Circumflex Coronary Blood Flow Research Articles

Tilisolol hydrochloride dilates coronary arteries through an ATP-sensitive K+-channel opening mechanism in dogs

Tilisolol is a beta-blocking agent with vasodilatory properties that was recently shown to possess a potassium (K+) channel opening activity. We investigated whether tilisolol has vasodilatory effects on coronary circulation in dogs. Mongrel dogs were chronically instrumented for measurements of circumflex coronary artery diameter (CoD) and coronary blood flow (CBF). We compared the effects of tilisolol on dog coronary arteries with those of two beta-blockers, propranolol and arotinolol. Both propranolol (1 mg/kg, intravenously, i.v.) and arotinolol (0.25 mg/kg, i.v.) decreased CoD and increased coronary vascular resistance (CVR). Tilisolol (2 mg/kg, i.v.) decreased CVR but had no significant effect on CoD. To investigate the mechanism of the coronary action of tilisolol, we examined differences in the response to tilisolol in the absence and presence of glibenclamide, an ATP-sensitive K+ channel blocker. Tilisolol (1,2,4, and 8 mg/kg, i.v.) produced a dose-dependent decrease in CVR without glibenclamide, whereas pretreatment with glibenclamide significantly suppressed this effect. Without glibenclamide, tilisolol had no significant effect on CoD at doses of 1-4 mg/kg (i.v.). However, at the higher dose of 8 mg/kg (i.v.), tilisolol significantly increased CoD (1.00 +/- 0.15%, p < 0.01). After pretreatment with glibenclamide, tilisolol (1-8 mg/kg, i.v.) produced a significant decrease in CoD. Therefore, we concluded that tilisolol exerts its vasodilatory effect on the coronary circulation through an ATP-sensitive K+ channel opening mechanism, and that its vasodilatory action is more prominent in coronary resistance vessels than in large coronary arteries.

In vivo vasodilatory action of atrial natriuretic peptides in canine coronary circulation.

To investigate the role that atrial natriuretic peptides (ANP) play in regulating coronary circulation in vivo, we examined the effects of intravenous (iv) ANP and/or HS-142-1 (HS), a specific ANP receptor antagonist, in chronically instrumented dogs on circumflex coronary artery diameter (CoD) and coronary blood flow (CBF). At ANP plasma levels of 366.7, 785.0, and 1850.0 pg/ml, which were induced by continuous iv infusion of ANP at 25, 50, and 100 ng/kg per min respectively, ANP increased CoD by 1.2 +/- 0.3%*, 2.2 +/- 0.5%*, and 2.9 +/- 0.5%*, and decreased mean systemic blood pressure by 2.3 +/- 1.0%, 4.3 +/- 1.5%* and 5.3 +/- 1.8%* (*p < 0.05), respectively. A significant increase in the plasma cGMP level was also observed. However, neither CBF nor heart rate changed significantly. Pretreatment with HS (3 mg/kg) almost completely suppressed these hemodynamic effects of ANP along with inhibiting the increases in the plasma cGMP level. However, under control conditions, HS itself (3 mg/kg, iv) produced no significant changes in coronary parameters. Thus, ANP significantly increased CoD at plasma levels 10- to 20-fold higher than those in the control. These findings suggest that in patients under pathological conditions such as severe congestive heart failure increased endogenous ANP may contribute to the regulation of coronary circulation as a compensatory mechanism. It may also have direct vasodilatory effects on epicardial vessels, since HS suppressed both its coronary effects and the increase in plasma cGMP levels. However, in normal subjects, endogenous ANP may have little direct effect on coronary circulation.

Effects of stellate ganglion block on cardiac coronary circulation

Since the stellate ganglion contains cardiac sympathetic nerves, stellate ganglion block (SGB) may influence cardiac and coronary hemodynamics. We investigated this influence of SGB by measuring the heart rate (HR), the left circumflex coronary artery blood flow (CBF), the maximum rate of increase of the left ventricular pressure (LV max dP/dt), the cardiac output (CO), the myocardial oxygen consumption (MVO2), and the myocardial oxygen extraction ratio (MOER) in nine dogs before and after performing SGB by means of injection of 2 ml 1% mepivacaine. Left SGB resulted in a decrease of 10% in CBF and a decrease of 15% in LV max dP/dt, but HR, CO, and MVO2 remained unchanged. On the other hand, right SGB resulted in a decrease of 30% in CBF and a decrease of 25% in LV max dP/dt, as well as a decrease of 20% in HR, 15% in CO, and 25% in MVO2. SGB on either side resulted in an increase in MOER that was slight but nonetheless significant (P<0.05) in that it suggested a relative deficit in CBF with respect to MVO2. Inhalation of 100% oxygen decreased MOER to the pre-SGB level in either side, thus improving the myocardial oxygen supply-demand relationship. This study suggests the possibility that SGB has deteriorative effects on the myocardial oxygen supply-demand relationship. Those effects were counteracted by the inhalation of 100% oxygen.

Selective Impairment of Vagally Mediated, Nitric Oxide–Dependent Coronary Vasodilation in Conscious Dogs After Pacing-Induced Heart Failure

Activation in conscious dogs of the carotid chemoreflex or cardiac receptors results in coronary vasodilation that is mediated by a vagal cholinergic mechanism. Our previous study showed that the coronary vasodilation following activation of carotid chemoreflex is also mediated by nitric oxide (NO). In addition, NO production is depressed after the development of heart failure. Therefore, we hypothesized that the coronary vasodilation after activation of reflexes that elicit efferent vagal coronary vasodilation would be blunted in conscious dogs after pacing-induced heart failure due to the disappearance of NO. Mongrel dogs were chronically instrumented using sterile techniques for measurements of systemic hemodynamics and left circumflex coronary blood flow (CBF). Without the heart rate controlled, intra-atrial injection of veratrine (4 micrograms/kg) caused bradycardia (-36 +/- 3 beats per minute). With the heart rate controlled, veratrine increased CBF in a dose-dependent manner: for example, 4 micrograms/kg of veratrine increased CBF by 54 +/- 5% from 38 +/- 4.9 mL/min (P < .05). The increases in CBF induced by veratrine were markedly blunted by nitro-L-arginine (NLA). Activation of carotid chemoreflex by nicotine increased CBF by 121 +/- 9% from 32 +/- 4 mL++/min (P < .05) with the heart rate controlled and caused bradycardia (-32 +/- 5 beats per minute) without the heart rate controlled. After the development of heart failure, in response to activation of carotid chemoreflex or cardiac receptors the coronary vasodilation was almost abolished (CBF increased by only 23 +/- 8% or 11 +/- 3%, P < .05 compared with control). There still was a marked bradycardia after injections of nicotine or veratrine (-50 +/- 11 or -48 +/- 7 beats per minute). Our results indicate that vagally mediated coronary vasodilation is selectively attenuated in conscious dogs after pacing-induced heart failure, whereas the vagally mediated bradycardia is preserved. Since muscarinic receptor-induced coronary vasodilation is mediated by NO, the disappearance of NO from blood vessels leads to a defect in the integrated neural regulation of coronary blood flow and myocardial function during heart failure.

930-106 Potentiation of Atrial Natriuretic Peptide Mediated Coronary Vasodilatation by Beta Adrenergic Stimulation

Increases in circulating atrial natriuretic peptide (ANP) and norepinephrine (NE) occur during the evolution of heart failure. While NE may augment ANP synthesis, a modulating action upon the biological actions of ANP is unclear. In vitro, the beta-adrenergic agonist ( β A) isoproterenol (ISO) down-regulates the AN Pclearance receptor which indirectly augments the biologically active ANP receptor. In vivo, the β A antagonist propranolol attenuates natriuretic peptide mediated coronary vasodilatation. We therefore hypothesized that, in vivo, ISO would potentiate subthreshold coronary vasodilating actions of ANP. Five anesthetized dogs were instrumented to measure left circumflex (LCx) coronary blood flow (CBF). Intracoronary (IC) ANP (100 nglbolus) was administered in the LCx before and after the IC-ISO (1 mg over 15 min). Acetylcholine (ACh 1 nglkg) and sodium nitroprusside (SNP 100 nglkg) were administered to determine the influence of ISO on endothelial dependent and independent vasodilatation. In the control state ( * p &lt; 0.05). both IC-ACh and IC-SNP resulted in marked coronary vasodilatation (▵ CBF ACh 76 ± 6 * mllmin and SNP 37 ± 7 * ) while IC-ANP did not alter CBF. IC-ISO increased basal CBF (52 ± 11 ml/min to 87 ± 21 * ) and LV contractility (+ dP/dt 1803 ± 93 mmHgL/sec to 2395 ± 151 * ). and decreased coronary vascular resistance (CVR 2.6 ± 0.3 RU to 1.4 ± 0.2 * ) and coronary perfusion pressure (105 ± 7 mmHg to 87 ± 7 * ). In the presence of ISO, IC-ANP significantly increased CBF (87 ± 21 ml/min to 117 ± 26 * ) while ACh and SNP-mediated coronary vasodilation were similar to control changes. In summary, IC-ISO augments ANP-mediated coronary vasodilatation but does not enhance ACh or SNP mediated vasodilatation. This observation suggests a functional link between the natriuretic peptide system and the β -adrenergic system in the control of CBF. The elevation in circulating catecholamines observed in CHF may, therefore, serve in part to augment endogenous ANP-mediated coronary vasodilation and thus be coronary protective in the progression of CHF.

Nicotine exacerbates postischemic contractile dysfunction of 'stunned' myocardium in the canine model. Possible role of free radicals.

There is no doubt that high doses of nicotine have deleterious effects on cardiovascular function. However, the effects of lower and more clinically relevant doses of nicotine have received little attention, and the consequences of nicotine in the setting of ischemia/reperfusion are virtually unknown. The first objective of this study was to determine whether nicotine, given either before or after ischemia and at a dose mimicking that absorbed by humans during inhalation of one cigarette, exacerbated contractile dysfunction of canine myocardium "stunned" by brief transient ischemia. The second aim was to provide preliminary insight into the mechanism of action of nicotine on the stunned myocardium. Anesthetized open chest dogs underwent 15 minutes of left anterior descending coronary artery (LAD) occlusion and 3 hours of reperfusion. In protocol 1, each dog was randomized to receive nicotine at 30 minutes before LAD occlusion (80 micrograms/kg dissolved in 15 mL of saline, given i.v. over 10 minutes), nicotine at 1 hour after reperfusion (80 micrograms/kg as above), or saline. Segment shortening (assessed by sonomicrometry) in both the LAD and circumflex beds, heart rate, arterial pressure, and coronary blood flow were monitored throughout the protocol, and regional myocardial blood flow (by injection of radiolabeled microspheres) was measured during LAD occlusion and at 5 minutes after nicotine/saline infusion. All groups were equally ischemic during LAD occlusion. As expected, segment shortening in the LAD bed of control animals was depressed after reperfusion, averaging 54 +/- 6% and 50 +/- 4% of baseline at 1 and 3 hours after reflow. Nicotine given before occlusion did not alter segment shortening before LAD occlusion and did not exacerbate dyskinesis during occlusion. However, segment shortening in the LAD bed recovered to only 29 +/- 9% and 22 +/- 5% of baseline at 1 and 3 hours after reperfusion (P < .01 versus corresponding control values). Furthermore, nicotine given at 1 hour after reperfusion caused a significant deterioration in segment shortening, from 47 +/- 11% immediately before infusion (P = NS versus control at 1 hour after reflow) to 7 +/- 13% at 3 hours after reperfusion (P < .01 versus 1 hour after reperfusion; P < .01 versus control at 3 hours after reflow). This dose of nicotine did not alter heart rate, arterial pressure, or blood flow; did not cause myocyte necrosis; and did not impair contractile function in the normally perfused circumflex bed. In protocol 2, all dogs received a continuous infusion of the free radical scavenging agent N-2-mercaptopropionyl glycine (MPG; 50 mg.kg-1 x h-1) beginning 45 minutes after reperfusion and, at 1 hour after reflow, received either nicotine or saline as described in protocol 1. MPG given after reperfusion did not alter contractile function in control animals. However, MPG prevented the deterioration in postischemic function observed with nicotine in protocol 1; segment shortening averaged 54 +/- 11% and 56 +/- 9% of baseline at 1 and 3 hours after reperfusion (P = NS). Nicotine, given before occlusion or after reflow, significantly exacerbated contractile dysfunction of post-ischemic stunned myocardium in this canine model. This exacerbated dysfunction was not a secondary consequence of unfavorable alterations in hemodynamics or coronary blood flow and may be mediated by free radicals acting on myocytes that had been reversibly injured by the brief ischemic insult.

Defective endothelium-mediated control of coronary circulation in conscious dogs after heart failure

The goal of this study was to determine whether coronary endothelial function was altered after pacing-induced heart failure in conscious dogs. Fourteen mongrel dogs were chronically instrumented for measurements of systemic hemodynamics, left circumflex coronary artery diameter (CD) and blood flow, and for left ventricular pacing for 4 wk. Heart failure developed during this pacing regimen and was characterized by a significant reduction in arterial pressure, an increase in left atrial pressure, a resting tachycardia, a depression of left ventricular dP/dt to isoproterenol injection, a significant reduction of the slope of the end-systolic pressure-diameter relationship, and all of the characteristic clinical signs. During heart failure, the dilation of CD after release of a brief coronary artery occlusion, acetylcholine, and arachidonic acid was attenuated, whereas prostaglandin (PG) I2- and nitroglycerin-induced dilations of CD were unchanged. The coronary blood flow responses to occlusion, acetylcholine, and nitroglycerin were depressed, but not to PG. Large coronary arteries and microvessels were isolated from normal and failing hearts. Both isolated large coronary arteries and microvessels from failing hearts produced significantly less nitrite, the immediate metabolite of nitric oxide in aqueous solution, than those of normal hearts. Thus endothelium-mediated control of the coronary circulation was depressed during heart failure. A decrease in the production of nitric oxide-endothelium-derived relaxing factor was most likely responsible for this depression.

Zatebradine, a specific bradycardic agent, enhances the positive inotropic actions of dobutamine in ischemic myocardium

Objectives. This investigation determined whether attenuation of the tachycardia produced by dobutamine administration would improve perfusion and function distal to a severe coronary artery stenosis.Background. Tachycardia adversely affects perfusion and function distal to a coronary artery stenosis. It is not known whether a specific bradycardic agent can improve blood flow and function in an ischemic zone during administration of dobutamine.Methods. The effects of dobutamine (2, 5 and 10 μg/kg body weight per min) alone and in combination with zatebradine (0.5 mg/kg), a specific bradycardic agent, on hemodynamic status, segment shortening (ultrasound length transducers) and myocardial perfusion (microspheres) were studied in anesthetized dogs with severe left circumflex coronary artery stenosis.Results. A 50% reduction in left circumflex coronary artery blood flow (58 ± 4 to 29 ± 2 ml/min [mean value ± SEM]) produced a decrease in systolic shortening in the ischemic zone. Only a dose of dobutamine that did not elevate heart rate (2 μg/kg per min) produced an increase in segment shortening in the ischemic zone. High doses of dobutamine (10 μ/kg per min) caused an increase in heart rate without improvement in function and a reduction in the subendocardial/subepicardial flow ratio (0.74 ± 0.06 to 0.48 ± 0.05). Zatebradine administered in the presence of dobutamine caused a decrease in heart rate, an increase in subendocardial/subepicardial blood flow ratio (0.48 ± 0.05 to 0.78 ± 0.09) and allowed an increase in ischemic zone segment shortening. When normalized for changes in heart rate, ischemic zone subendocardial flow increased by 123 ± 41% (0.39 ± 0.09 to 0.71 ± 0.12 ml/100 g per beat). Atrial pacing abolished the effects of zatebradine.Conclusions. The present data suggest that the perfusion-contraction matching that accompanies a decrease in heart rate results in enhancement of inotropic stimulation of an ischemic zone. The actions of zatebradine are related to an increase in subendocardial blood flow per beat that allows improvement of regional contractile function.

Intracoronary air-filled albumin microspheres for myocardial blood flow measurement

Objectives. The aim of this study was to explore the possibility of quantifying coronary blood flow by myocardial contrast echocardiography with air-filled serum albumin microspheres (Albunex).Background. Air-filled albumin microspheres have been proposed as an intravascular tracer for the study of myocardial perfusion by contrast echocardiography.Methods. In six anesthetized open chest dogs, the left circumflex coronary artery was cannulated and perfused by a roller pump with blood from the femoral artery. Both air-filled albumin microspheres (0.4 ml, 2 × 108spheres/ml) and technetium-99m-labeled albumin were injected as a bolus into the coronary cannula at baseline and after treatment with dipyridamole (0.56 mg/kg body weight intravenously for 4 min). Two-dimensional echographic images of the left ventricular short axis were digitized to generate myocardial time-intensity curves; myocardial radioactivity was measured by an external detector to generate radionuclide time-activity curves.Results. After dipyridamole, left circumflex coronary artery blood flow (as measured by both the pump and an electromagnetic flow meter) significantly increased (from 1.06 ± 0.28 to 3.61 ± 1.43 ml/min per g of myocardium). Peak intensity and rise time of contrast echo curves were able to differentiate baseline myocardial perfusion from coronary hyperemia but did not show any significant correlation with coronary blood flow. A weak inverse correlation with coronary blood flow was provided by myocardial mean transit time of air-filled albumin microspheres (r = 0.33). Conversely, a close inverse correlation with coronary blood flow was obtained by myocardial mean transit time of technetium-99m-labeled albumin (r = 0.95). Myocardial transit time of air-filled albumin microspheres (1.95 ± 0.60 s) was also markedly shorter than that of labeled albumin (5.35 ± 3.43 s, p < 0.001) and the measurements were less reproducible.Conclusions. In this experimental study, coronary blood flow was not adequately quantified by myocardial contrast echocardiography with intracoronary injection of air-filled albumin microspheres.

Intracoronary papaverine but not adenosine reduces regional ventricular function

Whether intracoronary papaverine or adenosine leads to reductions in regional left ventricular function was tested. Fifteen anaesthetised dogs were prepared to record aortic pressure, left ventricular pressure dP/dt, electrocardiogram, regional ventricular shortening, and phasic and mean left circumflex coronary blood flow, and to give intracoronary boluses of papaverine (2, 4, or 6 mg) or adenosine (0.37 and 1.87 mg). Injected doses were chosen to mimic those given in the clinical setting. Papaverine (6 mg) reduced aortic pressure (mean 96(SD 17) to 89(18) mm Hg; p < 0.05), segmental shortening of the infused left circumflex zone (12(5) to 7(9)%; p < 0.05), and area of the pressure-length loop of the infused zone (120(71) to 53(47) mm.mm Hg; p < 0.05). Papaverine increased coronary blood flow (48(25) to 259(95) ml.min-1; p < 0.05), coronary vascular conductance (0.40(0.20) to 2.93(0.94) ml.mm Hg-1.min-1; p < 0.05), heart rate (88(27) to 100(28) beats.min-1; p < 0.05), and the segmental shortening (17(6) to 19(3)% p < 0.05) and area of the pressure-length loop (130(32) to 177(33) mm.mm Hg; p < 0.05) of the non-infused left anterior descending region. The hyperaemia elicited by papaverine was greater than that of reactive hyperaemia (p = 0.008). Papaverine also increased the QT interval corrected for heart rate (0.35(0.04) to 0.45(0.05) s; p < 0.05). When adenosine was given, coronary blood flow and coronary vascular conductance were increased to similar degrees as those during reactive hyperaemia (41(12) to 210(75) ml.min-1 and 0.46(0.14) to 2.43(0.83) mm Hg.ml-1.min-1, respectively; NS). No effects on segmental shortening or the area of the pressure-length loop in either zone were found. Also, adenosine had no effect on the QT interval. These adverse effects of intracoronary papaverine have important implications in its use in patients, particularly in those in whom abnormal cardiac function already exists. Adenosine, on the other hand, seems to be without deleterious effects.

Influence of heparin and systemic lysis on coronary blood flow after reperfusion induced by the novel recombinant plasminogen activator BM 06.022 in a canine model of coronary thrombosis

Objectives. We sought to evaluate whether anticoagulation by an intravenous heparin infusion prevents deterioration of coronary blood flow restored by the novel recombinant plasminogen activator BM 06.022, and to compare the effects of profound fibrinogenolysis with those of an intravenous bolus injection of heparinBackground. Recent clinical studies indicate that heparin appears to be effective in reducing reocclusion when combined with recombinant tissue-type plasminogen activator (rt-PA), but that heparin is associated with an increased bleeding incidence. Therefore, the need for heparin has to be critically evaluated in the development of BM 06.022.Methods. BM 06.022 is an unglycosylated variant of human tissue-type plasminogen activator. Thrombus formation in anesthetized open chest dogs was induced by electrical injury. Left circumflex coronary artery blood flow was monitored for 4 h using an electromagnetic flow probe. Twenty dogs were randomized to receive intravenous heparin (100 IU/kg bolus plus 100 IU/kg per h) in group B or saline solution in group A before an intravenous bolus injection of 200 KU/kg (=0.34 mg/kg) BM 06.022 1 h after thrombus formation. Another 14 dogs were randomized to receive a single intravenous bolus injection of 200 IU/kg heparin plus 200 kU/kg BM 06.022 in group D or saline solution plus 1,000 kU/kg BM 06.022 in group C.Results. In the absence of a systemic lytic state, heparin infusion prolonged (p < 0.05) the cumulative patency time (sum of time intervals during which the coronary artery was patent) to 204.3 ± 7.4 min (group B) compared with 34.6 ± 10.8 min with saline solution (group A), and increased (p < 0.05) the area under the curve for coronary blood flow versus time (AUCFlow) to 34.0 ± 3.4 ml · h · min−1compared with 7.7 ± 4.6 ml · h · min−1. Profound fibrinogenolysis after administration of 1,000 kU/kg BM 06.022 (group C) and a single intravenous heparin injection (group D) did not differ in their effects on the cumulative patency time (182 ± 30.3 vs. 177.5 ± 25.4 min) and AUCFlow(36.0 ± 10.3 vs. 30.5 ± 4.8 ml · h · min−1), but these values were improved (p < 0.05) compared with those obtained after administration of saline solution plus 200 kU/kg BM 06.022 (group A).Conclusions. In the absence of a systemic lytic state, intravenous heparin is required as an adjunct to BM 06.022 to maintain coronary blood flow in dogs.

Effects of dopexamine on hemodynamics and oxygen consumption after beta blockade in lambs

Dopexamine is a synthetic catecholamine with predominantly beta 2 and dopaminergic adrenergic receptor activities. We investigated its effects on systemic and myocardial hemodynamics and oxygen consumption (VO2) in a newborn species and studied its predominant mechanism of action. Prospective dose-response study with each animal serving as it own control. Eight chronically instrumented, unanesthetized lambs, 9 to 11 days of age. After surgical instrumentation and recovery for 72 hrs, animals were infused with dopexamine at increasing doses (1, 10, and 100 micrograms/kg/min) for 5 mins each before and after beta 1 (metoprolol) and beta 1, beta 2 (propranolol) adrenergic receptor blockade. All studies were performed during normoxia. Heart rate (HR) increased with increasing infusion rates of dopexamine and systemic arterial pressure and vascular resistance decreased. Cardiac index, left ventricular pressure development, and systemic VO2 were unchanged, as was the rate x pressure product. Left circumflex coronary artery blood flow and myocardial VO2 were unaltered. After beta 1-blockade, dopexamine produced an increase in HR and decreased systemic arterial pressure and vascular resistance. After beta 1-adrenergic receptor blockade, no change was noted in systemic or myocardial VO2, coronary blood flow, or rate x pressure product. After beta 1, beta 2-blockade with propranolol, increasing infusion rates of dopexamine resulted in decreases in systemic pressure and vascular resistance. Dopexamine produced significant cardiovascular effects mediated primarily by beta 2-adrenergic receptors, and also produced residual peripheral arterial vasodilation after combined beta 1- and beta 2-blockade. The latter finding suggests that dopaminergic receptor stimulation may partly mediate dopexamine's effects in newborn lambs.

High dose intravenous aspirin, not low dose intravenous or oral aspirin, inhibits thrombus formation and stabilizes blood flow in experimental coronary vascular injury

Objectives. The purpose of this study was to assess the antithrombotic potential of various forms of aspirin administration.Background. Platelet activation in response to endothelial injury has been implicated in acute coronary syndromes.Methods. Delivering 100-/gmA anodal direct current to the intima of the left circumtlex coronary artery in dogs at a site of moderate external stenosis provides a thrombogenic model of vascular injury. Animals were treated with aspirin (Group I, 20 mg/kg intravenously [n - 11]; Group II, 4.6 mg/kg intravenously [n = 6]; Group III, 4.6 mg/kg orally 18 h before the experiment [n = 7]J or vehicle (Group IV, control [n = 11]).Results. The time required for thrombotic occlusion to occur was longer and the incidence of thrombosis was lower in Group 1 (Group I, 238 ± 7 min [n = 2]; Group II, 127 ± 25 min [n = 3]; Group III, 156 ± 35 min [n = 6]; Group IV, 90 ± 11 min [n = 11]) (p < 0.05). Thrombus mass was smaller In Group I (Group 1, 5.0 ± 0.8 mg; Group II, 12.2 ± 2.6 mg; Group HI, 11.6 ± 3.9 mg; Group IV, 9.1 ± 1.6 mg) (p < 0.05). Initial hemodynamic variables did not differ among groups. An increase in mean arterial pressure was noted for several hours after intravenous aspirin administration in Group I(99 ± 5 to 110 ± 4 mm Hg) (p < 0.05). Left circumflex coronary artery blood flow was stable for 5 h in Group I (Group I, 31 ± 2 to 26 ± 4 ml/min) but decreased in all the other groups (Group II, 26 ± 4 to 10 ± 5 ml/min; Group III, 27 ± 5 to 7 ± 7 ml/min; Group IV, 29 ± 4 to 0 ml/min) (p ⩽ 0,05). The in vivo area or left ventricle perfused by the left circumflex coronary artery was not different among groups. Platelet counts were similar and did not change over the course of the protocol. Ex vivo arachidonic acid-induced platelet aggregation decreased in all groups after aspirin (p ⩽ 0.001). Indium-III-labeled platelet adherence to the coronary vasculature was decreased in distal vessel segments after all doses of aspirin (p < 0.05), Platelet deposition in thrombi was similar for all treatment groups.Conclusions. High dose intravenous aspirin has salutary effects. It stabilizes left circumflex coronary- artery blood flow, prolongs the time to thrombosis, reduces the incidence of thrombolic occlusion, reduces thrombus mass and limits platelet adherence to sites of arterial injury. Low dose aspirin given intravenously or orally was ineffective. When persistent intracoronary thrombi precipitate unstable coronary syndromes, high dose intravenous aspirin may be useful in the acute period even though platelets continue to interact with injured vascular segments through aspirin-insensitive mechanisms.

Effects of nitric oxide synthesis inhibition on the goat coronary circulation under basal conditions and after vasodilator stimulation.

1. The role of nitric oxide in the coronary circulation under basal conditions and when exposed to various vasodilator stimuli was studied in instrumented, anaesthetized goats, by examining the action of inhibiting endogenous nitric oxide production with NG-nitro-L-arginine methyl ester (L-NAME). 2. In 12 goats, left circumflex coronary blood flow (electromagnetically measured), systemic arterial blood pressure and heart rate were continuously recorded. L-NAME (3-4, or 8-10 mg kg-1 injected i.v.) decreased resting coronary blood flow by 20 and 28%, increased mean arterial pressure by 23 and 30% and increased coronary vascular resistance by 47 and 65%, respectively, without affecting heart rate, or blood gases or pH. These haemodynamic effects were reversed by L-arginine (200-300 mg kg-1 by i.v. injection, 5 goats). 3. Acetylcholine (0.001-0.1 micrograms), sodium nitroprusside (0.01-0.3 mg), and diazoxide (0.1-3 mg), injected intracoronarily in 6 goats, produced dose-dependent increases in coronary blood flow; sodium nitroprusside (0.1-0.3 mg) also caused hypotension and tachycardia. 4. During the effects of L-NAME, the coronary vasodilatation to acetylcholine was attenuated, to sodium nitroprusside was increased, and to diazoxide was unaffected, in comparison with control conditions. The hypotensive effects of sodium nitroprusside were also increased during treatment with L-NAME. 5. Graded coronary hyperaemic responses occurred after 5, 10 or 20 s of coronary occlusion. The magnitude of hyerpaemia for each occlusion duration was increased during treatment with L-NAME, in comparison to control.6. The results suggest: (a) endogenous nitric oxide is involved in regulation of coronary circulation by producing a basal vasodilator tone, (b) acetylcholine-induced coronary vasodilatation is mediated, in part, by nitric oxide, and (c) inhibition of basal endogenous nitric oxide production induces supersensitivity of coronary vessels to nitrovasodilators and enhances hyperaemic responses after short periods of ischaemia of the myocardium.

Inhibition of Granulocyte cAMP-Phosphodiesterase by Rolipram In Vivo Is Not Sufficient to Protect the Canine Myocardium from Reperfusion Injury

The purpose of this study was to determine whether the selective type IV cAMP-phosphodiesterase inhibitor rolipram could reduce the reperfusion injury that occurs during myocardial infarction in the anesthetized dog. This question was tested in pentobarbital-anesthetized dogs subject to 90 min of regional myocardial ischemia and 5 h of reperfusion. Dogs were treated with 1 mg/kg of rolipram (i.v., 15 min before reperfusion) followed by a 1 mg/kg/h infusion over the duration of the 5 h of reperfusion. Rolipram was tested in vitro for efficacy in inhibition of isolated human neutrophil superoxide generation. Rolipram produced significant inhibition of superoxide production over the concentration range of 0.1-100 microM rolipram when neutrophils were stimulated with a 10(-7) M concentration of the chemotactic peptide f-Met-Leu-Phe. Rolipram significantly inhibited superoxide generation from human and canine granulocytes in whole blood stimulated by zymosan. Therapeutic concentrations of rolipram in the blood of dogs were achieved during the course of the experiments with a plasma concentration of 0.761 +/- 0.095 micrograms/ml (2.76 +/- 0.34 microM) at the time of reperfusion, and 0.574 +/- 0.098 micrograms/ml (2.08 +/- 0.36 microM) at the end of the reperfusion period. The relative severity of myocardial ischemia between the two treatment groups was similar as assessed with radiolabeled microsphere measurement of myocardial blood flow. Transmural myocardial blood flows were not significantly different between the two groups after coronary occlusion (control, 0.05 +/- 0.01 ml/min/g, n = 6, vs. rolipram, 0.18 +/- 0.07 ml/min/g, n = 6; p = 0.48).(ABSTRACT TRUNCATED AT 250 WORDS)

Coronary and systemic vascular response to inspiratory resistive breathing.

To evaluate the coronary and systemic cardiovascular response to graded inspiratory resistive breathing, seven dogs were studied 2-4 wk after chronic instrumentation to measure circumflex coronary artery and ascending aortic blood flows as well as aortic and left ventricular (LV) blood pressures. The experiments were performed under chloralose anesthesia (to exclude any confounding emotional effects by dyspnea on cardiovascular variables) and hyperoxic conditions (to prevent chemoreflex activation by hypoxemia). In a randomized fashion, the dogs were subjected to graded inspiratory resistive breathing (spontaneous breathing alone and moderate and severe resistive loading, corresponding to resistances of approximately 0, 40, and 110 cmH2O.s.l-1, respectively). Each run lasted 10 min. Compared with mechanical ventilation with the respiratory muscles at rest, spontaneous breathing alone and moderate and severe inspiratory resistive loading induced pronounced and significant increases in circumflex coronary blood flow (19, 32, and 62%, respectively), which were almost exclusively accounted for by significant decrements in coronary vascular resistance and were paralleled (r = 0.88, P less than 0.0001) by significant increments (18, 31, and 57%) in heart rate transmural-aortic pressure product, an indicator of LV myocardial O2 demand. An increase in myocardial O2 consumption during resistive breathing was confirmed by analysis of coronary sinus blood samples in additional experiments (n = 3). Cardiac output significantly increased (10, 14, and 35%) because of increases in heart rate (15, 24, and 49%), with LV stroke volume and diastolic dimensions remaining unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

Neural, humoral, and metabolic control of coronary vascular resistance during exercise.

Neural, humoral, and metabolic effects on coronary vascular resistance were examined during exercise in conscious dogs, chronically instrumented for the measurement of aortic pressure, heart rate, and left circumflex coronary blood flow. Exercise significantly decreased coronary vascular resistance (CVR) in intact (INT) group, in which CVR was controlled by neural, humoral, and metabolic factors. In cardiac denervated (CD) group with pretreatment of alpha blocker (phentolamine, 2 mg/kg), in which CVR was controlled only by metabolic factor, exercise significantly decreased CVR. To eliminate metabolic effect on CVR, CVR was normalized by the product of CVR and double product (DP = mean aortic pressure x heart rate). CVR.DP did not change throughout the exercise in dogs with CD with alpha blocker. Thus, metabolic effect on CVR during exercise can be excluded by the product of CVR and DP. This calculation was applied to INT group with alpha blocker and CD group without blockers. The 12 km/h exercise significantly increased CVR.DP from 4.1 +/- 0.3 x 10(4) to 6.4 +/- 0.9 x 10(4) in INT group with alpha blocker, in which CVR was controlled only by neural factor, and from 2.8 +/- 0.2 x 10(4) to 4.5 +/- 0.5 x 10(4) in CD group, in which CVR was controlled only by humoral factor. These data suggest that 1) neural and humoral coronary vasoconstriction occurs during exercise, 2) neural and humoral vasoconstriction is overwhelmed by metabolic vasodilation, and 3) CVR.DP is a beneficial calculation for excluding metabolic effect on CVR during exercise.

Contribution of extravascular compression to reduction of maximal coronary blood flow

Effects of ventricular compression on maximally dilated left circumflex coronary blood flow were investigated in seven mongrel dogs under pentobarbital anesthesia. The left circumflex artery was perfused with the animals' own blood at a constant pressure (63 mmHg) while left ventricular pressure was experimentally altered. Adenosine was infused to produce maximal vasodilation, verified by the hyperemic response to coronary occlusion. Alterations of peak left ventricular pressure from 50 to 250 mmHg resulted in a linear decrease in total circumflex flow of 1.10 ml.min-1 x 100 g heart wt-1 for each 10 mmHg of peak ventricular to coronary perfusion pressure gradient; a 2.6% decrease from control levels. Similar slopes were obtained for systolic and diastolic flows as for total mean flow, implying equal compressive forces in systole as in diastole. Increases in left ventricular end-diastolic pressure accounted for 29% of the flow changes associated with an increase in peak ventricular pressure. Doubling circumferential wall tension had a minimal effect on total circumflex flow. When the slopes were extrapolated to zero, assuming linearity, a peak left ventricular pressure of 385 mmHg greater than coronary perfusion pressure would be required to reduce coronary flow to zero. The experiments were repeated in five additional animals but at different perfusion pressures from 40 to 160 mmHg. Higher perfusion pressures gave similar results but with even less effect of ventricular pressure on coronary flow or coronary conductance. These results argue for an active storage site for systolic arterial flow in the dilated coronary system.

Coronary Effects of a Combined Beta Adrenoceptor Blocking and Calcium Antagonist Therapy in Running Dogs

The effects of YM-16151 (1 mg/kg, i.v.), a combined beta 1-adrenoceptor blocking and calcium antagonist drug, on large (circumflex artery) and small coronary arteries and on systemic hemodynamics were investigated in chronically instrumented conscious dogs at rest and during treadmill exercise. These effects were compared to those in the same animals of nicardipine (0.1 mg/kg, i.v.), atenolol (1 mg/kg, i.v.) and their combination (at the same doses). Circumflex artery diameter (CxAD) and coronary blood flow increased and coronary vascular resistance (CVR) decreased during control exercise under saline. YM-16151 and the nicardipine-atenolol combination similarly dilated large and small coronary arteries at rest, but dilation of large conductance vessels was abolished during exercise, while CVR decreased further. Both YM-16151 and the nicardipine-atenolol combination only slightly increased the rate-pressure product at rest, but strongly opposed its exercise-induced rise. Nicardipine maximally increased CxAD, decreased CVR, and enhanced the rate-pressure product at rest and during exercise. Conversely, atenolol decreased CxAD and the rate-pressure product and increased CVR at rest, but large coronary arteries remained constricted during exercise despite the concomitant dilation of small resistance vessels. Thus, in the coronary vascular bed of conscious dogs, YM-16151 really behaves as a hybrid drug, combining beta 1-adrenoceptor blocking and calcium antagonist properties, both at rest and during exercise. As a result, YM-16151 increases oxygen supply at rest and decreases oxygen demand during exercise. Finally, this study emphasizes the major role of beta 1-adrenoceptors in the mediation of exercise-induced dilation of large coronary arteries.

Regional coronary haemodynamic effects of two inhibitors of nitric oxide synthesis in anaesthetized, open‐chest dogs

1. The role of endothelial nitric oxide synthesis from L-arginine in the regulation of coronary vascular tone and myocardial tissue perfusion was evaluated in anaesthetized, open-chest dogs. Coronary blood flow was measured with an electromagnetic flow probe placed around the left circumflex coronary artery. Coronary vascular resistance was calculated from mean arterial blood pressure and mean coronary blood flow, whereas regional myocardial tissue flow was determined by use of the radioactive microspheres technique. 2. NG-monomethyl L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME), administered directly into the left circumflex artery, induced a small increase in arterial blood pressure and an increase in coronary vascular resistance. However, myocardial tissue perfusion, assessed by the microspheres technique (whether subendocardial, subepicardial, or transmural), was unaffected by L-NMMA or L-NAME. 3. Acetylcholine, administered intracoronarily, induced an increase in left circumflex coronary blood flow and a decrease in coronary vascular resistance, without affecting systemic haemodynamics. This coronary vasodilator effect of acetylcholine was markedly inhibited by L-NMMA and L-NAME, the latter being a more potent antagonist than the former. 4. These results indicate that the endothelial L-arginine pathway is largely responsible for the coronary vasodilator effect of acetylcholine. However, although basal release of nitric oxide from L-arginine apparently contributes to the regulation of resting coronary vascular tone, blockade of this pathway does not affect myocardial tissue perfusion, possibly because of compensatory mechanisms occurring at the level of small arterioles and/or capillaries.