Calcium-channel blockers preserve coronary endothelial reactivity after ischemia-reperfusion

BACKGROUND: Calcium-channel blockers have been reported to improve myocardial recovery after ischemia-reperfusion, but their effects on coronary blood flow regulation remain to be defined. Experiments were designed to evaluate the effects of calcium antagonists on coronary artery vasoregulation exposed to ischemia-reperfusion. METHODS: Three groups of hearts (n = 6) were pretreated with a 10-minute infusion of either diltiazem, verapamil, or nifedipine at concentrations of 10(-9) mol/L to 10(-6) mol/L and exposed to 30 minutes of no-flow ischemia and 45 minutes of reperfusion. Another group (n = 6) received no pretreatment and was used as control. Endothelium-dependent and -independent relaxations were tested by assessing coronary flow increase to 5-hydroxytryptamine (10(-6) mol/L) and sodium nitroprusside (10(-5) mol/L) infusion, respectively. Left ventricular pressure, its first derivative, and coronary basal flow were recorded before and after ischemia as well as during calcium antagonist infusion. RESULTS: Endothelium-dependent relaxation after ischemia was significantly improved with all three drugs in a dose-dependent fashion; nifedipine was found to be the more potent. Endothelium-independent relaxation was also significantly preserved with calcium antagonists regardless of the type, whereas left ventricular hemodynamics were not. During perfusion, nifedipine was found to have the most negative inotropic effect and to be the most potent vasodilator on the coronary circulation. Diltiazem was the less effective drug on both left ventricular hemodynamics and coronary circulation. CONCLUSIONS: This study indicates that preischemic infusion of calcium antagonists enhance endothelium-dependent and -independent coronary artery relaxation in the isolated rat heart model in a dose- and drug-dependent fashion. This can be achieved at low doses without affecting left ventricular hemodynamics and should contribute to preserve coronary artery autoregulation.     

Perfusion of ischemic myocardium during anesthesia with sevoflurane

BACKGROUND: Sevoflurane produces direct vasodilation of coronary arteries in vitro and decreases coronary vascular resistance in vivo, pharmacologic properties that may contribute to the development of "coronary steal." This investigation examined the effects of sevoflurane on the distribution of regional myocardial perfusion in chronically instrumented dogs with steal-prone coronary artery anatomy. METHODS: Dogs were chronically instrumented for measurement of aortic and left ventricular pressure, diastolic coronary blood flow velocity and subendocardial segment length. After recovery from surgery, dogs underwent repetitive, brief, left anterior descending coronary artery (LAD) occlusions via an implanted hydraulic vascular occluder to enhance collateral development. A progressive left circumflex coronary artery (LCCA) stenosis was also obtained using an ameroid constrictor. After development of LCCA stenosis, the LAD was totally occluded to produce a model of multivessel coronary artery disease. Systemic hemodynamics, regional contractile function and myocardial perfusion measured with radioactive microspheres were assessed in the conscious state and during sevoflurane anesthesia at 1.0 and 1.5 MAC with and without restoration of arterial blood pressure and heart rate to conscious levels. RESULTS: Total LAD occlusion with simultaneous LCCA stenosis increased heart rate, mean arterial pressure, left ventricular systolic and end-diastolic pressures, end-diastolic segment length, and rate-pressure product in conscious dogs. Subsequent administration of sevoflurane caused dose-related decreases in arterial pressure, left ventricular systolic pressure, double product, and peak rate of increase of left ventricular pressure at 50 mmHg. Perfusion of normal myocardium was unchanged during sevoflurane anesthesia. In contrast, sevoflurane caused dose-dependent decreases in blood flow to myocardium supplied by the stenotic LCCA, which returned to control levels after restoration of heart rate and arterial pressure. No reduction in collaterally derived blood flow to the occluded region was produced by 1.0 or 1.5 MAC sevoflurane. No redistribution of blood flow away from the occluded LAD region to normal or stenotic myocardium occurred during sevoflurane anesthesia. In fact, increases in the ratio of blood flow between occluded and normal zones or occluded and stenotic zones were observed in the subepicardium during 1.5 MAC sevoflurane with maintenance of the heart rate and arterial pressure at conscious levels. CONCLUSIONS: The results demonstrate that sevoflurane does not reduce or abnormally redistribute myocardial blood flow derived from coronary collateral vessels in a chronically instrumented canine model of multivessel coronary artery obstruction.     

The absence of stereoselective P-glycoprotein-mediated transport of R/S-verapamil across the rat jejunum

We have studied the potential stereoselective transport and metabolism of R/S-verapamil in rat jejunum, in-situ. A regional single-pass perfusion of the rat jejunum was performed on 24 rats in six separate groups. The effective permeability (Peff) was assessed for three different concentrations of verapamil, 4, 40 and 400 mg L(-1). The Peff of each enantiomer was also determined at 400 mg L(-1) when chlorpromazine (10 mM) was added to the perfusion solution. Two other groups of rats received R/S-verapamil as an intravenous infusion and the intestinal secretion and metabolism were studied by simultaneously perfusing the jejunum with a control or with chlorpromazine (10 mM) added. The concentrations in the outlet perfusate of each enantiomer of verapamil and norverapamil were assayed with HPLC. R/S-Verapamil is a high permeability drug in the proximal rat small intestine throughout the luminal concentration range studied and complete intestinal absorption was expected. There was an increase of Peff from 0.42 x 10(-4) cm s(-1) to 0.80 x 10(-4) cm s(-1) (P < 0.05) at concentrations from 4 to 400 mg L(-1), respectively. The observed concentration-dependent jejunal Peff and fraction absorbed (P < 0.05) of R/S-verapamil is consistent with the saturation of an efflux mechanism. When chlorpromazine (a P-glycoprotein inhibitor/substrate) was added the jejunal Peff increased to 1.47 x 10(-4) cm s(-1). There was no difference between the Peff of the two enantiomers in any of these experiments. The efflux of R/S-norverapamil into the rat jejunum was high after intravenous administration of R/S-verapamil, suggesting extensive metabolism in the enterocyte. In conclusion, both R/S-verapamil enantiomers are P-glycoprotein substrates, but there is no stereoselective transport of R/S-verapamil in the rat jejunum. The results also suggests that R/S-norverapamil is formed inside the enterocytes.     

Systemic and coronary hemodynamic effects of repetitive cocaine administration in conscious dogs

The cardiovascular actions of cocaine are complex, and previous studies suggest that tachyphylaxis to the positive chronotropic and pressor effects of cocaine may develop after repetitive administration. We examined changes in systemic and coronary hemodynamics when single or multiple doses of intravenous (i.v.) cocaine were administered to conscious dogs. Dogs were chronically instrumented for measurement of aortic blood pressure (BP) and left ventricular pressure (LVP), LV dP/dtmax and dP/dt50, subendocardial segment length (%SS), diastolic coronary blood flow (CBF) velocity, and cardiac output (CO). Myocardial oxygen consumption was estimated by the pressure-work index (PWI). In one series of experiments, a single dose of cocaine (0.1, 0.2, 0.4, 0.8, or 1.6 mg/kg) was administered on 5 consecutive days in random fashion and peak changes in systemic and coronary hemodynamics were recorded. These doses were then randomly repeated in a second group of experiments with a 1-h interval between doses on the same day. Peak and steady-state changes in cardiovascular variables were recorded within and between each dose, respectively. In other experiments, higher doses of cocaine (0.8 or 1.6 mg/kg; separate groups) were administered four times at 1-h intervals in the same dogs and peak and steady-state changes in hemodynamics were determined. Cocaine caused dose-related increases in heart rate (HR), mean arterial pressure (MAP), LV systolic pressure (LVSP) and end-diastolic pressure (LVEDP), PWI, CO, and diastolic coronary vascular resistance and decreases in %SS when administered on different days. Cocaine also caused significant increases in baseline HR, MAP, LVSP, and PWI between doses given on the same day at 1-h intervals, but the absolute value of the peak response to cocaine of these hemodynamic parameters was independent of dosing regimen. These results were confirmed when we administered four doses of 0.8 mg/kg cocaine at 1-h intervals. The results indicate that baseline changes in systemic hemodynamic variables are a predominant feature of repetitive administration of lower doses of cocaine (< or = 0.8 mg/kg), but administration of higher doses of cocaine (> or = 8 mg/kg) at 1-h intervals caused tachyphylaxis to the hypertensive actions and myocardial oxygen consumption effects of cocaine.     

Coronary pressure as a determinant of B-type natriuretic peptide gene expression in isolated perfused adult rat heart

The role of coronary flow in the regulation of ventricular B-type natriuretic peptide (BNP) gene expression was studied in isolated perfused rat heart preparation. The increase of coronary flow from 5 ml/min to 20 ml/min for 2 h resulted in a 132+/-6 mm Hg increase in aortic perfusion pressure. The changes in BNP mRNA and immunoreactive BNP (IR-BNP) levels in response to hemodynamic stress were compared to those of c-fos and adrenomedullin (ADM) gene expression. The increase of coronary flow resulted in 1.5-fold increases in the left ventricular BNP mRNA (P < 0.001) and IR-BNP (P < 0.05) levels in 2-month old rats. There was also a 1.5-fold (P < 0.05) increase in ventricular c-fos mRNA levels, whereas ADM mRNA levels decreased by 74% (P < 0.001) in the left ventricle. In 18-month old rats, the increase in coronary flow decreased left and right ventricular BNP mRNA levels by 18% (P < 0.05) and 39% (P < 0.001), respectively. There were no changes in IR-BNP peptide and c-fos mRNA levels, whereas ADM mRNA levels decreased by 46% (P < 0.001) in the left ventricles. The results show that increased aortic perfusion pressure results in differential expression of cardiac genes including up-regulation of ventricular BNP and c-fos gene expression and down-regulation of ADM gene expression. Furthermore, aging seems to elevate the threshold at which hemodynamic stress of the heart results in a response at BNP gene level.     

Na-H exchange inhibition with cariporide limits functional impairment caused by repetitive ischemia

Intracellular calcium ([Ca]i) overload on reperfusion may be one of the mechanisms responsible for ischemia-induced regional myocardial dysfunction. Because inhibiting the Na-H exchanger (NHE) limits intracellular sodium ([Na]i) and subsequent [Ca]i accumulation, we hypothesized that NHE inhibition would attenuate regional dysfunction in response to 25 cycles of ischemia (I, 2-min) and reperfusion (R, 8-min) of the left circumflex coronary artery (LCx) in conscious swine. Six animals were instrumented to measure arterial pressure, regional myocardial blood flow (colored microspheres), systolic wall thickening (WTh) in the normally perfused (left anterior descending, LAD) and LCx regions (sonomicrometry), LCx blood flow velocity (Doppler), and to reversibly occlude the LCx (hydraulic occluder). Each animal completed three protocols separated by 7 days: ISC, 25 I/R cycles; CAR, 25 I/R cycles + NHE inhibition (cariporide); and VEH, vehicle administration for 4.2 h. Regional myocardial blood flow was measured during LCx occlusion in the first protocol and 10 min after I/R 25 in all protocols. Systemic hemodynamics were similar among and within each protocol. Blood flow measured during LCx occlusion confirmed that perfusion was reduced (p < 0.05) to this compared with the LAD region. During ISC, LCx WTh was reduced (p < 0.05) after five IR cycles, and a stable reduction (approximately 55% of baseline; p < 0.05) was present after 20 I/R cycles. During CAR, LCx systolic WTh was reduced (p < 0.05) only after 15 and 25 I/R cycles (approximately 80 and 72%, respectively). The decrease in LCx WTh was greater in ISC than in CAR (p < 0.05). LCx WTh was not altered during VEH, while LAD WTh was similar within and among all protocols. Regional blood flow measured after 25 I/R cycles was not different among protocols. Our results indicate that NHE inhibition delays the onset and limits the degree of regional dysfunction in response to repeated bouts of ischemia and reperfusion.     

The influence of phytohemagglutinin P on CD4+ and CD8+ cells in the course of experimental trichinellosis in mice]

Perfusion balloon catheters are designed to provide continuous transcatheter blood flow and thereby reduce myocardial ischemia during coronary angioplasty. To compare the transcatheter flow rates of active and passive (auto-) perfusion catheters, a well-controlled experimental study was performed in a circulation model that duplicates the phasic, predominantly diastolic flow pattern of the left coronary artery. Mean diastolic coronary driving pressure varied between 20 and 100 mm Hg. For the autoperfusion catheters, a strong relationship between transcatheter flow and diastolic coronary driving pressure was found. For example, a coronary driving pressure of 80 mm Hg provided a coronary flow of 30 ml/min (RX-Perfusion [RP], ACS), 28 ml/min (Speedflow [SF], Schneider), 20 ml/min (Lifestream [LS], ACS), and 19 ml/min (Flowtrack [FT], ACS). Reduction of driving pressure to 40 mm Hg decreased the absolute transcatheter flow, which was now 16 ml/min (RP), 13 ml/min (SF), and 10 ml/min (LS and FT). The relative catheter flow (the ratio of absolute flow to baseline coronary flow rate without a catheter in place), was independent of actual coronary driving pressure and ranged between 21% +/- 1% (RP) and 14% +/- 1% (FT and LS). For the active perfusion system (Coreflo, Leocor, a maximal transcatheter flow of 82 ml/min was found. Using this active perfusion system, the relative catheter flow increased with decreasing coronary driving pressure:80 --> 40 mm Hg: 56% --> 107%. For all catheters, the distal perfusion decreased between 30% (3.0 mm RP) and 50% (3.0 mm LS) by a 0.014-inch guidewire placed through the inner channel of the catheter. Because of the strong relationship between coronary driving pressure and transcatheter flow, the residual flow through all autoperfusion catheters becomes critical (<20 ml/min), when the coronary driving pressure drops below 50 mm Hg. By contrast, active perfusion systems are independent of the actual coronary driving pressure and are therefore advantageous for prolonged dilation in patients with low aortic pressure.     

Cocaine significantly impairs myocardial relaxation

OBJECTIVES: To determine the immediate effects of intravenous "recreational" doses of cocaine on myocardial ventricular relaxation and contraction and on coronary blood flow. To determine the cardiac effects of cocaine after the administration of propranolol, as propranolol has been used to limit the cardiovascular effects of cocaine. DESIGN: Prospective study. SUBJECTS: Twenty mongrel dogs. INTERVENTIONS: We continuously recorded central aortic pressure, left atrial and ventricular pressures, coronary artery blood flow, and electrocardiograms in each dog. We determined from the left ventricular pressure waveforms the maximum rate of pressure increase [(dP/dt)max] and the time constant of isovolumic ventricular relaxation as our indices of ventricular contraction and relaxation. MEASUREMENTS AND MAIN RESULTS: In our initial series of experiments, we obtained pressure, coronary artery blood flow, and electrocardiographic recordings in ten anesthetized dogs before and for 40 mins after the intravenous administration of cocaine, in doses of 2.5 and then 5 mg/kg. In our second series of experiments in ten additional dogs, we injected 0.5 mg/kg of propranolol intravenously 30 mins before the injection of cocaine (2.5 mg/kg), and obtained hemodynamic and electrocardiographic recordings before and for 40 mins after the injection of propranolol and cocaine. Cocaine, 2.5 mg/kg, abruptly increased the time constant of isovolumic ventricular relaxation from 22.9 +/- 1.2 to 29 +/- 2.2 msecs at 1 min (p < .05) and to 35.3 +/- 2 msec at 40 mins (p < .01) but did not significantly change the mean arterial pressure, left atrial pressure, heart rate, coronary blood flow, or the maximum rate of left ventricular pressure increase [(dP/dt)max]. Cocaine also progressively displaced the electrocardiographic ST segments by 3.2 +/- 0.6 mm (p < .01) over 40 mins. Cocaine, 5 mg/kg, rapidly increased the time constant of isovolumic ventricular relaxation from 28.5 +/- 2.5 to 41 +/- 3 msecs in 1 min (p < .05) and to 48.7 +/- 4 msecs at 40 mins (p < .01) and reduced (dP/dt)max from 2905 +/- 370 to 1422 +/- 121 mm Hg/sec at 1 min (p < .01); (dP/dt)max returned to 2351 +/- 415 mm Hg/sec during the next 39 mins. Cocaine did not significantly change either the mean arterial or left atrial pressures. However, this dose of cocaine did decrease, over 40 mins, the heart rate from 184 +/- 11 to 139 +/- 11 beats/min (p < .01) and reduced coronary blood flow by 20% (p < .01). Cocaine also displaced the electrocardiographic ST segments by 3.3 mm over 40 mins (p < .05). Cocaine and propranolol abruptly increased the time constant of isovolumic ventricular relaxation from 26.4 +/- 1.3 to 43.2 +/- 2.1 msecs (p < .01) at 1 min and to 46.8 +/- 1.5 msecs at 3 mins (p < .01). The time constant of isovolumic ventricular relaxation remained abnormally increased at 43.0 +/- 1.4 msecs at 40 mins. Cocaine and propranolol reduced (dP/dt)max from 2760 +/- 458 mm Hg/sec to a minimum value of 1400 +/- 119 mm Hg/sec at 2 mins (p < .01). However, (dP/dt)max then returned to 2201 +/- 359 mm Hg/sec during the next 38 mins. Cocaine and propranolol did not significantly change the mean arterial and left atrial pressures, or heart rate, but did reduce coronary blood flow, over 40 mins, by 25% (p < .001). Cocaine also maximally displaced the electrocardiographic ST segments by 1 +/- 0.2 mm (p < .01). CONCLUSIONS: Cocaine substantially impairs myocardial ventricular relaxation for periods of at least 40 mins. Propranolol significantly intensifies cocaine's depressant effect on ventricular relaxation.     

Changes in serum levels of N-terminal procollagen type III propeptide as an index of postinfarction ventricular remodeling

The cardiovascular effects of slow (over two minutes) intravenous infusions of thiopentone 750 mg in conscious instrumented sheep breathing 100% oxygen were examined for 30 minutes following the start of the infusion. The maximum rate of rise of left ventricular pressure (an index of myocardial contractility) decreased significantly from 1 to 10 minutes, to a minimum of 45% of baseline. Heart rate increased by up to 33% above baseline from 0.5 min onwards. Both mean arterial pressure and cardiac output were decreased from between 1 and 7 min. Left ventricular minute work was transiently decreased, but left coronary blood flow and myocardial oxygen consumption showed little or no change from baseline. We conclude that in vivo, thiopentone administered at a relatively slow rate caused large reductions in myocardial contractility, and therefore cardiac reserve, in the absence of significant changes in myocardial blood flow or oxygen consumption.     

Dual-energy X-ray absorptiometry derived structural geometry for stress fracture prediction in male U.S. Marine Corps recruits

OBJECTIVES: To evaluate the effects of losartan administration on cardiovascular mass, systemic and coronary hemodynamics (rest, maximal treadmill exercise, and dipyridamole infusion) and on resting regional hemodynamics in conscious spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats. RESULTS: Although losartan administration (two doses: 10 and 30 mg/kg per day for 3 weeks by gavage) reduced left ventricular mass at the higher dose in WKY rats and with both doses in SHR, only the higher dose reduced arterial pressure in SHR. Losartan administration did not affect cardiac index, myocardial or other organ flows (radiomicrosphere) at rest in both strains. Significant increases in cardiac index and coronary flow and decreases in coronary vascular resistance were observed during exercise in both strains and these responses were not affected by losartan administration. Compared with those in WKY rats, coronary flow and flow reserve (dipyridamole) were decreased and minimal coronary vascular resistance was increased in untreated SHR. Administration of a higher losartan dose increased coronary flow reserve and decreased minimal coronary vascular resistance (measured during dipyridamole infusion) in SHR. CONCLUSIONS: These data demonstrated that losartan administration reduced left ventricular mass, a response that did not seem to be solely dependent on afterload. Furthermore, cardiac and stroke indices and coronary flow reserve were not changed in SHR during maximal treadmill exercise after hypertrophy reversal, even with the lower dose of losartan and when the ventricular afterload was similar to that of untreated SHR.     

Effect of benidipine on microvascular remodeling and coronary flow reserve in two-kidney, one clip Goldblatt hypertension

OBJECTIVE: To determine whether chronic treatment with benidipine, a calcium antagonist, leads not only to regression of left ventricular hypertrophy, but also to an improvement in coronary flow reserve and microvascular remodeling. DESIGN AND METHODS: Two-kidney, one clip Goldblatt hypertensive rats were assigned either to a benidipine-treatment group or to a group without treatment after their kidneys had been clipped for 4 weeks. Benidipine was administered to rats in the treatment group for 6 weeks. At the end of the treatment, the systemic hemodynamics and coronary blood flow were determined in conscious unrestrained rats by using nonradioactive colored microspheres injected through the left atrium. The coronary blood flow was determined in rats of both groups with the rats at rest and after near-maximal vasodilatation induced by carbochrome. For evaluation of the microvascular remodeling capillary density, the wall : lumen ratio of arterioles and perivascular fibrosis were quantified by using an image analyzer after fixation of heart tissue. RESULTS: Benidipine treatment lowered the blood pressure significantly with a decrease in total peripheral resistance, and the left ventricular mass decreased markedly compared with that of untreated hypertensive rats. The coronary flow reserve of the untreated hypertensive rats was lower than that of the controls, but benidipine treatment improved the coronary flow reserve. We found a significant decrease in capillary density, and significant increases in wall : lumen ratio and perivascular fibrosis in untreated hypertensive rats. These changes in microvasculature were improved by benidipine treatment. CONCLUSION: Taken together, these results suggest that benidipine exerts favorable effects as an antihypertensive drug by reversing cardiac hypertrophy and improving the coronary flow reserve and microvascular remodeling.     

Effects of hypoxia on the hemodynamic actions of prostaglandin E1

The effect of prostaglandin E1 (PGE1) on central and peripheral hemodynamics was studied in seven conscious dogs under conditions of normoxia and hypobaric hypoxia to ascertain if hypoxia attenuated the cardiovascular actions of PGE1. Silastic catheters were chronically implanted in the pulmonary artery, left atrium, and aorta. Acute hypoxia was produced in a hypobaric chamber maintained at 446 mmHg pressure (14,000 feet). PGE1 at sea level (normoxia) resulted in significant increases in heart rate, cardiac output, left ventricular stroke work and pulmonary blood volume as well as significant decreases in aortic, pulmonary arterial, and left atrial pressures. During hypobaric hypoxia, PGE1 produced essentially identical effects on all hemodynamic parameters except pulmonary blood volume and pulmonary arterial pressure where marked attenuation of PGE1 action occurred.     

Effects of a metalloproteinase that truncates P-selectin glycoprotein ligand on neutrophil-induced cardiac dysfunction in ischemia/reperfusion

This study was designed to test the effects of polymorphonuclear leukocytes (PMNs) in the presence and absence of a P-selectin blocker, mocarhagin, in provoking cardiac dysfunction in isolated perfused rat hearts following ischemia and reperfusion. Control rat hearts not subjected to ischemia were perfused without blood cells for 80 min. Additional control rat hearts were perfused with 100 x 10(6) PMNs in the presence and absence of 0.2 microgram/ml mocarhagin over a 5-min perfusion followed by a 45-min observation period. No significant reduction in coronary flow (CF), left ventricular developed pressure (LVDP), or the first derivative of LVDP (dP/dt max) was observed at the end of the observation period in any non-ischemic group. Similarly, global ischemia (I) for 20 min followed by 45 min of reperfusion (R) produced no sustained effects on the final recovery of any of these parameters in any group of hearts perfused in the absence of PMNs. I/R hearts perfused with PMNs exhibited decreases of 50-60% in all measurements of cardiac function (P < 0.001). These PMN perfused I/R hearts also exhibited marked increases in cardiac myeloperoxidase (MPO) activity indicating a significant PMN infiltration, and enhanced P-selection expression on the coronary microvascular endothelium. All cardiodynamic effects as well as MPO accumulation and PMN infiltration were attenuated markedly by the metalloproteinase, mocarhagin, which inhibits P-selectin-mediated cell adhesion by cleaving its high-affinity receptor, PSGL-1, present on neutrophils. These results provide evidence that neutrophils provoke post-reperfusion cardiac dysfunction, and that this may be largely due to P-selectin-induced adherence of neutrophils to the endothelium.     

Coronary vasodilatory capacity is impaired in patients with dilated cardiomyopathy

Increases in wall stress because of left ventricular enlargement and/or alterations in coronary vasomotor tone might affect myocardial blood flow and vasodilatory capacity in patients with dilated cardiomyopathy. To test this hypothesis myocardial blood flow was measured at rest and during intravenous administration of dipyridamole (0.56 mg/kg) using dynamic nitrogen 13-ammonia positron emission tomography (two-compartment model) in 10 patients with dilated cardiomyopathy (mean left ventricular ejection fraction 28 +/- 8% 1 woman, 9 men; 47 +/- 13 years of age). Ten age and gender matched healthy volunteers served as controls. Coronary artery disease was ruled out by coronary angiography and left ventricular hypertrophy by two dimensional-echocardiography. Baseline heart rate (70 +/- 13 v 64 +/- 12 bpm), systolic blood pressure (111 +/- 20 v 114 +/- 12 mm Hg) and rate pressure product (7,686 +/- 1264 v 7,306 +/- 1,645) were similar in patients and controls. During dipyridamole administration, the rate pressure product increased similarly in both groups. Myocardial blood flow at rest did not differ between groups of patients and volunteers (0.69 +/ -0.27 v 0.67 +/- 0.17 mL/g/min) but correlated with the rate pressure product only in controls (myocardial blood flow, 0.18 + 0.000068214; rate pressure product, .67; P < .05). Hyperemic myocardial blood flow was lower in patients (1.57 +/- 0.39 v 1.92 +/- 0.31 mL/g/min, p < .05, whereas myocardial flow reserve did not differ between groups of patients and controls (2.57 +/- 1.15 v 3.02 +/- 0.94). Coronary vasodilatory capacity is reduced in patients with severe nonischemic cardiomyopathy. Increases in extravascular compressive forces or increased serum catecholamine levels, which in turn induce coronary vasoconstriction, might account for this finding.     

Effects of enoximone and R 80122, a new selective phosphodiesterase III inhibitor, on hemodynamics and myocardial energetics in patients with ischemic heart disease

The present study was designed to compare the effects of enoximone and R 80122, a highly selective phosphodiesterase (PDE) III inhibitor, on left ventricular hemodynamics and myocardial blood flow and metabolism in patients with coronary artery disease. Twenty male, anesthetized patients, ASA physical status III, were studied before they underwent coronary artery bypass grafting (CABG) surgery. They were allocated randomly to receive either 0.3 mg/kg R 80122 (Group 1) or 1 mg/kg enoximone (Group 2) intravenously (IV). All patients were taking maintenance doses of either beta-receptor antagonists or calcium-channel-blocking drugs and nitrates. After receiving flunitrazepam, 2 mg orally, anesthesia was induced with fentanyl, midazolam, and pancuronium IV. Following control measurements after the induction of anesthesia, the PDE III inhibitor was infused over 2 min and measurements were repeated 5, 30, and 60 min after drug administration. There were no external stimuli to the patients during any of the measurement periods. R 80122 and enoximone decreased mean arterial pressure (MAP) by 20% and systemic vascular resistance (SVR) by 36% and 38%, respectively, while cardiac index (CI) increased by 27% and 30%, respectively. There were increases in heart rate (HR) by 10% and 19%, respectively, and in contractility (dp/dtmax) by 18% and 38%, respectively. Coronary perfusion pressure (CPP) decreased by 23% and 22%, respectively, and coronary vascular resistance (CVR) by 38% and 21%, respectively. Myocardial blood flow (MBF) and myocardial oxygen uptake (MVO2) increased in both groups, the increase in MBF being statistically significant (+34%) only in Group 1, whereas the changes in myocardial metabolism were not significant in either group.(ABSTRACT TRUNCATED AT 250 WORDS)     

Tachycardia alone fails to change the myocardial pharmacokinetics and dynamics of lidocaine, thiopental, and verapamil after intravenous bolus administration in sheep

Previous reports have suggested that tachycardia alone can increase the rate of myocardial uptake of some drugs. As part of a systematic study of the determinants of the myocardial uptake and effects of drugs in critical illness, the effect of tachycardia induced by intracardiac pacing on the myocardial disposition and effects of lidocaine, verapamil, and thiopental were studied in chronically instrumented sheep. For each drug, seven sheep received either 100 mg of lidocaine, 10 mg of verapamil, or 750 mg of thiopental over 2 min in unpaced and paced (140 beats/min) states on separate occasions and in random order. Arterial and coronary sinus (effluent from the heart) blood samples were taken at regular intervals for 30 min, and the maximum rate of change of left ventricular pressure (LV dP/dtmax) was measured as an index of myocardial contractility. There were no differences between unpaced and paced studies in the time courses of arterial and coronary sinus concentrations, or the time-courses of myocardial contractility and blood flow, after bolus iv injections of these drugs. Tachycardia alone does not appear to influence the myocardial kinetics or dynamics of lipophilic drugs that can rapidly diffuse into the heart.     

Effects of respiratory alkalosis and acidosis on myocardial blood flow and metabolism in patients with coronary artery disease

BACKGROUND: Variation of the arterial carbon dioxide partial pressure (PaCO2) is not uncommon in anesthetic practice. However, little is known about the myocardial consequences of respiratory alkalosis and acidosis, particularly in patients with coronary artery disease. The aim of the current study was to investigate the effects of variation in PaCO2 on myocardial blood flow (MBF), metabolism, and systemic hemodynamics in patients before elective coronary artery bypass graft surgery. METHODS: In 10 male anesthetized patients, measurements of MBF, myocardial contractility, metabolism, and systemic hemodynamics were made in a randomized sequence at PaCO2 levels of 30, 40, and 50 mmHg, respectively. The MBF was measured using the Kety-Schmidt technique with argon as a tracer. End-diastolic left ventricular pressure and the maximal increase of left ventricular pressure were assessed using a manometer-tipped catheter. RESULTS: The cardiac index significantly changed with varying PaCO2 levels (hypocapnia, - 9%; hypercapnia, 13%). This reaction was associated with inverse changes in systemic vascular resistance index levels. The MBF significantly increased by 15% during hypercapnia, whereas no change was found during hypocapnia. Myocardial oxygen and glucose uptake and the maximal increase of left ventricular pressure were not affected by varying PaCO2 levels. CONCLUSIONS: In anesthetized patients with coronary artery disease, short-term variations in PaCO2 have significant effects on MBF but do not influence global myocardial oxygen and glucose uptake. Changes in systemic hemodynamics associated with respiratory alkalosis and acidosis are caused by changes in systemic vascular resistance rather than by alterations in myocardial contractility.     

Dexmedetomidine produces similar alterations in the determinants of left ventricular afterload in conscious dogs before and after the development of pacing-induced cardiomyopathy

BACKGROUND: The authors tested the hypothesis that intravenous dexmedetomidine produces alterations in left ventricular (LV) afterload that are deleterious to cardiac performance in conscious dogs with pacing-induced cardiomyopathy. METHODS: Dogs (n = 8) were fitted with instruments for long-term measurement of LV and aortic blood pressure, aortic blood flow, and subendocardial segment length and received dexmedetomidine (1.25, 2.5, and 5 microg/kg) in a cumulative manner before and after 19+/-3 (mean +/- SEM) days of rapid LV pacing. LV afterload was measured with aortic input impedance [Zin(omega)] and quantified with a three-element Windkessel model. Hemodynamics and Zin(omega)) were assessed under control conditions and 5 and 60 min after administration of each dose. RESULTS: Dexmedetomidine caused early and late decreases in heart rate, the maximum rate of increase of LV pressure, mean aortic blood flow, and stroke volume in dogs before and after pacing. Dexmedetomidine caused similar early increases in total arterial resistance and decreases in total arterial compliance in dogs before and after pacing. Early dexmedetomidine-induced increases in resistance and decreases in compliance caused similar reductions in mean aortic blood flow in cardiomyopathic compared with healthy dogs. Resistance and compliance returned to control values, and characteristic aortic impedance decreased late after dexmedetomidine in healthy dogs. In contrast, resistance remained elevated late after dexmedetomidine in dogs with dilated cardiomyopathy. CONCLUSIONS: Dexmedetomidine causes similar alterations in hemodynamics and LV afterload in conscious dogs with and without pacing-induced cardiomyopathy.     

Hemodynamic benefits of right ventricular outflow tract pacing: comparison with right ventricular apex pacing

To assess optimal hemodynamics in relation to stimulation site during right ventricular pacing, 17 consecutive patients who underwent cardiac catheterization were studied. In all patients, right ventricular apex and right ventricular outflow tract stimulation was performed at 85, 100, and 120 beats/min. Cardiac index at both pacing sites was compared using the left ventricular outflow tract continuous wave Doppler technique. Comparison of the two stimulation sites demonstrated that right ventricular outflow tract pacing resulted in a higher cardiac index at 85 beats/min (2.42 +/- 1.2 vs 2.04 +/- 1.0 L/min per m2, P < 0.002) at 100 beats/min (2.78 +/- 1.4 vs 2.35 +/- 1.1 L/min per m2, P < 0.001) and 120 beats/min (3.00 +/- 1.5 vs 2.61 +/- 0.9 L/min per m2, P < 0.001). From a total of 51 paired observations, 45 showed an increase in cardiac index during outflow tract pacing as compared to apex pacing. Right ventricular outflow tract pacing at 120 beats/min resulted in a lower cardiac index than right ventricular apex pacing in patients with significant coronary artery disease and/or impaired left ventricular function (ejection fraction < or = 50%), whereas right ventricular outflow tract pacing produced higher cardiac indices in the absence of these abnormalities. Right ventricular outflow tract pacing resulted in higher cardiac indices as compared to apex pacing in all other subgroups at all other pacing sites tested. It is concluded that stimulation of the right ventricular outflow tract offers a significant hemodynamic benefit during single chamber pacing as compared to conventional apex pacing, particularly in the absence of significant coronary artery disease and/or left ventricular dysfunction.     

Hemodynamic characteristics, myocardial kinetics and microvascular rheology of FS-069, a second-generation echocardiographic contrast agent capable of producing myocardial opacification from a venous injection

OBJECTIVES: We sought to 1) study the effects of FS-069 on cardiac and systemic hemodynamic function, myocardial blood flow, left ventricular wall thickening and pulmonary gas exchange when injected intravenously; and 2) compare the myocardial kinetics and microvascular rheology of FS-069 and Albunex when injected directly into a coronary artery. BACKGROUND: FS-069 is a second-generation echocardiographic contrast agent composed of perfluoropropane-filled albumin microspheres; it is capable of consistent and reproducible myocardial opacification from a venous injection. METHODS: Nine dogs were used to study the effects of FS-069 on hemodynamic function, pulmonary gas exchange, left ventricular wall thickening and myocardial blood flow and to characterize its myocardial kinetics when injected intravenously. These dogs were also used to compare the myocardial kinetics of FS-069 with those of Albunex during intracoronary injections. Nine Sprague-Dawley rats were used to compare the microvascular rheology of these two contrast agents, and in vitro modeling was performed to assess whether the microvascular findings of FS-069 can explain its echocardiographic behavior during direct coronary injections. RESULTS: There were no effects of 30 rapid venous injections of FS-069 (every 20 s) on cardiac output; mean aortic, pulmonary or left atrial pressures; and peak positive and negative first derivative of left ventricular pressure (dP/dt). Similarly, there were no effects of this agent on radiolabeled microsphere-measured regional myocardial blood flow, left ventricular wall thickening or pulmonary gas exchange. When injected intravenously, the myocardial transit of this agent resembled a gamma-variate form. When diluted FS-069 was injected directly into the coronary artery; however, its transit resembled the integral of gamma-variate function, with persistent myocardial opacification lasting several minutes, which was different from that of Albunex. Intravital microscopy revealed that, unlike Albunex, when no bubbles are entrapped within the microcirculation after an arterial injection, a very small fraction of the diluted, larger FS-069 microbubbles are entrapped. In vitro modeling confirmed that this small fraction of microbubbles can result in persistent myocardial opacification. CONCLUSIONS: FS-069 produces no changes in hemodynamic function, myocardial blood flow, left ventricular wall thickening or pulmonary gas exchange when injected intravenously in large amounts. When diluted FS-069 is injected into the coronary artery, a very small fraction of the larger bubbles are entrapped within the microcirculation, resulting in a persistent contrast effect. Thus, although FS-069 is a safe intravenous echocardiographic contrast agent, it cannot provide information on myocardial blood flow when injected directly into a coronary artery.