Circumflex Coronary Artery Diameter Research Articles

Chronic exercise training preserves prostaglandin-induced dilation of epicardial coronary artery during development of heart failure in awake dogs☆

Although it has been shown that long-term exercise training preserves endothelium-mediated nitric oxide vasodilator function in chronic heart failure (CHF), whether exercise training exerts similar beneficial effects on endothelial/prostaglandin-mediated vasodilator capacity in coronary circulation during the development of CHF has not been determined. Fifteen mongrel dogs were surgically instrumented for measurement of left ventricular pressure, aortic pressure, coronary blood flow and left circumflex coronary artery diameter. Dogs ( n = 5) who underwent 4 weeks of cardiac pacing (210 b/min for 3 weeks and 240 b/min for the 4th week) developed CHF as characterized by significant reduction in left ventricular systolic pressure, mean arterial pressure and left ventricular dP/dt, increases in left ventricular end-diastolic pressure and heart rate, as well as clinical signs of CHF. Endothelial prostaglandin-mediated vasodilation of the epicardial coronary artery was impaired, as manifested by an attenuated arachidonic acid (AA)-induced dilation of the artery (epicardial artery diameter increased by: 0.78 ± 0.84% in CHF versus 4.6 ± 0.89% in normal, P < 0.05); however, prostacyclin (PGI 2)-induced and nitroglycerin-induced vasodilation of the coronary circulation were not altered. In contrast, dogs ( n = 6) with cardiac pacing plus daily exercise training (4.4 ± 0.3 km/h, 2 h/day) only developed mild cardiac dysfunction, and the response of the epicardial coronary artery diameter to AA was preserved (epicardial artery diameter increased by 4.2 ± 0.98% from baseline, P > 0.05 compared to its respective control). Thus, long-term exercise training preserves endothelial/prostaglandin-mediated dilation of epicardial coronary artery during development of CHF.

Contribution of endogenous endothelin to large epicardial coronary artery tone in dogs and humans.

Nitric oxide (NO) may normally impair endothelin (ET) activity in epicardial coronary arteries. Lifting this inhibitory feedback could reveal ET-dependent effects involving ET(A)- and/or ET(B)-receptor activation. In conscious dogs, the blockade of ET(A) receptors (intracoronary Ro-61-1790) increased external circumflex coronary artery diameter (CD) (sonomicrometry) by 0.10 +/- 0.01 from 3.04 +/- 0.12 mm (P < 0.01) without altering coronary blood flow (Doppler). Similarly, CD increased (0.09 +/- 0.01 from 2.91 +/- 0.14 mm; P < 0. 01) when Ro-61-1790 was given after blockade of NO formation with intracoronary N(omega)-nitro-L-arginine methyl ester (L-NAME). In contrast, ET(B)-receptor blockade (intracoronary Ro-46-8443) did not influence baseline CD with and without L-NAME. In vitro, increases in tension caused by N(omega)-nitro-L-arginine (L-NNA) or PGF(2alpha) in arterial rings were reduced by ET(A)- but not ET(B)-receptor blockade. ET(A)-receptor blockade also reduced the increase in tension caused by L-NNA in human coronary arterial rings. Thus ET(A) receptors, but not ET(B) receptors, account for ET-dependent constriction in canine epicardial coronary arteries in vivo. ET-dependent effects were independent of the level of NO formation in vitro and in vivo. In human epicardial coronary arterial rings, ET(A)-receptor blockade also caused significant relaxation.

Exercise reduces epicardial coronary artery wall stiffness: roles of cGMP and cAMP.

Exercise enhances the dilation of the epicardial coronary arteries by vasodilator drugs and blood flow. Our goal was to determine whether coronary artery elastic properties were affected by brief exercise training. Arterial pressure and left circumflex coronary artery diameter were measured in dogs. Venous bolus injections of acetylcholine 5 microg x kg(-1) (ACH) and nitroglycerin 25 microg x kg(-1) (NTG) or infusions of adenosine 0.5 microM/kg/min (ADO) were given. Fifteen-second coronary artery occlusions were performed. Dogs exercised 2 h x d(-1) for 7 d at 10.9 km x h(-1). Experiments were repeated. Pressure and coronary radius data were used to calculate vessel wall stress and incremental wall modulus, Einc. Baseline Einc and radius were not changed by exercise. Before exercise Einc increased similarly from baseline for all vasodilators. After exercise, the increase in Einc with ADO was unchanged. However, the increase was attenuated during ACH, abolished with occlusion, and reversed with NTG despite enhanced dilation. Data suggest that functional remodeling of epicardial arteries begins soon after starting exercise training, before changes in resting vessel diameter, is mediated by cGMP, and contributes to increased vascular dilation. Brief exercise training enhances the vasodilating capability and elastic properties of large coronary arteries.

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.

Endothelial modulation of beta-adrenergic dilation of large coronary arteries in conscious dogs.

Endothelium-derived relaxing factors have been described as important intermediates in beta-adrenergic vasodilation of resistance coronary vessels, but their involvement at the level of large epicardial coronary arteries remains controversial. Therefore, we examined the role of vascular endothelium in the beta-adrenergic-mediated vasodilation of large epicardial coronary arteries in conscious dogs. Nine dogs were instrumented for measurement of left circumflex coronary artery diameter (CD) by sonomicrometry and coronary blood flow velocity (CBFv) with a Doppler technique in response to graded doses of isoproterenol (0.001 to 0.1 microgram/kg IV bolus). Under control conditions, isoproterenol induced dose-dependent increases in CD and CBFv. When CBFv was kept constant at its baseline value by inflation of a cuff occluder, isoproterenol still induced dose-dependent increases in CD, but the latter were of lesser magnitude than those observed under normal CBFv conditions (110 +/- 20 versus 170 +/- 30 microns, respectively, ie, a reduction of 33% of the dilatory response at 0.1 microgram/kg, P < .01). In the same dogs, the coronary endothelium was then mechanically removed at the site of CD measurement by a balloon angioplasty technique. After this procedure, the dose-dependent increases in CD induced by isoproterenol under either normal or controlled CBFv conditions were overimposable, and their magnitude was similar to that of the increases observed in the presence of an intact endothelium when CBFv was kept constant. After beta 1-adrenergic receptor blockade by atenolol (1 mg/kg), isoproterenol-induced increases in CD were abolished either when CBFv was kept constant or after endothelium removal. In conscious dogs, the direct stimulating effect of isoproterenol on beta 1-adrenergic receptors is endothelium-independent at the level of large coronary arteries. The endothelium reinforces the dilatory response to isoproterenol through an indirect, flow-dependent mechanism.

Comparisons of the effects of nicorandil, pinacidil, nicardipine and nitroglycerin on coronary vessels in the conscious dog: role of the endothelium

1. The vasodilator properties of nicorandil on large and small coronary arteries were compared to those of nicardipine, pinacidil, nitroglycerin and acetylcholine in six conscious dogs. 2. Intravenous bolus injections of acetylcholine (0.1 micrograms kg-1), nitroglycerin (0.3-3 micrograms kg-1), pinacidil (10-100 micrograms kg-1), nicardipine (3-30 micrograms kg-1) and nicorandil (10-100 micrograms kg-1) dose-dependently increased circumflex coronary artery diameter and decreased coronary vascular resistance, indicating vasodilator effects on both conduit and resistance coronary arteries. 3. Three days after removal of the endothelium of the circumflex coronary artery (balloon angioplasty), pinacidil- and nicardipine-induced dilation of large coronary arteries was greatly reduced (both -76%, P < 0.01) whereas that produced by nitroglycerin and nicorandil was decreased only slightly and to a similar extent for both drugs (-19%, P < 0.01 and -28%, P < 0.05, respectively). 4. Thus in conscious dogs, nicardipine- and pinacidil-induced dilatation of large coronary arteries is endothelium-dependent. In contrast, the vasodilator effects of nitroglycerin and nicorandil on conduit vessels are endothelium-independent. 5. Finally, our results demonstrate that nicorandil dilates the large coronary arteries through its nitrate-like action and that the ATP-potassium channel opening properties of the drug are not involved in this effect in the conscious dog.

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.

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.

Chronic exercise enhances endothelium-mediated dilation of epicardial coronary artery in conscious dogs.

Whether endothelium-derived relaxing factor (EDRF)/nitric oxide (NO) plays a role in the dilation of the left circumflex coronary artery during acute exercise and whether endothelium-mediated dilation of this artery is altered after chronic exercise training have not been determined previously. Nine dogs were chronically instrumented for measurements of systemic hemodynamics, left circumflex coronary artery diameter, and blood flow. Acute treadmill exercise (10.9 km/h) caused dilation of the circumflex coronary artery by 4.33 +/- 0.84% and an increase in coronary blood flow by 32 +/- 5.2 mL/min. After the administration of intravenous nitro-L-arginine, the dilation of the circumflex coronary artery was converted to vasoconstriction (-4.13 +/- 1.58%), whereas the increase in coronary blood flow was not altered (24 +/- 3.6 mL/min). Chronic exercise training (2 hours each day at a speed of 10.9 km/h for 7 days) enhanced acetylcholine-induced dilation and reactive dilation (following release of a brief coronary artery occlusion) of the large coronary artery (P < .05), whereas the coronary blood flow responses were not changed. These enhanced acetylcholine-induced and reactive dilations of the circumflex coronary artery were due to a greater release of EDRF/NO since they were eliminated by nitro-L-arginine. Thus, in the circumflex coronary artery, EDRF/NO-dependent dilation was enhanced after 7 days of exercise training. This may represent the mechanism responsible for the perception that chronic exercise induces cardiovascular "well being."

Differential responsiveness of conduit and resistance coronary arteries to endothelin A and B receptor stimulation in anesthetized dogs.

The effects of endothelin-1 (ET-1), an ET(A)/ETB-receptor agonist, and IRL 1620, a potent and selective ETB-receptor agonist, were assessed on left circumflex coronary artery diameter (sonomicrometry) and flow (electromagnetic flow probe) in pentobarbital-anesthetized dogs. Intracoronary (i.c.) bolus injections of ET-1 (80 pmol/dose) caused large, sustained coronary diameter decreases (281 +/- 39 microns) and transient flow increases (5.6 +/- 2.6 ml/min), followed by transient (10.0 +/- 1.9 ml/min) and then sustained flow reductions (6.6 +/- 2.5 ml/min) before terminating in ventricular fibrillation after two to five doses (max delta s; n = 4 dogs). IRL 1620 boluses (5-2,000 pmol/dose i.c.; max delta s; n = 3) also dose-dependently and transiently increased (16.8 +/- 1.4 ml/min; 200 pmol), then transiently decreased (12.8 +/- 1.5 ml/min; 1,600 pmol) flow but had minimal effects on diameter (delta = -23 +/- 4 microns; 2,000 pmol). Doses of IRL 1620 beyond 400 pmol were accompanied by a slowly responding, sustained decrease in baseline flow (-9.2 +/- 2.7 ml/min) and baseline diameter (232 +/- 150 microns). In a separate group of dogs (n = 5), IRL 1620 (400 pmol i.c.) was evaluated before and after sequential inhibition of cyclooxygenase (indomethacin; 10 mg/kg i.v.) and then nitric oxide synthase (N omega-nitro-L-arginine methyl ester, L-NAME; 50 mg/kg i.v.). Indomethacin alone did not affect the flow increase to IRL 1620 (11.0 +/- 2.0 versus 11.8 +/- 1.8 ml/min) but blunted the flow decrease by 30 +/- 6% (10.6 +/- 1.4 versus 7.1 +/- 0.7 ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of alpha-adrenergic blockade with prazosin on large coronary diameter during exercise.

Exercise-induced dilation of coronary resistance vessels is limited by alpha-adrenergic mechanisms. However, the effect of alpha-adrenergic mechanisms on large coronary arteries during exercise is not known. In the present study, sonomicrometry was used to measure circumflex coronary arterial diameter during treadmill exercise before and after alpha 1-adrenergic blockade with prazosin in eight instrumented dogs. Before infusion of prazosin, exercise caused a fall in coronary vascular resistance (2.1 +/- 0.4 to 1.6 +/- 0.2 units, p less than 0.05) and dilation of the circumflex coronary artery (4.66 +/- 0.37 to 4.79 +/- 0.34 mm, p less than 0.05). Intracoronary infusion of prazosin during exercise caused a further decrease in coronary vascular resistance (1.6 +/- 0.2 to 1.4 +/- 0.2 units, p less than 0.05) and a further increase in circumflex coronary arterial diameter (4.79 +/- 0.34 to 4.83 +/- 0.34 mm, p less than 0.05). Intracoronary infusion of vehicle without prazosin during exercise did not cause a further decrease in coronary vascular resistance or increase in coronary diameter. Prazosin caused no significant increase in heart rate, aortic pressure, or coronary blood flow. Therefore, both small coronary resistance vessels and large epicardial coronary arteries dilated during exercise and dilated further after alpha-adrenergic blockade. This finding indicates that alpha 1-adrenergic activity during exercise limits dilation of both large and small coronary arteries.

Differential effects of nitrovasodilators, K(+)-channel openers, and nicorandil on large and small coronary arteries in conscious dogs.

When administered intravenously to conscious dogs, nicorandil, nitrovasodilators (nitroglycerin and SIN-1), and the K(+)-channel opener cromakalim exhibited marked differential effects on large epicardial and small resistance coronary arteries. Nitrovasodilators markedly increased the left circumflex coronary artery diameter at doses at which coronary resistance was not significantly decreased. In contrast, both cromakalim and nicorandil dilated large and small coronary arteries in the same conditions. When coronary blood flow was held to its control value by partial inflation of a hydraulic occluder implanted around the artery, the nitroglycerin- and nicorandil-induced increases in large coronary diameter remained unchanged whereas the response to cromakalim was reduced significantly. This coronary dynamic profile indicates that both nitrovasodilators and nicorandil directly dilate large coronary vessels, whereas the effect of cromakalim on these vessels is mediated partially through a flow-dependent mechanism. This suggests that nicorandil mainly dilates large coronary arteries through its nitroglycerin-like properties, whereas its ability to dilate coronary resistance vessels depends mainly on its K(+)-channel opener-like properties.

Effects of long-term nicorandil application on coronary arteries in conscious dogs.

Nicorandil acting as both nitrovasodilator and K(+)-channel opener was analyzed with regard to its dilator activity in large coronary arteries. In addition, it was tested for potential development of tolerance in six chronically instrumented conscious dogs that received a 5-day continuous i.v. infusion. Increasing dosages of nicorandil (3, 10, and 30 micrograms.kg-1.min-1) caused dose-dependent strong increases in left circumflex coronary artery diameter (1.3 +/- 0.4%, 5.3 +/- 2.2%, and 8.4 +/- 2.8% above control, respectively). However, 100 micrograms.kg-1.min-1 nicorandil produced substantial hypotension, reflex tachycardia, and reduction of the dilator response in large coronary arteries. During long-term nicorandil administration (10 micrograms.kg-1.min-1 i.v. for 5 days), the diameter of the left circumflex coronary artery was increased by 8.8 +/- 2.5%. This was accompanied by a decrease in mean arterial pressure of 13.3 +/- 6.4% and an increase in heart rate by 41.5 +/- 21.0% compared with controls. On the fifth day of continuous nicorandil infusion, dose-response relations for both nicorandil- and nitroglycerin-induced epicardial artery dilations were shifted to 3.5-fold higher doses. We conclude that nicorandil dilates large coronary arteries in dogs, long-term nicorandil administration does not cause a development of tolerance, long-term nicorandil administration is not associated with the development of cross-tolerance to nitroglycerin, and the small shift of the dose-response relations is considered to reflect a hemodynamic adaptation process due to long-term nicorandil exposure.

Influence of low perfusion pressure on effect of endothelin on coronary vascular bed

The goal of this study was to evaluate the influence of low coronary perfusion pressure on the coronary vasoconstriction induced by endothelin. For this purpose, the circumflex coronary arteries of 12 open-chest dogs were cannulated and perfused at a controlled pressure. Total coronary blood flow was measured with an electromagnetic flowmeter and the transmural distribution of coronary blood flow with the radioactive microspheres technique. In addition, the circumflex coronary artery diameter was measured by sonomicrometry with piezoelectric crystals, and the coronary cross-sectional area was calculated. At a coronary perfusion pressure of 100 mmHg, endothelin induced a marked coronary vasoconstriction and a redistribution of coronary blood flow toward the endocardium. At a low coronary perfusion pressure of 40 mmHg, these effects of endothelin were still present. The constriction of the large coronary artery occurred even with a lower dose of endothelin at a low coronary perfusion pressure compared with the normal perfusion pressure. This was not the case when angiotensin II was given the same way. We conclude that endothelin is a potent coronary vasoconstrictor even at a low perfusion pressure. Thus one may speculate that endothelin plays a role in the coronary spasm which has been shown in patients with angina pectoris.

Impaired vasodilatation of epicardial coronary arteries and resistance vessels following myocardial ischemia and reperfusion in anesthetized dogs

To study whether the reactivity of the large coronary artery in vivo is affected by coronary artery occlusion and reperfusion, left circumflex coronary artery diameter, coronary blood flow, systemic arterial blood pressure, and heart rate were measured in anesthetized, open-chest dogs. Intracoronary injections of acetylcholine and glyceryl trinitrate (an endothelium-independent vasodilator) produced increases in both coronary artery diameter (0.06 ± 0.02 mm and 0.15 ± 0.02 mm, respectively) and coronary blood flow (58±15 mL/min and 50 ± 11 mL/min, respectively) under control conditions. Neither arterial blood pressure nor heart rate was affected by the vasodilators. After 60 minutes of coronary artery occlusion and 30 minutes of reperfusion, baseline coronary artery diameter and coronary blood flow were reduced (P & 0.05), and the increases produced by acetylcholine and glyceryl trinitrate in coronary artery diameter (0.01 ± 0.02 mm and 0.09 ± 0.01 mm, respectively) and coronary blood flow (2014 mL/min and 19 ± 5 mL/min, respectively) were significantly attenuated (P&0.05). Electron microscopy revealed endothelial cell injury and focal regions of detachment from underlying subendothelium and adherence of leukocytes to the endothelium of the ischemic large coronary artery. Leukocyte plugging of capillaries in the ischemic myocardium was also occurred. In isolated arterial ring preparations, acetylcholine-induced relaxation (maximum = 59% 19%) was attenuated by ischemia and reperfusion (maximum = 15%14%; P<0.05), whereas glyceryl trinitrate-induced relaxation was not affected. Thus, coronary artery occlusion and reperfusion attenuate endothelium-dependent and -independent dilatation of large coronary arteries and coronary resistance vessels in vivo, whereas only endothelium-dependent relaxation is inhibited in isolated arterial ring experiments. Thus, endothelial dysfunction is not the only factor contributing to reduced vasodilator responses after ischemia and reperfusion. The ischemia-induced constriction of the coronary circulation may restrict the responsiveness to exogenous vasodilators. Also, reduced vasodilator reserve caused by capillary plugging may contribute to the attenuation of the normal increases in coronary blood flow produced by both endothelium-dependent and -independent vasodilators.

Effect of stenosis on exercise-induced dilation of large coronary arteries

The effects of a flow-limiting stenosis on external circumflex coronary arterial diameter during treadmill exercise were studied in 10 instrumented dogs. Coronary arterial diameter was measured by sonomicrometry proximal to the stenosis-producing hydraulic occluder so that the effects of a post-stenotic pressure drop were excluded. With no stenosis, heart rate increased (116 +/- 7 to 183 +/- 10 beats/min, p less than 0.001), aortic pressure increased (97 +/- 3 to 105 +/- 5 mm Hg. p less than 0.005), circumflex coronary blood flow increased (48 +/- 8 to 72 +/- 8 ml/min, p less than 0.001), and circumflex coronary diameter increased (3.82 +/- 0.29 to 3.93 +/- 0.27 mm, p less than 0.01). In the presence of a flow-limiting stenosis, heart rate increased (120 +/- 6 to 176 +/- 9 beats/min, p less than 0.001), aortic pressure did not change significantly (95 +/- 4 to 92 +/- 4 mm Hg), circumflex coronary blood flow increased slightly (39 +/- 8 to 46 +/- 9 ml/min, p less than 0.005), and circumflex coronary arterial diameter did not change significantly (3.78 +/- 0.29 to 3.80 +/- 0.28 mm). The stenosis prevented the increase in aortic pressure, blunted the increase in circumflex coronary blood flow (24 +/- 4 versus 7 +/- 2 ml/min, p less than 0.005), and prevented the increase in circumflex coronary arterial diameter. Therefore normal coronary arteries dilated during exercise and a flow-limiting stenosis prevented exercise-induced coronary dilation proximal to the stenosis, possibly due to both the failure of aortic pressure to increase and less flow-induced endothelium-dependent dilation.

Effects of endothelin on the coronary vascular bed in open-chest dogs.

The goal of the present study was to evaluate the effects of endothelin, a newly discovered very potent vasoconstrictor secreted by endothelial cells, on the coronary vascular bed. For this purpose, the effects of endothelin injected intracoronarily were tested in open-chest anesthetized dogs with the circumflex coronary artery cannulated and perfused at a constant pressure of 100 mm Hg. Circumflex blood flow, transmural distribution of coronary blood flow (radioactive microspheres), circumflex coronary artery diameter (piezoelectric crystals), and circumflex luminal surface area were measured. Endothelin decreased coronary blood flow by 30% and 61% with doses of 1 and 3 micrograms, respectively. A dose of 10 micrograms was lethal. The decrease of coronary blood flow was larger in the subepicardium than in the subendocardium, which explains that the endocardial-epicardial blood flow ratio increased from 1.27 +/- 0.05 to 1.98 +/- 0.23 (p less than 0.001) with a dose of 3 micrograms endothelin. Circumflex surface area decreased by 7% (p = NS) and 20% (p less than 0.01) with doses of 1 and 3 micrograms endothelin, respectively. The action of endothelin was not modified by the concomitant alpha-adrenergic blockade, serotonergic blockade, angiotensin converting enzyme inhibition, or cyclooxygenase inhibition. We conclude that endothelin is a potent coronary vasoconstrictor with a selective effect on the subepicardium. At least part of the increase of coronary vascular resistance is due to a constriction of the large coronary arteries. Further studies are required to determine the physiopathological role of endothelin, especially in coronary vasospasm.

Reflex epicardial coronary vasoconstriction elicited by nicotine in anaesthetized dogs

The effects of arterial chemoreceptor activation by nicotine on coronary artery diameter was studied in anaesthetized, artificially ventilated dogs. Left circumflex coronary artery diameter, coronary blood flow, calculated mean coronary resistance, systemic arterial blood pressure and heart rate were measured. In control dogs (n = 10) the injection of nicotine (100 micrograms) into the carotid artery evoked an increase of arterial pressure (+22 +/- 9 mm Hg) and a decrease in heart rate (-36 +/- 13 beats/min), and tended to increase coronary blood flow (+7 +/- 4 ml/min). Intracarotid nicotine had no effect on large coronary artery diameter (+0.02 +/- 0.03 mm) or total coronary resistance (+0.04 +/- 0.09 mm Hg min/ml) under these conditions. When heart rate was controlled by (1) beta-adrenoceptor blockade (propranolol, 1 mg/kg i.v.) plus pacing of the right ventricle (n = 4) or (2) beta-adrenoceptor blockade plus bilateral vagotomy (n = 7), the chemoreflex-induced constriction of the large coronary artery (-0.07 +/- 0.02 mm and -0.12 +/- 0.03 mm, respectively; p less than 0.05). In contrast, there was no chemoreflex-induced change in total coronary resistance after beta-adrenoceptor blockade plus pacing (+0.01 +/- 0.09 mm Hg min/ml, but after beta-adrenoceptor blockade plus vagotomy coronary resistance was increased (+0.75 +/- 0.31 mm Hg min/ml; p less than 0.05). The constriction of both large and small coronary arteries was abolished by phentolamine (0.5 mg/kg i.v.). These results suggest that carotid body chemoreceptor stimulation by nicotine can produce reflex alpha-adrenoceptor-mediated constriction of both large and small coronary arteries, and that the constriction of the small vessels is balanced by vagally-mediated dilatation.

Alpha-adrenergic vasoconstriction and receptor subtypes in large coronary arteries of calves.

We investigated alpha-adrenoceptor subtype distribution in large coronary arteries from both functional and biochemical perspectives. The effects of intracoronary administration of the selective alpha 1-adrenoceptor agonist phenylephrine (0.1-5.0 micrograms/kg ic), of the selective alpha 2-adrenoceptor agonist B-HT 920 (0.1-5.0 micrograms/kg ic), and of the mixed alpha 1 + 2-adrenoceptor agonist norepinephrine (0.01-0.5 micrograms/kg ic) were examined on measurements of left circumflex coronary artery diameter in conscious calves. After beta-adrenergic blockade, equivalent reductions in large coronary artery diameter were observed with phenylephrine (-6.9 +/- 0.7%), B-HT (-5.9 +/- 0.5%), and norepinephrine (-6.0 +/- 0.4%). Phenylephrine-induced constrictions were abolished by prazosin, an alpha 1-selective antagonist, but unaffected by rauwolscine, an alpha 2-selective antagonist. Conversely, the B-HT-induced constriction was abolished by rauwolscine but unaffected by prazosin. Coronary constriction with norepinephrine was attenuated with either prazosin or rauwolscine and abolished by the two antagonists combined. Ligand-binding studies in which [3H]prazosin and [3H]rauwolscine and sarcolemmal membranes were used revealed an alpha 1-adrenoceptor density of 15 +/- 3.1 fmol/mg protein with a dissociation constant (KD) of 0.7 +/- 0.2 nM and an alpha 2-adrenoceptor density of 68 +/- 5.1 fmol/mg protein, with a KD of 7.4 +/- 1.2 nM. Thus large coronary arteries of the calf contain both alpha 1- and alpha 2-adrenoceptor subtypes, each of which elicits constriction of the large coronary artery in the conscious animal.