Extramural Arteries Research Articles

Endothelin antagonist-induced coronary and systemic arteritis in the beagle dog.

Two endothelin antagonists, ZD1611 (3-[4-[3-(3-methoxy-5-methylpyrazin-2-ylsulfamoyl)-2-pyridyl]phenyl]-2,2-dimethylpropanoic acid) and ZD2574 (2-(4-isobutylphenyl)-N-(3-methoxy-5-methylpyrazin-2-yl)pyridine-3-sulfonamide), selective for the ET(A) receptor and intended for use in pulmonary hypertension, were tested in Beagle dogs at various doses for periods of up to 4 weeks. These studies included in vivo telemetric hemodynamic assessment, full histopathological and ultrastructural pathological evaluation of coronary arteries. Both drugs produced arteritis in small- and medium-sized coronary arteries after single or multiple doses, some of which were at or below the ED50. The distribution of lesions was predominantly in extramural arteries over the atria and atrioventricular groove of the right side of the heart and consisted of epicardial hemorrhage and arteritis. Systemic arteritis was also present at a lower incidence than the coronary arteritis, was located at different sites and appeared inconsistently. Ultrastructural changes in coronary arteries suggested that damage was the result of mechanical factors. Although these patterns of vascular injury possessed features in common with those induced in dogs by high doses of vasodilating antihypertensive drugs and inotropic agents, they were atypical, as there was no left ventricular myocardial necrosis, papillary muscle damage, or subendocardial hemorrhage suggestive of ischaemia or excessive inotropism. Moreover, physiological monitoring showed no evidence of exaggerated systemic hypotension or reflex tachycardia at doses associated with vascular damage. Consequently, the changes might be the result of a localized pharmacological process such as intense, prolonged vasodilatation in unsupported arteries that are well endowed with endothelin receptors and particularly sensitive to endothelin antagonism.

Gastric mucosal blood flow regulation in response to different stimuli.

We compared changes in gastric mucosal blood flow (GMBF) and left gastric artery blood flow (LGABF) in response to pharmacological, physiological, and pathological stimuli. GMBF and LGABF were measured by the hydrogen gas clearance and perivascular ultrasonic transit time techniques, respectively, under baseline conditions and following intravenous infusion of vasopressin or pentagastrin, isovolemic hemodilution, or gastric perfusion with HCl-taurocholate. Blood flow changes following vasopressin or hemodilution were significantly larger in the left gastric artery than in the gastric mucosa. In contrast, the increment in blood flow associated with pentagastrin-stimulated acid secretion was significantly greater in the gastric mucosa than in the extramural artery. Barrier disruption with acid-taurocholate induced similar changes in both measurement sites. The gastric hyperemia induced by either mechanism was significantly attenuated by blockade of NO synthesis. These data demonstrate that although functional changes in GMBF are primarily supported by changes in blood flow at the extramural gastric arteries, the gastric mucosal microvasculature is also under the influence of independent local control mechanisms.

Carbon monoxide-induced relaxation and distribution of haem oxygenase isoenzymes in the pig urethra and lower oesophagogastric junction.

1. The distribution of the carbon monoxide (CO) producing enzymes haem oxygenase (HO)-1 and -2 was studied by immunohistochemistry in the pig's lower urinary tract, including bladder extramural arteries, and the oesophagogastric junction (OGJ). In isolated smooth muscle from the urethra and the OGJ, the mechanisms for CO-induced relaxations were characterized by measurement of cyclic nucleotide levels and by responses to the guanylate cyclase inhibitor methylene blue and some K+ channel inhibitors. 2. HO-2 immunoreactivity was observed in coarse nerve trunks within the smooth muscle of the urethra and OGJ, and in nerve cell bodies of the enteric plexuses of the OGJ. Furthermore, the vascular endothelium of the intramural vessels of the urethra, bladder and OGJ, and the extramural vessels of the bladder, displayed HO-2 immunoreactivity. Two different antisera against HO-1 were used, but only one displayed immunoreactivity in neuronal structures. HO-1 immunoreactivity, as displayed by this antiserum, was seen in nerve cells, coarse nerve trunks and varicose nerve fibres in the smooth muscle of the urethra and OGJ. Some HO-2 and/or HO-1 (as displayed by both HO-1 antisera) immunoreactive cells with a non-neuronal appearance were observed within the smooth muscle of the OGJ, bladder and urethra. 3. In the urethral preparations, exogenously applied CO (72 microM) evoked a relaxation amounting to 76 +/- 6%. The relaxation was associated with an increase in cyclic GMP, but not cyclic AMP, content. CO-evoked relaxations were not significantly reduced by treatment with methylene blue, or by inhibitors of voltage-dependent (4-aminopyridine), high (iberiotoxin, charybdotoxin) and low (apamin) conductance Ca(2+)-activated, and ATP-sensitive (glibenclamide) K+ channels. Bladder strips, and ring preparations from the extramural arteries of the bladder, did not respond to exogenously administered CO (12-72 microM). 4. In the OGJ, exogenously applied CO evoked a relaxation of 86 +/- 6%, which was associated with an increase in cyclic GMP, but not cyclic AMP, content. Treatment with 30 microM methylene blue raised the spontaneously developed muscle tone, and reduced the maximum relaxation evoked by CO to 33 +/- 9%. Addition of 4-aminopyridine, apamin, glibenclamide, iberiotoxin, charybdotoxin or glibenclamide had no effect on the relaxations. 4-aminopyridine (0.1-1 mM), iberiotoxin (0.1 microM) and charybdotoxin (0.1 microM) increased the spontaneously developed tone, and a combination of charybdotoxin and apamin reduced CO-induced (24 microM CO) relaxations. 5. The present findings demonstrate the presence of HO in both neuronal and non-neuronal cells in the pig OGJ and lower urinary tract. CO produces relaxation of the smooth muscle in the OGJ and urethra, associated with a small increase in cyclic GMP concentration in both regions. Relaxations evoked by CO in the urethra do not seem to involve voltage-dependent, low and high conductance, or ATP-dependent K+ channels. However, in the OGJ relaxations evoked by CO can be attenuated by methylene blue and a combination of charybdotoxin and apamin.

Vascular bed‐dependent roles of the peptide CGRP and nitric oxide in acid‐evoked hyperaemia of the rat stomach.

1. Acid back-diffusion through a disrupted gastric mucosal barrier is known to increase gastric mucosal blood flow via a neural mechanism. The present study examined how the acid-evoked change in the gastric microcirculation compares with blood flow changes in the left gastric artery, one of the major arteries supplying the stomach, and whether the dilator mediators in the left gastric artery are identical to those in the gastric mucosa. 2. The experiments were performed on rats anaesthetized with urethane. Blood flow in the left gastric artery was measured by the ultrasonic transit time shift technique, and blood flow in the gastric mucosa was assessed by the hydrogen gas clearance method. 3. Gastric acid back-diffusion evoked by perfusion of the stomach with 15% ethanol in 0.15 M HCl increased blood flow in the left gastric artery by a factor of 4.7, which was significantly larger than the 2.9-fold increase in blood flow through the gastric mucosa. Blood pressure and heart rate were not altered appreciably. 4. The acid-evoked hyperaemia in the left gastric artery was left unaltered by atropine and the substance P receptor antagonist RP-67580. 5. The calcitonin gene-related peptide (CGRP) antagonist CGRP (8-37) had no effect on gastric blood flow but prevented the dilator action of CGRP and inhibited the acid-evoked hyperaemia in the gastric mucosa to a larger degree than the hyperaemia in the left gastric artery. 6. Blockade of nitric oxide synthesis by N omega-nitro-L-arginine methyl ester (L-NAME) caused constriction of the left gastric artery and the gastric mucosal microvessels. The acid-evoked vasodilatation in the gastric mucosa was blocked by L-NAME, whereas the dilator response in the left gastric artery was not significantly depressed. 7. The data show that the gastric hyperaemic response to acid back-diffusion results from dilatation of mucosal microvessels and extramural arteries. The dilator mechanisms, however, differ between the two vascular beds. CGRP and nitric oxide are important vasodilator mediators in the gastric mucosa but are of less relevance in the left gastric artery.

Nitric oxide-dependent and -independent hyperaemia due to calcitonin gene-related peptide in the rat stomach.

1. Calcitonin gene-related peptide (CGRP) potently enhances mucosal blood flow in the rat stomach. The aim of this study was to examine whether CGRP also dilates extramural arteries supplying the stomach and whether the vasodilator action of CGRP involves nitric oxide (NO). 2. Rat CGRP-alpha (0.03-1 nmol kg-1, i.v.) produced a dose-dependent increase in blood flow through the left gastric artery (LGA) as determined by an ultrasonic transit time technique in urethane-anaesthetized rats. Blockade of NO synthesis by NG-nitro-L-arginine methyl ester (L-NAME, 20 and 60 mumol kg-1, i.v.) significantly reduced basal blood flow (BF) in the LGA and attenuated the hyperaemic activity of CGRP by a factor of 2.8-4. D-NAME tended to enhance basal BF in the LGA but had no influence on the dilator activity of CGRP. The ability of vasoactive intestinal polypeptide to increase left gastric arterial blood flow remained unaltered by L-NAME. 3. L-NAME (20 and 60 mumol kg-1, i.v.) evoked a prompt and sustained rise of mean arterial blood pressure (MAP) and caused a slight decrease in the hypotensive activity of CGRP. In contrast, D-NAME induced a delayed and moderate increase in MAP and did not influence the hypotensive activity of CGRP. 4. Rat CGRP-alpha dilated the isolated perfused bed of the rat LGA precontracted with methoxamine and was 3 times more potent in this respect than rat CGRP-beta. The dilator action of rat CGRP-alpha in this preparation was not affected by L-NAME or D-NAME (40 microM). 5. L-NAME (60 micromol kg-1, i.v.) reduced gastric mucosal blood flow as assessed by laser Doppler flowmetry and diminished the hyperaemic activity of rat CGRP-alpha in the gastric mucosa by a factor of 4.5, whereas D-NAME was without effect.6. These data show that CGRP is a potent dilator of mucosal and extramural resistance vessels in the rat stomach. Its dilator action involves both NO-dependent and NO-independent mechanisms.

Does systolic subepicardial perfusion come from retrograde subendocardial flow?

To examine the influence of cardiac contraction on systolic coronary flow and transmural blood flow distribution, we measured phasic blood flow velocity in distal extramural coronary arteries by Doppler velocimeter and regional myocardial blood flow by radiolabeled microspheres while the heart was beating and during prolonged diastoles in 12 dogs. A servo-controlled coronary perfusion circuit allowed mean coronary pressure to be selected and maintained during beating and diastolic conditions. In epicardial arteries just proximal to their entrance into the myocardium, blood flow was either negligible or reverse in direction during systole. When the heart was beating, subepicardial blood flow was 24.2 +/- 12.3% higher than during asystole (5.05 +/- 0.91 and 4.11 +/- 0.79 ml.min-1.g-1 for beating and prolonged diastoles, respectively; P less than 0.01). In the subendocardium, flow was 49.8 +/- 14.7% lower in the beating condition than during prolonged diastoles (4.23 +/- 1.46 and 8.26 +/- 1.71 ml.min-1.g-1 for beating and asystole, respectively; P less than 0.01). When heart rate was increased stepwise from 60 to 150 beats/min, subendocardial flow fell approximately linearly; flow to the superficial layer was relatively unaffected. In beating hearts, lowering mean left main coronary artery (LMCA) pressure from 80 to 50 mmHg resulted in more systolic reverse flow and a fall in inner-to-outer flow ratio from 0.82 +/- 0.18 to 0.66 +/- 0.34 (P less than 0.05). Because mean LMCA pressure was held constant when the heart was stopped, differences in regional blood flow between beating and diastolic conditions were primarily due to cardiac contraction. Because little or no blood entered the myocardium from the extramural arteries during systole, we conclude that the decrease in subendocardial flow and the increase in subepicardial flow were caused by retrograde pumping of blood from the deep layer to the superficial layer of the left ventricle. Systolic retrograde flow to the subepicardium may help explain this layer's relative protection from ischemia.

Cardiotoxicity of a new inotrope/vasodilator drug (SK&F 94120) in the dog.

The cardiotoxicity and haemodynamic changes induced by IV administration of high doses of SK&F 94120, a novel positive inotrope/vasodilator, were studied in the dog. Inotropism was observed at a dose of 0.375 mg/kg. Mean blood pressure was reduced in a dose-related manner, reaching a nadir of 43.7 mm Hg at 24 mg/kg. Heart rate was increased at doses of 1.5 mg/kg and above. ECG examination revealed a shortening of PR interval and an increase in T-wave amplitude. At doses of 15 mg/kg and above, occasional AV dissociation with accrochage were sometimes seen shortly after the start of the infusion. Ventricular extrasystoles were only seen at doses of 120 mg/kg and above. A dose-related increase in severity and incidence of haemorrhages, deposition of haemosiderin and fibroplasia were seen in the left ventricular endocardium and atrioventricular valves at doses of 15 mg/kg and above. Focal myocardial necrosis, predominantly of the left ventricular papillary muscle, and mild periarteritis of medium-sized extramural arteries, mostly in the right atrium, were seen at doses of 45 mg/kg and above. Intimal proliferation of intra- and extramural coronary vessels was observed. A necrotising peri/panarteritis of these arteries was noted at doses of 200 and 400 mg/kg. The cardiotoxicity observed was considered to be due to the exaggerated pharmacologic effects seen at these high dose levels.

Vascular changes in radiation bowel disease.

A series of 20 cases of radiation bowel disease (RBD) was studied qualitatively and the arterial changes were studied quantitatively. A control series of 45 cases was studied. In the control cases there were positive correlations between the medial thickness of all vessels studied and the diastolic blood pressure as well as the incidence of intimal fibrosis in both intramural and extramural arteries. The medial thickness in all the arteries in cases of RBD was significantly higher than in the controls. This was probably due to the large number of fibrin thrombi which increased the vascular resistance. The degree of intimal fibrosis of the intramural arteries and arterioles was significantly greater than in the controls. Similarly the incidence of intimal fibrosis in all arterioles and intramural arteries was greater than the control group. The degree of intimal fibrosis was related to the dose of radiation received. The effect of radiation was an on-going process since the percentage of arterioles with intimal fibrosis increased with the time after radiotherapy. Blood pressure and age played no part in these correlations in RBD. The most consistently observed qualitative changes in RBD were in the arteries, arterioles and to a lesser extent the veins. These showed fibrin thrombi, fibrinoid necrosis, subendothelial oedema and fibrin. Various stages of healing were seen in the vessels. We believe that the blood vessels are the main site of injury in RBD and that the endothelial cell is the initial target for radiation damage.

Isolated human cystic artery: responses to common agonist and antagonist drugs.

The extramural artery of the human gall bladder (cystic artery), a small artery (outside diameter 1.3 +/- 0.03 mm) with a thick muscular wall and little elastin within the tunica media, has catecholamine fluorescence localized to the adventitia-medial border. Isolated helical strips of the artery are responsive to norepinephrine (NE), 5-hydroxytryptamine (5HT) and vasopressin (VP) at low concentrations, but at the maximal frequency of transmural electrical stimulation used (16 Hz), the response is only 10--20% of the NE maximum response. Phentolamine (2.7 X 10(-6) M) antagonized responses to NE, 5HT and, to a lesser degree, electrical stimulation and these actions are similar to those reported in other mammalian tissue. In vitro use of reserpine (1.6 X 10(-5) M) and guanethidine (4 X 10(-5) M) also produced effects which were predictable from effects observed in other mammalian tissues; except reserpine diminished responsiveness to NE and 5HT and guanethidine enhanced responses to the early administered electrical stimulation.

Haemodynamic and coronary actions of ouabain during coronary infusion.

The investigations were carried out on 24 mongrel dogs which were anaesthetized with chloralose or sodium pentobarbital. Ouabain was added to the coronary blood (50, 100 and 200 ng/ml coronary blood or 0.7, 1.4 and 2.8 X 10(-7) M) over periods of 30 or 60 min by intracoronary infusion of the glycoside. Under chloralose anaesthesia, ouabain at concentrations of 100 and 200 ng/ml coronary blood augmented left ventricular dp/dt significantly. No significant changes were observed in coronary resting flow and flow per beat at the same time. Likewise, the maximum reactive hyperaemic blood flow remained constant, indicating the absence of any changes in the tone of the large extramural arteries. Under sodium pentobarbital anaesthesia small decreases in heart rate and increases in left ventricular dp/dt were seen only at the highest ouabain concentration (200 ng/ml). All flow parameters remained unchanged. These experiments provide evidence that concentrations of ouabain which 100- and 200-fold exceed therapeutic maintenance levels and 10- and 20-fold exceed the concentrations that produce constriction of helically cut pig and rabbit coronary arteries in vitro, do not diminish the coronary blood supply of the anaesthetized dog in vivo.

Intramural blood supply of porcine heart. A postmortem angiographic study.

AbstractThe intramural arteries, arterioles and capillaries of the hearts of 23 crossbred pigs, six months old, of Yorkshire and Swedish landrace were presented.The vascular pattern was basically the same in both the ventricular walls. Large branches of two types emerged from the extramural arteries and traversed the myocardial wall, terminating in the subendocardial zone. The largest vessels supplied the papillary muscles and trabeculae carneae. The terminals of these branches formed the subendocardial anastomotic network. No other anastomoses were observed in the ventricular walls. The capillaries had a course parallel to the muscle fibers and anastomosed freely. Most of the interventricular septum was supplied by branches from both the left and the right descending arteries. Only a minor part of the septum was supplied by the anterior and posterior septal arteries.The ventricular vascular pattern of the pig was found to be very similar to that of the human heart. It was concluded that the pig, in contrast to the dog, has ideal attributes for comparative cardiovascular research in man.

Serum lipids and their relation to blood glucose and cardiovascular measurements in a rural population of Jamaican adults

Total cholesterol and triglycerides were determined in fasting serum for a population sample of rural Jamaican adults aged 25–64 yr. Cholesterol values were generally lower than in populations in developed countries while triglyceride values were similar to those found in some studies in developed countries and much lower than those in other studies in the same countries. Correlation and covariance analysis showed that persons with above average lipids were heavier for their height, had larger infrascapular skinfold thickness and had higher levels of insulin in serum taken after a fast and 1 hr after an oral challenge of 100 g glucose. Evidence is given that persons responding positively to a standard effort pain questionnaire or having certain ECG changes suggestive of ischaemia cannot be discriminated from persons without these findings by cholesterol or triglycerides. This result is discussed in the light of findings in a longitudinal study of a sample of persons drawn from the same rural area and it is suggested that some of the changes indicative of cardiac ischaemia may have arisen from disease of vessels other than the major extramural arteries.

Amyloid coronary artery disease, primary systemic amyloidosis and paraproteinemia

A patient had primary systemic amyloidosis with severe cardiac involvement and IgG paraproteinemia. Numerous intramural coronary arteries were occluded by amyloid deposits, but arteriosclerosis of the extramural arteries was absent. The amyloid coronary artery disease was associated with angina pectoris, a myocardial infarct, and mural thrombi which resulted in cerebral, renal, pulmonic, and coronary arterial emboli.

Amyloid Coronary Artery Disease, Primary Systemic Amyloidosis and Paraproteinemia

A patient had primary systemic amyloidosis with severe cardiac involvement and IgG paraproteinemia. Numerous intramural coronary arteries were occluded by amyloid deposits, but arteriosclerosis of the extramural arteries was absent. The amyloid coronary artery disease was associated with angina pectoris, a myocardial infarct, and mural thrombi which resulted in cerebral, renal, pulmonic, and coronary arterial emboli.