Effects of nifedipine and indomethacin on leukotriene C4- and D4-induced coronary constriction at normal and reduced coronary perfusion in dogs

The effects of intracoronary leukotriene C4 (LTC4) and D4 (LTD4) (both 0.1 microgram/kg) were studied in 23 anesthetized open-chest dogs at normal (= mean aortic pressure) and reduced (51 +/- 2 and 32 +/- 2 mm Hg) coronary perfusion pressures. The left anterior descending coronary artery was cannulated and blood flow measured. Subendocardial fiber segment length was obtained with ultrasonic crystals. At normal coronary perfusion pressure, LTC4 and LTD4 reduced coronary blood flow from 81 +/- 6 and 78 +/- 7 ml/min per 100 g by 41 +/- 4% and 41 +/- 4% (both p less than 0.0005), respectively. However, segment length shortening was not depressed by LTC4 or LTD4. At reduced coronary perfusion pressure, LTC4 and LTD4 diminished coronary blood flow from 35 +/- 5 and 32 +/- 3 ml/min per 100 g, by 28 +/- 5% (p less than 0.0025) and 30 +/- 5% (p less than 0.005). Thus, reduction of coronary blood flow was less by both LTC4 (p less than 0.01) and LTD4 (p less than 0.05) at reduced rather than at normal coronary perfusion pressure. Segment length shortening was depressed by LTC4 from 6.5 +/- 1.2% to 2.4 +/- 1.6% (p less than 0.05) and by LTD4 from 5.6 +/- 1.4% to 3.1 +/- 0.9% (p less than 0.05), respectively. Indomethacin (5 mg/kg, i.v.) and nifedipine (10 micrograms/kg, i.v.) did not abolish the LT-induced coronary artery constriction. However, in animals pretreated with indomethacin or nifedipine, reduction of coronary blood flow by LTs was not attenuated at reduced coronary perfusion.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effects of short-term intravenous administration of diltiazem on left ventricular function and coronary hemodynamics in patients with coronary artery disease

The hemodynamic effects of diltiazem were investigated in 15 patients with suspected coronary artery disease undergoing routine cardiac catheterization. Diltiazem was given in a high dose of 500 micrograms/kg over a period of 5 min and measurements made before and after drug administration during spontaneous heart rate and during matched atrial pacing. Spontaneous heart rate did not change (-5%; NS). Left ventricular (LV) systolic pressure decreased 24% (p less than 10(-6)) and LV end-diastolic pressure (LVEDP) did not change (-5%; NS). During coronary blood flow measurement, mean aortic pressure decreased 30% (p less than 10(-6)) as global (coronary sinus) and regional (great cardiac vein) coronary vascular resistance diminished with no change in coronary blood flow. Myocardial oxygen consumption decreased 19% (p less than 0.02). During matched pacing, although no change occurred in calculated systolic isovolumic indexes of contractility, end-systolic pressure-volume index decreased 15% (p less than 0.05). The time constant of isovolumic relaxation assessed by a biexponential model decreased. No net change occurred in either global or regional wall motion. In summary, high-dose diltiazem was administered safely to patients with coronary artery disease. It is concluded that, at this dose, diltiazem acted as a peripheral and coronary vasodilator. Hemodynamic changes consistent with a direct negative inotropic and chronotropic effect of the drug were observed. Myocardial oxygen consumption decreased with no change in coronary blood flow.     

Coronary collateral blood flow in acute myocardial ischemia is not increased by dihydropyridine-induced coronary vasodilatation

The effect of two dihydropyridine derivatives, nifedipine and felodipine, on myocardial blood flow distribution 1 h after ligation of the left anterior descending coronary artery (LAD) was studied in open-chest dogs by means of radioactive microspheres. The myocardium normally perfused from the LAD was first labeled with 125I-labeled microspheres injected directly into the LAD before ligation. Microspheres used for blood flow measurements were given in the left atrium. An intravenous infusion rate of 0.3 nmol/kg/min felodipine slightly depressed mean aortic blood pressure (approximately 5 mm Hg) and decreased coronary vascular resistance in normal myocardium. Nifedipine, at three times the dose of felodipine, had a comparable hypotensive effect, but the decrease in coronary vascular resistance was not statistically significant. The two dihydropyridines were also compared in a dose range that was four times higher. The mean arterial blood pressure reduction (approximately 30% for both drugs) was counterbalanced by inflation of an intraaortic balloon to avoid a drastic decrease in afterload and coronary perfusion pressure. Under these circumstances, felodipine and nifedipine decreased coronary vascular resistance and increased blood flow to nonischemic myocardium comparably. However, in severely ischemic, truly collateral-dependent myocardium without admixture of interdigitating healthy myocardium, the blood flow was unaffected after administration of both felodipine and nifedipine. Although felodipine was three times more potent than nifedipine with regard to vasodilatation in the normal myocardium, the difference in vascular selectivity between the two agents did not influence the effect on the "true" collateral blood flow in acute myocardial ischemia.     

Enhancement of canine coronary collateral flow by nafazatrom

The ability of oral nafazatrom treatment (10 mg/kg) 2 h preceding occlusion of the left anterior descending coronary artery for 6 h to limit expansion of myocardial injury was studied in anaesthetized canine hearts. Collateral blood flow was obtained with a load line analysis, employing aortic pressure, post-stenotic coronary pressure, and retrograde coronary flow from the occluded vessel. Contractile changes in the subendocardial ischemic perfused muscles were measured with ultrasonic techniques. Infarct size was determined post-mortem by a biochemical staining method and excision of necrosis. Post-stenotic coronary pressure was slightly below aortic pressure in both groups before coronary occlusion, and fell to 29 and 27% of aortic pressure in vehicle- and drug-treated hearts, respectively, after the insult. Retrograde flow was 2.4 ± 0.6 vs. 4.1 ± 0.7 ml/min in tylose- or nafazatrom-treated hearts. Collateral flow amounted to 1.5 ± 0.06 vs. 2.5 ± 0.04 ml/min in controls and drug-protected hearts. Contractility (dP/dt_max) and the %-segment shortening were greater in the ischaemic myocardium after nafazatrom treatment. Infarct size was 38 ± 5.2 vs. 17 ± 3.4 g/100 g left ventricle in the vehicle controls and nafazatrom group, respectively. Nafazatrom reduced infarct size by 46%. Besides other mechanisms, this was due to improved %-segment shortening and increased periinfarction collateral blood supply to jeopardized but viable myocardium. The drug may be of value in ischaemic heart disease as shown by the enhanced regional myocardial perfusion and improved contractility.     

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.     

Hemodynamic and cardiac effects of nicardipine in patients with coronary artery disease

The hemodynamic and cardiac effects of the calcium antagonist nicardipine, alone (n = 10 patients) or combined with propranolol (0.1 mg/kg i.v.; n = 9 patients), were assessed in patients with coronary artery disease. In the absence of beta-blockade, nicardipine (5 or 10 mg i.v.) increased heart rate (+23 and +15 beats/min after 5 and 10 mg, respectively; p less than 0.01) and cardiac output (from 4.7 +/- 1.1 to 7.4 +/- 1.3 L/min after 5 mg and from 5.1 +/- 1.1 to 8.6 +/- 1.6 L/min after 10 mg; p less than 0.005). Systemic vascular resistance decreased with both doses (-46 and -57%; p less than 0.005), whereas mean aortic pressure decreased by 14 mm Hg after 5 mg and by 28 mm Hg after 10 mg (p less than 0.004); left ventricular end-diastolic pressure was unchanged. Nicardipine also decreased significantly end-systolic left ventricular volume and increased ejection fraction (from 63 to 71% after 5 mg and from 54 to 63% after 10 mg; p less than 0.008) and velocity of shortening. Peak (+) dP/dt and (dP/dt)/DP40 (value of dP/dt at a developed pressure of 40 mm Hg) were unchanged, and Emax, the maximal left ventricular pressure/volume ratio, improved slightly (+8%; p less than 0.05). After beta-blockade, nicardipine (2.5 mg i.v.) still decreased mean aortic pressure (-16 mm Hg; p less than 0.05) and systemic vascular resistance, and improved the ejection phase indices; cardiac output and ventricular relaxation, both depressed after propranolol administration, were also normalized after infusion of nicardipine.(ABSTRACT TRUNCATED AT 250 WORDS)     

Perfusion with non-oxygenated Tyrode solution causes maximal coronary vasodilation in canine hearts

1. Coronary vasodilator effects of non-ischaemic hypoxia (perfusion with non-oxygenated Tyrode solution) and ischaemic hypoxia (coronary occlusion) were compared. 2. The left anterior descending coronary artery (LAD) of six in situ canine hearts was perfused selectively at controlled pressure with normal arterial blood or with non-oxygenated Tyrode solution. LAD flow was measured continuously with an electromagnetic flowmeter. Reactive hyperaemic blood flow responses following 3 min Tyrode perfusion were compared with responses following 3 min complete coronary occlusion. 3. Control LAD blood flow was 26.9 +/- 4.6 ml/min. A 3 min period of Tyrode perfusion caused a peak reactive hyperaemic blood flow of 151 +/- 31 ml/min, which was not significantly different from that caused by 3 min occlusion, 123 +/- 17 ml/min. The duration and total volume of reactive hyperaemia flow following Tyrode perfusion were smaller than values following occlusion. 4. The present findings demonstrate that myocardial hypoxia per se is a sufficient vasodilatory stimulus to account for the peak reactive hyperaemic flow following 3 min occlusion, but that the prolonged reactive hyperaemic response depends on vasodilator metabolites which accumulate in ischaemic myocardium.     

Nisoldipine and perfusion of post-stenotic myocardium in conscious pigs with different degrees of concentric stenosis.

1. The effects of oral nisoldipine on the perfusion and wall function of a myocardial segment distal to a fixed coronary artery stenosis were studied in 2 groups of conscious pigs with different degrees of stenosis. In group 1 (n = 8) systolic wall thickening (SWT) of the post-stenotic segment was more than 15% (27 +/- 4%); in group 2 (n = 7) SWT was less than 10% (7 +/- 1%). 2. The systemic haemodynamic profiles at baseline and during nisoldipine were similar in both groups. Dose-titrations of nisoldipine (0.24 +/- 0.02 mg kg-1 and 0.47 +/- 0.04 mg kg-1) were performed to obtain increases in heart rate of 25% and 50%, respectively. These increases were accompanied by increases in cardiac output (up to 50%) and left ventricular (LV)dP/dt max (60%), while systemic vascular resistance (35%) and mean arterial blood pressure (10%) were reduced. Left ventricular systolic and end-diastolic blood pressure and stroke volume were not affected. 3. In both groups, nisoldipine caused increases in blood flow to the non-stenotic area which favoured the subepicardium more than the subendocardium. Blood flow to the post-stenotic area of group 1 was normal at baseline and was only slightly enhanced (preferentially to the subepicardium) by nisoldipine. In the post-stenotic area of group 2 transmural and subendocardial blood flow were lower at baseline compared to the control area. Nisoldipine did not affect subepicardial blood flow but reduced subendocardial blood flow.(ABSTRACT TRUNCATED AT 250 WORDS)     

The slow-channel calcium blocking agent, nitrendipine, and coronary collateral blood flow

The effects of a new dihydropyridine slow-channel calcium blocking agent, nitrendipine, on hemodynamics and myocardial blood flow in normal and ischemic areas distal to either an acute or chronic coronary artery occlusion were studied in anesthetized dogs. Nitrendipine produced significant and dose-related decreases in mean aortic blood pressure and increases in flow through the nonobstructed coronary artery. In acute coronary artery occlusion experiments, only small changes in perfusion of the ischemic zone were observed following nitrendipine. On the other hand, in dogs with a chronic coronary artery occlusion and well-developed collateral circulation, nitrendipine produced significant and dose-related increases in subepicardial perfusion within the central ischemic zone. No change in subendocardial blood flow during drug-induced hypotension was observed, but when aortic pressure was held constant, there was an increase in subepicardial, subendocardial, and overall transmural myocardial perfusion. The data demonstrate that nitrendipine improves oxygen supply to collateral-dependent myocardium via an increase in coronary collateral blood flow in a model of chronic coronary occlusion.     

Acute doxorubicin cardiotoxicity: functional, metabolic, and morphologic alterations in the isolated, perfused rat heart

The acute effects of doxorubicin on coronary perfusion and left ventricular pressures and intracellular phosphate metabolite levels, the latter obtained by 31P nuclear magnetic resonance, were measured simultaneously in isolated, isovolumic rat hearts (Langendorf preparation) perfused at constant flow. Nineteen experimental hearts were perfused for 70 min with oxygenated HEPES-buffered solution containing 6 mg/L doxorubicin. These were compared with 18 control hearts (C), perfused under identical conditions but without doxorubicin, by repeated measures analysis of variance. In the experimental group, coronary perfusion pressure steadily increased to 226.3 +/- 13.8% (mean +/- SEM) of initial levels (p less than 0.0001 vs. C). Because flow was constant, the increase in coronary perfusion pressure in experimental hearts indicates a greater than twofold increase in coronary resistance. Intracellular phosphocreatine and ATP decreased to 80.3 +/- 3.9% (p less than 0.005 vs. C) and 82.1 +/- 6.4% (p less than 0.05 vs. C), whereas inorganic phosphate increased to 149.7 +/- 19.1% (p less than 0.05 vs. C) of initial levels, respectively. Accompanying these changes, diastolic pressure steadily increased to 521.7 +/- 91.4% of initial levels (p less than 0.0001 vs. C). Developed pressure initially increased to 107.1 +/- 4.5% at 30 min, and thereafter decreased to 76.2 +/- 6.3% at 70 min (p less than 0.05 vs. C). Typical structural alterations in myocyte nuclei were noted. Cellular calcium was not increased in doxorubicin-exposed hearts. Thus, acute doxorubicin cardiotoxicity is characterized by an increase in coronary resistance and is closely correlated with alterations in ventricular function and a decrease in intracellular high-energy phosphate content.(ABSTRACT TRUNCATED AT 250 WORDS)     

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.     

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.     

Alterations of coronary vascular responses to noradrenaline, acetylcholine and isoprenaline during acute myocardial ischaemia in dogs.

1. The reactivity of coronary arteries to noradrenaline (NA), acetylcholine (ACh) and isoprenaline (Iso) during acute myocardial ischaemia was studied in anaesthetized, open-chest dogs. 2. The left anterior descending coronary artery (LAD) was cannulated and perfused via an extracorporal circuit at constant flow. Ischaemia was produced by decreasing the perfusion blood flow of the LAD to 50% (moderate ischaemia) and 27% (severe ischemia) of normal. A dose of each agent which had no significant myocardial effects was chosen. Heart rate was held constant by ventricular pacing during ACh administration. 3. Under normal conditions, the infusion of NA, ACh and Iso into the LAD produced significant decreases in coronary vascular resistance (P less than 0.01). However, under either moderate or severe ischaemic conditions intracoronary NA resulted in a marked increase in coronary vascular resistance (P less than 0.01), which was completely blocked by phentolamine, an alpha-adrenoceptor blocker; intracoronary ACh and Iso did not have a significant effect on coronary vascular resistance (P greater than 0.05). 4. These results indicate that coronary arterial responsiveness to some intrinsic vasoactive substances, such as NA and ACh, is altered during acute myocardial ischaemia. This may be important in the pathophysiology of myocardial ischaemia.     

Blood flow regulation during acute regional ischemia in feline hearts: importance of postjunctional alpha 1- and alpha 2-adrenoceptors.

Influence of postjunctional alpha 1- and subsequent alpha 2-adrenergic antagonism on myocardial blood flow was measured in a group of anesthetized cats with acute occlusion of the left anterior descending coronary artery (LAD) and a control group (n = 10 for both). The relatively selective postjunctional alpha 1-(doxazosin) and alpha 2-adrenergic (SK&F 104078) antagonists were applied after beta-adrenergic blockade (propranolol). Regional myocardial blood flow was obtained with radiolabeled microspheres. Major hemodynamic determinants for perfusion were kept constant both within and between groups by right atrial pacing and aortic obstruction. Mean coronary resistance in nonischemic myocardium was permanently lower in the occlusion group as compared with controls (p less than 0.01). Subsequent alpha 2-adrenergic antagonism reduced mean coronary resistance in controls only (p less than 0.05). Cardiac output (CO) and dP/dt was reduced in LAD-occluded hearts after alpha 2-adrenergic blockade (p less than 0.01, p less than 0.05). The study demonstrates the significance of postjunctional alpha 2-adrenergic-mediated vasoconstriction in well-perfused myocardium of control hearts, whereas such vasoconstriction was deteriorated in LAD-occluded hearts. A role for myocardial alpha 2-adrenoceptors for maintenance of global cardiac function in acute regional ischemia was also indicated.     

Comparative effects of a new nicotinamide nitrate derivative, nicorandil (SG 75), with nifedipine and nitroglycerin on true collateral blood flow following an acute coronary occlusion in dogs

The effects of nicorandil (NC), nifedipine (NF), and nitroglycerin (GTN) on true collateral blood flow were studied following an acute occlusion of the left anterior descending (LAD) coronary artery in anesthetized dogs. Ischemic tissue samples contaminated with overlap blood flow from the normal region were eliminated by using a special balloon reservoir technique for administration of radioactive microspheres. The effects of each drug on true collateral blood flow were determined following 1 h of coronary occlusion with the radioactive microsphere technique and an indirect index of collateral perfusion, retrograde pressure. NC (25 micrograms/kg/min, i.v.), NF (1.0 micrograms/kg/min, i.v.), and GTN (1.5 micrograms/kg/min, i.v.) infusions reduced mean arterial and left ventricular systolic pressures similarly (10-20 mm Hg). None of the drugs had any effect on true collateral blood flow in the presence of a decrease in aortic blood pressure. However, when aortic pressure was maintained by use of a cuff around the descending thoracic aorta, NC and NF increased collateral flow as measured by the microsphere technique as well as retrograde pressure. In addition, NC produced a significant increase in subendocardial blood flow, which resulted in an increase in the endocardial-epicardial blood flow ratio (endo/epi). GTN had no significant effect on any index of collateral function. These results indicate the importance of aortic pressure in determining the effects of vasodilators on coronary collateral function. Furthermore, NC may have more desirable effects on collateral blood flow than NF or GTN when hypotension is minimized, since this was the only agent that selectively increased subendocardial blood flow.     

Nicorandil and cardiovascular performance in anaesthetized pigs with a concentric coronary artery stenosis

Summary The present investigation compares the systemic and regional haemodynamics in nicorandil-treated and solvent-treated pigs with a concentric stenosis around the left anterior descending coronary artery. The stenosis per se led to a decrease in mean arterial blood pressure, cardiac output, stroke volume, maximum rate of rise in left ventricular pressure and transmural (more marked in the endocardium than in the epicardium) blood flow to and myocardial wall motion in the post-stenotic segment. Infusions of nicorandil (15 and 30 g · kg^–1 · min^–1, intravenously) decreased arterial blood pressure, cardiac output and the maximum rate of rise in left ventricular blood pressure. There was a tendency for epicardial blood flow in the non-stenotic segment to increase but blood flow to the ischaemic myocardium (epicardium as well as endocardium) was further compromised. Using the postsystolic wall thickening as an index for the viability of the myocardium and the Bretschneider formula for myocardial oxygen demand and the calculated myocardial oxygen consumption, we found that nicorandil further compromised the oxygen balance but did not jeopardize the viability of the myocardium. Regionally, nicorandil decreased renal blood flows but enhanced blood flows to the brains and adrenals. It is concluded that nicorandil lacks beneficial effects on the ischaemic myocardium in pigs with a concentric coronary artery stenosis. Apparently, the potential adverse effect (decrease in coronary perfusion pressure) of nicorandil outweighs its potential salutary effects (coronary vasodilatation and decrease in myocardial oxygen consumption due to peripheral vasodilatation). Send of fprint requests to P. D. Verdouw at the above address     

Dilatation of coronary stenosis as the salutary effect of nitroglycerin in relief of myocardial ischemia in the dog

To clarify the role of coronary responses to nitroglycerin (NTG) in relieving myocardial ischemia, we examined the effects of NTG in canine models of dynamic and fixed coronary stenoses. Application of coronary stenosis in the proximal left circumflex artery decreased resting coronary blood flow by approximately 40% and caused a significant depression of left ventricular (LV) dP/dt. During fixed coronary stenosis created with an externally applied constrictor device, intravenous NTG, 5 micrograms/kg, reduced mean aortic pressure by 12 +/- 1.1 mm Hg (mean +/- SEM, p less than 0.01) and coronary blood flow by 9 +/- 1.0% (p less than 0.01) but did not affect stenosis resistance and LV dP/dt. During dynamic coronary stenosis produced with an intraluminal microballoon occluder, intravenous NTG caused a marked increase in coronary blood flow by 40 +/- 8.3% (p less than 0.01) and a decrease in stenosis resistance by 62 +/- 9.3% (p less than 0.01), as compared with postocclusion values, concomitant with a significant improvement in LV dP/dt. Intracoronary infusion of NTG, 1.0 microgram/kg/min, had few systemic and coronary hemodynamic effects during fixed coronary stenosis, whereas intracoronary NTG increased coronary blood flow and reduced stenosis resistance, depending on its dose, during dynamic coronary stenosis. These results indicate that NTG is capable of increasing coronary blood flow and alleviating myocardial ischemia due to direct stenosis-dilating effects related to the vasomobility of the coronary stenosis.     

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.     

Effect of vasodilator drugs on coronary occlusion and reperfusion arrhythmias in anesthetized dogs

The effect of vasodilator drugs on the incidence of ventricular arrhythmias induced during 30 min of occlusion and 15 min of reperfusion of the left anterior descending coronary artery (LAD) was studied in 65 pentobarbital-anesthetized open-chest dogs. Intravenous administration of captopril (0.5 mg/kg), enalapril (0.5 mg/kg), felodipine (4 micrograms/kg), or ketanserin (0.1 mg/kg) 30 min before LAD occlusion reduced mean arterial blood pressure by 15.5 +/- 0.6% (mean +/- SEM). Nifedipine (5 micrograms/kg bolus + 1 microgram/kg min-1) infusion reduced mean arterial blood pressure by 24.8 +/- 1.8%. In none of the dogs was the diastolic blood pressure reduced below 70 mm Hg. During LAD occlusion, reduction in arterial blood pressure by these drugs was associated with a reduced incidence of ventricular premature depolarizations, ventricular tachycardia, and ventricular fibrillation (VF). During LAD reperfusion, the incidence of VF in saline-treated animals was 6/9, whereas for captopril it was 6/9, enalapril 1/9, felodipine 7/9, nifedipine 3/8, and ketanserin 3/9 animals. Thus, only enalapril significantly lowered the incidence of VF (p less than 0.05). The mechanism responsible for this antifibrillatory effect of enalapril is unknown. The muscle mass of the left ventricle supplied by the LAD distal to the site of occlusion in dogs which survived was similar to that of dogs which developed ventricular fibrillation.     

Coronary hemodynamics following intravenous or intracoronary injection of diltiazem in man

We measured coronary sinus blood flow by continuous thermodilution technique and aortic pressure after administration of diltiazem to 23 patients with coronary artery disease. In one group of patients (n = 12) the drug was infused at a rate of 0.15 mg/kg during 2 min followed by an infusion of 0.05 mg/kg during 8 min. Heart rate was unchanged except at 5 min when it decreased slightly. Aortic pressure was significantly (p less than 0.01) decreased, while coronary sinus flow increased slightly and transiently. A second group of patients (n = 5) received an intracoronary injection of 0.15 mg/kg of diltiazem into the left coronary artery. In a third group of patients (n = 7) 0.05 mg/kg of diltiazem was injected into the left coronary artery. In both these two groups the drug induced a marked increase of coronary sinus flow and a decrease of aortic pressure, while myocardial oxygen consumption was unchanged. This effect was dose related, since the rise in coronary flow was 47% with an injection of 0.15 mg/kg but only 23% with a dose of 0.05 mg-kg. These changes were short-lasting with values returning to normal within 10 min after the injection. We conclude that diltiazem is a potent dilator of coronary arteries.