Persistence of systolic coronary flow reversal predicts irreversible dysfunction after reperfused anterior myocardial infarction.

OBJECTIVE: To investigate serial assessments of systolic coronary flow reversal in the infarct related artery for predicting poor left ventricular functional recovery after reperfused acute myocardial infarction. SETTING: Regional hospital. PATIENTS AND METHODS: 49 patients with anterior acute myocardial infarction had transthoracic Doppler echocardiography to record coronary flow velocity in the left anterior descending coronary artery immediately after successful primary coronary angioplasty (day 0), and at 48 hours, one week, and three weeks. MAIN OUTCOME MEASURES: Coronary flow velocity at each time point; regional wall motion score index (RWMSI) at day 0 and at three weeks. Irreversible dysfunction was defined as a decrease in RWMSI to < 0.22. RESULTS: Measurements of coronary flow velocity could be made in 45 patients. Patients were divided into three groups: no systolic flow reversal (group 1, n = 27), systolic flow reversal observed only on day 0 (group 2, n = 8), and systolic flow reversal persisting until 48 hours (group 3, n = 10). Although baseline RWMSI was similar among the three groups, the value at three weeks was significantly higher in group 3 than in the other two groups. In predicting irreversible dysfunction, the persistence of systolic flow reversal up to 48 hours had a higher positive predictive value (100%) than the presence of systolic flow reversal on day 0 (67%, p < 0.04). The negative predictive value of systolic flow reversal at 48 hours (83%) was comparable in accuracy to the presence of systolic flow reversal on day 0 (85%, NS). CONCLUSIONS: In reperfused anterior acute myocardial infarction, serial assessment of coronary flow velocity in the left anterior descending coronary artery is feasible using transthoracic Doppler echocardiography, and the persistence of systolic flow reversal at 48 hours is a more specific marker of irreversible dysfunction than peak creatine kinase or diastolic deceleration time.

Natural history of endometrial hyperplasia. Study of 77 patients.

Seventy-seven patients with endometrial hyperplasia, 48 with simple hyperplasia without atypia (SH), 17 with complex hyperplasia without atypia (CH), one with simple hyperplasia with atypia (SHA), and 11 with complex hyperplasia with atypia (CHA) were prospectively followed-up by total curettage every 12 months for 3 years. Progression to carcinoma occurred in only one of the 77 patients; she showed grade 1 adenocarcinoma. The overall regression rates were 79% for SH, 100% for SHA, 94% for CH, and 55% for CHA, respectively. In patients with CHA whose disease reverted to normal endometrium, regression was most likely to occur within the first year.

Clinical value of dilatation and curettage for abnormal uterine bleeding.

Dilatation and curettage was performed under anesthesia in outpatients in 1,837 patients aged over 26 with a history of abnormal uterine bleeding not associated with pregnancy or ovulation. Fifty-one (2.8%) patients were found to have malignant disease. Of these, 47 patients had endometrial carcinoma. An additional 111 (6.0%) patients were found to have endometrial hyperplasia. The incidence of either malignant disease or endometrial hyperplasia was 9.7% in patients over the age of 40. Complications of this method were noted in 12 (0.7%) patients; only three patients needed to stay in hospital.

Mutual alignment errors due to the variation of wave-front aberrations in a free-space laser communication link.

Optical devices in free-space laser communication systems are affected by their environment, particularly in relation to the effects of temperature while in orbit. The mutual alignment error between the transmitted and received optical axes is caused by deformation of the optics due to temperature variation in spite of the common optics used for transmission and reception of the optical beams. When a Gaussian beam wave for transmission is aligned at the center of a received plane wave, 3rd-order Coma aberrations have the most influence on the mutual alignment error, which is an inevitable open pointing error under only the Tip/Tilt tracking control. As an example, a mutual alignment error of less than 0.2 microrad is predicted for a laser communication terminal in orbit using the results from space chamber thermal vacuum tests. The relative power penalty due to aberration is estimated to be about 0.4 dB. The results will mitigate surface quality in an optical antenna and contribute to the design of free-space laser communication systems.

Definition of the anterior choroidal artery territory in rats using intraluminal occluding technique.

This manuscript delineates the territory of the anterior choroidal artery (AChA) in rats, as defined by the induction of an AChA infarction. By advancing a 0.24-mm surgical suture up the internal carotid artery (ICA) to a point 0.5-2 mm proximal to the middle cerebral artery (MCA) origin, the AChA could be occluded and a reliable AChA distribution infarction was produced in 62% (23/37) of animals. The infarct volume, as defined by TTC staining, was 55+/-7 mm(3). Maps of the infarction, generated by measuring the entire area of overlapping coronal slices, demonstrated that the internal capsule was always damaged. Other areas that might be affected included the hippocampus, thalamus, amygdaloid complex, piriform cortex, dorsal caudatoputamen, and lateral ventricular wall. Positioning the coated suture proximal to the AChA produced a much smaller infarct involving the medial and lateral hypothalamus, preoptic region, optic chiasm, and marginal region of the internal capsule near to the lateral hypothalamus exempt from AChA territory damage. A causative relationship between AChA occlusion and a deep cerebral infarct centered on the internal capsule was further established by: (1) identifying the AChA on the non-ischemic side with colored silicone perfusion, and subsequent similar delineation on the ischemic side, and (2) delineating infarction in the silicone perfused AChA region using hematoxylin and eosin staining and the TUNEL method. The AChA usually originated from the ICA (91% of cases), 1.75+/-0.12 mm proximal to the MCA bifurcation. Approximately 27% of the AChAs had periamygdaloid branch(es) on its initial segment.

Caspases determine the vulnerability of oligodendrocytes in the ischemic brain.

Although oligodendrocytes (OLGs) are thought to be vulnerable to hypoxia and ischemia, little is known about the detailed mechanism by which these insults induce OLG death. From the clinical viewpoint, it is imperative to protect OLGs as well as neurons against ischemic injury (stroke), because they are the only myelin-forming cells of the central nervous system. Using the Cre/loxP system, we have established a transgenic mouse line that selectively expresses p35, a broad-spectrum caspase inhibitor, in OLGs. After hypoxia, cultured OLGs derived from wild-type mice exhibited significant upregulation of caspase-11 and substantial activation of caspase-3, which led to cell loss. Expression of p35 or elimination of caspase-11 suppressed the caspase-3 activation and conferred significant protection against hypoxic injury. Expression of p35 in OLGs in vivo resulted in significant protection from ischemia-induced cell injury, thus indicating that caspases are involved in the ischemia-induced cell death of OLGs. Furthermore, the induction of caspase-11 was evident in the ischemic brains of wild-type mice, and OLGs exhibited resistance to brain ischemia in mice deficient in caspase-11, suggesting that caspase-11 is critically implicated in the mechanism(s) underlying ischemia-induced OLG death. Caspases may therefore offer a good therapeutic target for reducing ischemia-induced damage to OLGs.

Late results of acute medial necrosis in rabbit aorta.

To clarify whether acute medial necrosis of the aorta induces aneurysms and intimal thickening at a later stage, we first attempted to induce acute aortic medial necrosis in 47 normal rabbits by the administration of Russell's viper venom intraperitoneally and of angiotensin II intravenously as used in a previous study and then followed the rabbits for 1 and 2 months respectively. As a control, 18 adult normal rabbits were used. Six control and 20 treated rabbits were sacrificed after aortagraphy at the end of one month, while the remaining 12 control and 27 treated rabbits were sacrificed at the end of 2 months. We evaluated the aortic lesions by gross observations and both light and electron microscopic examinations. In addition, at the end of one month, aortagraphy was performed to measure the luminal diameter of the aorta of the 6 control and 20 treated rabbits. We macroscopically found the saccular lesions to be surrounded by small crater like lesions mainly at the thoracic aortas in 18 out of 47 treated rabbits. These lesions consisted of the necrosis and calcification of the aortic media and the destruction of the elastic fiber along with intimal thickening. However, no aneurysmal dilatation was found in the aortagraphy findings. We thus conclude that acute medial necrosis produced saccular and crater like lesions but these lesions were not confirmed by aortagraphy.

A gene on SCA4 locus causes dominantly inherited pure cerebellar ataxia.

BACKGROUND: Several different genes or their loci have been identified for autosomal dominant cerebellar ataxia (ADCA). However, other types of ataxia remain unassigned. OBJECTIVE: To identify a new locus for ADCA. METHODS: Six Japanese families with ADCA with pure cerebellar syndrome (ADCA type III) were examined. These families had been molecularly excluded for spinocerebellar ataxia (SCA) types 1 through 3, 5 through 8, and 10. Clinical examination was undertaken, and a genome-wide linkage search was performed on 250 microsatellite DNA markers. RESULTS: Strong evidence for linkage was found with markers on human chromosome 16q, and haplotype and multipoint analyses further refined the gene locus in a 10.9-cM interval between D16S3089 and D16S515. Linkage disequilibrium was further found with the marker D16S3107 within the interval. The locus was exactly the candidate interval of SCA4, a rare form of ADCA clinically characterized by ataxia with sensory neuropathy and pyramidal tract signs. This would suggest that SCA4 and our ADCA type III are likely to be allelic disorders with different clinical features. CONCLUSION: The current study provides evidence that a gene on the SCA4 locus causes a pure cerebellar syndrome.

Local adenovirus-mediated transfer of C-type natriuretic peptide suppresses vascular remodeling in porcine coronary arteries in vivo.

OBJECTIVE: This study was designed to examine whether or not adenovirus-mediated gene transfer of C-type natriuretic peptide (CNP) can prevent coronary restenotic changes after balloon injury in pigs in vivo. BACKGROUND: Gene therapy to prevent restenosis after percutaneous transluminal coronary angioplasty (PTCA) might be useful but requires a method applicable for in vivo gene delivery into the coronary artery as well as the efficient vector encoding a potent antiproliferative substance. We tested whether the adenovirus-mediated gene transfer of CNP by use of an infiltrator angioplasty balloon catheter (IABC) might prevent the coronary restenotic changes after balloon injury. METHODS: Balloon angioplasty was performed in the left anterior descending and the left circumflex coronary artery in pigs. Immediately after the balloon injury, adenovirus solution encoding either CNP (AdCACNP) or beta-galactosidase (AdCALacZ) gene was injected with IABC into the balloon-injured coronary segments. Expression of CNP was assessed by immunohistochemical staining and cyclic guanosine 3',5'-monophosphate (cGMP) measurement. Coronary restenotic changes were evaluated by both angiographic and histological examinations. RESULTS: CNP was highly expressed in the media and the adventitia of the coronary artery at the AdCACNP-transfected but not at the AdCALacZ-transfected segment. In the AdCALacZ-transfected segment, vascular cGMP levels tended to be reduced as compared with the untreated segment, whereas in the AdCACNP-transfected segment, vascular cGMP levels were restored. Angiographic coronary stenosis was significantly less at the AdCACNP-transfected than at the AdCALacZ-transfected segment. Histological examination revealed that this was achieved primarily by the marked inhibition of the geometric remodeling of the coronary artery by the CNP gene transfer. CONCLUSIONS: Adenovirus-mediated CNP gene transfer with the IABC system may be a useful gene therapy to prevent restenosis after PTCA in vivo.

Sarpogrelate, a selective 5-HT2A serotonergic receptor antagonist, inhibits serotonin-induced coronary artery spasm in a porcine model.

Serotonin is one of the most important vasoactive substances and has been implicated in the pathogenesis of coronary artery spasm and of acute coronary syndrome. We have recently demonstrated that local and long-term treatment with interleukin-1beta(IL-1beta) causes coronary arteriosclerotic changes and hyperconstrictive responses to serotonin in pigs in vivo. However, it remains to be examined which serotonergic (5-HT) receptor subtype mediates coronary spasm and whether alterations in serotonergic receptors are involved in the abnormality. In this study, we examined the inhibitory effect of sarpogrelate, a selective 5-HT2A serotonergic receptor antagonist, on the serotonin-induced coronary spasm as well as the possible alterations of serotonergic receptors in our porcine model. A segment of the porcine coronary artery was carefully dissected and aseptically wrapped with cotton mesh absorbing IL-1beta-bound microbeads from the adventitia. Two weeks after the procedure, angiographic study was performed, followed by binding assay for 5-HT1B and 5-HT2A serotonergic receptors and reverse transcription-polymerase chain reaction (RT-PCR) analysis for mRNA of those receptors. Angiographic study showed coronary vasospastic responses to serotonin at the IL-1beta-treated site. Sarpogrelate dose-dependently inhibited the serotonin-induced coronary spasm, but it did not affect the prostaglandin F2alpha-induced vasoconstriction. Radiolabeled receptor-binding assay showed that receptor affinity or receptor number of the 5-HT1B, or 5-HT2A receptors did not differ significantly between the spastic and the control sites. Furthermore, RT-PCR analysis showed that the expression of neither 5-HT2A nor 5-HT1B receptor mRNA was significantly altered at the spastic site. These results indicate that serotonin-induced coronary spasm is mediated primarily by 5-HT2A receptor in our porcine model, although the 5-HT2A receptor was not up-regulated, suggesting that alteration in the signal-transduction pathway for vascular smooth muscle contraction beyond the 5-HT2A receptor plays a primary role in the pathogenesis of coronary spasm in our porcine model.

[An autopsy case of dementia with Lewy bodies who showed the typical parkinsonism in the initial five years].

A 76-year-old man with parkinsonism and dementia was reported. He developed resting tremor at age 69 followed by hypokinesia, rigidity and small step gait. L-dopa ameliorated his symptoms with no hallucinations for the initial 5 years. His mental level did not decrease during that period. He was admitted to our hospital because of dehydration and fever at age 74. Subsequently, his cognitive function deteriorated, with visual hallucination. Serial brain CT studies displayed a progressive cerebral cortical atrophy without focal lesions. He died of respiratory distress syndrome and disseminated coagulopathy resulting from pneumonia, dehydration and syndrome malin. Postmortem examination revealed a marked bilateral loss of melanin-containing neurons with Lewy bodies in the substantia nigra and locus ceruleus. Lewy bodies were also in the basal nucleus of Meynert, with moderate neuronal cell loss. The distribution of Lewy bodies was widespread in the cerebral cortical areas, corresponding to the neocortical subtype according to the consensus guideline for the pathologic diagnosis of dementia with Lewy bodies. According to the criteria of the Consortium to Establish a Registry for Alzheimer's Disease, the age-related plaque score in the present case suggested Alzheimer's disease, although cortical neurofibrillary changes corresponded to stage II by the criteria of Braak and Braak. These pathological findings established the diagnosis of dementia with Lewy bodies from the quantitative and distributional viewpoints. Based on recent neuropathological evidence, a spectral theory, which presents idiopathic Alzheimer's disease and Parkinson's disease as the two extremes of a spectrum of neurodegeneration, has been proposed. Dementia with Lewy bodies is located in the middle of this spectrum. Pathological evaluation based on quantitative consensus guidelines is important to establish the diagnosis in patients with parkinsonism and dementia, since neuropathological changes of Alzheimer's disease, Parkinson's disease and dementia with Lewy bodies are often observed in a mixed manner in these patients.

Experimental model of small deep infarcts involving the hypothalamus in rats: changes in body temperature and postural reflex.

BACKGROUND AND PURPOSE: Intraluminal middle cerebral artery (MCA) occlusion in rats has been reported to cause hyperthermia assumed to be caused by hypothalamic damage. To clarify the effects of hypothalamic ischemia on body temperature and to obtain a model simulating lacunar infarction, we attempted to produce small infarcts in deep structures (including the hypothalamus). METHODS: A surgical suture was advanced to occlude the origin of the hypothalamic (HTA) and/or anterior choroidal arteries (AChA) without compromise of the anterior or middle cerebral artery origins. After treatment, rectal temperature and postural reflex were examined repeatedly for 3 days under nonanesthetic conditions. The AChA and HTA and their link with small deep infarction were then confirmed by TTC, hematoxylin and eosin, and TUNEL stains and by microsurgical dissection after colored silicone perfusion into the cerebral arteries. RESULTS: Advancement of the suture near to but not occluding the MCA origin (0.5 to 1.9 mm proximal) produced small, deep, nonneocortical strokes in 25 of 36 animals without producing MCA ischemic changes. These infarctions mainly affected the hypothalamus in 13 animals (HTA area: infarct volume 6+/-1 mm(3)) and involved both the internal capsule and hypothalamus in 12 animals (HTA+AChA area infarct volume 48+/-10 mm(3)). Rats with HTA infarction alone exhibited persistent hyperthermia for 72 hours; some also had transient mild postural abnormality. The AChA+HTA infarct group showed a transient elevation of body temperature for 24 hours and definitive postural abnormality. In the remaining 11 animals, the suture was inadvertently advanced across the MCA origin, producing a large infarct that affected both the neocortex (MCA territory) and nonneocortical structures (volume 381+/-30 mm(3), n=11). The MCA infarct group displayed a transient hyperthermia and severe postural abnormality. CONCLUSIONS: When properly positioned, the intraluminal suture method permits selective AChA and/or HTA obstruction without inducing MCA territory ischemia. This model confirms that selective hypothalamic infarction produces significant and sustained temperature regulation abnormalities. The model also may be useful in investigating the pathophysiology of small, deep, end-vessel infarction.

Endothelial vasodilator function is preserved at the spastic/inflammatory coronary lesions in pigs.

BACKGROUND: The question of whether or not endothelial vasodilator function in the spastic coronary artery is preserved is still controversial. We recently developed a porcine model in which long-term and local treatment with interleukin-1beta (IL-1beta) from the adventitial site causes coronary arteriosclerotic changes and vasospastic responses to autacoids. The aim of this study was to examine the endothelial vasodilator function in our new porcine model of the spasm both in vivo and in vitro. METHODS AND RESULTS: A segment of the porcine coronary artery was aseptically wrapped with cotton mesh that held absorbed IL-1beta-bound microbeads. Two weeks after the procedure, intracoronary administration of serotonin caused coronary vasospasm at the IL-1beta-treated site (n = 10). Coronary vasodilatation to bradykinin, substance P, or an increase in coronary blood flow was preserved at the spastic site. Vasodilator responses to 3-morpholinosydnonimine (an NO donor) and nitroglycerin also were comparable between the 2 sites. The vasoconstricting response to N(G)-monomethyl-L-arginine and the extent of the augmentation of the serotonin-induced vasoconstriction were comparable between the 2 sites. Organ chamber experiments showed that endothelium-dependent relaxations to bradykinin, the calcium ionophore A23187, and even the vasospastic agonist serotonin were preserved at the spastic site, whereas contractions to serotonin were augmented at the spastic site regardless of the presence or absence of the endothelium (n = 6). Endothelium-independent relaxations to sodium nitroprusside were also preserved at the spastic site. CONCLUSIONS: These results indicate that endothelial vasodilator function is preserved at the spastic site and that the spasm is caused primarily by smooth muscle hypercontraction in our porcine model.

Rho-kinase-mediated pathway induces enhanced myosin light chain phosphorylations in a swine model of coronary artery spasm.

OBJECTIVE: We recently demonstrated in our swine model of coronary artery spasm that enhanced myosin light chain (MLC) phosphorylations (both MLC mono- and diphosphorylations) play a central role in the pathogenesis of the spasm. However, the molecular mechanism for and the phosphorylation sites for the enhanced MLC phosphorylations were unknown. In the present study, we addressed these points using hydroxyfasudil, a novel inhibitor of protein kinases, which we found preferentially inhibits Rho-kinase. METHODS: The specificity of the inhibitory effects of hydroxyfasudil on Rho-kinase, MLCK, MRCK beta and PKC were examined by kinase assay in vitro. The left porcine coronary artery was chronically treated with interleukin-1 beta (IL-1 beta, 2.5 micrograms). Two weeks after the operation, coronary artery vasomotion was examined both in vivo and in vitro. MLC phosphorylations were examined by Western blot analysis and the sites for the phosphorylations by anti-phosphorylated MLC antibodies that identified the monophosphorylation site as Ser19 and diphophorylation sites as Ser19/Thr18 of MLC. RESULTS: Inhibitory effects of hydroxyfasudil was at least 100 times more potent for Rho-kinase as compared with other protein kinases tested. Intracoronary serotonin (10 micrograms/kg) caused coronary hyperconstriction at the IL-1 beta-treated site in vivo, which was dose-dependently inhibited by hydroxyfasudil (p < 0.01). The coronary segment taken from the spastic site also showed hypercontractions to serotonin in vitro, which were again dose-dependently inhibited by hydroxyfasudil (p < 0.01). Western blot analysis showed that MLC monophosphorylation was significantly greater in the spastic segment than in the control segment, while MLC diphosphorylation was noted only at the spastic segment (p < 0.01). The sites for the mono- and diphosphorylated MLC were identified as the monophosphorylated site Ser19 and diphosphorylated sites Ser19/Thr18 of MLC, respectively. Both types of MLC phosphorylations at the spastic segment were markedly inhibited by hydroxyfasudil (p < 0.01). CONCLUSION: These results indicate that hydroxyfasudil-sensitive Rho-kinase-mediated pathway appears to mediate the enhanced MLC phosphorylations (on Ser19 and Ser19/Thr18 residues) and plays a central role in the pathogenesis of coronary artery spasm.

Intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent suppresses the restenotic changes of the coronary artery in pigs in vivo.

OBJECTIVES: This study was designed to examine whether or not intramural delivery of ST638 (a specific tyrosine kinase inhibitor) with biodegradable stent can suppress the restenotic changes of the coronary artery in vivo. BACKGROUND: Clinical and animal studies demonstrated that restenosis after coronary intervention results from a combined effect of neointimal formation and geometric remodeling (decrease in total cross-sectional area). Thus, the most effective strategy to prevent the restenosis appears to inhibit both the neointimal formation and geometric remodeling by antiproliferative agent and stent, respectively. We have previously shown that ST638 markedly suppresses the restenotic changes of the porcine coronary artery when applied from the adventitial site. METHODS: A poly-L-lactic acid biodegradable stent was coated with either ST638 (0.8 mg) or equimolar of its inactive metabolite, ST494. A pair of these stents were implanted alternatively in the left anterior descending or circumflex coronary artery in pigs (n=6). Three weeks after the procedure, coronary stenosis was assessed by angiography followed by histological examination. RESULTS: Coronary stenosis was significantly less at the ST638 stent site than at the ST494 stent site (47+/-5% vs. 25+/-4%, p < 0.01). Histological examination also showed that the extent of neointimal formation and that of geometric remodeling were significantly less at the ST638 stent site than at the ST494 stent site (p < 0.05). CONCLUSIONS: These results indicate that intramural delivery of a specific tyrosine kinase inhibitor with biodegradable stent overcomes the proliferative stimuli caused by balloon injury, the stent itself, and the drug coating on the stent, resulting in the suppression of the restenotic changes of the coronary artery in vivo. This strategy might also be useful in the clinical setting in humans.

A case of Klippel-Trenaunay syndrome associated with Huntington's disease.

We report here on a patient with Klippel-Trenaunay syndrome who was later diagnosed with Huntington's disease. Consistent with the later diagnosis, a (CAG)n repeat longer than the normal range was observed on chromosome 4p. The presence of these two diseases in the same individual may represent coincidence or a true correlation which must be confirmed by other evidence. To our knowledge, this is the first published report of the concurrent presence of these diseases in the same individual.

Platelet activating factor causes hyperconstriction at the inflammatory coronary lesions in pigs in vivo.

BACKGROUND: Although platelet activating factor (PAF) is an important vasoactive substance released from activated leukocytes, platelets and endothelial cells, little is known about its effect at the inflammatory coronary lesions in vivo. OBJECTIVE: To examine the coronary vasomotor responses to PAF at the inflammatory lesions in our swine model with interleukin-1 beta (IL-1 beta) in vivo. METHODS: Under aseptic conditions, the proximal segment of the porcine left coronary artery was dissected and wrapped with cotton mesh absorbing IL-1 beta. Two weeks after the operation, coronary vasomotion in response to intracoronary administration of 0.3 and 1 microgram/kg PAF, 1, 3, and 10 micrograms/kg serotonin, 1, 3 and 10 micrograms/kg histamine, and 5 and 50 micrograms/kg prostaglandin F2 alpha was examined by coronary arteriography. RESULTS: At the IL-1 beta-treated site, PAF, serotonin and histamine, but not prostaglandin F2 alpha, caused hyperconstriction (n = 8). A synergy of the vasoconstricting effects of PAF and serotonin was also noted (n = 6). Administration of TCV-309, a selective PAF receptor antagonist, abolished the hyperconstrictive responses to PAF but not those to other agonists (n = 6). The PAF-induced coronary hyperconstrictions were significantly inhibited by administrations of the protein kinase C inhibitors staurosporine and sphingosine, but not by administrations of ryanodine, thapsigargin, or indomethacin (n = 4 each). CONCLUSIONS: These results indicate that PAF causes hyperconstriction at the inflammatory coronary lesions in vivo by itself as well as in a synergistic manner with serotonin and that the PAF-induced hyperconstrictions are substantially mediated by a protein kinase C-dependent pathway in vivo.