Coronary Conductance Arteries Research Articles

Physiological antagonism of endothelin-1 in human conductance and resistance coronary artery.

The ability of four endogenous vasodilators, nitric oxide (NO; 0.01 - 30 microM), atrial (ANP), brain (BNP) and C-type (CNP) natriuretic peptide (0.1 - 300 nM), to reverse endothelin-1 (ET-1; 10 nM) constrictions in human resistance and conductance coronary arteries (CA) in vitro was investigated. ET-1 (0.1 - 300 nM) constricted resistance CA more potently than conductance CA (P<0.05; EC(50) values 2.98 nM (95% CI: 1.49 - 5.95 nM and 8.58 (4.72 - 15.6 nM) respectively)). The NO-donor diethylamine NONOate fully reversed the ET-1 constriction in conductance CA (E(MAX) 127+/-9.16%), however only partial reversal was observed in resistance CA (E(MAX) 78.8+/-8.13; P<0.05). The soluble guanylate cyclase inhibitor 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (100 microM) reduced the maximum response to diethylamine NONOate to 76.9+/-14.4% in conductance CA (P<0.05), but had no effect on resistance CA (E(MAX) 77.2+/-18.4%). There was no difference between responses to ANP in conductance and resistance CA (EC(50) values 4.25 nM (0.84 - 21.4 nM) and 18.4 nM (2.92 - 116 nM), E(MAX) 53.1+/-14.7% and 48.6+/-11.8% respectively). BNP was a more potent vasodilator of conductance than resistance CA. In conductance CA the mean EC(50) value was 2.4 nM (0.74 - 7.75 nM), E(MAX) 54.5+/-14.9%. Concentration-response curves to BNP were incomplete in resistance CA. Concentration-response curves to CNP were incomplete in both conductance and resistance CA. The greater potency of ET-1 in resistance vessels may exacerbate the effects of increased circulating levels of the peptide in disease. Only NO could fully reverse ET-1 mediated constrictions in conductance CA, and none of the dilators tested could completely counteract constrictions in resistance CA.

Biomolecular Basis for Cold-Induced Contraction of Coronary Arteries in the Newborn Lamb: Implication in Myocardial Dysfunction after Hypothermic Cardiopulmonary Bypass ♦ 98

Introduction: Despite improved overall outcome after open heart surgery, early myocardial dysfunction remains a problem in the infant and the neonate in the post hypothermic cardiopulmonary bypass recovery period. We hypothesize that a vasoconstriction of the conductance coronary arteries (CA) occurs when exposed to cold, and that this cold induced contraction involves protein tyrosine kinase (PTK)-/protein tyrosine phosphatase (PTP)-dependent signal transduction pathways. Methods: Newborn lamb 3-mm CA ring segments (1mm diameter) were studied in tissue bath (Krebs buffer, 21%O2, 5%CO2) for isometric contraction during a 2-hour exposure to hypothermia (7° & 17°C). In parallel, 8-mm CA ring segments were evaluated for changes in protein tyrosine phosphorylation using standard electrophoretic and immunoblotting techniques (monoclonal anti-phosphotyrosine antibody & chemiluminescence detection). Na-orthovanadate (SOV), a potent PTP inhibitor, and genestein (Gen), a non selective PTK inhibitor, were used separately and in combination to evaluate their effect on contractile behavior and tyrosine phosphorylation of CA during cooling (7° or 17°C) vs. 37°C. Results: Tissue bath cooling to 17°C resulted in sustained contraction (25% KCl, n=4), reversible upon rewarming. CA segments subjected to 7°C cooling demonstrated a transitory contraction at≈17°C, more prominent during rewarming (5-15% KCl). Cold-induced contraction was abolished in the presence of Gen and significantly enhanced(2-fold) in the presence of SOV, the latter being partially inhibited in the presence of Gen. There was increased tyrosine phosphorylation of 25, 30-33 and 100-110 kDa proteins detected at 17°C compared to 37°C (n=4), similarly enhanced by SOV and abolished by Gen.

Diverse Relaxation Responses of Canine Large and Small Conductive Coronary Arteries to Glyceryl Trinitrate and Nitric Oxide on the One Hand and to 8-Bromoguanosine 3’: 5’ Cyclic Monophosphate on the Other

Glyceryl trinitrate (GTN) and nitric oxide (NO) preferentially relaxed the large (2 mm in diameter) conductive coronary artery (CCA) of the dog, while 8-bromoguanosine 3’:5’ cyclic monophosphate preferentially relaxed the small one (0.6 mm in diameter). Nither L-cysteine nor L-acetylcysteine affected GTN-induced relaxation in small- and large-CCA. These results indicate that not different biotransformation of GTN to NO, but a process or processes operative between activation of guanylate cyclase and that of cyclic GMP-dependent protein kinase seems to be responsible for the preferential dilatation of large-CCA.

Coronary vasodilation induced by angiotensin-converting enzyme inhibition in vivo: differential contribution of nitric oxide and bradykinin in conductance and resistance arteries.

We studied in coronary conductance and resistance arteries the coronary vasodilator effects of the angiotensin-converting enzyme inhibitor ramiprilat and the contribution of nitric oxide, bradykinin, and prostaglandins to this vasodilation. In seven anesthetized dogs, a Doppler guidewire was placed in the circumflex coronary artery to measure coronary flow velocity, and an ultrasound imaging catheter was introduced over the Doppler wire to measure coronary cross-sectional area. Drugs were infused directly into the left main coronary artery to minimize systemic effects. Ramiprilat increased both epicardial cross-sectional area and coronary blood flow velocity, resulting in an increase in absolute coronary blood flow. Pretreatment with N omega-nitro-L-arginine methyl ester (100 micromol/L intracoronary) to block nitric oxide synthase attenuated ramiprilat-induced increase in epicardial coronary cross-sectional area (P<.05) but not in coronary flow velocity or coronary blood flow. In contrast, pretreatment with the selective bradykinin antagonist HOE 140 (10 micromol/L) attenuated ramiprilat-induced increase in flow velocity (P<.025) and coronary blood flow (P<.05) but not epicardial coronary cross-sectional area. Pretreatment with indomethacin (5 mg/kg body wt IV) did not alter ramiprilat-induced increase in epicardial cross-sectional area, nor did it significantly influence coronary blood flow. Other than decreasing angiotensin II production, acute ramiprilat-induced vasodilation in canine coronary conductance arteries is mediated in part by nitric oxide. Ramiprilat-induced vasodilation in resistance arteries is in part mediated by the action of bradykinin.

Effect of the New Nitrate Ester ITF 296 on Coronary and Systemic Hemodynamics in the Conscious Dog

The coronary and systemic hemodynamic effects of the novel nitrate ester ITF 296 were investigated in conscious, resting dogs and compared with nitroglycerin and nicorandil. ITF 296 at 1-25 micrograms/kg i.v. elicited selective, long-lasting, and dose-dependent increases in large epicardial coronary artery diameter (CD) without affecting coronary blood flow (CBF) or coronary vascular resistance (CVR). Blood pressure (BP) and heart rate (HR) were also unaltered. At 125 micrograms/kg, ITF 296 further increased CD but simultaneously reduced CVR and mean aortic pressure and increased CBF and HR. Nitroglycerin 1-25 micrograms/kg induced a shorter and less selective dilatation of large coronary conductance arteries, as it was accompanied by a decrease in CVR at all doses used. Nicorandil produced a selective increase in left circumflex CD only at the lowest dose used (10 micrograms/kg), whereas higher doses were effective on both CD and CVR. ITF 296 significantly reduced left ventricular end-diastolic pressure and increased stroke volume (SV) and cardiac output (CO) at doses that did not alter HR or BP, indicating an increase in cardiac efficiency. In contrast, the increases in CO produced by nitroglycerin and nicorandil were dependent on the augmentation of HR, because SV was unchanged at all doses used. Nitroglycerin dose-dependently decreased BP, whereas ITF 296 reduced BP only at the highest dose used. In conclusion, ITF 296 induces a selective, flow-independent dilatation of large coronary conductance arteries without affecting the tone of small coronary resistance vessels or systemic hemodynamics over a broad range of doses. An equally selective effect was elicited by nicorandil only at the lower dose used, whereas no selective effect of nitroglycerin on the diameter of coronary conductance arteries was seen at the doses utilized in this study.

Enhancement of noradrenergic constriction of large coronary arteries by inhibition of nitric oxide synthesis in anaesthetized dogs.

1. Coronary vascular responses to bilateral carotid occlusion (BCO) and the intravenous infusion of tyramine (Tyr, 20 micrograms kg-1 min-1) and noradrenaline (NA, 0.5 microgram kg-1 min-1) were examined after bilateral vagotomy and antagonism of beta-adrenoceptors. BCO, Tyr and NA decreased large coronary artery diameter and increased mean coronary resistance and systemic arterial pressure without affecting heart rate. 2. Inhibition of nitric oxide (NO) synthase with NG-nitro-L-arginine (L-NNA, 5 and 15 mg kg-1) significantly increased mean arterial pressure and decreased heart rate and large coronary artery diameter. Mean coronary resistance was unaffected by either dose of L-NNA. L-NNA significantly reduced depressor and coronary vasodilator responses to the endothelium-dependent vasodilator acetylcholine (ACh, 10 micrograms kg-1, i.v.). Systemic and coronary vasodilator responses to sodium nitroprusside (SNP, 5 micrograms kg-1) were unaffected by L-NNA with the exception that the dilatation of the large coronary artery was significantly enhanced by the higher dose. 3. L-NNA significantly enhanced constriction of the large coronary arteries caused by BCO, Tyr and NA but did not affect the increases in mean coronary resistance or systemic arterial pressure. 4. Inhibition of NO synthesis enhances adrenergic constriction of large coronary arteries caused by both neuronally released and exogenous noradrenaline. In contrast, L-NNA did not affect adrenergic constriction of coronary or systemic resistance vessels. Endothelium-derived NO may play an important role in the modulation of noradrenergic vasoconstriction in coronary conductance arteries.

Effects of physiological levels of estrogen on coronary vasomotor function in postmenopausal women.

Estrogen replacement therapy has been associated with a reduction in cardiovascular events in postmenopausal women. One of the mechanisms responsible may be a beneficial effect of estrogen on coronary vascular function. We therefore studied the short-term effects of estrogen on coronary artery dimensions and microvascular resistance in postmenopausal women. Twenty postmenopausal women 61 +/- 7 years old participated in this study. Seven had angiographic evidence of atherosclerosis of the left coronary artery. Coronary artery diameters were measured by quantitative coronary angiography. Blood flow velocity was measured with a Doppler wire placed in a proximal left coronary artery segment. Left coronary artery infusions of acetylcholine (range, 10(-8) to 10(-5) mol/L estimated delivered concentrations) and of adenosine (n = 18) and sodium nitroprusside (n = 10) were performed before and during concomitant continuous intracoronary infusion of 17 beta-estradiol to test endothelium-dependent and independent vasodilation, respectively. Intracoronary infusion of estradiol increased coronary sinus estradiol levels from postmenopausal (16 +/- 11 pg/mL) to premenopausal (282 +/- 121 pg/mL) levels. Estradiol did not affect basal coronary artery diameter, blood flow, or resistance. Epicardial coronary artery constriction induced by acetylcholine infusion in the control study (maximum, 10 +/- 15% from baseline) was prevented during repeat acetylcholine infusion with concomitant estradiol administration (P < .001). Estradiol potentiated the vasodilator coronary microvascular response to acetylcholine as manifest by significantly greater coronary flow (P < .001) and lower coronary resistance (P < .02). The reduction in coronary resistance from baseline in response to acetylcholine was significantly potentiated by estradiol (P = .01), with a mean decrease in coronary vascular resistance during acetylcholine infusion of 20 +/- 38% before and 35 +/- 33% during concomitant estradiol administration. The effect of estradiol on coronary dynamics was similar in women with and women without angiographically apparent left coronary artery atherosclerosis and was most prominent in women with the most impaired responses to acetylcholine at both the epicardial (r = -.72, P < .001) and microvascular (r = -.59, P = .006) coronary artery levels. In contrast, estradiol did not affect the coronary epicardial or microvascular vasodilator responses to adenosine or sodium nitroprusside. Physiological levels of 17 beta-estradiol acutely and selectively potentiate endothelium-dependent vasodilation in both large coronary conductance arteries and coronary microvasuclar resistance arteries of postmenopausal women. This effect may contribute to the reduction in cardiovascular events observed with estrogen replacement therapy.

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 resistantce 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 Bow 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 μg), ergonovine (200 μg) 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 59% at the doses of 100 and 200 μg, 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 bood 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.

Prostaglandin E1 and Nitroglycerin Effects on Canine Epicardial Conductance and Distal Coronary Resistance Vessels

Prostaglandin E1 (PGE1) has been reported to be a coronary vasodilator and has been considered clinically in the treatment of coronary vasospasm, but its mechanism of action is not known. To evaluate the vasomotor effect of PGE1, epicardial coronary and distal resistance vessel responses were compared by PGE1 and nitroglycerin infusion into the left anterior descending (LAD) artery of the closed-chest dog. Coronary angiography and 133Xe washout flow measurements were used to quantitate proximal and distal vessel responses, respectively. To evaluate potential inhibitory actions, vessels were contracted by continuous LAD infusion of prostaglandin F2 alpha (PGF2 alpha) or serotonin before dose-response testing with PGE1 or nitroglycerin. PGE1 alone produced a 20% dilation of the LAD in vivo but only with the highest dose (2.0 micrograms/min). PGE1, however, did not reverse epicardial vessel constriction induced by PGF2 alpha or serotonin. LAD flows (resistance vessel response) were increased comparably by PGE1 alone and with PGF2 alpha added (100 and 93% above control flow, respectively) but to a lesser extent with serotonin added (57% above control). In contrast, nitroglycerin completely reversed epicardial artery constrictions induced by PGF2 alpha and serotonin. Our findings indicate that although PGE1 is a vasodilator in vivo, it does not demonstrate a major effect in dilating epicardial conductance coronary arteries and therefore may not be beneficial in antagonizing endogenous contractile factors in treatment of coronary vasospasm. PGE1 does increase coronary blood flow by dilating distal resistance vessels. The beneficial effects of PGE1 in humans with unstable angina therefore are probably not due to vasorelaxing effects on epicardial coronary conductance arteries.