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A M Heagerty

Publications and source records attributed to A M Heagerty.

At least 55 records · Page 3Linked to original sources
PubMed1995

In vitro responses of human peripheral small arteries in hypercholesterolemia and effects of therapy.

BACKGROUND: Studies in both animals and humans with raised lipid levels have demonstrated abnormalities in vascular function usually manifested by an impairment in endothelium-dependent vasorelaxation. This is believed to be an early event in atheroma formation. There are few data on the effects on vascular function in humans of lowering serum lipids. We conducted a study to investigate the effects of cholesterol reduction on the in vitro function of human peripheral small arteries in middle-aged patients with hypercholesterolemia. METHODS AND RESULTS: Subcutaneous gluteal fat biopsies were taken from 18 hypercholesterolemic (HC) patients (mean +/- SEM serum total cholesterol, 9.7 +/- 0.57 mmol/L) and 16 age- and sex-matched control subjects (mean cholesterol, 4.69 +/- 0.18 mmol/L). Subcutaneous small arteries (internal diameter, < 330 microns) were dissected and mounted on a wire myograph for isometric tension measurements. The HC patients showed impaired relaxation to acetylcholine (10(-9) to 10(-6) mol/L) after preconstriction with the thromboxane A2 analogue U46619 (10(-6) mol/L, mean maximum relaxation, 42.9 +/- 5.4%) compared with control subjects (85.7 +/- 4.0%, P < .00001). Incubation with the nitric oxide substrate L-arginine (3 mmol/L) improved the endothelium-dependent vasorelaxation response to acetylcholine (70.9 +/- 6.0%, P < .01) in patients but not in control subjects. Also, there was a smaller but significant difference in responses to the endothelium-independent agent sodium nitroprusside (10(-9) to 10(-6) mol/L) between the HC group (mean maximum relaxation, 76.9 +/- 6.0%) and the control subjects (89.7 +/- 6%; P < .01). A total of 10 patients had a second gluteal skin biopsy and repeat functional studies after successful cholesterol-lowering therapy after a mean period of 9.9 +/- 4.7 months. A significant reduction in total and LDL cholesterol was achieved (5.29 +/- 0.2 and 3.23 +/- 0.21 mmol/L, respectively; P < .001). This restored vasorelaxation to control values in response to both acetylcholine (mean maximum relaxation, 83.3 +/- 3.8%; P < .0001) and sodium nitroprusside (87.9 +/- 4.8%, P < .01). Although both groups were normotensive, there were significantly higher blood pressures in the HC group compared with control subjects (139 +/- 4.1 versus 123 +/- 3.0 mm Hg systolic, P < .01; 84 +/- 1.3 versus 75 +/- 2.2 mm Hg diastolic, P < .01). There was no difference in initial blood pressures between the entire group of 18 and the 10 patients who had repeat biopsies. The blood pressures fell to control values after cholesterol reduction (129.33 +/- 4.93 mm Hg systolic and 72.33 +/- 2.93 diastolic mm Hg, P < .02 relative to pretreatment values). CONCLUSIONS: These results demonstrate abnormalities of both endothelium-dependent and -independent relaxation in human peripheral small arteries that are normalized with effective lipid lowering. The changes in blood pressure may have been secondary to the improvement in vascular function.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

Phospholipase D-induced phosphatidate production in intact small arteries during noradrenaline stimulation: involvement of both G-protein and tyrosine-phosphorylation-linked pathways.

To investigate membrane lipid metabolism during smooth-muscle activation, the role of phospholipase D (PLD) in the production of phosphatidate (PA) was studied in rat small arteries stimulated with noradrenaline. Incubation with [3H]myristate preferentially labelled phosphatidylcholine (PtdCho), and in the presence of 0.5% ethanol [3H]phosphatidylethanol ([3H]PEt) was formed, demonstrating PLD activity. Noradrenaline (NA) stimulation resulted in an increase in PtdCho derived [3H]PA and [3H]PEt formation, indicating PLD activation. Stimulation of [14C]choline release confirmed PLD-mediated hydrolysis of PtdCho. Propranolol, an inhibitor of PA phosphohydrolase, increased [3H]PA levels in non-stimulated tissue and decreased the rate of degradation of both [3H]PA and [3H]PEt, implying that this is an active route for PA metabolism in small arteries. However, [3H]diacylglycerol levels were not increased during NA stimulation. Fluoroaluminate increased [3H]PEt formation and [14C]choline release, whereas high K+ in the presence of alpha 1-adrenoceptor blockade did not. Pervanadate increased phosphotyrosine levels in small arteries, and markedly stimulated [3H]PEt formation and [14C]choline release. The combination of pervanadate and NA stimulation resulted in a dramatic increase in [3H]PEt formation, which was greater than the sum of the individual responses to the two agonists. Pervanadate and fluoroaluminate in combination appeared to give an additive response, whereas high K+ did not alter the pervanadate-induced formation of [3H]PEt. Phosphotyrosine levels were increased by NA in the presence of tyrosine phosphatase inhibitors. This effect was blocked by genistein, a tyrosine kinase inhibitor. These data demonstrate that in NA-stimulated small arteries PLD-induced PtdCho hydrolysis contributes to accumulation of PA, but not of diacylglycerol. Furthermore, regulation of PLD activity appears to require G-protein and tyrosine-phosphorylation-linked pathways.

Animals↗
PubMed1995

Effect of one-kidney, one clip hypertension on the structure and function of porcine intramyocardial small arteries.

OBJECTIVE: To determine the influence of experimental hypertension on the structure and function of porcine coronary small arteries. METHODS: Miniature pigs underwent partial left renal artery constriction and contralateral nephrectomy. Blood pressures were recorded, using indwelling carotid artery catheters. After 4 weeks the pigs were killed, the heart was removed and subepicardial third-order branches of the left anterior descending artery were dissected and mounted in a myograph for morphological and functional assessment. RESULTS: Final mean +/- SEM systolic and diastolic blood pressures were, respectively, 197 +/- 9 and 142 +/- 7 mmHg (n = 21) for the hypertensive pigs and 125 +/- 4 and 80 +/- 4 mmHg (n = 11) for the sham-operated control pigs. Hypertension was associated with significant left ventricular hypertrophy. The media thickness: lumen diameter ratio was increased significantly in hypertensive intramyocardial small arteries, caused mainly by remodelling (remodelling index 92%) rather than by medial growth. Maximal contractile responses to potassium and acetycholine were significantly depressed in the arteries from hypertensive pigs, whereas endothelium-dependent relaxation responses to bradykinin, substance P and serotonin were not significantly influenced by hypertension. CONCLUSIONS: These results demonstrate that even short-term hypertension induces both structural and functional changes in left ventricular intramyocardial small arteries.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1995

A comparison of the effect of angiotensin converting enzyme inhibition and angiotensin II receptor antagonism on the structural changes associated with hypertension in rat small arteries.

OBJECTIVE: To investigate whether, when angiotensin converting enzyme inhibitors are administered to young, genetically hypertension-prone animals, the demonstrated attenuation of blood pressure development and prevention of the structural changes usually observed in small arteries is attributable to the prevention of angiotensin II production. DESIGN: We have treated spontaneously hypertensive rats (SHR) aged 4-20 weeks with either lisinopril (1 or 10 mg/kg) or the angiotensin II receptor antagonist D 8731 (1, 20 or 50 mg/kg). METHODS: Blood pressure was measured and structural parameters in small arteries from four vascular beds were examined using isometric myography. RESULTS: At age 20 weeks lisinopril had attenuated blood pressure development and prevented cardiac hypertrophy (but not vascular hypertrophy) in a dose-dependent manner. The highest dose of lisinopril had reduced the blood pressure of the SHR to below that of the Wistar-Kyoto (WKY) rats and prevented most structural changes, but there was a slight reduction in body weight in those rats. Comparable blood pressure control with D 8731 was associated with similar structural parameters. CONCLUSION: The prevention of hypertension-associated vascular structural alteration appears to be dependent upon the degree of blood pressure control.

Angiotensin Receptor Antagonists↗
PubMed1995

Comparison of small artery sensitivity and morphology in pressurized and wire-mounted preparations.

Two in vitro techniques, the pressurized flow chamber and the wire myograph, commonly employed to study the structure and function of small arteries, were compared. Mesenteric arteries from Wistar-Kyoto (WKY) rats were studied at a transmural pressure (44 +/- 1 mmHg) at which they elicit optimum contraction in each system. Differences in morphological parameters were minor, but there was a marked difference in the vasoconstrictor response of arteries mounted in the wire myograph and pressure system. Endothelium-intact pressurized arteries were significantly more sensitive to norepinephrine and constricted to angiotensin II, whereas wire-mounted vessels did not. These differences in agonist-induced contraction remained after removal of the endothelium. Blockade of amine uptake mechanisms indicated that the difference in norepinephrine sensitivity between the systems resulted from an enhanced influence of neuronal amine uptake in wire-mounted arteries. These data demonstrate that the technique employed has important functional implications for the study of small artery responses in vitro and that the results of investigations into the pathophysiology of small arteries are dependent on the method used and must be interpreted with caution.

Acetylcholine↗
PubMed1995

Effect of antihypertensive treatment on small arteries of patients with previously untreated essential hypertension.

In a double-blind randomized trial, the effects of treatment with an angiotensin-converting enzyme (ACE) inhibitor (perindopril) and a beta-blocker (atenolol) on small artery structure were compared in previously untreated essential hypertensive patients. Subjects (diastolic blood pressure > or = 100 and < or = 120 mm Hg) were randomly assigned to treatment for 12 months with either perindopril (n = 13, 4 to 8 mg/d) or atenolol (n = 12, 50 to 100 mg/d); the dosage was adjusted upward and in some cases combined (n = 5, perindopril; n = 2, atenolol) with thiazide diuretic to achieve target blood pressure (diastolic blood pressure below 90 mm Hg). Before and at the end of treatment, gluteal biopsies were taken under local anesthetic; from these biopsies, two small arteries were dissected and mounted on a myograph for morphometry. The reduction in blood pressure with atenolol (drop in mean blood pressure 28.4 +/- 1.8 mm Hg) was greater than with perindopril (20.6 +/- 1.8 mm Hg, P < .05). Perindopril treatment caused an increase in small artery diameter (231 +/- 14 to 274 +/- 13 microns, P < .05) and a reduction in the ratio of media thickness to lumen diameter (7.94 +/- 0.65% to 5.96 +/- 0.42%, P < .05), whereas atenolol had no effect (246 +/- 14 to 231 +/- 13 microns and 7.14 +/- 0.47% to 6.79 +/- 0.45%, respectively). The change in small artery morphology caused by perindopril was not accompanied by any change in media cross-sectional area, suggesting that the change was due to "remodeling."(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1995

Hypertension and the vasculature: arterioles and the myogenic response.

OBJECTIVE: This editorial was invited by the Journal of Hypertension as one of a series designed to examine our current knowledge of several aspects of the pathophysiology of hypertension. This article considers small arteries and arterioles. SETTING: The conclusion that established hypertension is characterized by a normal cardiac output and a raised peripheral resistance represents the integration of findings from haemodynamic studies using a variety of models of the disease examined by several different techniques. In some ways it assumes that all vascular beds conform to the same pattern of responsiveness. However, given the obvious heterogeneity of functions performed by specialized tissues, the recognized variations in receptor populations and the differences in innervation found in the vascular wall throughout the circulation, this might not be the case. Resistance to blood flow occurs throughout the vascular tree, but the majority is found at the level of arterioles. Upstream small arteries demonstrate growth and remodelling changes which result in luminal narrowing, but the exact contribution of such vessels to resistance is still not known. Perhaps the most interesting recent finding in this context is that blood pressure can fall immediately after a pressor stimulus has been removed, despite the demonstration of such structural changes in small arteries. Furthermore, some whole-animal studies have been reported which fail to show the expected vascular amplification when the circulation is stressed in total. CONCLUSION: Viewing the vascular tree as an integrated circuit with specialized functions when nourishing specific tissues suggests that when the resistance in one vascular bed increases because of a constrictor challenge, this might not be representative of the circulation as a whole: indeed, resistance may fall elsewhere. It is probable that structural changes in small arteries represent the consequence of hypertension. The pathogenesis of hypertension may reside downstream in arterioles, where a myogenic response might play a fundamental role.

Animals↗
PubMed1995

Small-artery changes in hypertension.

OBJECTIVE: To summarize the arguments challenging the pathological significance of the structural changes observed in small arteries in hypertension in maintaining peripheral vascular resistance or in serving as amplifiers in the development of the disease. SETTING: While the existence of a change in vascular wall architecture in small arteries exposed to prolonged hypertension is not in dispute, a number of issues remain contentious. These focus first on the nature of the change in morphology observed, second on whether the small arteries (150-300 mu m) make a significant contribution to peripheral resistance, third on whether such changes are a cause of raised blood pressure or merely a consequence, and finally on whether they can serve as amplifiers of a pressor stimulus. CONCLUSIONS: A careful review of the literature suggests that the techniques used to investigate these issues can give discrepant results, and that given the heterogeneity of functions performed by specialized tissues, the variations recognized in receptor populations and the differences in innervation found in the arterial wall, to extrapolate findings from one vascular bed to all of them might be inappropriate. The evidence suggests that in small arteries the structural changes observed are adaptive, and that enhanced reactivity may not be seen in whole-animal studies. In the absence of a primary effect at this level of the circulation, a pathogenetic mechanism for hypertension must be sought elsewhere. We suggest that this may reside in the haemodynamically important arterioles where derangement of the myogenic response may have a crucial effect.

Animals↗
PubMed1994

Membrane-associated diacylglycerol kinase activity is increased by noradrenaline, but not by angiotensin II, in arterial smooth muscle.

In rat small arteries, noradrenaline stimulates the sustained production of arachidonoyl-phosphatidic acid, whereas there is only a slight and transient increase with angiotensin II [Ohanian, Ollerenshaw, Collins and Heagerty (1990) J. Biol. Chem. 265, 8921-8928]. Diacylglycerol kinase (DGK) is the enzyme responsible for generating phosphatidic acid from 1,2-diacylglycerol (DAG). To investigate whether agonists influence DGK activity, we have studied this enzyme in both particulate and soluble fractions prepared from rat small arteries. Soluble DGK activity was inhibited by octyl glucoside. Therefore a deoxycholate assay was used for this fraction, whereas an octyl glucoside mixed-micelle assay was used to examine particulate fractions. Particulate DGK selectively phosphorylated long-chain DAG at a rate 2.5-3-fold higher than that for the synthetic substrate dioctanoylglycerol. In contrast, the substrate preference of the soluble isoenzyme(s) was: dioctanoylglycerol > arachidonoyl-DAG= dioleoylglycerol. Stimulation of intact arteries with noradrenaline (15 microM) increased membrane-associated DGK activity 3-fold, transiently. Angiotensin II (100 nM) stimulation did not alter the DGK activity of this fraction. The activity of the soluble DGK was increased by both agonists, but only transiently. These results demonstrate that rat small arteries contain a membrane-associated DGK which metabolizes arachidonoyl-containing substrate. Also, the activity of this enzyme is regulated differentially by vasoconstrictor hormones. It is concluded that modulation of DGK activity may represent one point at which agonists using the same signal-transduction pathway may tailor the cellular response.

Angiotensin II↗
PubMed1994

Winning rhythm?

Explore the source record for details and available documents.

Animals↗
PubMed1994

Influence of arterial diameter on vasomotor responses in the porcine coronary vasculature.

OBJECTIVE: The aim was to determine whether regional differences in arterial responses to vasoconstrictor and vasorelaxant agonists exist within the minipig coronary vasculature. METHODS: Hearts were obtained from miniature pigs (20-40 kg) immediately after death. First and third order arterial branches of the left anterior descending artery were dissected from within the subepicardium and mounted as ring preparations in a small vessel myograph for measurement of isometric tension under standardised conditions. Contractile responses to acetylcholine, noradrenaline, and U46619, and the relaxation responses to noradrenaline, bradykinin, and substance P were measured. Arterial tone was increased with KCl or acetylcholine prior to addition of vasodilator agonists. RESULTS: First order branches were more sensitive to the constrictor influence of acetylcholine than third order branches [pD2 values 6.42(SEM 0.07), n = 13, and 6.26(0.07), n = 13, for first and third order respectively, p < 0.05]. U46619 did not induce contractile responses in arteries less than 210 microns in diameter. Noradrenaline only induced small contractile responses in the presence of propranolol following removal of the endothelium. In arteries preconstricted with 40 mM KCl, noradrenaline induced relaxation which was inhibited by propranolol and was uninfluenced by arterial calibre. In the presence of propranolol, noradrenaline-mediated relaxations of acetylcholine-preconstricted arteries were endothelium dependent and alpha 2 adrenoceptor mediated, and greater in first order than in third order branches [58(5)%, n = 9, and 26(8)%, n = 9, for first and third order branches respectively, p < 0.05]. Relaxations mediated by bradykinin and substance P were not influenced significantly by arterial calibre but were greater in arteries preconstricted with acetylcholine than with KCl. CONCLUSIONS: In isolated minipig coronary arteries the vasoconstrictor responses to acetylcholine and U46619, and the endothelium dependent, noradrenaline mediated relaxations, differ according to the branching order studied. These data provide further evidence for a regional heterogeneity of vascular responses in the porcine coronary vasculature.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1994

Effect of dietary polyunsaturated fatty acids on contraction and relaxation of rat femoral resistance arteries.

We investigated the effects of dietary polyunsaturated fatty acids (PUFA) derived from fish oil (n-3 PUFA) and plant seed oil (n-6 PUFA), in amounts relevant to human consumption, on the alpha 1-adrenoceptor-mediated contractile responses of isolated rat resistance arteries. Rats were fed semisynthetic diets, deriving 40% of total calories from fat. The control diet, which had sufficient linoleic acid to prevent essential fatty acid deficiency, had a polyunsaturated/saturated fatty acid (P/S) ratio of 0.3. The n-3 PUFA were given as a daily oral supplement of fish oil. For the n-6 PUFA diet, the proportion of linoleic acid in the diet was increased to obtain P/S ratio of 2.0. Diets were administered for 8 weeks. At the end of the feeding period, second-order branches of the femoral artery (< 300-micros diameter) were mounted in pairs in an isometric myograph, and responses to norepinephrine (NE) 3 nM-10 microM with addition of yohimbine 1 microM and timolol 1 microM were examined. Subsequently, the vessels were preconstricted with NE to 60% of their maximal response and relaxation to acetylcholine 1 nM-0.1 mM was observed. Dietary n-3 PUFA supplements led to attenuation of the contractile responses of isolated resistance arteries (p < 0.01, repeated-measures analysis of variance, ANOVA-RM) versus control. The n-6 PUFA diet did not exert this effect although there was a downward trend. Diet did not affect EC50 values for NE. Neither n-3 nor n-6 PUFA diet influenced relaxation responses. The fatty acid composition of myocardial phospholipid fractions was significantly altered by both diets.(ABSTRACT TRUNCATED AT 250 WORDS)

Acetylcholine↗
PubMed1994

In vitro perfusion studies of human resistance artery function in essential hypertension.

To simulate in vivo conditions as closely as possible to in vitro conditions, we examined the morphological and functional characteristics of isolated human subcutaneous small arteries from 17 essential hypertensive patients and 14 normotensive control subjects using a perfusion myograph. Vessel segments were cannulated and exposed to conditions of constant flow and pressure. The ratio of media thickness to lumen diameter in arteries from hypertensive patients increased significantly. With the endothelium intact, sensitivity to extraluminally applied norepinephrine was not different, and this was not affected by inhibition of neuronal amine uptake with cocaine. After removal of the endothelium, sensitivity to norepinephrine was augmented in normotensive vessels to a greater extent than in hypertensive vessels. Endothelium-dependent relaxation to acetylcholine was significantly reduced in arteries from hypertensive patients, but endothelium-independent relaxation to sodium nitroprusside was not different from that observed in vessels from normotensive control subjects. These data demonstrate that sensitivity to exogenous norepinephrine is not different in essential hypertension but that there is defective endothelium-dependent dilatation, suggesting a contributory role for endothelium dysfunction in human essential hypertension.

Arteries↗
PubMed1993

Regulation of beta myosin heavy chain, c-myc and c-fos proto-oncogenes in thyroid hormone-induced hypertrophy of the rat myocardium.

1. In order to investigate the molecular mechanisms determining the hypertrophic response of the ventricular myocardium to thyroid hormone administration, changes in left and right ventricular expression of the c-myc, c-fos and H-ras proto-oncogenes in response to treatment with 3,3',5-tri-iodothyronine were defined. 2. Adult female Wistar rats were treated with daily subcutaneous injections of 3,3',5-tri-iodothyronine (50 micrograms) for 1, 3, 7 or 14 days (n = 6 in each treatment group) and the results from 3,3',5-tri-iodothyronine-treated animals were compared with those obtained from untreated controls (n = 6). Changes in the weight of the left and right ventricles in response to 3,3',5-tri-iodothyronine treatment were measured; changes in expression of the c-myc, c-fos and H-ras proto-oncogenes were determined in parallel by measurement of specific messenger RNAs by Northern and dot hybridization, as well as changes in expression of beta myosin heavy chain messenger RNA. 3. Treatment with 3,3',5-tri-iodothyronine resulted in increases in both left and right ventricular weights after 3 days, an effect maintained up to 14 days. Despite an increase in left ventricular weight, levels of beta myosin heavy chain, c-myc, c-fos and H-ras mRNAs in the left ventricle were unchanged; in contrast, an increase in right ventricular weight was associated with increased expression of beta myosin heavy chain, c-myc and c-fos messenger RNAs.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

In vitro perfusion studies of resistance artery function in genetic hypertension.

To examine the function of resistance-sized arteries in hypertension under in vitro conditions that approximate in vivo conditions as much as possible, we mounted segments of second-order mesenteric resistance arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive control rats aged 12 to 13 weeks in a perfusion myograph and exposed them to conditions of constant flow and pressure. The endothelial integrity was validated both functionally and histologically. Vascular sensitivity to norepinephrine was examined when the hormone was applied either intraluminally or extraluminally and before and after removal of the endothelium. Both endothelium-dependent and -independent dilatation was assessed by the intraluminal application of acetylcholine and sodium nitroprusside, respectively. Sodium nitroprusside was applied to arteries after endothelium removal. Arterial responses were measured by changes in intraluminal diameter recorded with a video camera and imaging system. Vessels from SHR demonstrated depressed endothelium-dependent relaxation but similar endothelium-independent relaxation and greater sensitivity to norepinephrine with both intraluminal and extraluminal application. Removal of the endothelium abolished the differences in sensitivity to norepinephrine between the two strains. The results demonstrate that resistance arteries from SHR when examined under in vitro perfusion display enhanced sensitivity to norepinephrine due to depressed endothelium-dependent dilatation, and the data suggest that functional modifications in the endothelium may play an important role in hypertensive vascular disease.

Acetylcholine↗