Decrease In Coronary Resistance Research Articles

Sexually dimorphic adaptation of cardiac function: roles of epoxyeicosatrienoic acid and peroxisome proliferator-activated receptors.

Epoxyeicosatrienoic acids (EETs) are cardioprotective mediators metabolized by soluble epoxide hydrolase (sEH) to form corresponding diols (DHETs). As a sex‐susceptible target, sEH is involved in the sexually dimorphic regulation of cardiovascular function. Thus, we hypothesized that the female sex favors EET‐mediated potentiation of cardiac function via downregulation of sEH expression, followed by upregulation of peroxisome proliferator‐activated receptors (PPARs). Hearts were isolated from male (M) and female (F) wild‐type (WT) and sEH‐KO mice, and perfused with constant flow at different preloads. Basal coronary flow required to maintain the perfusion pressure at 100 mmHg was significantly greater in females than males, and sEH‐KO than WT mice. All hearts displayed a dose‐dependent decrease in coronary resistance and increase in cardiac contractility, represented as developed tension in response to increases in preload. These responses were also significantly greater in females than males, and sEH‐KO than WT. 14,15‐EEZE abolished the sex‐induced (F vs. M) and transgenic model‐dependent (KO vs. WT) differences in the cardiac contractility, confirming an EET‐driven response. Compared with M‐WT controls, F‐WT hearts expressed downregulation of sEH, associated with increased EETs and reduced DHETs, a pattern comparable to that observed in sEH‐KO hearts. Coincidentally, F‐WT and sEH‐KO hearts exhibited increased PPAR α expression, but comparable expression of eNOS, PPAR β, and EET synthases. In conclusion, female‐specific downregulation of sEH initiates an EET‐dependent adaptation of cardiac function, characterized by increased coronary flow via reduction in vascular resistance, and promotion of cardiac contractility, a response that could be further intensified by PPAR α.

Intact nitric oxide production is obligatory for the sustained flow response during hypercapnic acidosis in guinea pig heart

The mechanisms underlying hypercapnic coronary dilation remain unsettled. This study tests the hypothesis that flow dependent NO production is obligatory for the hypercapnic flow response. In isolated, constant pressure (CP) perfused guinea pig hearts a step change of arterial pCO(2) from 38.6 to 61.4 mm Hg induced a bi-phasic flow response with an early transient (maximum 60 s) and a consecutive persisting flow rise (121.6+/-6.6 (S.D.) % after 10 min). In contrast, when perfused with constant flow (CF), perfusion pressure only transiently (2 min) fell by 7.4+/-4.8 % following the step change of arterial pCO(2). In CP perfused hearts L-NAME (100 micromol/l) specifically abolished the delayed flow rise during hypercapnic acidosis (102.37+/-2.9% after 10 min), whereas the inhibitor had no effect on perfusion pressure response in CF perfused hearts. Under CP perfusion arterial hypercapnia resulted in a transient rise of coronary cGMP release (from 0.69+/-0.35 to 1.12+/-0.68 pmol/ml), which was abolished after L-NAME. Surprisingly, the K(+)ATP channel blocker glibenclamide did not have any significant effect on the hypercapnic flow response but largely blunted reactive hyperemia after a 20 s flow stop. The delayed steady state hypercapnic flow response in guinea pig heart requires intact NO production. The absence of a persisting decrease in coronary resistance under CF perfusion points to an important role of shear stress dependent NO production.

Angiotensin-Converting Enzyme Inhibition Restores Flow-Dependent and Cold Pressor Test–Induced Dilations in Coronary Arteries of Hypertensive Patients

Cold pressor test (CPT)-induced and flow-dependent epicardial coronary artery dilations are impaired in patients with hypertension. ACE inhibition can attenuate sympathetic coronary constriction and potentiate or restore endothelium-dependent relaxations. This study was designed to determine whether the ACE inhibitor perindoprilat can restore normal coronary dilative responses in hypertensive patients. Coronary vasomotor responses to CPT and to maximal increase of blood flow induced by papaverine were studied in 10 untreated patients with essential hypertension, no other risk factors, and angiographically normal coronary arteries before and after intravenous ACE inhibition by perindoprilat. Diameters of proximal and distal left anterior descending (LAD) and circumflex coronary arteries were measured by quantitative angiography. Estimates of coronary blood flow and resistance index were calculated with an intracoronary Doppler catheter in the distal LAD. Perindoprilat did not modify the hemodynamic responses to CPT and papaverine. In response to CPT, perindoprilat changed the epicardial coronary constriction (-8.4 +/- 5.8%, P < .001) into a significant dilation (+12.0 +/- 6.4%, P < .001). Perindoprilat significantly increased the coronary blood flow (from 33.7 +/- 10.0 to 57.9 +/- 20.5 mL/min, P < .01) and enhanced the decrease in coronary resistance (from 4.28 +/- 1.27 to 2.96 +/- 0.84 mm Hg.mL-1.min-1, P < .001) caused by CPT. Flow-dependent dilation of the proximal LAD was abolished in the control condition and was restored after perindoprilat (12.6 +/- 4.7%, P < .001). ACE inhibition restored CPT-induced and flow-mediated coronary artery dilations in patients with essential hypertension. These results indicate that impaired coronary vasomotor responses may be reversible in recently diagnosed hypertension.

Prolonged neonatal myocardial preservation with a highly buffered low-calcium solution

Optimal methods of myocardial preservation remain controversial in the neonate. This study compared prolonged hypothermic storage of neonatal hearts with modified University of Wisconsin solution (group I) with a solution formulated to promote anaerobic glycolysis by providing proton buffering with histidine (100 mmol/L) and exogenous glucose and insulin (group II). Hearts from piglets aged 3 to 5 days were given a single dose of either solution ( n = 6 each), subjected to 20 hours of global ischemia at 4° C, and reperfused with an erythrocyte-enhanced perfusate in an isovolumic Langendorff preparation. After 1 hour of reperfusion, in comparison with hearts preserved with University of Wisconsin solution, those in group II demonstrated (mean ± standard error of the mean) greater left ventricular developed pressure (101 ± 7 versus 62 ± 9 mm Hg, p < 0.01) and the first derivative of left ventricular pressure (816 ± 23 versus 614 ± 69 mm Hg · sec -1, p < 0.05). Diastolic indices were reduced to a similar degree in the two groups. Myocardial oxygen consumption was significantly greater (38.8 ± 2.4 versus 11.8 ± 2.4 μl oxygen · min · g -1, p < 0.01) in group II hearts. Group I hearts vasoconstricted (6% increase in coronary vascular resistance) in response to an intracoronary infusion of acetylcholine (20 nmol·min -1); in contrast, acetylcholine produced coronary dilation in group II hearts (5% decrease in coronary resistance, p < 0.02) that was similar to that observed in nonischemic control hearts. These results demonstrate enhanced preservation of myocardial contractility, oxidative metabolism, and vascular function in neonatal hearts provided by a solution designed to buffer protons and promote anaerobic glycolysis during ischemia. (J THORAC CARDIOVASC SURG 1994;108:772-9)

Potent vasoconstriction mediated by endothelin ETB receptors in canine coronary arteries.

Endothelin (ET) 1 is a powerful vasoconstrictor of coronary arteries and may play a role in coronary spasm, atherosclerosis, and myocardial infarction. Previous studies have demonstrated that intracoronary ET caused marked vasoconstriction of the coronary circulation; however, it remains unclear which ET receptor types are present and which of these receptors mediate this vasoconstriction. To characterize the ET receptors present in dog coronary arteries, competition binding assays with radiolabeled ET-1 using ET-1, ET-3, ETA receptor antagonist BQ-123, and sarafotoxin S6c were performed. Three binding sites were apparent in the left circumflex coronary artery: an ETA receptor, a high-affinity ETB receptor, and a lower-affinity ETB receptor. To investigate the in vivo effects of ETB receptor stimulation, intracoronary sarafotoxin S6c, a highly selective ETB agonist, was administered in anesthetized open-chest dogs in a constant-pressure coronary artery perfusion model. Sarafotoxin S6c doses of 0.1 and 0.3 microgram caused a transient pronounced decrease in coronary resistance. Doses of 1.0 and 3.0 micrograms caused marked decreases in coronary diameter and blood flow, as well as myocardial segmental shortening. These effects of sarafotoxin S6c were not inhibited by constant infusion of BQ-123. The present study demonstrates the presence of ETB receptors in the canine coronary circulation that can mediate both vasodilation and vasoconstriction. These findings have important implications for an understanding of the pathophysiological function of ET in the coronary vasculature and for the development of therapeutically effective ET antagonists.

Endothelium-dependent effects of platelet-activating factor in the coronary circulation.

In experiments on anesthetized dogs, the effect of intracoronary administration of different doses of platelet-activating factor (PAF) has been investigated. One of the branches of the left coronary artery was catheterized via the main carotid artery. The coronary artery was autoperfused with blood from the subclavian artery. Intracoronary administration of small doses of PAF (100 and 200 ng/kg) caused a dose-dependent decrease in coronary resistance (CR) and an increase in coronary blood flow (CF). When 200 ng/kg of PAF was used, these changes were 30 and 34% vs. control, respectively. Dose increase to 300 ng/kg led to a biphasic reaction. Intracoronary administration of larger PAF doses produced opposite effects, i.e., increase in CR and decrease in CF. Chemical de-endothelialization by saponin (5 mg/5 ml, 1.5-2 min) transformed coronary dilation to small doses of PAF to constriction. The CR rose from 2.8 +/- 0.3 to 5.6 +/- 0.9 mm Hg/ml/min (p < 0.01) and CF dropped two-fold. The PAF receptor antagonists BN 52021 (6 mg/kg) and WEB 2086 (3 mg/kg) completely abolished PAF-induced coronary reactions. Hence, PAF-induced vasodilation of the canine coronary circulation is endothelium dependent.

Comparison of coronary vasodilation with intravenous dipyridamole and adenosine

Although both intravenous dipyridamole and adenosine have been used to produce coronary valuation during cardiac imaging, the relative potency of the commonly administered doses of these agents has not been evaluated, Accordingly, the coronary and systemic hemodynamic effects of intravenous adenosine (140 μg/kg per min) and intravenous dipyridamole (0,56 mg/kg over 4 min) were compared with a maximally dilating dose of intracoronary papaverine in 15 patiente. Coronary blood flow responses were assessed using a Doppler catheter in a nonstenotic coronary artery. The protocol was discontinued in two patients because of transient asymptomatic atriaventricular (AV) block during adenosine infusion.The mean heart rate increased more with adenosine (11 ± 9 beats/min) and dipyridamole (11 ± 7 beats/min) than with papaverine (4 ± 3 beats/min, p < 0.05 vs. adenosine and papaverine). The mean arterial pressure decreased less with dipyridamole (−20 ± 3 mm Hg) and papaverine (−9 ± 4 mm Hg) than with adenosine (t-16 ± 5 mm Hg, p < 0.01 vs. dipyridamole and papaverine). The peak/rest coronary blood flow velocity ratio was greater with papaverine (3.9 ± 1.1) than with adenosine (3.4 ± 1.2, p ≤ 0.05 vs. papaverine) or dipyridamole (3.1 ± 1.2, p < 0.01 vs. papaverine). A larger decrease in coronary resistance as measured by the coronary vascular resistance index occurred with papaverine (0.25 ± 0.06) and adenosine (0.26 ± 0.09) than with dipyridamole (0.31 ± 0.10, p < 0.01 vs. papaverine, p < 0.05 vs. adenosine). The maximal coronary blood flow velocity was reached more quickly after the start of adenosine infusion (55 ±34 s) than after the start of dipyridamole infusion (287 ± 101 s, p < 0.0001). The proximal coronary artery diameter was unchanged during dipyridamole or adenosine infusion. Thus, the vasodilator potency of adenosine was greater than that of dipyridamole when changes in coronary resistance were considered, though increases in flow were similar with the two agents. The rapid onset of action of adenosine compared with that of dipyridamole may allow a reduction in the duration or diagnostic studies. The incidence of AV block during adenosine infusion requires evaluation in larger studies.

Action of synthetic atrial natriuretic factor on contractility and coronary perfusion in isolated working rat hearts

The effects of atrial natriuretic factor were studied in isolated working rat hearts. Increasing concentrations, from 0.1 to 100 nM, of a synthetic rat-ANF (atrial natriuretic factor) were added to the perfusate. ANF had no effect on heart rate, contraction cycle or coronary resistance in concentrations up to 3 nM. At concentrations above 10 nM, peak dP/dt and oxygen consumption showed a slight dose-dependent increase. The greater decrease in coronary resistance, and the lowering of coronary oxygen extraction, suggest that ANF has a small coronary dilating effect. No arrhythmias were observed at any concentration of ANF.

Calcitonin gene-related peptide increases coronary flow and decreases coronary resistance

Calcitonin gene-related peptide (CGRP) is a potent vasodilator, but its effects on in situ ventricular function are unknown. We studied effects of intracoronary CGRP (100, 200, and 600 pmole/min, for 10 min) in 21 open-chest chloralose-anesthetized dogs. Systemic, pulmonary, left ventricular (LVP), central venous, and pulmonary capillary wedge pressures were continuously monitored. Left ventricular wall thickness (WT) and circumflex coronary blood flow were also measured. CGRP was infused into the proximal circumflex artery. During CGRP infusion there were no changes in heart rate, cardiac index, pulmonary artery pressure, or systemic vascular resistance, no percentage change in ventricular WT, and no changes in dWT/dt, peak dP/dt, or the slope of endsystolic points on WT/LVP loops. But there were significant changes in coronary flow (CQ), coronary resistance (CRES) and mean arterial blood pressure (MAP) from control (C)∗ ( P < 0.05). C 100 pmole 200 pmole 600 pmole CQ (% change from C) 0 38 ± 12∗ 39 ± 9∗ 57 ± 19∗ CRES (mm Hg/ml/mn) 2.25 1.3 ± 0.1∗ 1.2 ± 1∗ 0.8 ± 0.1∗ MAP (mm Hg) 90 79 ± 6 63 ± 8∗ 52 ± 5∗ CGRP is a potent coronary artery vasodilator causing notable dose-dependent decreases in coronary resistance and a rise in myocardial flow, despite a decreased MAP (all P < 0.05). CGRP does not affect ventricular contractility in vivo.

Effects of left ventricular receptor stimulation on coronary blood flow in conscious dogs.

The present study was undertaken to determine the effects of intracoronary administration of the veratrum alkaloid veratridine on coronary blood flow and resistance in conscious, chronically instrumented intact and sinoaortic denervated dogs. Ten dogs were instrumented with a Doppler flow probe on the left anterior descending coronary artery. A chronic catheter was placed in the left circumflex coronary artery and in the aorta and left atrium. A Konigsberg pressure cell was placed in the left ventricle, and pacing leads were attached to the left atrium and ventricle. While heart rate was kept constant, bolus intracoronary injections of veratridine (0.1-0.4 microgram/kg) were administered in the unblocked state after beta 1-receptor blockade, after alpha-receptor blockade, and after cholinergic blockade. In the unblocked state, late diastolic coronary resistance fell by 34.7 +/- 5.0%. The maximum response was achieved at a time when arterial pressure was not significantly different from control. After beta 1-blockade, coronary resistance fell by 29.1 +/- 7.9%. After combined alpha- and beta-blockade, coronary resistance fell by 25.4 +/- 6.5% in response to veratridine. The addition of atropine completely blocked the decrease in coronary resistance, changing it by an average of -0.10 +/- 2.5%. The responses in sinoaortic denervated dogs were similar to those in intact animals. The response was abolished by vagotomy. We conclude that cardiac receptor stimulation causes a reflex decrease in coronary resistance in the awake dog that is completely accountable by a cholinergic mechanism.

Post-ischemic cardiac chamber stiffness and coronary vasomotion: the role of edema and effects of dextran

Contributions of edema to left ventricular (LV) chamber stiffness and coronary resistance after ischemia were studied in isolated buffer-perfused rabbit hearts, with constant LV chamber volume, subjected to 30 min global ischemia and 60 min reperfusion. During reperfusion hearts were perfused with standard buffer or with 3% dextran to increase oncotic pressure and decrease water content. LV chamber volume was adjusted to an initial diastolic pressure (LVEDP) of 10 mmHg. In nonischemic hearts (n = 6) LVEDP was 11 +/- 0.3 mmHg and water content was 5.0 +/- 0.1 ml/g dry weight after 90 min of perfusion. In untreated ischemic hearts (n = 8) LVEDP was 51 +/- 4 mmHg and water content was 6.0 +/- 0.1 ml/g dry weight after 60 min reperfusion (P less than 0.001 v. nonischemic). In dextran-treated ischemic hearts (n = 8) LVEDP was 38 +/- 3 mmHg (P less than 0.05 v. untreated ischemic) and water content was 5.2 +/- 0.1 ml/g dry weight (P less than 0.001 v. untreated ischemic). Coronary resistance in untreated ischemic hearts increased by 26% from 2.0 +/- 0.06 to 2.6 +/- 0.06 mmHg/ml/min after 60 min reperfusion. In treated hearts coronary resistance increased by 16% from 1.9 +/- 0.09 to 2.2 +/- 0.09 mm/Hg/ml/min (P less than 0.01 v. untreated ischemic). To determine whether the decrease in coronary resistance with dextran could be ascribed to active vasodilation, dilator responses to 2 min hypoxia or 10(-4)M adenosine were tested in nonischemic and reperfused ischemic hearts. Dilator responses were stable in nonischemic hearts or hearts reperfused after 15 min ischemia but after 30 min ischemia the dilator response to hypoxia was reduced by 72% (P less than 0.025) and the dilator response to adenosine was eliminated (P less than 0.02). Thus the response to dextran was unlike that of a direct vasodilator. These data suggest that myocardial edema plays a significant role in maintaining increased ventricular chamber stiffness and coronary resistance during reperfusion after ischemia.

Effect of diltiazem on coronary reactive hyperemia in patients with flow-limiting coronary artery stenosis

The acute effects of diltiazem on coronary reactive hyperemia were studied in 12 patients with flow-limiting coronary stenosis. Reactive hyperemia was elicited by injection of 8 ml contrast medium into the left coronary artery, while coronary sinus blood flow and left ventricular and aortic pressures were continuously recorded. Relative magnitude of hyperemia was estimated by the ratio of coronary flow at peak hyperemia to baseline flow (hyperemic ratio). Coronary resistance was calculated as the ratio between mean aortic pressure minus left ventricular mean diastolic pressure and coronary sinus blood flow. The 12 patients studied had flow-limiting coronary stenosis since their hyperemic ratio was significantly restrained when compared to that of seven control subjects (1.45 ± 0.17 vs 2.02 ± 0.24, respectively; < 0.001). The intravenous infusion of ditiazem (0.30 mg · kg −1) reduced heart rate, mean aortic pressure, and myocardial oxygen consumption (all p < 0.001). After diltiazem the hyperemic ratio was blunted when compared to the basal state (1.36 ± 0.15 vs 1.45 ± 0.17, respectively; p < 0.05), and hyperemia volume was reduced (−33%; p < 0.001). The decrease in coronary resistance at peak hyperemia was also reduced from −30 ± 8% to −25 ± 8% ( p < 0.05). We conclude that diltiazem blunts coronary reactive hyperemia in patients with demonstrated flow-limiting coronary stenosis. This reduction of coronary flow response to a hyperemic stimulus could favorably influence blood flow distribution in patients with significant coronary stenosis.

Effects of nicardipine on left ventricular function and energetics in man

The effects of nicardipine, a new dihydropyridine calcium antagonist, on left ventricular function and energetics were studied in 13 patients. Nicardipine was administered as a 2 mg bolus (i.v.) followed by an infusion titrated to maintain a 10–20 mm Hg decrease in systolic pressure. Nicardipine increased heart rate 19% ( P < 0.001) while left ventricular end-diastolic pressure was not significantly changed and stroke volume (ml) increased 13% ( P < 0.01). Peak values for the first and second time derivatives of left ventricular pressure were increased by 26% ( P < 0.01) and 50% ( P < 0.02) respectively. Peak aortic blood flow, peak aortic blood acceleration, and the peak rate of change of ejection power were increased 86% ( P < 0.001), 123% ( P < 0.01), and 113% ( P < 0.001), respectively. Stroke work was not changed during nicardipine infusion. External power increased by 40% ( P < 0.01); however, the ratio of oscillatory to total power was not significantly different. Although the product of heart rate and systolic aortic pressure was not significantly altered with nicardipine, myocardial oxygen consumption increased 18% ( P < 0.02) with a disproportionate increase in coronary blood flow of 41% ( P < 0.001) and decrease in coronary resistance of 39% ( P < 0.001). The time constant for left ventricular isovolumic relation decreased 22% ( P < 0.001) during nicardipine infusion while the minimum value of dP dt was unchanged. Thus, when administered intravenously in man, nicardipine is a potent coronary and systemic vasodilator producing reflex tachycardia, increased indices of myocardial contractile state, and improved isovolumic relaxation with an associated increase in myocardial oxygen consumption.

Inhibition by AD 6 (8-monochloro-3-beta-diethylaminoethyl-4-methyl-7-ethoxycarbonylmetoxy coumarin) of platelet aggregation in dog stenosed coronary artery

The action of ADA as an anti-thrombotic agent was studied in a model of coronary artery thrombosis and on platelet aggregation in the dog. AD 6 (10 - 100 pM) in vitro inhibited aggregation induced by ADP, epinephrine, collagen and PAF (platelet aggregating factor) used at their threshold concentration for maximal aggregation. Arterial thrombosis was induced in a coronary vessel by critically reducing (about 70%) the vessel lumen. Thrombus formation was estimated by measuring coronary flow in the stenosed vessel. Using this procedure on the left descending coronary artery (LAD), we obtained reproducible blood flow changes in 18 dogs. AD 6was given i.v. at three different doses. At 0.25 mg/kg two out of four dogs showed decreased thrombus formation at the stenosis site. Seven out of eleven dogs treated with 0.5 mg/kg and two out of three treated with 1.5 mg/kg showed decreased thrombus formation. Major decreases in coronary resistance, evaluated by measuring blood flow in the unstenosed left circumflex artery (LCX), were evident only after the highest dose. We conclude that AD 6 has an inhibitory action on dog platelet aggregation and reduces thrombus formation in a stenosed coronary vessel.

Coronary and systemic hemodynamic effects of nicardipine

Systemic and coronary hemodynamic effects of a new dihydropyridine calcium antagonist, nicardipine, were studied in 15 patients. Nicardipine was administered as a 2-mg bolus intravenously followed by an infusion titrated to maintain a 10 to 20-mm Hg decrease in systolic pressure. Nicardipine increased both heart rate from 69 ± 3 to 81 ± 3 beats/min and cardiac output from 7.3 ± 0.5 to 9.9 ± 0.5 liters/min (both p < 0.001) as systemic vascular resistance decreased from 1,183 ± 70 to 733 ± 33 dynes s cm −5 (p < 0.001). Left ventricular end-diastolic pressure remained constant, at 14 ± 1 vs 14 ± 1 mm Hg as stroke volume increased from 108 ± 6 to 123 ± 6 ml/m 2 (p < 0.001). Coronary blood flow increased from 102 ± 9 to 147 ± 13 ml/min, while coronary resistance decreased from 1.17 ± 0.1 to 0.7 ± 0.1 mm Hg/ml/min (both p < 0.001). Heart rate-systolic blood pressure product did not change (104 ± 5 vs 106 ± 5 beats/min mm Hg × 10 −2, difference not significant) with drug administration. At the same heart rate before and during nicardipine administration (using atrial pacing in 6 patients), significant augmentation of coronary flow was still observed. Thirteen of 14 patients showed a greater percent decrease in coronary resistance than systemic vascular resistance. Nicardipine differs from other calcium antagonists with respect to consistent augmentation of coronary blood flow. This effect appears to be the result, in part, of increased potency in the coronary bed compared with the systemic vascular bed.

Chest pain and “normal” coronary arteries—Role of small coronary arteries

To study the mechanism of chest pain in patients with insignificant epicardial coronary artery disease, 50 patients underwent great cardiac vein (GCV) flow, oxygen content and lactate determinations at rest and during pacing, and left ventricular end-diastolic pressure (LVEDP) measurements at rest and after pacing. Twenty-four patients having typical chest discomfort during pacing demonstrated significantly lower increase in flow from baseline (36 ± 18% versus 86 ± 24%, p < 0.001) and decrease in coronary resistance (−17 ± 12% versus −43 ±7%, p < 0.001) compared with 26 patients without pacing-induced chest pain, despite no significant difference in myocardial oxygen consumption (MVO 2) between the 2 groups. Lactate consumption at a heart rate (HR) of 150 beats/min was significantly less (28.3 ± 21.5 versus 51.3 ± 35.8 mM· ml/min, p < 0.001) and the increase in LVEDP from rest to after pacing was significantly greater (5 ±2 versus 1 ± 2 mm Hg, p < 0.001) in the chest pain group. After administration of ergonovine, 0.15 mg intravenously, to 46 of these patients, 31 had typical pain either at rest (1 patient) or during pacing. This group had significantly lower increase in flow (38 ± 20% versus 107 ± 38%, p < 0.001), and decrease in coronary resistance (-16 ± 12% versus −45 ± 11%, p < 0.001) compared with the 15 patients not having chest pain, despite no significant difference in MVO 2 between the 2 groups. Patients with chest pain also had lower lactate consumption at a HR of 150 beats/min (39.2 ± 23.6 versus 65.3 ± 46.3 mM·ml/min, p < 0.01), greater arterial-GCV oxygen difference (12.5 ± 1.3 versus 11.6 ± 1.0 ml O 2/100 ml, p < 0.05), and a more marked increase in LVEDP from rest to after pacing (11 ± 3 versus 5 ± 2 mm Hg, p < 0.001). Quantitative coronary arteriography demonstrated no significant luminal narrowing of the epicardial coronary arteries in response to ergonovine. These data are consistent with the hypothesis that some patients with chest pain and angiographically normal epicardial coronary arteries have dynamic abnormalities of the small coronary arteries or coronary microcirculation that cause abnormal vasodilator reserve or vaso-constriction, resulting in myocardial ischemia and angina pectoris.

Nitroglycerin and nitroprusside increase coronary blood flow in dogs by a mechanism independent of prostaglandin release

The hypothesis that local release of vasodilator prostaglandins mediates, in part, the decrease in coronary resistance after nitroglycerin (NG) administration was tested. NG (60 μg/min) and nitroprusside (NP) (30 μg/min) were infused for 10 minutes into the left circumflex coronary artery of 9 open-chest, chloralose-anesthetized dogs before and after blockade of prostaglandin synthesis with indomethacin (5 mg/kg). Also, to eliminate the effects of reflex tachycardia on the responses to NG and NP, these experiments were repeated in 6 dogs with heart rate held constant by pacing. NG infusion into dogs without pacing resulted in a maximal increase in coronary blood flow of 55% and after 8 minutes of infusion an increase of 20%, from a baseline of 57 ml/min. NP infusion resulted in a maximal increase in blood flow of 89% and after 8 minutes an increase of 71%, from a baseline of 64 ml/min. In dogs with heart rate held constant, NG infusion caused a maximal increase in coronary artery blood flow of 132% and after 8 minutes of infusion an increase of 18%, from a baseline of 48 ml/min; NP infusion resulted in increase from 51 ml/min of 132% and 62%, respectively. In neither group of dogs did indomethacin significantly change the increases in coronary blood flow or decreases in coronary resistance to NG or NP. Thus, both NG and NP, when infused into the coronary artery of dogs, cause increases in coronary blood flow and decreases in coronary resistance by a mechanism which is independent of prostaglandin release.

Characterization of the beta-adrenoceptors in coronary vasculature of the dog heart.

In the present study an attempt has been made to characterize the beta-adrenoceptors of coronary vasculature in dog. Blockade of beta 1-adrenoceptors with ICI 50172 or beta 2-adrenoceptors with RB2 showed only partial antagonism of isoprenaline-induced decrease in coronary resistance. However, combined treatment with ICI 50172 and RB2 completely blocked the isoprenaline-induced fall in coronary resistance. Essentially similar results were observed in controlled heart rate experiments where the drugs were administered locally into the coronary circulation. These results demonstrate the involvement of both beta 1 and beta 2 adrenoceptors in isoprenaline-induced coronary vasodilation.

The effect of mild-to-moderate mental stress on coronary hemodynamics in patients with coronary artery disease.

Eleven men with coronary artery disease were studied to determine whether they would manifest inappropriate coronary vasoconstriction in response to mental stress. Mental stress was induced by having the patient perform difficult mental arithmetic in time with a clicking metronome. Aortic blood pressure and thermodilution coronary sinus blood flow were recorded continuously before and during the mental arithmetic. For the group, heart rate rose from 70 to 82 beats/min, systolic blood pressure rose from 161 to 181 mm Hg and diastolic blood pressure rose from 71 to 78 mm Hg. Coronary resistance decreased by 16%. The index of myocardial oxygen consumption rose by 40%, and there was an equivalent rise in coronary sinus blood flow of 41%, with no changes in coronary arteriovenous oxygen difference. Because the increase in myocardial oxygen consumption was accompanied by a proportional increase in coronary sinus blood flow, a decrease in coronary resistance and no change in myocardial oxygen extraction, we conclude that the response of patients with coronary artery disease to at least moderately severe mental stress is not characterized by abnormal coronary vasoconstriction.

Effects of minoxidil on coronary collateral flow and acute myocardial injury following experimental coronary artery occlusion.

Although vasodilators may improve left ventricular function when left ventricular failure develops in patients with acute myocardial infarction, their effect on the coronary collateral circulation and on infarct size is not well established. Accordingly, the effects of minoxidil, a potent coronary and peripheral vasodilator, on collateral blood flow and ischaemic damage following coronary occlusion were studied. In open-chest anaesthetised dogs, two 20 min occlusions of the left anterior descending coronary artery were carried out. Acute myocardial injury, as reflected by epicardial S-T segment elevation and regional myocardial blood flow, measured by the radio-labelled microsphere technique, were determined during each occlusion. Minoxidil (1 mg·kg−1) was administered before the second occlusion and reduced mean arterial pressure from 15.7 ± 0.5 to 9.3± 0.4kPa (118± 4 to 70± 3 mmHg). Regional myocardial blood flow to the nonischaemic zone rose from 91 ± 7 to 225 ± 36 cm3·min−1·100−1, while flow to the border and centre of the ischaemic zone fell significantly (from 48 ± 2 to 15 ± 2 and from 33 ± 5 to 6± 2 cm3·min−1 ·100 g−1, respectively). At the same time, myocardial ischaemic injury increased: mean S-T segment elevation (S-T) and the number of sites exhibiting S-T segment elevation increased from 2.6 ± 0.5 to 5.2± 0.5 mV and from 4.1 ± 0.5 to 7.0 ± 0.5 sites, respectively. Thus, although minoxidil increased regional myocardial blood flow to the normal myocardium, it further decreased flow to the ischaemic area and intensified ischaemic damage. The reduction of collateral flow may result not only from a fall in perfusion pressure but also from the decrease in coronary resistance in the normal myocardium, leading to a redistribution of coronary blood flow.