The EGCg-induced redox-sensitive activation of endothelial nitric oxide synthase and relaxation are critically dependent on hydroxyl moieties

Several rich sources of polyphenols stimulate the endothelial formation of nitric oxide (NO), a potent vasoprotecting factor, via the redox-sensitive activation of the PI3-kinase/Akt pathway leading to the phosphorylation of endothelial NO synthase (eNOS). The present study examined the molecular mechanism underlying the stimulatory effect of epicatechins on eNOS. NO-mediated relaxation was assessed using porcine coronary artery rings in the presence of indomethacin, and charybdotoxin plus apamin, inhibitors of cyclooxygenases and EDHF-mediated responses, respectively. The phosphorylation level of Akt and eNOS was assessed in cultured coronary artery endothelial cells by Western blot, and ROS formation using dihydroethidine. (−)-Epigallocatechin-3-O-gallate (EGCg) caused endothelium-dependent relaxations in coronary artery rings and the phosphorylation of Akt and eNOS in endothelial cells. These responses were inhibited by membrane-permeant analogues of superoxide dismutase and catalase, whereas native superoxide dismutase, catalase and inhibitors of major enzymatic sources of reactive oxygen species including NADPH oxidase, xanthine oxidase, cytochrome P450 and the mitochondrial respiration chain were without effect. The EGCg derivative with all hydroxyl functions methylated induced neither relaxations nor the intracellular formation of ROS, whereas both responses were observed when the hydroxyl functions on the gallate moiety were present. In conclusion, EGCg causes endothelium-dependent NO-mediated relaxations of coronary artery rings through the Akt-dependent activation of eNOS in endothelial cells. This response is initiated by the intracellular formation of superoxide anions and hydrogen peroxide, and is critically dependent on the gallate moiety and on the presence of hydroxyl functions possibly through intracellular auto-oxidation.     

Microvascular and macrovascular endothelial cells produce different constrictor substances.

The media from cultured microvascular and macrovascular endothelial cells (conditioned media, CM) were collected and tested for constrictor activity in sheep coronary artery rings and tracheal smooth muscle strips in vitro (isometric force), expressed as percentage of contraction produced by 80 mM KCl. Both microvascular (micro) and macrovascular (macro) CM caused a sustained slow-onset contraction (P less than 0.05) of the coronary artery rings by 71 +/- 10% (micro; n = 7) and 67 +/- 8% (macro; n = 6) and tracheal smooth muscle strips by 33 +/- 14% (micro; n = 6) and 34 +/- 6% (macro; n = 11); the calcium antagonist gallopamil (10(-7) M) attenuated these effects by 25-55%. Unconditioned medium and medium conditioned by cultured tracheal smooth muscle cells had no constrictor activity on coronary artery rings or tracheal smooth muscle strips. Synthetic endothelin (ET-1) also produced contraction of coronary artery rings and tracheal smooth muscle strips. The mean levels of ET-1 measured by radioimmunoassay were 1,200 pg/ml in the macro CM and 33 pg/ml in the micro CM. Depleting macro CM of ET-1 by affinity columns constructed with protein A agarose and anti-ET-1 antibody removed the contractile activity for coronary artery rings and tracheal smooth muscle strips. Thus ET-1 did not appear to be the contractile substance in the micro CM. Preliminary characterization of the contractile substance in micro CM revealed that it was heat stable, had a molecular weight of less than 10,000, was inactivated by trypsin, and retained its activity after two cycles of freeze-thawing.(ABSTRACT TRUNCATED AT 250 WORDS)     

Incidence of anomalous origin of coronary artery in 1879 Chinese adults on dual-source CT angiography

Background and Objective. Dual-source CT (DSCT) has been used to detect coronary artery anomalies. The purpose of this study was to assess the incidence of anomalous origin of the coronary artery in Chinese adults. Methods. We summarised all patients who underwent DSCT coronary angiography (CTCA) from December 2006 to February 2008, and data of anomalous origin of the coronary artery in Chinese adults were recorded. Results. 1879 patients underwent CTCA during that period; 24 patients with an anomalous origin of the coronary artery were detected, giving an incidence of 1.3%. Fifteen patients had an anomalous origin of the right coronary artery (12 from left coronary sinus, 3 high takeoff), eight patients had an anomalous origin of the left coronary artery (LCA from posterior sinus of Valsalva in three cases, LCX from the right coronary sinus, LCX from RCA, high takeoff, LCA from right coronary sinus, and single coronary artery in one case, respectively), and one patient had an anomalous origin of both coronary arteries (high takeoff). Conclusion. The incidence of anomalous origin of the coronary artery in Chinese adults in this study is 1.3%. DSCT can clearly visualise the anomalous origin and course of the coronary artery and is a useful screening modality. (Neth Heart J 2010;18:466-70.)     

Coronary endothelial dysfunction from ischemia and reperfusion: effect of reactive oxygen metabolite scavengers

Using anesthetized mongrel dogs exposed to 60 min of ligation of the left anterior descending coronary artery followed by 60 min of reperfusion, we examined the effect of superoxide dismutase (SOD) and dimethylthiourea (DMTU) on evidence of endothelial injury in coronary rings studied in vitro. In 13 dogs treated with saline rings from the normal left circumflex coronary artery (LCF) relaxed by 98 +/- 4% when exposed to 10(-5) M acetylcholine whereas rings from the left anterior descending coronary artery (LAD) relaxed by 79 +/- 7% (p less than 0.05). In the same rings maximum relaxation with the ionophore A23187 was 107 +/- 5% versus 87 +/- 8% (p less than 0.05) for the LCF and the LAD, respectively. Comparisons of concentration-response curves through a range of doses of both acetylcholine and A23187 revealed significant differences for both vasodilators between the LCF and the LAD (p less than 0.01 for each). Nine dogs were treated with bovine SOD infused in the left atrium the last 20 min of ligation and throughout reperfusion (140 units/kg/min) and six other dogs were treated with DMTU 500 mg/kg i.v. given the last 30 min of the ligation period. Neither SOD nor DMTU prevented endothelial injury in the LAD. Despite pretreatment with these agents, there were significant reductions in maximum relaxation and in total concentration-response curves in the LAD as compared with the results in rings from the LCF with both acetylcholine and A23187. There were normal responses to nitroprusside in both the LCF and LAD in all three experimental groups.(ABSTRACT TRUNCATED AT 250 WORDS)     

A novel major histocompatibility complex locus confers the risk of premature coronary artery disease in a Chinese Han population

Several novel loci have been proved to be associated with coronary artery disease and/or myocardial infarction risk by genome-wide association studies, however, the available coronary artery disease risk variants explain only a small proportion of the predicted genetic heritability of the disease. Recently, a novel coronary artery disease locus on chromosome 6p21.3 in the major histocompatibility complex was identified in an European population. We hereby investigated whether this single nucleotide polymorphisms (rs3869109) confers the risk of premature coronary artery disease in a Chinese Han population. A total of 422 patients were studied including 210 cases with coronary stenosis ≥50 % or previous myocardial infarction (male <55 years and female <65 years) and 212 controls without documented coronary artery disease. Ligase detection reaction was performed to detect rs3869109. The 3 genotypes AA, AG, and GG were present in rs3869109. There were significant differences between the control and premature coronary artery disease groups in the frequencies of the rs3869109 variants and alleles (all P < 0.05). The distribution of 3 genotypes and alleles at rs3869109 does not differ between women and men (all P > 0.05). There was a significant association between rs3869109 genotypes and the severity of premature coronary artery disease (P = 0.038). Multivariate logistic regression showed that carriers with AG and GG genotypes at rs3869109 have a higher risk of premature coronary artery disease than carriers of AA genotype (odds ratio [OR] 1.997, 95 % CI: 1.166–3.419, P = 0.012; OR 1.695, 95 % CI: 1.044–2.752, P = 0.033; respectively). Our results indicate that the rs3869109 variants are associated with premature coronary artery disease in a Chinese Han population, suggesting this genetic risk marker is useful in early coronary artery disease risk prediction.     

Release and properties of endothelium-derived relaxing factor (EDRF) from endothelial cells in culture

Cultured bovine endothelial cells were seeded onto the intimal surface of endothelium-denuded rings of canine coronary artery. These rings did not previously relax to acetylcholine, substance P, bradykinin, and A23187. After seeding, the same rings relaxed to bradykinin and A23187, but not to acetycholine or substance P. Indomethacin pretreatment did not affect these responses. Cells from the same source were then grown to confluence on microcarrier beads, poured into small columns, and perfused with Krebs' solution. The perfusate from the columns was bioassayed on endothelium-denuded rings of coronary artery from either the dog or pig. Challenge of the column in the presence of indomethacin with either bradykinin or A23187 as well as acetylcholine or substance P caused release of a substance that relaxed both types of artery. Its activity half-life was 6.4 +/- 0.4 sec at 37 degrees C and it was hydrophilic and negatively charged. Prostacyclin (PGI2) as a candidate for EDRF was ruled out because 1) indomethacin failed to block its release and 2) the pig coronary artery, although insensitive to PGI2, relaxed to the endothelium-derived substance. These results show that, in response to a number of dilator drugs, cultured endothelial cells release a vascular relaxing substance (EDRF) that has characteristics similar to the EDRF of normal endothelium. The chemical nature of EDRF awaits clarification.     

Involvements of calcium channel and potassium channel in Danshen and Gegen decoction induced vasodilation in porcine coronary LAD artery

Danshen (Salviae Miltiorrhizae Radix) and Gegen (Puerariae Lobatae Radix) have been widely used in treating cardiovascular diseases for thousands of years in China. The present study was carried out to evaluate the effects of a Danshen and Gegen decoction (DG) on the vascular reactivity of a porcine isolated coronary artery and the underlying mechanisms involved. Porcine coronary rings were precontracted with 15nM U46619. The involvement of endothelium-dependent mechanisms was explored by removing the endothelium; the involvement of potassium channels was investigated by the pretreatment of the artery rings with various blockers, and the involvement of the calcium channels was investigated by incubating the artery rings with Ca(2+)-free buffer and priming them with high [K(+)] prior to adding CaCl(2) to elicit contraction. The involvement of Ca(2+) sensitization was explored by evaluating the Rho-activity expression. The results revealed that DG elicited a concentration-dependent relaxation on a U46619-precontracted coronary artery ring. These relaxation responses were not altered by the pretreatment of inhibitors of endothelium-related dilator synthases, cGMP and cAMP pathway inhibitors, potassium channel (BK(Ca), SK(Ca), K(V) and K(ATP)) blockers and endothelium removal. The K(IR) channel blocker BaCl(2) only slightly attenuated the DG-induced relaxation. However, the Ca(2+)-induced artery contraction was inhibited by DG. Additionally, the expression of the phosphorylated myosin light chain was inhibited by DG whereas the activity of RhoA was not affected. Therefore, DG could be a useful cardioprotective agent for vasodilation in patients who have hypertension.     

Coronary artery anomalies detected by MSCT-coronary angiography in the adult

Background. Before coronary evaluation by modern imaging techniques was feasible, premorbid diagnoses of coronary artery anomalies (CAAs) were usually made fortuitously by invasive coronary angiography (ICA). However, this technique is limited by its invasive and projectional nature. Coronary magnetic resonance angiography (CMRA) and multi-slice computed tomography (MSCT) broadened clinical information by enabling visualisation of the coronary arteries in their anatomical environment. Methods. This case series visualises and reviews anomalous coronary artery from the opposite sinus (ACAOS) and coronary artery fistulae. All CAAs were detected by means of 64-slice dual source computed tomography after 1000 cardiac scans at the Erasmus MC, Rotterdam, the Netherlands. Results. Eight ACAOS cases, one anomalous left coronary artery from the pulmonary artery (ALCAPA) and one congenital aneurysm of an aortic sinus were found. Seven out often detected CAAs were considered malignant whereas three CAAs of the ACAOS type (retroaortic path) were considered benign. Significant coronary artery disease was found in three out of eight ACAOS cases. In one of the ACAOS cases complete evaluation of the anomalous coronary artery was limited by motion artifacts. All five cases of right ACAOS were referred for MSCT because the right coronary artery could not be located by invasive angiography. Conclusion. All CAAs were easy to diagnose because of 3D imaging and high temporal and spatial resolution. High resolution made it possible to not only depict coronary artery abnormalities, but also to quantify luminal and vessel properties such as stenosis grade, aspects of plaque, anomalous vessel length, luminal area ratio and the asymmetry ratio. Because of its comprehensiveness, MSCT can be an effective imaging modality in patients suspected of coronary artery abnormalities caused by coronary artery disease, CAAs, or a combination of both. (Neth Heart J 2008;16:369-75.)     

Effects of peroxide on contractility of coronary artery rings of different sizes

Reactive oxygen species (ROS, free radicals) produced during cardiac ischemia and reperfusion can damage the contractile functions of arteries. The sarcoplasmic reticulum (SR) Ca2+ pump in coronary artery smooth muscle is very sensitive to ROS. Here we show that contractions of de-endothelialized rings from porcine left coronary artery produced by the hormone Angiotensin II and by the SR Ca2+ pump inhibitors cyclopiazonic acid and thapsigargin correlate negatively with the tissue weight. In contrast, the contractions due to membrane depolarization by high KCl correlate positively. Peroxide also produces a small contraction which correlates negatively with the tissue weight. When artery rings are treated with peroxide and washed, their ability to contract with Angiotensin II, cyclopiazonic acid and thapsigargin decreases. Thus, the SR Ca2+ pump may play a more important role in the contractility of the smaller segments of the coronary artery than in the larger segments. These results are consistent with the hypothesis that ROS which damage the SR Ca2+ pump affect the contractile function of the distal segments more adversely than of the proximal segments.     

A rare combination of coronary anomalies

Coronary anomalies are found in less than 1% of diagnostic coronary angiograms. The clinical relevance of these anomalies varies from insignificant to potentially lethal. The major role of coronary angiography in interventional cardiology and coronary surgery underscores the importance of having knowledge of the variations in coronary anatomy and their clinical relevance. We report a rare case of a patient with a combination of coronary anomalies: coronary fistulae, a double circumflex coronary artery and anomalous origin of a circumflex artery from the proximal right coronary artery. (Neth Heart J 2009;17:387-9.)     

Loss of glypican-3 function causes growth factor-dependent defects in cardiac and coronary vascular development

Glypican-3 (Gpc3) is a heparan sulfate proteoglycan (HSPG) expressed widely during vertebrate development. Loss-of-function mutations cause Simpson-Golabi-Behmel syndrome (SGBS), a rare and complex congenital overgrowth syndrome with a number of associated developmental abnormalities including congenital heart disease. We found that Gpc3-deficient mice display a high incidence of congenital cardiac malformations like ventricular septal defects, common atrioventricular canal and double outlet right ventricle. In addition we observed coronary artery fistulas, which have not been previously reported in SGBS. Coronary artery fistulas are noteworthy because little is known about the molecular basis of this abnormality. Formation of the coronary vascular plexus in Gpc3-deficient embryos was delayed compared to wild-type, and consistent with GPC3 functioning as a co-receptor for fibroblast growth factor-9 (FGF9), we found a reduction in Sonic Hedgehog (Shh) mRNA expression and signaling in embryonic mutant hearts. Interestingly, we found an asymmetric reduction in SHH signaling in cardiac myocytes, as compared with perivascular cells, resulting in excessive coronary artery formation in the Gpc3-deficient animals. We hypothesize that the excessive development of coronary arteries over veins enables the formation of coronary artery fistulas. This work has broad significance to understanding the genetic basis of coronary development and potentially to molecular mechanisms relevant to revascularization following ischemic injury to the heart.     

Coronary reperfusion in dogs inhibits endothelium-dependent relaxation: role of superoxide radicals

Previous studies indicate that release of superoxide radicals during coronary reperfusion following occlusion may relate to the loss of endothelium-dependent coronary arterial relaxation. We examined coronary arterial ring relaxation in dogs subjected to temporary circumflex (Cx) coronary artery occlusion and treated with saline or the superoxide radical scavenger superoxide dismutase (SOD). In dogs treated with saline, Cx coronary ring relaxation in response to leukotriene D4 (LTD4) and acetylcholine (ACh) was attenuated (p less than 0.01), but coronary relaxation in response to nitroglycerin was preserved, suggesting loss of endothelium-dependent relaxation following coronary reperfusion. In contrast, Cx coronary relaxation in response to LTD4 and ACh was preserved in the SOD-treated dogs (p less than 0.01 compared to saline-treated dogs). To further examine the role of superoxide radicals in the loss of endothelium-dependent relaxation, normal nonischemic canine coronary artery and rat aortic rings were exposed to a superoxide radical generating system of xanthine and xanthine oxidase in vitro. Xanthine plus xanthine oxidase treatment caused a significant (p less than 0.01) decrease in the relaxant effects of ACh. Pretreatment of rat aortic rings with SOD protected against the loss of ACh-induced relaxation. These observations suggest that release of superoxide radicals during reperfusion is the basis of loss of endothelium-dependent coronary arterial relaxation. Treatment with superoxide radical scavengers prior to coronary reperfusion protects against this loss.     

Evaluation of a Novel Laser-assisted Coronary Anastomotic Connector - the Trinity Clip - in a Porcine Off-pump Bypass Model

To simplify and facilitate beating heart (i.e., off-pump), minimally invasive coronary artery bypass surgery, a new coronary anastomotic connector, the Trinity Clip, is developed based on the excimer laser-assisted nonocclusive anastomosis technique. The Trinity Clip connector enables simplified, sutureless, and nonocclusive connection of the graft to the coronary artery, and an excimer laser catheter laser-punches the opening of the anastomosis. Consequently, owing to the complete nonocclusive anastomosis construction, coronary conditioning (i.e., occluding or shunting) is not necessary, in contrast to the conventional anastomotic technique, hence simplifying the off-pump bypass procedure. Prior to clinical application in coronary artery bypass grafting, the safety and quality of this novel connector will be evaluated in a long-term experimental porcine off-pump coronary artery bypass (OPCAB) study. In this paper, we describe how to evaluate the coronary anastomosis in the porcine OPCAB model using various techniques to assess its quality. Representative results are summarized and visually demonstrated.     

Extracellular calcium-dependent and -independent effects of adenosine in bovine coronary artery

Adenosine relaxes the coronary arteries of various species through A2 receptors. The aim of the present investigation was to evaluate the relaxing effects of adenosine in relation to the role of calcium in bovine coronary arteries by studying the vasodilatory effect of adenosine in normal and calcium-free medium and on calcium-45 efflux into calcium-free medium. Acetylcholine (ACh) and norepinephrine (NE) were used to induce tone in coronary artery rings. Adenosine, 5'-(N-ethylcarboxamido)adenosine (NECA), and N6-(L-phenylisopropyl)adenosine (L-PIA) produced concentration-dependent relaxations of the coronary artery rings. Both in normal and calcium-free medium, the order of potency for adenosine analogs (NECA greater than L-PIA greater than adenosine) was similar and 8-phenyltheophylline antagonized the relaxation responses to adenosine and its analogs. Removal of extracellular calcium shifted the concentration-response curves to the right in a parallel fashion, slowed the rate of relaxation, and in NE contracted rings reduced the maximum responses for adenosine and its analogs. In calcium-free medium, adenosine was without an effect on calcium-45 efflux in the presence of ACh. However, adenosine inhibited the stimulated calcium-45 efflux induced by NE. The data suggest that the vasodilatory action of adenosine in bovine coronary smooth muscle has both extracellular calcium-dependent and -independent components.     

Primary percutaneous coronary intervention in the left main stem of a monocoronary artery

In a 71-year-old female with evolving anterior wall myocardial infarction, coronary angiography revealed a monocoronary artery which arose from the right sinus of Valsalva. Originating from a short common trunk, the left main stem showed a thrombotic lesion that occluded the left anterior descending coronary artery while the circumflex artery was obstructed. Intracoronary administration of abciximab, followed by stenting of the transition between the left anterior descending coronary artery and the main stem, and final kissing balloon inflation of the bifurcation resulted in an excellent angiographic result and favourable clinical outcome. (Neth Heart J 2009;17:274–6.)     

Resistin impairs endothelium-dependent dilation to bradykinin, but not acetylcholine, in the coronary circulation

Elevated plasma levels of fat-derived signaling molecules are associated with obesity, vascular endothelial dysfunction, and coronary heart disease; however, little is known about their direct coronary vascular effects. Accordingly, we examined mechanisms by which one adipokine, resistin, affects coronary vascular tone and endothelial function. Studies were conducted in anesthetized dogs and isolated coronary artery rings. Resistin did not change coronary blood flow, mean arterial pressure, or heart rate. Resistin had no effect on acetylcholine-induced relaxation of artery rings; however, resistin did impair bradykinin-induced relaxation. Selective impairment was also observed in vivo, as resistin attenuated vasodilation to bradykinin but not to acetylcholine. Resistin had no effect on dihydroethidium fluorescence, an indicator of superoxide (O(2)(-)) production, and the inhibitory effect of resistin on bradykinin-induced relaxation persisted in the presence of Tempol, a superoxide dismutase mimetic. To determine whether resistin impaired production of and/or responses to nitric oxide (NO) or prostaglandins (e.g., prostacyclin; PGI(2)), we performed experiments with N(omega)-nitro-L-arginine methyl ester (L-NAME) and indomethacin. The effect of resistin to attenuate bradykinin-induced vasodilation persisted in the presence of L-NAME or indomethacin, suggesting resistin may act at a cell signaling point upstream of NO or PGI(2) production. Resistin-induced endothelial dysfunction is not generalized, and it is not consistent with effects mediated by O(2)(-) or interference with NO or PGI(2) signaling. The site of the resistin-induced impairment is unknown but may be at the bradykinin receptor or a closely associated signal transduction machinery proximal to NO synthase or cyclooxygenase.     

Role of Orai1 and L-type CaV1.2 channels in Endothelin-1 mediated coronary contraction under ischemia and reperfusion

Ischemia and Reperfusion (I/R) injuries are associated with coronary artery hypercontracture. They are mainly originated by an exacerbated response to agonists released by endothelium such as Endothelin (ET-1), involving the alteration in intracellular calcium handling. Recent evidences have highlighted the implication of Store-Operated Calcium Channels (SOCC) in intracellular calcium homeostasis in coronary artery. However, little is known about the role of SOCC in the regulation of coronary vascular tone under I/R.The aim of this study was to evaluate the role of SOCC and l-type Ca²⁺ channels (LTCC) in coronary artery vasoconstriction originated by ET-1 in I/R. We used Left Anterior Descendent coronary artery (LAD) rings, isolated from Wistar rats, to study the contractility and intracellular Ca²⁺ concentration ([Ca²⁺]_i) under a simulated I/R protocol. We observed that responses to high-KCL induced depolarization and caffeine-induced Ca²⁺ release are attenuated in coronary artery under I/R. Furthermore, ET-1 addition in ischemia promotes transient and small rise of [Ca²⁺]_i and coronary vascular tone. Meanwhile, these effects are significantly potentiated during reperfusion. The resulting ET-1-induced vasoconstrictions and [Ca²⁺]_i increase were abolished by; GSK-7975A and gadolinium, inhibitors of SOCC; and nifedipine a widely used inhibitor of LTCC. Interestingly, using in situ Proximity Ligation Assay (PLA) in isolated coronary smooth muscle cells we found significant colocalization of LTCC Ca_V1.2 isoform with Orai1, the pore forming subunit of SOCC, and TRPC1 under I/R.Our data suggest that hypercontraction of coronary artery induced by ET-1 after I/R involves the co-activation of LTCC and SOCC, which colocalize significantly in the sarcolemma of coronary smooth muscle cells.     

RESPONSE study: Randomised Evaluation of Secondary Prevention by Outpatient Nurse SpEcialists

Background. Patients with coronary artery disease are at high risk of coronary events and death, but effective secondary prevention can reduce this risk. There is a gap between guidelines on secondary prevention and the implementation of these measures, which could potentially be reduced by nurse led prevention clinics (NLPC). Objectives. The aim of the current study is to quantify the impact of NLPC on the risk of cardiovascular events in patients with established coronary artery disease. Methods. A randomised, multicentre clinical trial of NLPC in addition to usual care or usual care alone in post-acute coronary syndrome patients. (Neth Heart J 2009;17:322–8.)     

A 4-AP-sensitive current is enhanced by chronic carbon monoxide exposure in coronary artery myocytes

A physiological role of carbon monoxide has been suggested for coronary myocytes; however, direct evidence is lacking. The objective of this study was to test the effect of chronic carbon monoxide exposure on the K(+) currents of the coronary myocytes. The effect of 3-wk chronic exposure to carbon monoxide was assessed on K(+) currents in isolated rat left coronary myocytes by the use of the patch-clamp technique in the whole cell configuration. Moreover, membrane potential studies were performed on coronary artery rings using intracellular microelectrodes, and coronary blood flow in isolated heart preparation was recorded. Carbon monoxide did not change the amplitude of global whole cell K(+) current, but it did increase the component sensitive to 1 mM 4-aminopyridine. Carbon monoxide exposure hyperpolarized coronary artery segments by approximately 10 mV and, therefore, increased their sensitivity to 4-aminopyridine. This effect was associated with an enhancement of coronary blood flow. We conclude that chronic carbon monoxide increases a 4-aminopyridine-sensitive current in isolated coronary myocytes. This mechanism could, in part, contribute to hyperpolarization and to increased coronary blood flow observed with carbon monoxide.     

Kinins mediate kallikrein-induced endothelium-dependent relaxations in isolated canine coronary arteries.

ACE inhibitors elicit the release of endothelium-derived relaxing factors in perfused isolated canine arteries (Mombouli and Vanhoutte, J. Cardiovasc. Pharmacol. 1991, 18: 926-927); this action is antagonized by bradykinin-receptor antagonists suggesting that it is mediated by local kinin generation. The effects of exogenous tissular kallikrein (porcine) were examined in vitro in the isolated canine coronary artery. Isometric tension was measured in blood vessel rings (with and without endothelium) contracted with prostaglandin F2 alpha. The kallikrein elicited relaxations in rings with, but not in those without, endothelium. This response was augmented by the angiotensin converting enzyme inhibitor perindoprilat, and it was antagonized by the selective B2-kinin receptor antagonist HOE 140 and aprotinin, an inhibitor of tissular kallikrein. These data suggest that in the canine coronary artery, kallikrein causes relaxations that may be mediated by kinins generated from endogenous kininogens present in the vascular wall.