes of isotonic saline (n = 6, in each group), on coronary blood flow capacity were studied in anesthetized swine. Intracoronary bolus injections of adenosine (20 micrograms/kg/0.2 ml) were administered without and during three levels of coronary stenosis, prior to and following each dose of drug, to obtain maximal coronary blood flows at different perfusion pressures in the autoregulatory range. Coronary perfusion pressures were varied by partial inflation of a balloon around the left anterior descending coronary artery. Special care was taken that the stenoses not lead to myocardial ischemia. Three indices of coronary blood flow capacity were used: absolute coronary flow reserve (ACFR, the ratio of maximal to resting coronary blood flow), the slope and the extrapolated pressure at zero flow (Pzf) of the pressure-maximal coronary flow (PMCF) relationship, and relative coronary flow reserve (RCFR, the ratio of maximal coronary blood flow with a stenosis to maximal coronary blood flow without a stenosis) at two of the three levels of stenosis. Nifedipine decreased ACFR from 4.5 +/- 1.9 to 1.9 +/- 0.3 (mean +/- SD; p less than 0.05), reflecting in part the increase in resting coronary blood flow. The nifedipine-induced changes in maximal coronary blood flow were not only due to a drop in perfusion pressure, as the slope of the PMCF relationship decreased from 2.27 +/- 0.49 ml/(min.mm Hg) to 1.54 +/- 0.51 ml/(min.mm Hg) (p less than 0.05), and Pzf decreased from 30 +/- 4 mm Hg to 20 +/- 7 mm Hg (p less than 0.05). Consequently, calculated maximal coronary blood flow was attenuated from 114 +/- 31 ml/min to 93 +/- 37 ml/min at 80 mm Hg, but was enhanced from 23 +/- 13 to 37 +/- 24 ml/min at 40 mm Hg coronary perfusion pressure. In concert with the change in the PMCF relationship, RCFR at equivalent severe stenosis increased from 0.33 +/- 0.06 to 0.47 +/- 0.10 (p less than 0.05). No changes were observed with metoprolol, epanolol, or saline. The effect of nifedipine on the PMCF relationship not only provides a mechanism for the drug's antiischemic action, but should also be considered in the interpretation of coronary flow reserve measurements in patients on nifedipine treatment.     

Adrenomedullin causes coronary vasodilation in humans: effects of inhibition of nitric oxide synthesis

Experimental studies have shown that adrenomedullin (AM) causes vasodilation, in part, mediated by endothelium-derived nitric oxide (NO). However, it remains to be clarified how NO is involved in AM-induced coronary vasoreactivity in humans. We examined whether NO contributes to the vasodilatory effects of adrenomedullin on human coronary arteries. In 10 patients with angiographically normal coronary arteries, adrenomedullin (low dose: 1 ng/kg/min; high dose: 10 ng/kg/min) was infused into the left coronary ostium before and after an infusion of N-monomethyl-L-arginine (L-NMMA, 40 micromol/min for 5 min), an NO synthase inhibitor. Coronary diameter and coronary blood flow (CBF) were evaluated by quantitative angiography and Doppler flow velocity measurements. Changes in these parameters in response to adrenomedullin were expressed as percent changes from baseline values. Adrenomedullin at a high dose dilated coronary arteries (3.7+/-0.5%, P<0.001). Adrenomedullin increased the coronary blood flow at both doses (low: 55.7+/-13.9%, P<0.01; high: 48.8+/-9.8%, P<0.001). After the infusion of L-NMMA, adrenomedullin-induced coronary vasodilation and increase in coronary blood flow were attenuated. These findings suggest that adrenomedullin dilates human coronary arteries through an increase in NO production, at least in part.     

Intracoronary enalaprilat improves metabolic coronary vasodilation in patients with idiopathic dilated cardiomyopathy

Coronary flow reserve is reduced in patients with idiopathic dilated cardiomyopathy (DCM). We examined acute effects of intracoronary enalaprilat on metabolic coronary vasodilation during pacing tachycardia in patients. Coronary blood flow (Doppler guidewire) and diameter (quantitative angiography) were measured in seven patients with DCM and seven control subjects. In the DCM group, tachypacing increased coronary blood flow by 37 +/- 22% from the baseline before enalaprilat and by 65 +/- 22% (p < 0.01 vs. before treatment) after enalaprilat (0.5 microg/kg/min for 5 min, i.c.) at comparable double product. Pacing-induced dilation of the epicardial coronary artery also was greater after enalaprilat (p < 0.05). Effects of enalaprilat on coronary blood flow and diameter during pacing tachycardia were abolished by pretreatment with intracoronary administration of the nitric oxide (NO) synthesis inhibitor, N(G)-monomethyl-L-arginine. These beneficial effects of enalaprilat on large and small coronary vasodilation were not observed in control patients. Thus, intracoronary enalaprilat acutely augmented dilator responses of the large and small coronary arteries to pacing tachycardia in patients with DCM, and NO appeared to play an important role in mediating the effects of enalaprilat. These favorable effects of enalaprilat on the coronary circulation may be of clinical significance in patients with heart failure due to nonischemic DCM. Further long-term studies of the effects of angiotensin-converting enzyme inhibition on coronary vasodilation will be needed in this population.     

Hemodynamic changes after subselective intracoronary administration of nisoldipine in humans.

Hemodynamic changes after the subselective intracoronary administration of 50 micrograms of nisoldipine were analyzed in 24 nonstenotic coronary arteries using a randomized, placebo-controlled, double-blind protocol. The following hemodynamic parameters were studied: (a) epicardial coronary artery diameter, assessed by quantitative angiography; (b) coronary blood flow velocity, measured by an intracoronary Doppler probe; (c) coronary blood flow, calculated from the above parameters; (d) coronary flow velocity reserve, assessed after intracoronary administration of 10 mg of papaverine hydrochloride; and (e) heart rate and arterial blood pressure. Since 3 patients were excluded due to unreliable Doppler signals, a total of 21 patients was eligible for complete analysis (placebo: n = 9; nisoldipine: n = 12). In placebo-treated patients, all studied parameters proved to be very stable on repeat measurement and no significant changes were found. In nisoldipine-treated patients, a significant increase in epicardial diameter (+19%; p = 0.0001) and coronary blood flow (+47%; p = 0.003) was found. The coronary blood flow velocity transiently increased after nisoldipine, with a maximum (+80%) after 2 min and returning to baseline within 10 min. Finally, nisoldipine resulted in a significant decrease in the coronary flow velocity reserve by 20% (p = 0.001). All coronary hemodynamic effects were observed in the absence of changes in heart rate and arterial blood pressure. Therefore, the present data demonstrate that nisoldipine acts as a potent dilator of epicardial as well as resistance vessels in nonstenotic human coronary arteries.     

Vasodilator responses of coronary conduit and resistance arteries to continuous nitroglycerin infusion in humans: a Doppler guide wire study

To examine the responses of coronary conduit and resistance arteries to the continuous i.v. administration of nitroglycerin in 15 patients with atypical chest pain, we measured coronary blood flow velocity in the left anterior descending coronary artery using a Doppler guide wire and the lumen diameter and cross-sectional area by quantitative coronary angiography. Systolic flow, diastolic flow, total coronary flow, and coronary vascular resistance were calculated. Stepwise increases in dose of nitroglycerin resulted in significant dose-dependent decrease in mean aortic pressure (p < 0.01) and increase in lumen diameter (p < 0.05). After nitroglycerin administration of 0.5 microg/kg/min, systolic flow decreased significantly by 89.9+/-15.7% (p < 0.01), and diastolic flow increased significantly by 74.2+/-37.1% (p < 0.05). Total coronary flow did not change significantly with the various doses of nitroglycerin. However, coronary vascular resistance decreased significantly at concentrations greater than 0.5 microg/kg/min nitroglycerin. Continuous nitroglycerin infusion did not reduce either diastolic or total coronary blood flow despite a significant reduction in coronary perfusion pressure. These results indicate that subendocardial blood flow might be maintained during continuous i.v. infusion of nitroglycerin within the clinical dose range.     

Effect of anesthesia on reactivity of large coronary arteries in the dog

Epicardial coronary arteries dilate after release of a transient coronary occlusion in awake chronically instrumented dogs but not in anesthetized dogs studied acutely after surgery. To determine whether anesthesia or surgical trauma is responsible for this lack of reactive dilation, we evaluated the effect of anesthesia on reactive coronary dilation in six chronically instrumented dogs. Circumflex coronary diameter was measured with sonomicrometry. Response to release of a 20- or 30-s coronary occlusion was studied before and after sodium pentobarbital (20 +/- 2 mg/kg) and before and after alpha-chloralose (100 mg/kg) plus either morphine or fentanyl and droperidol. Pentobarbital blunted the peak flow response to release of a transient coronary occlusion (114 +/- 15 vs. 128 +/- 16 ml/min, p less than 0.05) but did not affect the increase in large coronary diameter (before pentobarbital: 3.68 +/- 0.30-3.74 +/- 0.30 mm; after pentobarbital: 3.66 +/- 0.31-3.71 +/- 0.31 mm). alpha-Chloralose blunted the peak flow response to release of a transient coronary occlusion (96 +/- 12 vs. 141 +/- 25 ml/min, p less than 0.05) but did not affect the increase in large coronary diameter (before chloralose: 4.00 +/- 0.28-4.06 +/- 0.28 mm; after chloralose: 3.91 +/- 0.31-3.98 +/- 0.31 mm). Therefore, each drug blunted the peak flow response to release of a transient coronary occlusion, but dilation of large coronary arteries was not impaired. The lack of reactivity of large coronary arteries in acutely studied dogs is probably due to the trauma of recent surgery and not the anesthesia.     

Proarrhythmic activity of intracoronary endothelin in dogs: relation to the site of administration and to changes in regional flow.

The endothelium-derived peptide, endothelin, has been shown to exert powerful constrictor activity in both isolated and in situ coronary arteries. Recent in vitro data on isolated cardiac myocytes suggest that the substance might also possess electrophysiologic properties. We investigated the possibility that endothelin (ET-1) may exert proarrhythmic effects when infused selectively in the coronary circulation of open-chest-anesthetized dogs. Animals were instrumented for the measurement of left anterior descending (LAD) or left circumflex (LCX) coronary artery blood flow, left systolic ventricular pressure (LSVP), dP/dtmax, mean arterial pressure (MAP), and epicardial electrocardiogram (ECG; three leads). Data were recorded during infusion (2 min) of saline (n = 5) or increasing doses of endothelin (5-80 pmol/kg) given selectively in either the LCX (n = 10) or the LAD (n = 10). When infused into the LCX, endothelin produced a dose-dependent decrease in flow (40 +/- 23% at 80 pmol/kg, mean +/- SD, p less than 0.01) with a concomitant increase in coronary resistance and a decrease in dP/dtmax and MAP. ECG changes typical of myocardial ischemia paralleled the decrease in flow and culminated in ventricular fibrillation at the highest dose (80% of dogs). Endothelin caused similar hemodynamic effects when infused in the LAD, but fatal arrhythmias occurred for lower doses and for little or no change in coronary blood flow. Thirty percent of the animals died at 10 and 60% died at 20 pmol/kg, doses that induced only a moderate decrease (8 +/- 7 and 21 +/- 12%, respectively) in LAD total blood flow. Ventricular tachycardia always preceded ventricular fibrillation and death.(ABSTRACT TRUNCATED AT 250 WORDS)     

BRL 34915 ameliorates oxygen supply in ischemic myocardium by a simultaneous enhancement of coronary blood flow and a reduction of myocardial function.

In the presence of stenotic coronary arteries, oxygen supply in the poststenotic myocardium is reduced. A counterbalancing poststenotic metabolic vasodilatation is attenuated up to 30% by an alpha 2-adrenoceptor-mediated vasoconstrictor tone. In six open-chest dogs, we determined whether cumulative intracoronary doses (1, 4, and 14 micrograms) BRL 34915, a vasodilator with additional dose-dependent cardiodepressant properties, could enhance coronary blood flow and simultaneously reduce myocardial function in poststenotic myocardium, thereby increasing oxygen supply and decreasing oxygen demand. BRL 34915 increased mean left circumflex coronary blood flow [ml/(min.100 g)] dose-dependently from 59 +/- 12.4 (mean +/- SEM) (no BRL) to 227 +/- 43.9 (14 micrograms BRL) (p less than 0.05) in intact coronary arteries and from 36 +/- 7.2 (no BRL) to 74 +/- 13.2 (14 micrograms BRL) (p less than 0.05) distal to a severe stenosis, respectively. In contrast, posterior systolic wall thickening (%), was significantly decreased only by 14 micrograms BRL from 9.7 +/- 1.82 (no BRL) to 7.8 +/- 2.07 (14 micrograms BRL) (p less than 0.05) when coronary arteries were intact and from 8.7 +/- 2.02 (no BRL) to 4.1 +/- 1.39 (14 micrograms BRL) (p less than 0.05) in poststenotic myocardium. We conclude that BRL 34915 can both enhance coronary blood flow in the poststenotic myocardium and decrease myocardial function simultaneously, potentially narrowing the gap between oxygen supply and demand.