Coronary Vascular Tone Research Articles

Role of PGI2 and epoxyeicosatrienoic acids in relaxation of bovine coronary arteries to arachidonic acid.

Metabolites of arachidonic acid regulate several physiological processes, including vascular tone. The purpose of this study was to determine which metabolites of arachidonic acid are produced by bovine coronary arteries and which may regulate coronary vascular tone. Arachidonic acid induced a concentration-related, endothelium-dependent relaxation [one-half maximum effective concentration (EC50) of 2 x 10(-7) M and a maximal relaxation of 91 +/- 2% at 10(-5) M] of bovine coronary arteries that were contracted with U-46619, a thromboxane mimetic. The concentration of 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha), a metabolite of prostaglandin I2 (PGI2), increased from 82 +/- 6 to 328 +/- 24 pg/ml with arachidonic acid (10(-5) M). Treatment with the cyclooxygenase inhibitor indomethacin attenuated arachidonic acid-induced relaxations by approximately 50% and blocked the synthesis of 6-keto-PGF1 alpha. PGI2 caused a concentration-related relaxation (EC50 of 10(-8) M and a maximal relaxation of 125 +/- 11% at 10(-7) M). BW755C, a cyclooxygenase and lipoxygenase inhibitor, inhibited arachidonic acid-induced relaxation to the same extent as indomethacin. When vessels were treated with both indomethacin and BW755C, the inhibition of relaxation was the same as either inhibitor alone. SKF 525a, a cytochrome P-450 inhibitor, reduced arachidonic acid-induced relaxation by approximately 50%. When SKF 525a was given in combination with indomethacin, the relaxation by arachidonic acid was almost completely inhibited. SKF 525a inhibited the synthesis of epoxyeicosatrienoic acids (EETs).(ABSTRACT TRUNCATED AT 250 WORDS)

Role of adenosine and its interaction with adrenoceptor activity in ischaemic and reperfusion injury of the myocardium

Adenosine is recognised as an important regulator of myocardial function and coronary vascular tone in the ischaemic myocardium. It is produced by the enzymatic dephosphorylation of 5'-AMP by 5'-nucleotidase and the hydrolysis of SAH by SAH-hydrolase. 5'-Nucleotidase is thought to contribute to adenosine production aside from the accumulation of 5'-AMP in the ischaemic myocardium, while the hydrolysis of SAH plays a major role in adenosine production in the normoxic myocardium. 5'-Nucleotidase activity is reported to increase adenosine production through accumulation of ATP, ADP, H+, Mg2+ and inorganic phosphate during ischaemia. In addition, we have found that alpha 1 adrenergic receptors, activated in ischaemic hearts, increase both 5'-nucleotidase activity and adenosine production. Inactivation of adenosine deaminase and adenosine kinase may also contribute to adenosine production. On the other hand, the major role of endogenous adenosine is to increase coronary blood flow. This adenosine induced coronary vasodilatation is amplified by alpha 2 adrenoceptor stimulation. Adenosine induced vasodilatation is also enhanced by increasing H+ and opening ATP sensitive K+ channels, which occurs in the ischaemic myocardium. However, coronary vasodilatation is not the only effect of adenosine in the ischaemic myocardium. Stimulation of adenosine A2 receptors coupled to Gs proteins attenuates both free radical generation by activated leucocytes and aggregation of platelets. Adenosine A1 receptor activation coupled to G(i) proteins attenuates beta adrenoceptor mediated increases in myocardial contractility, Ca2+ influx into myocytes, and noradrenaline release from the presynaptic nerves. Any or all of these effects may attenuate ischaemic and reperfusion injury.(ABSTRACT TRUNCATED AT 250 WORDS)

Mechanisms of histamine-induced coronary vasodilatation: H1-receptor-mediated release of endothelium-derived nitric oxide.

Although the content of histamine in myocardial tissue is high, its contribution to the regulation of coronary blood flow has not been clearly defined. The aim of the present study was to investigate whether or not nitric oxide (NO), an important modulator of coronary vascular tone, is involved in histamine-induced coronary vasomotion and to characterize which histaminergic receptor subtype mediates this process. Isolated, constant-flow-perfused guinea pig hearts were challenged with histamine, the H1-receptor agonist pyridylethylamine (PYR) and the H2-receptor agonist dimaprit (DIM). Apart from coronary perfusion pressure (CPP), left ventricular pressure (LVP) and the development of contractile force (dp/dt), the release of NO and cyclic GMP (cGMP) were continuously measured. Histamine and DIM induced concentration dependently a coronary vasodilatation with an almost 50% decrease in CPP paralleled by an enhancement of LVP and dp/dt by more than 80%. PYR selectively reduced CPP by 47% without affecting LVP and dp/dt. Histamine- and PYR-induced coronary vasodilatation were paralleled by a more-than-twofold increase in basal cGMP release from isolated hearts, whereas DIM exerted no effects on cGMP release. Oxyhemoglobin (4 microM), an effective scavenger of NO, shifted the concentration-response curve for histamine- and PYR-induced changes in CPP significantly to the right and in parallel inhibited the increase in cGMP release. Histamine and PYR rapidly (within 2 s) decreased CPP, while the onset of DIM-induced coronary vasodilatation followed changes in LVP with a lag period of 10 s. Histamine increased basal NO release concentration dependently by a maximum of 351 +/- 21 pmol/min.(ABSTRACT TRUNCATED AT 250 WORDS)

Changes in myocardial capillary diffusion capacity during infusion of vasoactive drugs.

The present study investigated how variations in coronary vascular resistance and metabolic demand affected myocardial capillary diffusion capacity. Hearts from Wistar rats were perfused with Krebs-Henseleit-albumin buffer in a Langendorff preparation, where heart rate (HR), contractility (dP/dtmax) and myocardial oxygen consumption (MVO2) were recorded continuously. Myocardial capillary diffusion capacity was measured as the permeability surface area product (PS) for Cr-EDTA and vitamin B12 by the single injection colorimetric indicator dilution method. After base-line recordings without drugs, angiotensin II+Arginine-vasopressin was infused, which increased coronary vascular resistance by 90%, stimulated HR by 11%, decreased dP/dtmax by 21% and reduced MVO2 by 4%. PSCr-EDTA and PSB12 decreased by 24 and 27%, respectively, leaving the ratio PSCr-EDTA/PSB12 unchanged indicating unaltered capillary permeability. Moreover, the reductions in MVO2 and PS correlated significantly. During vasodilation: (1) nitroprusside-NA stimulated HR by 7% and decreased dP/dtmax by 14%; (2) adenosine reduced dP/dtmax by 37% and decreased MVO2 by 9%; and (3) isoproterenol increased HR, dP/dtmax and MVO2 by 53, 76 and 9%, respectively. However, all three vasodilators reduced PSCr-EDTA and PSB12 in parallel by 7-25% leaving PSCR-EDTA/PSB12 unchanged. Thus, maximal estimated diffusion capacities were obtained during spontaneous coronary vascular tone, most likely reflecting maximal capillary recruitment in the Krebs-Henseleit-albumin perfused heart. The derecruiting effects of the vasoconstrictors were partly overridden by metabolic factors, while the reductions of PS after vasodilation more likely were due to increased heterogeneity in coronary flow.

Calcitonin gene-related peptide in patients with and without early reperfusion after acute myocardial infarction

Plasma concentrations of calcitonin gene-related peptide (CGRP), a potent regulator of vascular tone, creatine kinase, myoglobin, and cardiac troponin T were assessed in 31 patients with acute myocardial infarction. In patients who had sustained acute myocardial infarctions, maximum CGRP concentrations (median, 3.2 pmol/L; interquartile range, 1.5 to 4.8 pmol/L) were markedly elevated as compared with healthy control subjects ( n = 23; median, 1.02 pmol/L; p = 0.02). However, no marked differences in CGRP levels were observed between patients with early reperfusion ( n = 19; median, 3.5 pmol/L) and patients without early reperfusion ( n = 12; median, 2.6 pmol/L; p = 0.96), as well as between those with congestive heart failure ( n = 8; median, 3.9 pmol/L) and those without congestive heart failure ( n = 23; median, 3.2 pmol/L; p = 0.62). CGRP did not correlate closely with myocardial protein release or hemodynamic parameters (heart rate and blood pressure) or the occurrence of arrhythmias. Therefore we conclude that elevated peripheral venous CGRP concentrations in patients who have sustained an acute myocardial infarction are independent of successful reperfusion and hemodynamic state. Although the cause of CGRP increase is not yet identified, CGRP may play a role in the regulation of coronary vascular tone in patients after acute myocardial infarction.

Arterial blood nicotine concentration and coronary vasoconstrictive effect of low-nicotine cigarette smoking

Low-nicotine cigarettes have been advertised to the public as less harmful to the cardiovascular system. We studied the effects of smoking two low-nicotine cigarettes on arterial and venous blood nicotine levels, hemodynamics, and coronary vascular tone in 12 patients referred for diagnostic coronary arteriography. All were chronic smokers as evidenced by their elevated baseline arterial and venous cotinine blood levels (139 ± 30 ng/ml and 155 ± 34 ng/ml, respectively). High-resolution coronary angiograms were evaluated “blindly” before and after smoking. An electronic caliper was used to measure the diameter of disease-free coronary segments of the left anterior descending and circumflex arteries. Arterial nicotine levels rose from 5 ± 1 ng/ml at baseline to 37 ± 7 ng/ml ( p < 0.01) after the first cigarette was smoked and to 45 ± 8 ng/ml ( p < 0.01) after the second cigarette. Venous nicotine levels rose from 8 ± 2 ng at baseline to 15 ± 3 ng/ml ( p < 0.05) after the first cigarette and to 20 ± 3 ng/ml ( p < 0.01) after the second cigarette. After the first cigarette heart rate increased 8 ± 2 beats/min ( p < 0.003) and double product 1229 ± 400 beats/min × mm Hg ( p < 0.02). Compared to baseline values, after the second cigarette heart rate increased 9 ± 1 beats/min ( p < 0.001) and double product 1767 ± 486 beats/min × mm Hg ( p < 0.01). Systolic, diastolic, and mean blood presure did not change significantly after either the first or second cigarette. The left anterior descending artery diameter changed from 2.31 ± 0.2 mm before smoking to 2.03 ± 0.2 mm after the first cigarette was smoked ( p < 0.01) and 2.10 ± 0.2 mm after the second cigarette ( p < 0.01). The circumflex artery diameter changed from 2.49 ± 0.2 mm before smoking to 2.19 ± 0.1 mm after the first cigarette ( p < 0.01) and to 2.21 ± 0.2 mm after the second cigarette ( p < 0.01). Correlation of changes in coronary diameter (constriction) with increments in arterial nicotine levels showed a borderline correlation with the first cigarette ( r = 0.46, p = 0.049) and a significant correlation with the second cigarette ( r = 0.61, p = 0.003). No correlation was found with venous nicotine levels. We conclude that smoking low-nicotine cigarettes evokes significant increases in arterial blood nicotine concentrations, which substantially exceed venous levels, increases heart rate and double product, and induces significant coronary vasoconstriction. Therefore smoking low-nicotine cigarettes produces adverse effects on the cardiovascular system.

Acetylcholine-induced coronary vasoconstriction and negative inotropy in the neonatal pig heart.

We investigated the influence of exogenously administered acetylcholine, nitric oxide, ADP, ATP, bradykinin, and substance P on coronary vascular tone in isolated, neonatal pig hearts (less than or equal to 4 d). Paced (180 bpm), isovolumically beating hearts underwent retrograde aortic perfusion, with an erythrocyte-enriched solution (hematocrit 0.15-0.20) at constant coronary flow (approximately 2.5 mL/min/g) corresponding to a perfusion pressure of approximately 60 mm Hg. Agonists were injected into the aortic root, and the peak change in coronary perfusion pressure from baseline and left ventricular pressure development were assessed. Nitric oxide (3 microL), ADP (30 nmol), ATP (30 nmol), bradykinin (125 ng), and substance P (50 ng) decreased the perfusion pressure (vasodilation) by 16.9 +/- 1.2, 25.3 +/- 4.4, 18.3 +/- 1.2, 18.9 +/- 1.4, and 7.1 +/- 1.6 mm Hg, respectively. Acetylcholine (0.5 and 1.0 nmol) produced a modest decrease in perfusion pressure (vasodilatation) of 4.2 +/- 0.8 and 3.8 +/- 0.5 mm Hg, respectively, whereas acetylcholine (5, 20, and 100 nmol) increased the perfusion pressure (vasoconstriction) by 16.7 +/- 2.7, 48.2 +/- 8.2, and 85.3 +/- 15.1 mm Hg, respectively. Acetylcholine also decreased left ventricular peak systolic pressure from 108.7 +/- 5.0 to 69.2 +/- 4.6, 56.3 +/- 6.1, and 48.2 +/- 6.4 mm Hg, for the 5, 20, and 100 nmol doses, respectively. Responses to acetylcholine were abolished by atropine (50 nmol). In a separate group of hearts, indomethacin (10(-6) M) reduced the peak change in perfusion pressure for the 5, 20, and 100 nmol doses of acetylcholine by 87%, 66%, and 48%, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Circadian variation in ischemic threshold. A mechanism underlying the circadian variation in ischemic events.

There is a circadian pattern in the occurrence of cardiac events in patients with coronary artery disease. Whether changes in coronary vascular tone contribute to these phenomena is unknown. We measured the ischemic threshold, defined as either the heart rate or rate-pressure product at 1-mm ST segment depression during treadmill exercise and used it as an index of the lowest coronary vascular resistance; the premise was that when ischemic threshold became lower, coronary vascular resistance was higher, and vice versa. Fifteen patients (group A) with stable coronary artery disease underwent four identical treadmill exercise tests in 24 hours, and ischemic threshold was measured as the heart rate at the onset of 1-mm ST depression. Before each treadmill test, postischemic forearm vascular resistance was measured after 5 minutes of forearm occlusion, using strain-gauge plethysmography. Sixteen additional patients (group B) underwent two treadmill tests at 8 AM and 1 PM, and ischemic threshold was measured as the heart rate-blood pressure product at 1-mm ST depression. A circadian variation was noted: In group A, the heart rate-derived ischemic threshold was lower at 8 AM and 9 PM compared with noon and 5 PM (p less than 0.03). Also, in group B, the rate-pressure product-derived ischemic threshold was 8 +/- 2% lower at 8 AM compared with 1 PM (p = 0.008). A circadian variation parallel to the observed variation in ischemic threshold was also noted in the postischemic forearm blood flow, which was lower in the morning and at night (p less than 0.004). There was a strong correlation between postischemic forearm blood flow and ischemic threshold (p less than 0.0001), such that ischemic threshold was lower at the time of day when postischemic forearm blood flow was lower, and vice versa. A lower ischemic threshold in the morning suggests that the ischemia-induced coronary vascular resistance is increased at this time, a finding supported by a similar variation in postischemic forearm vascular resistance. Parallel changes in forearm and coronary resistance suggest that generalized (neural or humoral factors) rather than local factors are responsible for the observed circadian changes. Increased coronary tone in the mornings may not only contribute to the higher incidence of transient ischemia but may help trigger acute cardiac events at this time.

Global myocardial ischemia and reperfusion impair endothelium-dependent relaxations to aggregating platelets in the canine coronary artery

Experiments were designed to determine whether endothelial cell injury contributes to increased coronary vascular tone after global cardiac ischemia and reperfusion. Canine hearts were exposed to global ischemia for 45 minutes and were reperfused for 60 minutes. Rings (5 to 6 mm long) of the left anterior descending coronary artery from reperfused hearts and from normal (control) hearts were suspended for isometric force measurement in organ chambers containing physiologic salt solution (37 degrees C, and 95% oxygen and 5% carbon dioxide). After contraction with prostaglandin F2 alpha, reperfused coronary arteries had significant impairment of endothelium-dependent relaxations to aggregating platelets (52% +/- 12% relaxation versus 102% +/- 11% for control segments; p less than 0.05). Reperfused arterial rings also exhibited impaired endothelium-dependent relaxations to the receptor-dependent agonist acetylcholine and the platelet-derived compounds adenosine diphosphate and serotonin. Importantly, endothelium-dependent relaxations to the non-receptor-dependent agonist A23187 were normal after ischemia and reperfusion. Quiescent (noncontracted) reperfused arterial rings lost the ability to counteract the constrictive effect of aggregating platelets on the coronary vascular smooth muscle (24% +/- 7% contraction versus 5% +/- 2% relaxation for control segments; p less than 0.05). Endothelium-independent contractions to potassium chloride and prostaglandin F2 alpha were similar in reperfused and normal arteries. Also, endothelium-independent relaxations to nitric oxide and isoproterenol were comparable in reperfused arteries and normal vessels. Thus global cardiac ischemia and reperfusion impair the normal endothelium-dependent relaxations to aggregating platelets and other receptor-dependent vasoactive drugs. This impairment of platelet-mediated coronary vasodilation may explain increased coronary vascular tone after cardiopulmonary bypass and could be an important pathophysiologic mechanism of postoperative coronary vasospasm.

Role of nitric oxide synthesis in the regulation of coronary vascular tone in the isolated perfused rabbit heart.

The aim was to study the effects on coronary vascular tone of three inhibitors of nitric oxide (NO) synthesis. Studies were performed on isolated perfused hearts of 74 male New Zealand White rabbits fed normal laboratory diet. Resting coronary perfusion pressure was increased to 40-60 mm Hg with the thromboxane mimetic 9,11-dideoxy-9 alpha,11 alpha-methanoepoxy prostaglandin F2 alpha (U46619). The effects of NG-monomethyl-L-arginine (L-NMMA), N-iminoethyl-L-ornithine (L-NIO), and NG-nitro-L-arginine methyl ester (L-NAME) (0.3-300 microM) on resting coronary perfusion pressure were determined. The effects of these compounds, at concentrations that increased the resting perfusion pressure to a similar extent, on the fall in perfusion pressure induced by acetylcholine (0.1 microM) and glyceryl trinitrate (1 microM) were also investigated. In these studies the resting perfusion pressure was maintained at 40-60 mm Hg by reducing the concentration of U46619. L-NMMA, L-NIO, and L-NAME induced concentration dependent increases in resting coronary perfusion pressure (n = 3-9, p < 0.05). L-NAME had the greatest potency and efficacy, increasing the resting pressure by 48.0(SEM 9.6) mm Hg at 30 microM. L-NIO and L-NMMA increased perfusion pressure by 27.3(3.0) and 19.5(5.8) mm Hg respectively at the maximum concentration studied (300 microM). However, at concentrations that were equieffective on resting perfusion pressure (15 mm Hg increase), L-NMMA (100 microM), but not L-NIO (25 microM) or L-NAME (4 microM), significantly inhibited the fall in pressure induced by acetylcholine by 57.2(5.0)%, n = 6, p < 0.05. This effect of L-NMMA++ was attributed to a shorter duration of fall and was reversed by L-arginine (300 microM). L-NMMA (100 microM) and L-NIO (25 microM) potentiated the effect of glyceryl trinitrate by increasing the peak fall in perfusion pressure by 75.6(11.0)% and 68.8(24.1)% respectively (n = 6 for each, p < 0.05). The differential effects of the three inhibitors on resting coronary perfusion pressure and the acetylcholine induced fall in coronary perfusion pressure suggest that basal and stimulated NO synthesis may be differentially regulated. Reduction in the synthesis of endogenous NO by these compounds potentiates the glyceryl trinitrate induced fall in perfusion pressure, which may have important clinical implications.

ATP-sensitive potassium channel is essential to maintain basal coronary vascular tone in vivo.

Glibenclamide, a known selective inhibitor of ATP-sensitive potassium channels, was infused into the coronary vasculature of anesthetized dogs and of isolated perfused rabbit hearts to assess the role of this channel in the maintenance of basal coronary resistance. Infusion of glibenclamide at a concentration of 55-80 microM in the dogs resulted in a twofold steady-state increase in coronary resistance with resultant tissue ischemia. Infusion of 1 microM glibenclamide in the isolated hearts resulted in a 67% increase in coronary resistance with resultant tissue ischemia. The ischemic changes were reversible upon removal of the drug. These findings indicate that the ATP-sensitive K+ channel plays a significant role in the maintenance of basal coronary resistance in vivo. Higher concentrations of glibenclamide (80-100 microM) in the in vivo dog heart consistently gave rise to an oscillating pattern of coronary flow. These oscillations were either eliminated or decreased in amplitude and frequency by the infusion of 8-phenyltheophylline, a specific competitive inhibitor of adenosine receptors. 31P-nuclear magnetic resonance spectroscopy performed at the peaks and troughs of these oscillations revealed oscillation of the phosphorylation potential at the same frequency. Thus adenosine release caused by tissue ischemia appears to play a major role in creating the oscillating pattern of coronary blood flow, that occurs during the inhibition of ATP-sensitive K+ channels by glibenclamide.

Molecular cloning, characterization, and genomic localization of a human potassium channel gene

Potassium (K+) channels are critical for a variety of cell functions, including modulation of action potentials, determination of resting membrane potential, and development of memory and learning. In addition to their role in regulating myocyte excitability, cardiac K+ channels control heart rate and coronary vascular tone and are implicated in the development of arrhythmias. We report here the cloning and sequencing of a K+ channel gene, KCNA1, derived from a human cardiac cDNA library and the chromosomal localization of the corresponding genomic clone. Oligonucleotides based on a delayed rectifier K+ channel gene were used in PCR reactions with human genomic DNA to amplify the S4–S6 regions of several different K+ channel genes. These sequences were used to isolate clones from a human cardiac cDNA library. We sequenced one of these clones, HCK1. HCK1 contains putative S2–S6 domains and shares ∼70% sequence homology with previously isolated Shaker homologues. HCK1 was used to screen human cosmid libraries and a genomic clone was isolated. By sequencing the genomic clones, a putative S1 domain and translation initiation sequences were identified. Genomic mapping using human-rodent somatic cell panels and in situ hybridization with human metaphase chromosomes have localized KCNA1 to the distal short arm of human chromosome 12. This work is an important step in the study of human cardiac K+ channel structure and function and will be of use in the study of human inherited disease.

Differential relaxant effect of high concentrations of intravenous anesthetics on endothelin-constricted proximal and distal canine coronary arteries.

This study determined the direct effect of three intravenous anesthetics on isolated canine coronary arteries constricted with the potent endogenous vasoconstrictor endothelin. Arteries were divided into groups of large (1.3-2.5 mm) and small (250-500 microns) vessels, and arterial rings were suspended in tissue baths. The rings were stretched to an optimal resting tension and then preconstricted with an EC50 concentration of endothelin that was equivalent for both groups. Incremental concentrations (5 x 10(-6) M to 1.6 x 10(-2) M) of thiopental, ketamine, and propofol were added to the baths, and the relaxant responses were recorded. Small arteries demonstrated greater vasodilation at equivalent drug concentrations than did large arteries. These results demonstrate antagonism of the vasoconstrictor endothelin by intravenous anesthetics. Distal vessels are more sensitive than proximal vessels to the relaxant effects of the intravenous anesthetics studied. Direct effects on coronary vascular tone, however, are only apparent at concentrations above those seen clinically. Despite the potential for a differential effect on proximal and distal coronary arteries, we conclude that thiopental, ketamine, and propofol do not possess a direct effect on the tone of large or small canine coronary arteries at concentrations seen in routine clinical practice.

Effect of vasoactive intestinal peptide and the distribution of receptors in human epicardial coronary arteries

Background The aim of this study was to elucidate a possible role for vasoactive intestinal peptide (VIP) in the regulation of coronary vascular tone. Its action and the distribution of [125I]-VIP binding sites were examined in isolated human coronary arteries. Methods A total of 97 segments were obtained from 23 patients undergoing cardiac transplantation. Results VIP (10−10 to 3 × 10−7 M) relaxed preconstricted coronary segments in a concentration-dependent manner, with a maximum response of 73.8% ± 8.5% of the maximum relaxation induced by 1 μg/mL of nitroglycerin. This action was inhibited by the specific receptor antagonist [4CI-D-Phe6, Leu17] VIP, with a reduction of the maximum effect from 73.8% ± 8.5% to 38.9% ± 5.4% (P < 0.001). Prior exposure to atropine and indomethacin, and removal of the endothelium had no effect on responses to VIP. Receptor autoradiography demonstrated that [125I]-VIP binding sites were displaced by unlabeled peptide and by [4CI-D-Phe6, Leu17] VIP in a concentration-dependent manner, with 50% inhibitory concentration values of 1.35 × 10−8 and 2.41 × 10−8 M, respectively. The binding was predominantly associated with smooth muscle and perivascular regions, with no binding to the endothelial cells. Conclusions Our results indicate that VIP elicits vasodilatation of the human coronary artery by acting mainly on specific receptors presumably present on the smooth muscle. This peptidergic control mechanism may play a role in the regulation of coronary artery tone.

The oxygen dependence of mitochondrial oxidative phosphorylation and its role in regulation of coronary blood flow.

The oxygen dependence of mitochondrial oxidative phosphorylation measured in isolated cells of cardiac and non-cardiac origin are affected by the metabolic state of the cells. The contribution of oxygen diffusion to the measured P50 value in resting cells is small. In cardiac myocytes, and possibly in the other cells as well, this contribution may become significant near maximal levels of respiration. The influence of cellular energy metabolism on the oxygen dependence of respiration in cardiac myocytes suggests strongly that mitochondrial oxidative phosphorylation in these cells is an oxygen sensor for adjusting coronary vascular tone during normal cardiac function.

Vasotonic myocardial ischemia

The concept that myocardial ischemia can be directly related to enhanced coronary vasomotor tone is now widely accepted. Earlier skepticism has, to a large extent, been neutralized by a steady stream of convincing evidence. Doubts, however, remain as to the real incidence of this phenomenon and its precipitating factors. It is also not clear whether coronary vasoconstriction is a primary event or merely a by-product or secondary factor in a more complex histochemical disturbance afflicting atherosclerotic or nearly normal coronary arteries as a result of yet poorly understood mechanisms. Nevertheless, the simplistic view of ischemia as strictly a result of increased myocardial demand has been swept away by the expanding understanding of the dynamic nature of coronary supply. While primary focal spasm of large epicardial coronary arterial segments is admittedly infrequent, other forms of vasoconstriction are probably not. These include spasm superimposed over fixed obstruction, and that occurring during the “hot war” of unstable ischemia as a result of potent vasoactive by-products. Furthermore, reduced coronary flow as a consequence of constriction of smaller prearteriolar, arteriolar, and collateral beds is believed to play a major role in ischemia in the face of normal epicardial coronary arteries. The so called “syndrome X” is an example of ischemia related to increased coronary resistance. It can result from either reduced responsiveness to vasodilating stimuli or increased sensitivity to vasoconstricting stimuli. The role of stress-related release of catecholamines and its detrimental effect on coronary flow is undergoing serious assessment at present. Potential target sites of such a systemic outpouring can theoretically include the whole extent of the coronary vascular bed. Thus increased coronary vascular tone appears to be quite nonhomogeneous. Its causes, severity,

Resiniferatoxin‐, capsaicin‐ and CGRP‐evoked porcine coronary vasodilatation is independent of EDRF mechanisms but antagonized by CGRP(8–37)

In the present study the effects of activation of capsaicin-sensitive C-fibre afferents by resiniferatoxin and capsaicin as well as the effects of the co-stored peptides calcitonin gene-related peptide substance P and neurokinin A on porcine coronary vascular tone in vitro was investigated. Resiniferatoxin, capsaicin, calcitonin gene-related peptide and neurokinin A all evoked a sustained, concentration-dependent vasodilatation of potassium (60 mM)-precontracted arteries. Substance P also caused vasodilatation of the precontracted arteries but this effect was transient and tachyphylaxis developed rapidly upon repeated administration. Incubation with the calcitonin gene-related peptide fragment (8-37) did not influence the vascular tone per se but markedly attenuated the dilatory effect of calcitonin gene-related peptide and totally abolished the vasodilatation induced by resiniferatoxin and capsaicin while leaving the effect of neurokinin A and substance P unaltered. Incubation with methylene blue, an inhibitor of endothelium-derived relaxing factor mechanisms, which completely blocked the substance P-evoked vasodilatation, as well as substance P-tachyphylaxis, did not influence the vasodilator response to resiniferatoxin, capsaicin or calcitonin gene-related peptide. The neurokinin A-evoked vasodilatation was most likely mediated through activation of neurokinin 1-receptors since it remained unchanged in the presence of the neurokinin 2-receptor antagonist dactinomycin and (Nle10)-neurokinin A (4-10), which selectively activates neurokinin 2-receptors, had only a minor dilatory effect on the precontracted arteries.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional coronary haemodynamic effects of two inhibitors of nitric oxide synthesis in anaesthetized, open‐chest dogs

1. The role of endothelial nitric oxide synthesis from L-arginine in the regulation of coronary vascular tone and myocardial tissue perfusion was evaluated in anaesthetized, open-chest dogs. Coronary blood flow was measured with an electromagnetic flow probe placed around the left circumflex coronary artery. Coronary vascular resistance was calculated from mean arterial blood pressure and mean coronary blood flow, whereas regional myocardial tissue flow was determined by use of the radioactive microspheres technique. 2. NG-monomethyl L-arginine (L-NMMA) and NG-nitro-L-arginine methyl ester (L-NAME), administered directly into the left circumflex artery, induced a small increase in arterial blood pressure and an increase in coronary vascular resistance. However, myocardial tissue perfusion, assessed by the microspheres technique (whether subendocardial, subepicardial, or transmural), was unaffected by L-NMMA or L-NAME. 3. Acetylcholine, administered intracoronarily, induced an increase in left circumflex coronary blood flow and a decrease in coronary vascular resistance, without affecting systemic haemodynamics. This coronary vasodilator effect of acetylcholine was markedly inhibited by L-NMMA and L-NAME, the latter being a more potent antagonist than the former. 4. These results indicate that the endothelial L-arginine pathway is largely responsible for the coronary vasodilator effect of acetylcholine. However, although basal release of nitric oxide from L-arginine apparently contributes to the regulation of resting coronary vascular tone, blockade of this pathway does not affect myocardial tissue perfusion, possibly because of compensatory mechanisms occurring at the level of small arterioles and/or capillaries.

Importance of basal nitric oxide synthesis in regulation of myocardial blood flow

The aim was to investigate whether basal coronary vascular tone and myocardial perfusion depend upon endothelial nitric oxide (NO) synthesis. Myocardial blood flow and vascular resistance of the left and right ventricles were studied before and after intravenous infusions of either NG-nitro-L-arginine (L-NA), a specific inhibitor of NO synthase, or L-arginine, the precursor of NO synthesis. Radiolabelled microspheres were used to study myocardial blood flow in small tissue sections. 14 anaesthetised male cats, weight 2.1-3.5 kg, were used. Measurements were made before and 15 and 40 min after L-NA treatment (30 mg.kg-1 bolus followed by 1 mg.kg-1.min-1 infusion; n = 8), and before and 15 min after L-arginine treatment (30 mg.kg-1 bolus followed by 10 mg.kg-1.min-1 infusion; n = 6). L-NA significantly reduced coronary blood flow to the left and right ventricle, by 30(SEM 9) and 48(6)% respectively, after 15 min, but only to the right ventricle, by 45(8)%, after 40 min. Mean arterial pressure and myocardial vascular resistance were raised during the L-NA infusion. In contrast, L-arginine did not elicit any change in the variables studied. The conductance of the coronary vascular bed and the resting myocardial blood flow is regulated by L-arginine derived nitric oxide, and exogenous L-arginine availability is not a limiting factor in this NO generation.

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. Therefore endothelium-derived NO has an important role in the regulation of coronary vascular tone in the large arteries and the resistance vessels.