Assessment of coronary conductance and resistance vessel reactivity in response to nitroglycerin, ergonovine and adenosine: in vivo studies with simultaneous intravascular two-dimensional and Doppler ultrasound.

OBJECTIVES: The aim of this study was to determine the differential effects of nitroglycerin, ergonovine and adenosine on the resistance vessels in vivo by using a Doppler-tipped guide wire in combination with an ultrasound imaging catheter. BACKGROUND: Catheter-based two-dimensional intravascular ultrasound yields images of the coronary arteries from which cross-sectional areas can be measured. Intravascular Doppler ultrasound techniques allow measurement of coronary blood flow velocity. The simultaneous use of the two techniques can yield anatomic and physiologic information on conductance and resistance vessels but has not been tried in the coronary arteries. METHODS: In 15 dogs, we studied coronary flow and vascular reactivity in response to pharmacologic agents using two approaches: 1) a 30-MHz, 4.3F imaging catheter placed alongside a 0.018-in. (0.046 cm) Doppler wire in the circumflex or left anterior descending coronary artery (n = 5); 2) the ultrasound imaging catheter introduced directly over a 0.014-in. (0.036 cm) Doppler wire (n = 10). Vasodilator and vasoconstrictor responses were studied by using intracoronary nitroglycerin (50, 100 and 200 micrograms), ergonovine (200 micrograms) and adenosine (6 mg). RESULTS: Nitroglycerin caused a dose-dependent increase in epicardial coronary artery cross-sectional area and, to a lesser extent, in average peak flow velocity, resulting in an increase in volumetric coronary blood flow of 39% and 50% at the doses of 100 and 200 micrograms, respectively. With these doses of nitroglycerin, the decrease in diastolic to systolic velocity ratio and the increased change in cross-sectional area from end-diastole to end-systole suggested an enhanced epicardial coronary artery compliance. With ergonovine, a 12% reduction in epicardial coronary artery cross-sectional area was seen, without a significant change in average peak velocity, resulting in a 15% decrease in volumetric coronary blood flow. Adenosine caused a 270% increase in average peak velocity but no change in epicardial coronary artery cross-sectional area, resulting in a 270% increase in volumetric blood flow. CONCLUSIONS: This study demonstrates that nitroglycerin and ergonovine predominantly influence coronary conductance arteries whereas adenosine mainly dilates coronary resistance vessels. These findings also demonstrate that the combined use of a two-dimensional and a Doppler ultrasound transducer within one catheter assembly can provide information on the differential effects of vasoactive agents on the epicardial and microvascular coronary circulation.

Multivessel coronary thrombosis treated with abciximab (ReoPro) in a patient with essential thrombocythemia.

A 50-year-old man was admitted with acute inferior and anterior myocardial infarction. The patient was diagnosed with essential thrombocythemia (ET) based on the findings of marked thrombocytosis of 1,113 x 10(3)/mm3, splenomegaly, and numerous clumping megakaryocytes on bone marrow biopsy. Emergent coronary angiography revealed extensive multivessel thrombosis involving the left main coronary artery and completely occluding the proximal right coronary artery. In addition to standard therapy with aspirin, heparin, and primary angioplasty of the right coronary artery, the patient received additional antiplatelet therapy with ticlopidine, hydroxyurea, and the platelet glycoprotein IIb/IIIa receptor-inhibiting monoclonal antibody drug abciximab (ReoPro). Serial coronary angiograms 1 and 5 days following the infarction showed progressive thrombus resolution. The pathophysiologic mechanisms and therapeutic challenges of ET-associated coronary thrombosis are discussed in this report.

Dipeptidyl carboxypeptidase from seminal fluid resembles the pulmonary rather than the testicular isoenzyme.

The specific activity, molecular weight and immunological behavior of pure dipeptidyl carboxypeptidase from rabbit seminal fluid were found to resemble the corresponding properties of the pulmonary rather than the testicular isozyme.

Tissue-specific expression of mRNAs for dipeptidyl carboxypeptidase isoenzymes.

The molecular weight of newly synthesized dipeptidyl carboxypeptidase (angiotensin-converting enzyme; peptidyldipeptide hydrolase, EC 3.4.15.1) polypeptide primed in a reticulocyte lysate by poly(A)-containing RNA from mature rabbit testis was only about 65% that of the immunologically related species programmed by pulmonary RNA. Furthermore, in contrast to the pulmonary RNA-dependent product, the synthesis of this testicular protein was not directed by RNA from testes of immature animals. These findings indicate that a shorter polypeptide chain and pubertal expression--the structural and regulatory properties that distinguish the testicular dipeptidyl carboxypeptidase isozyme--are determined pretranslationally.

Transvenous coronary ultrasound imaging. A novel approach to visualization of the coronary arteries.

BACKGROUND: Catheter-based ultrasound is a new imaging modality to examine endovascular detail in the coronary circulation. This technique requires direct placement of the catheter in the arterial segment of interest. METHODS AND RESULTS: We examined the feasibility of a less invasive approach by imaging the coronary arterial circulation by using a 5F (30 MHz) imaging catheter placed in the cardiac venous system. Using simultaneous fluoroscopy, we studied anesthetized closed-chest dogs (n = 6) and human subjects undergoing right heart catheterization (n = 11). After cannulation of the coronary sinus, the circumflex coronary artery (Cx) was visualized from the great cardiac vein (GCV), and on advancing the catheter into the anterior interventricular vein (AIV), the left anterior descending artery (LAD) was identified. Where artery and vein were parallel to each other, circular cross-sectional images of the coronary artery were obtained, whereas oblique and transverse orientation of artery to vein produced ellipsoid images or long-axis images. In the dogs, ultrasound-determined cross-sectional area of the coronary arteries (4.81 +/- 0.18 mm2) correlated closely with angiography (4.77 +/- 0.21 mm2) (r = 0.91, p less than 0.001). In humans, the Cx was readily visualized from the GCV in all subjects but because of anatomic variability, the LAD was seen less consistently from the AIV (73%). There was significant correlation between ultrasound-determined cross-sectional areas of the coronary arteries (8.25 +/- 0.34 mm2) with those from angiography (8.59 +/- 0.3 mm2) (r = 0.82, p = 0.001) in humans. In all subjects, the ultrasound transducer could be safely advanced into the AIV to the cardiac apex. Limitations of the technique include ultrasonic penetration problems, caused in part by the large size of human coronary veins and variability in artery-vein relations. CONCLUSIONS: We conclude that transvenous imaging of coronary arteries with intravascular ultrasound is a less invasive, promising new approach to the study of structure and morphology in the coronary vasculature.

Effect of selective angiotensin II receptor antagonism and angiotensin converting enzyme inhibition on the coronary vasculature in vivo. Intravascular two-dimensional and Doppler ultrasound studies.

BACKGROUND: Although angiotensin converting enzyme (ACE) inhibitors have been reported to increase coronary blood flow, the effect of selective angiotensin II (AT1)-receptor antagonism on the coronary circulation has not been defined. METHODS AND RESULTS: We examined the effects of the AT1-receptor antagonist Losartan (DuP 753, 0.2-3.2 mg/kg) on coronary arteries in vivo in 11 dogs, using a combination of intravascular two-dimensional and Doppler ultrasound. In six dogs, a 30-MHz, 4.3F ultrasound imaging catheter was placed in the midsegment of the circumflex coronary artery to measure cross-sectional area (CSA), and a 0.018-in. Doppler wire was placed alongside to measure coronary flow velocity. At peak effect (1.6 mg/kg), Losartan increased mean coronary CSA from 7.9 +/- 0.5 to 9.5 +/- 0.8 mm2 and average peak velocity (APV) from 32 +/- 10 to 56 +/- 18 cm/sec, resulting in an increase in coronary blood flow from 74 +/- 19 to 151 +/- 36 mL/min. The maximal effect of the ACE inhibitor enalaprilat (5 mg) was an increase in CSA from 7.7 +/- 0.7 to 8.4 +/- 0.8 mm2 and an increase in APV from 36 +/- 10 to 53 +/- 20 cm/sec, with an increase in coronary blood flow from 82 +/- 25 to 122 +/- 41 mL/min. Relative to maximal hyperemia with adenosine (6 mg i.c.), the magnitude of flow increase from baseline was 0.37 with the AT1-receptor antagonist and 0.19 with the ACE inhibitor (p < 0.05). These effects were seen without changes in heart rate or systemic arterial pressure. In an additional five dogs, the ultrasound imaging catheter was introduced directly over a 0.014-in. Doppler wire, and the effects of indomethacin, propranolol, and N omega-nitro-L-arginine methylester (L-NAME) on the vasodilator effect of Losartan (1.6 mg/kg) were examined. Indomethacin and propranolol had no effect on Losartan-induced vasodilation, suggesting that it was not mediated via prostaglandins or beta-adrenoceptors. However, Losartan-induced epicardial vasodilation was partially inhibited by L-NAME, suggesting an action partly dependent on endothelial release of nitric oxide. CONCLUSIONS: Thus, these acute studies in anesthetized dogs suggest that inhibition of AT1-receptors in the coronary circulation results in vasodilator responses greater in magnitude than ACE inhibition and partly endothelium dependent. The exact role for AT1-receptors in human coronary physiology and pathology remains to be defined.

Isolation of cDNA clones for the chicken neural cell adhesion molecule (N-CAM).

Enriched mRNA coding for the neural cell adhesion molecule (N-CAM) was prepared from 9-day embryonic chicken brains by immunoprecipitation of polysomes with antibodies to N-CAM. This mRNA programmed the translation in vitro of N-CAM polypeptide chains in a rabbit reticulocyte lysate system. Two independent N-CAM cDNA clones (designated pEC001 and pEC020) were derived from the enriched RNA. The specificity of pEC001 for N-CAM mRNA was verified by hybrid selection experiments. Both plasmids hybridized to two discrete 6- to 7-kilobase-long RNA species in poly(A)+ RNA from embryonic chicken brain and to lesser amounts of polydisperse material of smaller sizes (probably degradation products of the large RNAs). No hybridization was detected to poly(A)+ RNA from embryonic liver. Southern blotting experiments with pEC001 detected only one hybridizing fragment in chicken genomic DNA digested with several different restriction enzymes, suggesting that sequences corresponding to those within this region of N-CAM mRNA are present at most only a few times, and possibly only once, in the chicken genome.

Evidence for formation of a rabbit liver aldolase--rabbit liver fructose-1,6-bisphosphatase complex.

The ability of rabbit liver aldolase (D-fructose-1,6-bisphosphate D-glyceraldehyde-3-phosphatate-lyase, EC 4.1.2.13) and rabbit liver fructose-1,6-bisphosphatase (Fru-P2ase; D-fructose-1,6-bisphosphate 1-phosphohydrolase, EC 3.1.3.11) to partition into the gel phase of Ultrogel AcA 34 is decreased in a mixture of the two enzymes. Titration experiments indicate that a 1:1 complex is formed. The value for the distribution coefficient of the complex corresponds to a molecular mass of 300,000 daltons, the value expected for a dimer containing one mole of each enzyme protein. Complex formation was not observed when either liver enzyme was replaced by the corresponding isozyme from rabbit muscle. The susceptibility of liver Fru-P2ase to limited proteolysis by subtilisin was reduced in the presence of liver aldolase, but not when the latter was replaced by muscle aldolase, suggesting that the conformation of Fru-P2ase is altered in the complex. Limited proteolysis of liver aldolase abolishes its ability both to form the heterodimer and to protect Fru-P2ase from modification by subtilisin.

Differential contribution of nitric oxide to regulation of vascular tone in coronary conductance and resistance arteries: intravascular ultrasound studies.

We examined the role of nitric oxide in the maintenance of coronary vascular tone in 15 dogs. A 0.014 inch Doppler wire was introduced into the midsegment of the circumflex coronary artery and a 4.3F, 30 MHz two-dimensional ultrasound imaging catheter was introduced over the Doppler wire. Acetylcholine caused a dose-dependent vasodilation in both epicardial and resistance coronary arteries. However, N omega-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthetase caused a dose-dependent vasoconstriction mainly in the epicardial coronary arteries, partially reversed by L-arginine. The vasodilator response to acetylcholine was inhibited by L-NAME only in the epicardial circulation. Thus using combined intracoronary two-dimensional and Doppler ultrasound, we have demonstrated both basal and acetylcholine-induced release of nitric oxide in epicardial coronary arteries. The failure of L-NAME to decrease basal and acetylcholine-induced increases in flow velocity suggests that endothelium-dependent relaxation in coronary resistance vessels may not be mediated by nitric oxide alone.

Cyclosporine impairs release of endothelium-derived relaxing factors in epicardial and resistance coronary arteries.

BACKGROUND: Cyclosporin A is reported to impair endothelium-mediated vasorelaxation and induce endothelin release in some noncoronary vascular beds. We wished to determine whether acute cyclosporine administration induces endothelial dysfunction in coronary conductance or resistance arteries. METHODS AND RESULTS: We examined the effect of intracoronary acetylcholine, N omega-nitro-L-arginine methyl ester (L-NAME), L-arginine, nitroglycerin, and adenosine before and after acute cyclosporine administration (3 mg/kg IV over 30 minutes) in anesthetized dogs. Flow velocity was measured with a 0.014-in Doppler wire to assess resistance vessel responses, and epicardial coronary lumen area was simultaneously measured with a 4.3F, 30-MHz imaging catheter inserted over the Doppler wire. In 6 dogs, acetylcholine-induced increase in flow velocity was attenuated by cyclosporine in vehicle (137% to 55% at 10(-5) mol/L, P < .001), as was acetylcholine-induced epicardial vasodilation (14.1% to 6.7% at 10(-5) mol/L, P < .001). Vasodilation in response to intracoronary nitroglycerin (200 micrograms) and adenosine (6 mg) were unchanged by cyclosporine. Epicardial vasoconstriction with L-NAME (10(-4) mol/L) was reduced by cyclosporine (Pre, 7.4 +/- 0.9%; Post, 2.6 +/- 1.2%; P = .04), but L-arginine (10(-4) mol/L) had no effect after cyclosporine. In another 5 dogs, pure cyclosporine impaired acetylcholine-induced vasodilatation to the same degree as cyclosporine in vehicle (Cremophor); vehicle infusion did not impair endothelial function. In 5 more dogs, cyclosporine did not increase either arterial or coronary sinus concentrations of endothelin-1. CONCLUSIONS: The present study shows that cyclosporine acutely impairs release of endothelium-derived relaxing factor in canine conductance and resistance coronary arteries and provides evidence for decreased epicardial nitric oxide release after cyclosporine. The potential contribution of acute cyclosporine-induced coronary endothelial dysfunction to posttransplant vasculopathy needs further study.