Ancrod decreases the frequency of cyclic flow variations and causes thrombolysis following acute coronary thrombosis.

The potential use of ancrod, a purified isolate from the venom of the Malaysian pit viper, Agkistrodon rhodostoma, in decreasing the frequency of cyclic flow variations in severely stenosed canine coronary arteries and causing thrombolysis of an acute coronary thrombus induced by a copper coil was evaluated. Open-chest, anesthetized dogs were used. Ancrod was given intravenously (8 U/kg) over 1 hour and caused a significant reduction in the frequency of cyclic flow variations (5.8 +/- 0.7 to 3.6 +/- 0.8 cyclic flow variations per 30 minutes, p less than 0.05), whereas control animals failed to decrease the frequency of their cyclic flow variations over the same time period (5.3 +/- 0.3 to 5.0 +/- 0.4 cyclic flow variations per 30-minute period). Twenty-seven dogs had a coronary thrombus induced by a copper coil positioned directly in a major coronary artery; of these, four died of ventricular fibrillation prior to treatment, eight received an infusion of saline and showed no thrombolysis over 5 hours, and three died of ventricular fibrillation during the initial part of an intravenous infusion of ancrod. The remaining 12 dogs received ancrod intravenously (16 U/kg); six demonstrated lysis of the coronary thrombus (mean time to lysis, 65 +/- 20 minutes). The concentrations of ancrod used in these studies produced a severe decrease in systemic fibrinogen concentration and a significant decrease in the inhibitor of plasminogen activator levels. Thus, ancrod decreases the frequency of cyclic flow variations in stenosed canine coronary arteries and may cause coronary thrombolysis in approximately 50% of animals within 65 +/- 20 minutes of its intravenous administration.

Cigarette smoking-induced coronary vasoconstriction in atherosclerotic coronary artery disease and prevention by calcium antagonists and nitroglycerin.

In patients with coronary artery disease, cigarette smoking increases myocardial oxygen demand but may cause an inappropriate alpha-adrenergically mediated fall in myocardial oxygen supply. This study was performed to determine if smoking-induced coronary vasoconstriction is prevented by nitroglycerin, verapamil or nifedipine treatment. In 25 smokers with coronary artery disease (20 men, 5 women, aged 32 to 65 years), heart rate-systolic arterial pressure double product and coronary sinus blood flow (thermodilution) were measured before and during smoking both before and 30 to 60 minutes after administration of saline solution (n = 5, control subjects); nifedipine, 10 mg sublingually (n = 6); verapamil, 10 mg intravenously (n = 7); or nitroglycerin, 0.4 mg sublingually (n = 7). During the first smoking period, double product increased, but coronary sinus flow did not change or decreased. During the second smoking period, in the control subjects double product and coronary sinus flow responded in a manner similar to that observed previously. In those given nifedipine, double product did not change, but coronary sinus flow increased (-4 +/- 5% during the first smoking period [before nifedipine] and 17 +/- 12% during the second period [after nifedipine], p less than 0.01). In those given verapamil, double product and coronary sinus flow increased during smoking (-12 +/- 8% during the first smoking period [before verapamil], 10 +/- 9% during the second period [after verapamil], p less than 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

Vascular prostaglandin and thromboxane production in a canine model of myocardial ischemia.

Whereas numerous studies have investigated the role of prostacyclin and thromboxane A2 in the maintenance of coronary blood flow, most of these have focused on normal vessels. In the present investigation, we examined the prostaglandin- and thromboxane-synthesizing capacity of isolated coronary artery segments obtained from the site of a critical coronary artery stenosis. Cyclic flow variations were produced by placing a hard cylindrical constrictor on the proximal left anterior descending coronary artery in open-chest, anesthetized dogs. Cyclic flow variations are characterized by progressive declines in coronary blood flow, interrupted by sudden spontaneous restorations of flow. After cyclic flow variations had been induced, the hearts were removed, and the left anterior descending and circumflex coronary arteries were dissected. The vessels were cut into segments and incubated in the presence of increasing concentrations of arachidonic acid (10(-4)-10(-6) M). The synthesis of prostaglandin E2, thromboxane B2, and 6-keto prostaglandin F1 alpha by the coronary segments was measured by radioimmunoassay. When incubated in the presence of 10(-5) M arachidonic acid, coronary artery segments obtained from the left anterior descending coronary artery undergoing cyclic flow variations produced substantially more thromboxane B2 (142 +/- 27 vs. 29 +/- 3 pg/mg P less than 0.01) and less 6-keto prostaglandin F1alpha (125 +/- 12 vs. 350 +/- 30 pg/mg, P less than 0.01) than control circumflex coronary artery segments. Circumflex coronary vessels in which the endothelium was removed ex vivo produced 6-keto prostaglandin F1alpha levels comparable to those found in the left anterior descending coronary artery (147 +/- 17 pg/mg), but did not synthesize thromboxane B2 (23 +/- 2.6 pg/mg).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of propranolol and diltiazem alone and in combination on the recovery of left ventricular segmental function after temporary coronary occlusion and long-term reperfusion in conscious dogs.

We evaluated the ability of propranolol and diltiazem alone and in combination to enhance the recovery of left ventricular (LV) segmental function during 1 month of reperfusion after two temporary occlusions of the left anterior descending coronary artery (LAD) in conscious dogs instrumented with ultrasonic crystals for the measurement of regional net systolic wall thickening (NET). LV segments were classified according to their contractile function after 1 hr of LAD occlusion: class 1, greater than 67% of preocclusion (control) NET; class 2, 0% to 66.9%; class 3, less than 0% (paradoxical systolic wall thinning). Propranolol (1 mg/kg iv) or diltiazem (20 micrograms/kg/min) was given 65 min after LAD occlusion in dogs that had 2 (group I) or 4 hr (group II) of LAD occlusion. Diltiazem plus propranolol (same doses) were given to another group of dogs that underwent 4 hr (but not 2) of LAD occlusion. Untreated control dogs received 25 ml of saline and underwent 2 or 4 hr of LAD occlusion. The NET of class 2 and 3 segments in group I control dogs increased significantly during 1 month of reperfusion, from 32 +/- 5% and -43 +/- 6% to 66 +/- 9% and 26 +/- 9%, respectively (p less than .05). Neither diltiazem nor propranolol enhanced the long-term recovery of these segments in group I dogs. However, diltiazem prevented further deterioration of contractile dysfunction observed in control dogs immediately after reperfusion in both segment classes. The NET of class 2 segments in group II control dogs after 4 weeks of reperfusion remained at levels observed during LAD occlusion: 30 +/- 4% to 37 +/- 12%. Class 3 NET increased from -33 +/- 5% to 12 +/- 12% with 1 month of reperfusion, but these segments were essentially akinetic. Propranolol or diltiazem alone did not produce significant overall increases in NET, but diltiazem again prevented further declines in NET of class 2 and 3 segments during early reperfusion. However, the combination of diltiazem and propranolol significantly enhanced overall recovery of class 2 NET in group II dogs (44 +/- 3% to 88 +/- 7%) and prevented the worsening of NET associated with early reperfusion. Compared with untreated dogs, propranolol plus diltiazem also significantly decreased the extent of histologic necrosis in class 2 and 3 segments as well as the macrohistochemically determined infarct size in group II dogs.(ABSTRACT TRUNCATED AT 400 WORDS)

Cyclic blood flow variations induced by platelet-activating factor in stenosed canine coronary arteries despite inhibition of thromboxane synthetase, serotonin receptors, and alpha-adrenergic receptors.

The phospholipid platelet-activating factor (PAF) stimulates platelet aggregation and coronary vasoconstriction. In this study we determined whether PAF alters coronary flow patterns in vivo in a canine preparation with concentric coronary artery stenosis. This preparation is characterized by cyclic flow variations in coronary blood flow associated with transient platelet aggregation at the site of the coronary constriction. Thirty-nine male mongrel dogs were used in three protocols. In protocol 1, PAF (10(-9) or 10(-8) mol/min) was infused into the coronary artery proximal to the stenosis to determine (1) whether PAF induces cyclic flow variations and (2) whether PAF has an effect on systemic hemodynamics. Cyclic flow variations were induced in three of six dogs; in these animals, mean arterial pressure decreased by 5.5% and 42.1% 10 min after infusion of the lower and higher dose of PAF. In protocol 2, cyclic flow variations were abolished with either the thromboxane synthetase inhibitor UK38485 (mean dose 2.2 mg/kg iv), the serotonin antagonist ketanserin (0.5 mg/kg iv), or the alpha 2-adrenergic antagonist yohimbine (2 mg/kg iv). Subsequent administration of PAF restored the frequency of cyclic flow variations to the preantagonist levels. Thromboxane (Tx) B2 and 6-keto-PGF1 alpha, the stable metabolites of TxA2 and prostacyclin, respectively, were measured in blood obtained distal to the coronary stenosis. TxB2 levels increased substantially during cyclic flow variations and were returned to control values with the thromboxane synthetase inhibitor UK38485. Infusion of PAF subsequently restored cyclic flow variations without altering coronary arterial coronary arterial TxB2 levels.(ABSTRACT TRUNCATED AT 250 WORDS)

Failure of a slow channel calcium antagonist, verapamil, to retard atherosclerosis in the Watanabe heritable hyperlipidemic rabbit: an animal model of familial hypercholesterolemia.

Verapamil and other slow channel calcium antagonists have been reported to retard atherosclerosis in rabbits fed a high cholesterol diet. Because atherosclerosis in such a model may differ significantly from human atherosclerosis, experiments were conducted to prevent atherosclerosis with verapamil in the Watanabe heritable hyperlipidemic (WHHL) rabbit, which is a genetic, metabolic and pathologic model of homozygous familial hypercholesterolemia. At 2 months of age, 23 WHHL rabbits were divided into two groups since earlier studies showed no macroscopic atherosclerosis at 2 months. Group A (n = 11) was fed standard rabbit chow for 6 months. Group B (n = 12) received oral verapamil (46 mg/kg per day) absorbed in the identical chow as fed to Group A and subcutaneous verapamil (0.25 mg/kg twice daily 6 days a week). In Group B, mean serum verapamil concentrations (+/- SEM) averaged 16.9 +/- 1.9 ng/ml at 3 hours after subcutaneous injection. Sex ratios and serum cholesterol concentrations were the same in both groups. The percent of aortic surface area with visible plaque in Group A versus B was 49 +/- 7 versus 43 +/- 7%, respectively, of the entire aorta, and 61 +/- 5 versus 65 +/- 5%, respectively, of the proximal 3 cm of aorta (p = NS). Thus, verapamil did not suppress atherosclerosis in WHHL rabbits at serum drug levels greater than those reported to be effective in other models.

Effect of diltiazem and propranolol on left ventricular segmental relaxation during temporary coronary arterial occlusion and one month reperfusion in conscious dogs.

Using sonar microcrystals implanted in conscious dogs, we have characterized left ventricular segmental relaxation (LVSR) by measuring the mean rate to half end-diastolic thinning (RHEDT) and the late diastolic thinning fraction (TF). In protocol 1 (five nonischemic dogs), RHEDT correlated with changes in left ventricular dP/dt (r = .87) and systemic arterial pressure (r = -.80) but not with alterations in heart rate. Only systemic arterial pressure importantly influenced TF (r = -.65). In protocol 2 (21 dogs), LVSR paralleled net systolic segmental wall thickness (NET) during both 2 and 4 hr of coronary occlusion followed by 1 month reperfusion. Both LVSR and NET remained depressed during 2 and 4 hr of coronary occlusion and through 24 hr of reperfusion, but both also gradually improved afterwards. In protocol 3, 31 dogs underwent 4 hr of coronary occlusion with 1 month of reperfusion. Among these animals, 11 dogs (group S4) received saline after 1 hr of occlusion, nine dogs (group P4) received propranolol, and 11 dogs (group D4) received diltiazem. Drug therapy was stopped at 2 hr of reperfusion. In segments with mildly and moderately depressed NET, LVSR was significantly increased in group D4 vs group S4 animals during the diltiazem infusion. Expressed as mean percentage of control value +/- SEM, RHEDT of moderately dysfunctional segments in group D4 compared with group S4 measured 53 +/- 10% vs 25 +/- 5%, respectively, at 2 hr of occlusion of the left anterior descending coronary artery (p = .03), 76 +/- 17% vs 28 +/- 8%, respectively, at 4 hr of occlusion (p = .01), and 74 +/- 11% vs 33 +/- 10%, respectively, at 1 hr of reperfusion (p less than .05). The differences in TF at these same time points were 106 +/- 10% vs 70 +/- 9% (p less than .03), 105 +/- 7% vs 65 +/- 16% (p less than .02), and 106 +/- 11% vs 74 +/- 13% (p less than .05), respectively. The improvement in LVSR occurred independently of changes in NET. The values of LVSR in the diltiazem-treated dogs fell to the levels of groups S4 and P4 within 24 hr of stopping the intervention. Propranolol did not significantly alter LVSR over the short or long term. The increase in LVSR during administration of diltiazem did not appear to be mediated by changes in contractility or regional myocardial blood flow, but were probably mediated in part by afterload reduction and possibly by a reduction in calcium entry into ischemic myocardium.

The effects of alpha 2-adrenergic and serotonergic receptor antagonists on cyclic blood flow alterations in stenosed canine coronary arteries.

Platelets possess alpha 2-adrenergic and serotonergic (5-hydroxytryptamine) receptors which are thought to mediate the in vitro proaggregatory effects of epinephrine and serotonin, respectively. However, their importance in platelet aggregation in vivo is uncertain. In the present study, we evaluate the ability of yohimbine and ketanserin, relatively selective alpha 2-adrenergic and serotonin antagonists, respectively, to alter cyclic flow reductions in stenosed coronary arteries in open-chest, anesthetized dogs. These cyclic flow reductions, characterized by progressive declines in coronary blood flow interrupted by abrupt and, often spontaneous, restorations of flow, were produced by cylindrical constrictors placed on the left anterior descending coronary artery. A pulsed Doppler flow probe, placed proximal to the constrictor, was used to measure coronary blood flow. Regional myocardial blood flow was measured with 15-micron radiolabeled microspheres before coronary constriction and when coronary blood flow appeared to be at its nadir and zenith during cyclic flow reductions. After the cyclic flow reductions had been observed for 1 hour, yohimbine (1-2 mg/kg), ketanserin (0.25 or 0.5 mg/kg), or saline was given, and coronary blood flow and hemodynamics were monitored for another hour. The frequency of cyclic flow reductions and the mean of the three lowest nadirs of coronary blood flow (mean +/- SE) were compared between the first and second hours. Ketanserin, at doses of 0.25 and 0.50 mg/kg, virtually abolished cyclic flow reductions in all dogs tested. Yohimbine [1 mg/kg ( n = 14)] was partially effective in reducing the frequency (9.6 vs. 5.5 cyclic flow reductions/hr) and severity of cyclic flow reductions (nadirs of coronary blood flow = 6.2 +/- 2.4 vs. 20.9 +/- 6.1% of control). A higher dose of yohimbine [2 mg/kg (n = 7)] was no more effective. The frequency (9.3 +/- 0.9 vs. 9.3 +/- 1.0 CFR/hr) and severity (17.4 +/- 5.4 vs. 12.4 +/- 3.9% of control coronary blood flow) of cyclic flow reductions were not changed by saline. The relatively selective alpha 1-adrenergic antagonist, prazosin (0.01 mg/kg, iv), and the beta-adrenergic antagonist, propranolol (1-2 mg/kg, iv), did not affect the frequency or severity of cyclic flow reductions. Thus, the abilities of yohimbine to inhibit and ketanserin to abolish cyclic flow reductions in stenosed canine coronary arteries suggest that serotonin and, possibly, alpha 2-adrenergic agonists may influence cyclic flow alterations importantly in this model.