Flow-dependent, endothelium-mediated dilation of epicardial coronary arteries in conscious dogs: effects of cyclooxygenase inhibition

Endothelial damage or removal abolishes the dilation of epicardial coronary arteries induced by increments in flow through these arteries in vitro. Therefore, we tested whether or not the release of a cyclooxygenase product from endothelial cells in vivo is the mechanism of this flow-dependent dilation. In eight conscious dogs, instrumented to register the external diameter of two epicardial branches--anterior descending and circumflex--of the left coronary artery, increments in coronary flow increased and reductions in coronary flow decreased the diameter of the left circumflex epicardial artery by 182 +/- 11 micron/100% change in flow. When mean coronary flow in one epicardial branch was kept constant by a distal, flow-limiting stenosis during the application of flow-augmenting stimuli (temporal coronary occlusion or 80-400 micrograms/kg adenosine i.v.), no dilation of this artery was observed. Cyclooxygenase inhibition (suppressing the bradykinin-induced elevation of plasma 6-keto-PGF1 alpha) by indomethacin (5 mg/kg) or by diclofenac (10 mg/kg) increased smooth muscle tone in both epicardial arteries, but did not modify the flow-diameter relation (181 +/- 10 and 179 +/- 9 microns/100% change in flow, respectively). It is concluded that a tonic, instantaneous influence of coronary flow on the smooth muscle tone of the epicardial coronary arteries exists in vivo. It is unlikely that prostacyclin or another prostanoid is a mediator of this endothelium-mediated influence of flow on smooth muscle tone.     

Sustained dilatation of large coronary artery by alpha-human atrial natriuretic peptide in conscious dogs: a comparison with nitroglycerin

The effects of alpha-human atrial natriuretic peptide (alpha-hANP) on the coronary circulation were compared with those of nitroglycerin in 16 conscious dogs chronically instrumented with a pair of miniature sonomicrometers and an electromagnetic flow probe placed on the left circumflex coronary artery. alpha-hANP (1 and 10 micrograms) and nitroglycerin (0.1, 1 and 10 micrograms) were administered intracoronarily via a cannula implanted in the proximal left circumflex coronary artery. Both alpha-hANP and nitroglycerin dose dependently increased the coronary diameter and coronary blood flow. Although alpha-hANP (10 micrograms) and nitroglycerin (1 microgram) dilated the large coronary artery to almost the same extent (92 +/- 10 vs. 98 +/- 8 microns), the time course of the dilating action differed; the peak dilatation occurred at 5.6 +/- 0.8 and 0.9 +/- 0.07 min (P less than 0.01), and full recovery occurred at 31.5 +/- 3.8 and 5.5 +/- 1.3 min (P less than 0.01) after alpha-hANP and nitroglycerin, respectively. Topical application of alpha-hANP (50 micrograms) to the epicardial coronary artery of three anesthetized open-chest dogs did not affect the coronary diameter and coronary blood flow, while nitroglycerin (50 micrograms) increased both variables. Thus, intracoronary alpha-hANP dilates the large coronary artery more gradually and more sustainedly than nitroglycerin does.     

Effects of trapidil and nitroglycerin on coronary circulation in conscious dogs

Effects of trapidil and nitroglycerin (glyceryl trinitrate) on coronary blood flow or epicardial coronary diameter were studied in conscious dogs, instrumented with a Doppler flow probe or a pair of ultrasonic dimension crystals on the left circumflex coronary artery. Bolus intravenous injections of trapidil (0.5, 1.0 and 2.0 mg/kg i.v.) increased coronary blood flow, dose-dependently, such being comparable at the peak value seen with nitroglycerin (5, 10 and 20 micrograms/kg i.v.). Coronary blood flow following the intravenous administration of trapidil or nitroglycerin increased biphasically and returned to pre-drug levels in 1.4 +/- 0.2 min (trapidil 1 mg/kg i.v.) or 1.0 +/- 0.1 min (nitroglycerin 10 micrograms/kg i.v.), while the mean coronary diameter increased monophasically and approached the control level 5 min after drug administration. The first peak was observed before the maximal decrease in aortic pressure and the second peak was associated with concomitant increases in heart rate and myocardial contractility induced by a sudden hypotension. Propranolol, a beta-blocker, did not modify the initial peak but attenuated markedly the second peak (P less than 0.05) in case of trapidil (1.0 mg/kg i.v.) or nitroglycerin (10 micrograms/kg i.v.), which corresponded with reduced changes in reflex tachycardia and positive inotropism. Therefore, the direct effects of trapidil and nitroglycerin on coronary circulation of conscious dogs are an initial transient dilatation of the resistance vessels followed by a continuation of the dilatation of the conductance coronary vessels.     

Hemodynamic actions of nicorandil, a new antianginal agent, in the conscious dog

We studied the hemodynamic effects of nicorandil (SG-75) and nitroglycerin in conscious dogs before and after beta-adrenergic receptor blockade. Nicorandil (25-300 micrograms/kg/min) and nitroglycerin (5-60 micrograms/kg/min) produced increases in heart rate and decreases in aortic and left ventricular pressures. In the doses studied, nicorandil caused greater decreases in aortic and left ventricular systolic pressure than nitroglycerin; however, nitroglycerin reduced left ventricular end-diastolic pressure to a greater degree. Nicorandil but not nitroglycerin produced an increase in cardiac output secondary to an increase in heart rate. Global contractility (peak positive dP/dt) was increased in a dose-related manner during nicorandil infusion before beta-blockade. In spite of marked hypotensive responses to higher doses, mean coronary blood flow and coronary conductance were increased by nicorandil. In contrast, both parameters were reduced during nitroglycerin infusion. The effects of nicorandil on coronary blood flow were unaltered by beta-adrenergic blockade, suggesting that metabolic autoregulation is not an important mediator of the response. Nicorandil (75-300 micrograms/kg/min) produced a dose-related increase in transmural myocardial blood flow with the greatest increases in perfusion occurring in the subepicardium and midmyocardium. The results of the present study demonstrate that despite structural similarities, nicorandil and nitroglycerin have varying hemodynamic spectra.     

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.     

Enhanced subendocardial perfusion distal to a flow-limiting coronary artery stenosis in dogs: comparative effects of nicorandil, a potential new antianginal agent, and nitroglycerin

The purpose of this study was to compare the effects of nicorandil [SG-75; 2-nicotinamidoethyl nitrate (ester)] and nitroglycerin on the distribution of blood flow between subendocardium and subepicardium [endocardial/epicardial blood flow ration (endo/epi)] distal to a proximal flow-limiting coronary artery stenosis in anesthetized dogs. Myocardial blood flow distribution was determined by use of 15-micron radioactive microspheres. Various indices of reactive hyperemia (peak flow, duration, volume) and poststenotic coronary pressures were used to assess the severity of ischemia in the area distal to the stenosis. Partial ischemia was produced by a 10-s total left circumflex coronary occlusion followed by 110 s of reflow to 50-60% of the control flow. Microspheres were injected during steady-state conditions during the partial reflow period. In the absence of drug, coronary artery stenosis produced marked underperfusion of the subendocardium (endo/epi, 0.55 +/- 0.05). Following administration of nicorandil (60 micrograms/kg i.v.) or nitroglycerin (15 micrograms/kg i.v.), the endo-epi during a subsequent partial reflow (stenosis present) period was significantly increased (0.67 +/- 0.06). The duration of reactive hyperemia and reactive hyperemic flow were also decreased by both compounds following release of the stenosis. These results suggest that nicorandil and nitroglycerin reduce subendocardial ischemia distal to a flow-limiting coronary artery stenosis. This beneficial effect may partially explain the efficacy of these two compounds in the therapy of angina pectoris.     

Effects of intravenous nicorandil on coronary circulation in humans: plasma concentration and action mechanism

We investigated the cardiovascular profile of nicorandil, an antianginal agent, in humans. Pharmacologically, nicorandil acts as both an adenosine triphosphate (ATP)-sensitive K+ (K(ATP)) channel opener and a nitrate. We examined which of these mechanistic components has a predominant vasodilatory effect at clinical doses. Fourteen patients underwent cardiac catheterization. The effects of the continuous intravenous infusion of nicorandil (12 mg/45 min) were examined in angiographically normal coronary arteries. Coronary vascular resistance was calculated from coronary artery diameter and coronary blood flow velocity measured using an intravascular Doppler catheter. We compared the hemodynamic responses to nicorandil with those to the intracoronary injection of nitroglycerin (250 microg) and papaverine (12 mg). The epicardial coronary arteries responded to nicorandil at the lowest plasma concentration examined (dilation of +14.0 +/- 3.3% at approximately 170 ng/ml), whereas dilation of the coronary resistance arteries (i.e., a decrease in coronary vascular resistance) took place only at higher concentrations (>200 ng/ml). Nitroglycerin caused no further changes in coronary artery diameter or coronary vascular resistance. Papaverine caused no further increase in coronary artery diameter, but markedly decreased coronary vascular resistance (1.6 +/- 0.3 to 0.4 +/- 0.1 mm Hg/ml/min; p < 0.05). Nicorandil significantly decreased pulmonary capillary wedge pressure (i.e., reduced cardiac preload) at a plasma level of >200 ng/ml, but did not change either systemic or pulmonary vascular resistance. Thus nicorandil preferentially dilated epicardial coronary arteries rather than coronary resistance arteries, and had a stronger effect on preload than on afterload. These changes in human coronary hemodynamics suggest that the nitrate actions of nicorandil as a coronary vasodilator predominate over those as a K(ATP) opener.     

Spasmolytic action of nicorandil in canine conductive coronary arteries in vivo is not modified by glibenclamide.

The spasmolytic effects of nicorandil, cromakalim, and nitroglycerin on coronary arteries were investigated by angiographic technique in anesthetized dogs. With intracoronary arterial (i.a.) U 46619, a thromboxane A2 mimetic, the diameter of coronary arteries decreased in a sustained manner by 36.1 +/- 1.6% from control levels (coronary spasm). With a successive i.a. injection of nicorandil (300 micrograms), cromakalim (30 micrograms), or nitroglycerin (3 micrograms), the diameter recovered control levels (102.9 +/- 3.9, 96.8 +/- 5.6, and 100.1 +/- 4.3%, respectively). In dogs treated intravenously (i.v.) with glibenclamide, a pharmacologic antagonist of K-channel openers, the spasmolytic effect of cromakalim was significantly reduced, whereas the activity of nicorandil or nitroglycerin remained unaffected. We also investigated a possible modification by glibenclamide of the increase in coronary blood flow (CBF) induced by i.a. nicorandil and cromakalim in anesthetized dogs. The dose-dependent blood flow responses to cromakalim and nicorandil were significantly attenuated by glibenclamide, whereas the response to nitroglycerin remained unaffected. These results suggest that the spasmolytic effect of nicorandil on canine conductive coronary vessels is not mediated by K-channel opening but by a nitroglycerin-like action and that the dilatation of resistive coronary vessels induced by nicorandil may be largely due to its action as a K-channel opener.     

Vasodilating effects of nicorandil and nitroglycerin in anaesthetized open-chest dogs

Vasodilating effects of intravenous administrations of nicorandil (SG-75) and nitroglycerin were analyzed in anaesthetized open-chest dogs by measuring simultaneously, and continuously, coronary (CBF), vertebral (VBF), renal (RBF) and aortic blood flow (AoF). Nicorandil 10-300 micrograms/kg i.v. and nitroglycerin 1-30 micrograms/kg i.v. decreased aortic blood pressure and increased CBF in a dose-dependent fashion. The doses of nicorandil and nitroglycerin which reduced coronary vascular resistance to about 60% of the predrug value were 100 micrograms/kg and 10 micrograms/kg, respectively. Nicorandil 100 micrograms/kg i.v. significantly increased AoF and heart rate, significantly decreased left ventricular end-diastolic pressure and did not significantly change VBF, RBF and left ventricular dP/dt. Nitroglycerin 10 micrograms/kg i.v. significantly increased VBF and heart rate, significantly decreased left ventricular end-diastolic pressure and produced an initial increase followed by a decrease in AoF and RBF. When compared with these doses of both drugs, the ratio of percent decrease in coronary vascular resistance to that in total peripheral resistance was over 1.0 in both drugs and the value of this ratio in nicorandil was significantly larger than that in nitroglycerin. The duration of increase in CBF produced by nicorandil 10-300 micrograms/kg i.v. was dose-dependent, but was not changed by nitroglycerin 1-30 micrograms/kg i.v. The results indicate that nicorandil and nitroglycerin dilate coronary vasculature more markedly than other vascular beds and that the potency of selective coronary vasodilatation and the duration of action are more significant in nicorandil than in nitroglycerin.     

Acetylcholine induces constriction of epicardial coronary arteries in anesthetized dogs after removal of endothelium

The acetylcholine-induced relaxation of isolated coronary arteries is reversed to contraction in the absence of endothelium. The importance of endothelium for the regulation of coronary blood flow remains unclear. We thus tested the effects of acetylcholine on epicardial arteries and on coronary resistance vessels in situ in 8 anesthetized dogs. The left circumflex coronary artery was perfused at constant pressure. Epicardial vasomotion was evaluated by sonomicrometry, the vasomotion of coronary resistance vessels by calculated end-diastolic resistance. Acetylcholine (1 microgram/kg/min i.c.) decreased epicardial resistance by 8.6 +/- 1.6% and end-diastolic resistance by 65.8 +/- 6.3%. The epicardial coronary segment was perfused with distilled water for 65 +/- 5 s to denude it of endothelium. After removal of epicardial endothelium, the decrease in end-diastolic resistance caused by acetylcholine was unchanged (59.6 +/- 1.2%); however, epicardial resistance was increased by 7.7 +/- 1.7%. Application of glyceryl trinitrate (5 micrograms/kg/min i.c.) induced a similar decrease of epicardial resistance before and after removal of endothelium:7.9 +/- 1.4 and 6.2 +/- 1.9%, respectively. We conclude that acetylcholine-induced dilation of epicardial coronary arteries is endothelium-dependent in vivo. However, the constriction of epicardial coronary arteries in the absence of endothelium is insufficient to reduce blood flow and to induce myocardial ischemia.     

Effect of ouabain on large coronary artery diameter

Cardiac glycosides have previously been shown to constrict small coronary resistance vessels. This study evaluated the effect of a bolus intravenous dose of ouabain (20 micrograms/kg) on large left circumflex coronary arterial diameter measured by sonomicrometry in nine awake chronically instrumented dogs. Between 5 and 10 min after ouabain administration external circumflex coronary diameter decreased (3.87 +/- 0.21 to 3.83 +/- 0.21 mm, p less than 0.05). Twenty minutes after ouabain administration, coronary diameter had returned to control. At the time of the peak decrease in coronary diameter, heart rate had decreased (104 +/- 7 to 82 +/- 7 beats/min, p less than 0.05), circumflex coronary blood flow had decreased (45 +/- 7 to 38 +/- 6 ml/min, p less than 0.05), total circumflex coronary resistance had increased (2.7 +/- 0.4 to 3.5 +/- 0.6 U, p less than 0.05) and aortic pressure was unchanged (108 +/- 4 to 113 +/- 4 mm Hg). Alpha-adrenergic blockade with phentolamine did not prevent the decrease in circumflex coronary arterial diameter in each of five dogs (3.67 +/- 0.28 to 3.60 +/- 0.28 mm, p less than 0.05). Therefore, intravenous ouabain caused vasoconstriction of large coronary arteries. These vasocontrictor effects were not mediated by alpha-adrenergic mechanisms. This constriction could have important consequences in the presence of coronary stenoses.     

Comparison of KRN2391 with nicorandil and nifedipine on canine coronary blood flow: antagonism by glibenclamide.

The mode of action of KRN2391 [N-cyano-N'-(2-nitroxyethyl)-3- pyridinecarboximidamide monomethanesulfonate] in coronary circulation was examined in anesthetized dogs in comparison with those of nicorandil and nifedipine. Administration of KRN2391 (10 micrograms/kg i.v.), nicorandil (300 micrograms/kg i.v.), and nifedipine (3 micrograms/kg i.v.) caused an increase in coronary blood flow (CBF) and decreases in mean blood pressure (MBP) and in coronary vascular resistance (CVR). Heart rate (HR) was slightly and simultaneously increased by the drugs. Glibenclamide (5 mg/kg i.v.) blocked the changes of these parameters caused by KRN2391 and nicorandil, but not those caused by nifedipine. The present study suggests that the mechanism of action through ATP-sensitive K channels which are blocked by glibenclamide may contribute, at least in part, to the effects of KRN2391 and nicorandil on CBF and blood pressure (BP).     

Coronary effects of a combined beta adrenoceptor blocking and calcium antagonist therapy in running dogs.

The effects of YM-16151 (1 mg/kg, i.v.), a combined beta 1-adrenoceptor blocking and calcium antagonist drug, on large (circumflex artery) and small coronary arteries and on systemic hemodynamics were investigated in chronically instrumented conscious dogs at rest and during treadmill exercise. These effects were compared to those in the same animals of nicardipine (0.1 mg/kg, i.v.), atenolol (1 mg/kg, i.v.) and their combination (at the same doses). Circumflex artery diameter (CxAD) and coronary blood flow increased and coronary vascular resistance (CVR) decreased during control exercise under saline. YM-16151 and the nicardipine-atenolol combination similarly dilated large and small coronary arteries at rest, but dilation of large conductance vessels was abolished during exercise, while CVR decreased further. Both YM-16151 and the nicardipine-atenolol combination only slightly increased the rate-pressure product at rest, but strongly opposed its exercise-induced rise. Nicardipine maximally increased CxAD, decreased CVR, and enhanced the rate-pressure product at rest and during exercise. Conversely, atenolol decreased CxAD and the rate-pressure product and increased CVR at rest, but large coronary arteries remained constricted during exercise despite the concomitant dilation of small resistance vessels. Thus, in the coronary vascular bed of conscious dogs, YM-16151 really behaves as a hybrid drug, combining beta 1-adrenoceptor blocking and calcium antagonist properties, both at rest and during exercise. As a result, YM-16151 increases oxygen supply at rest and decreases oxygen demand during exercise. Finally, this study emphasizes the major role of beta 1-adrenoceptors in the mediation of exercise-induced dilation of large coronary arteries.     

N-nitro L-arginine causes coronary vasoconstriction and inhibits endothelium-dependent vasodilatation in anaesthetized greyhounds.

1. The effect of N-nitro-L-arginine (L-NNA), an inhibitor of nitric oxide biosynthesis, on large coronary artery diameter and coronary blood flow was examined in anaesthetized greyhounds. The effects of L-NNA on the coronary vascular responses to acetylcholine (ACh), glyceryl trinitrate (GTN) and 5-hydroxytryptamine (5-HT) were also assessed. 2. L-NNA (5 mg kg-1), infused into the left circumflex coronary artery, increased systemic mean arterial pressure and decreased the external diameter of the artery. Infusion of L-NNA decreased coronary blood flow in 5 of the 7 dogs tested and increased mean coronary resistance but neither of these effects was statistically significant. There was no change in heart rate. 3. Intra-arterial injection of both ACh (0.01-0.05 micrograms kg-1) and GTN (0.1-0.5 micrograms kg-1) increased large coronary artery diameter and coronary blood flow. Coronary vascular responses to the endothelium-dependent vasodilator ACh were significantly reduced by L-NNA, whereas the responses to the endothelium-independent vasodilator GTN were not significantly affected. 4. 5-HT (0.1 microgram kg-1, injected into the left circumflex coronary artery) decreased coronary artery diameter but increased coronary blood flow. After the administration of L-NNA the 5-HT-induced dilatation of the coronary resistance vessels was significantly attenuated whereas the constriction of the circumflex coronary artery was increased in 3 out of 3 dogs in which diameter could be measured, although the latter effect was not statistically significant. 5. These data indicate that L-NNA causes coronary and systemic vasoconstriction and selectively inhibits endothelium-dependent vasodilatation in the coronary circulation of the anaesthetized greyhound.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pharmacological profile of carvedilol as a beta-blocking agent with vasodilating and hypotensive properties

Carvedilol is a new beta-receptor blocking and vasodilating drug that is presently undergoing clinical trials in hypertension and coronary heart disease. In this article, the pharmacodynamic properties of carvedilol are compared with those of standard drugs. The beta-blocking activity was characterized in isolated organs and in conscious rats, rabbits, and dogs. For the beta 1-blockade in guinea pig atria, the pA10 values were 7.44 +/- 0.16 for carvedilol and 6.77 +/- 0.08 for propranolol. Carvedilol is a noncardioselective beta-blocker. The i.v. doses that inhibited the tachycardia by 50% induced by 1 microgram/kg isoprenaline were 62 micrograms/kg in dogs, 138 micrograms/kg in rabbits and 841 micrograms/kg in rats. In rabbits carvedilol was slightly more active and in rats less active than propranolol. In all models, carvedilol was much more active than labetalol or prizidilol. In contrast to propranolol, carvedilol relaxed rat aortic strips. A dose-dependent decrease in arterial blood pressure was seen in different in vivo models. The total peripheral and coronary resistance were decreased in conscious dogs. The doses required for both beta-blockade and decrease in blood pressure were in the same range. The drug was also active after oral administration. There is no hint for development of tolerance.     

Antiarrhythmic and cardiovascular effects of MP 115

We studied the effects on experimental cardiac arrhythmias of MP 115, a tertiary amine, in dogs anaesthetised with pentobarbitone sodium. Low doses of the drug (0.2-2.1 mg/kg i.v.) abolished ventricular tachycardia resulting from cardiotoxic doses of ouabain in 12 of 15 experiments. The ventricular arrhythmic response to the intravenous administration of adrenaline was prevented in dogs respired with 1% halothane in room air. Higher doses given intravenously to conscious dogs by sequential injections or infusion abolished the ventricular tachycardia 1 day after ligation of the anterior descending branch of the left coronary artery (effective plasma concentration, 5.0 +/- 1.6 micrograms/ml). Studies in normal dogs anaesthetised with pentobarbitone sodium (30 mg/kg) showed that the drug (0.1-1.0 mg/kg) caused reductions in arterial blood pressure and peripheral resistance. In isolated rabbit ear arteries perfused at a constant flow rate, MP 115 (1-10 microM) competitively antagonised the vasoconstrictor response to noradrenaline and had a more potent effect on the responses to 5-hydroxytryptamine. The vasoconstrictor responses to histamine, barium, and potassium were only reduced at higher concentrations. Poor oral absorption and central nervous system toxicity limit further development of this compound.     

Effect of anesthesia on reactivity of large coronary arteries in the dog

Epicardial coronary arteries dilate after release of a transient coronary occlusion in awake chronically instrumented dogs but not in anesthetized dogs studied acutely after surgery. To determine whether anesthesia or surgical trauma is responsible for this lack of reactive dilation, we evaluated the effect of anesthesia on reactive coronary dilation in six chronically instrumented dogs. Circumflex coronary diameter was measured with sonomicrometry. Response to release of a 20- or 30-s coronary occlusion was studied before and after sodium pentobarbital (20 +/- 2 mg/kg) and before and after alpha-chloralose (100 mg/kg) plus either morphine or fentanyl and droperidol. Pentobarbital blunted the peak flow response to release of a transient coronary occlusion (114 +/- 15 vs. 128 +/- 16 ml/min, p less than 0.05) but did not affect the increase in large coronary diameter (before pentobarbital: 3.68 +/- 0.30-3.74 +/- 0.30 mm; after pentobarbital: 3.66 +/- 0.31-3.71 +/- 0.31 mm). alpha-Chloralose blunted the peak flow response to release of a transient coronary occlusion (96 +/- 12 vs. 141 +/- 25 ml/min, p less than 0.05) but did not affect the increase in large coronary diameter (before chloralose: 4.00 +/- 0.28-4.06 +/- 0.28 mm; after chloralose: 3.91 +/- 0.31-3.98 +/- 0.31 mm). Therefore, each drug blunted the peak flow response to release of a transient coronary occlusion, but dilation of large coronary arteries was not impaired. The lack of reactivity of large coronary arteries in acutely studied dogs is probably due to the trauma of recent surgery and not the anesthesia.     

Dilation of epicardial arteries in conscious dogs induced by angiotensin-converting enzyme inhibition with enalaprilat

Vasodilators may provoke myocardial ischemia in patients with coronary heart disease. Therefore, we analyzed in conscious dogs the effect of angiotensin-converting enzyme (ACE) inhibition by enalaprilat on parameters potentially important to provocation of myocardial ischemia, such as sympathetic activity, myocardial oxygen consumption, and vascular tone in coronary conduit and resistance vessels. Under normal sodium intake (2-4 mEq/kg/day), enalaprilat (0.03 and 0.3 mg/kg i.v. during 5-min infusion with 30-min intervals, n = 8) did not modify the norepinephrine release rate into plasma (a parameter of overall sympathetic activity). The higher dosage reduced myocardial oxygen consumption (to 87 +/- 2% of control), mean arterial pressure (MAP) (to 90 +/- 1%) and coronary conduit artery tone (normalized delta diameter: +3.2 +/- 0.7%) without dilating coronary resistance vessels. Following renin-angiotensin activation by sodium deprivation (3 X 1 mg/kg furosemide plus 7 days sodium intake less than 0.2 mEq/day), enalaprilat similarly lowered myocardial oxygen consumption and reduced vascular tone both in coronary conduit (normalized delta diameter: +4.0 +/- 0.9%) and resistance vessels (delta coronary flow: +45 +/- 12%). Although MAP declined to 76 +/- 6%, heart rate and norepinephrine release rate were not modified significantly. We propose that the dilation of epicardial arteries results from a direct intramural action. Enalaprilat seems unlikely to provoke myocardial ischemia even in states with a strongly activated renin-angiotensin system.     

Intracoronary enalaprilat improves metabolic coronary vasodilation in patients with idiopathic dilated cardiomyopathy

Coronary flow reserve is reduced in patients with idiopathic dilated cardiomyopathy (DCM). We examined acute effects of intracoronary enalaprilat on metabolic coronary vasodilation during pacing tachycardia in patients. Coronary blood flow (Doppler guidewire) and diameter (quantitative angiography) were measured in seven patients with DCM and seven control subjects. In the DCM group, tachypacing increased coronary blood flow by 37 +/- 22% from the baseline before enalaprilat and by 65 +/- 22% (p < 0.01 vs. before treatment) after enalaprilat (0.5 microg/kg/min for 5 min, i.c.) at comparable double product. Pacing-induced dilation of the epicardial coronary artery also was greater after enalaprilat (p < 0.05). Effects of enalaprilat on coronary blood flow and diameter during pacing tachycardia were abolished by pretreatment with intracoronary administration of the nitric oxide (NO) synthesis inhibitor, N(G)-monomethyl-L-arginine. These beneficial effects of enalaprilat on large and small coronary vasodilation were not observed in control patients. Thus, intracoronary enalaprilat acutely augmented dilator responses of the large and small coronary arteries to pacing tachycardia in patients with DCM, and NO appeared to play an important role in mediating the effects of enalaprilat. These favorable effects of enalaprilat on the coronary circulation may be of clinical significance in patients with heart failure due to nonischemic DCM. Further long-term studies of the effects of angiotensin-converting enzyme inhibition on coronary vasodilation will be needed in this population.     

Antagonism of vasopressin-induced coronary artery constriction by the vasopressin antagonist d(CH2)5Tyr(Me)-AVP

d(CH2)5Tyr(Me)-AVP is a potent inhibitor of the systemic vasoconstrictor action of vasopressin (AVP). In order to examine the effectiveness of this agent in blocking AVP-induced coronary vasoconstriction, 11 pentobarbital-anesthetized mongrel dogs were instrumented for the measurement of left circumflex (LCX) coronary blood flow, systemic arterial blood pressure, heart rate, lead II electrocardiogram, left ventricular end-diastolic pressure, left ventricular developed pressure, and left ventricular +/- dP/dt. Direct injection of AVP (0.01-1 microgram) into the LCX produced a dose-dependent decrease in coronary artery blood flow (maximum reduction: 60.5 +/- 8.1% after 1 microgram), - dP/dt (maximum reduction: 41.8 +/- 5.3% after 1 microgram), and +dP/dt (maximum reduction: 14.6 +/- 5.3%), whereas a dose-dependent increase in left ventricular end-diastolic pressure was observed (maximum increase: 62.6 +/- 20.2%). No significant changes occurred in heart rate, mean blood pressure, or left ventricular developed pressure. Intravenous administration of d(CH2)5Tyr(Me)-AVP reduced (1 microgram/kg) or abolished (5 micrograms/kg) the effects of AVP on coronary blood flow +/-dP/dt and left ventricular end-diastolic pressure. In addition, doses of 1,2, and 5 micrograms/kg of d(CH2)5Tyr(Me)-AVP alone produced increases of LCX blood flow of 5.1 +/- 1.5, 2.0 +/- 0.7, and 6.8 +/- 1.7 ml/min, respectively (p less than 0.05). We conclude that d(CH2)5Tyr(Me)-AVP is effective in preventing the coronary artery constriction and hemodynamic sequelae of intracoronary administered AVP.