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A S Izzard

Publications and source records attributed to A S Izzard.

17 recordsLinked to original sources
PubMed2005

Adenosine and hypoxic dilation of rat coronary small arteries: roles of the ATP-sensitive potassium channel, endothelium, and nitric oxide.

The aims of the study were to examine the roles of the ATP-sensitive potassium (K(ATP)) channel, the endothelium, and nitric oxide (NO) in the responses of rat coronary small arteries to adenosine and hypoxia. Segments of rat coronary vessel were investigated in vitro using pressure myography; all vessels studied developed stable spontaneous myogenic tone during equilibration. Glibenclamide (a K(ATP) channel inhibitor) reversed pinacidil but not 2-deoxyglucose-induced dilation. Both adenosine and hypoxia dilated the vessels, and glibenclamide did not reverse these responses. Endothelial removal or N(G)-nitro-L-arginine methyl ester (L-NAME) inhibited the dilation to adenosine by approximately 50%; subsequent addition of glibenclamide was without effect. Hypoxic dilation was completely inhibited by endothelium removal or L-NAME. We conclude that adenosine- and hypoxia-induced dilation of rat coronary arteries does not appear to involve the K(ATP) channel. Adenosine-induced dilation is partially and hypoxic dilation is completely dependent on endothelium-derived NO.

ATP-Binding Cassette Transporters↗
PubMed1999

Impaired flow-dependent dilatation in distal mesenteric arteries from the spontaneously hypertensive rat.

1. The aim of the study was to examine the hypothesis that flow-dependent dilatation is impaired in distal mesenteric arteries from adult spontaneously hypertensive rats (SHR) compared with normotensive Wistar-Kyoto rat (WKY) controls and to assess the role of nitric oxide (NO). 2. Arterial segments were cannulated, pressurized to 80 mmHg and allowed to develop spontaneous myogenic tone. Flow was increased incrementally in vessels from both strains and responses were also assessed before and after incubation with the NO synthase inhibitor Nomega-nitro-L-arginine methyl ester (L-NAME). Responses to flow in control vessels were also assessed before and after intraluminal perfusion with antibody-complement to disrupt the endothelium. 3. At a flow rate of 5 microliter min-1, arteries from the WKY dilated significantly (22 +/- 5%, P < 0.01, n = 29) compared with the diameter at zero flow, whereas arteries from the SHR did not (4 +/- 4%, n.s., n = 16). Incubation with L-NAME had no inhibitory effect on the responses to flow in either rat strain. In control arteries, antibody-complement treatment abolished the dilatation in response to both flow and acetylcholine (ACh, 1 microM). 4. We conclude that flow-dependent dilatation is impaired in distal mesenteric arteries from adult SHR compared with WKY controls. Furthermore, flow-dependent dilatation is endothelium dependent, but L-NAME insensitive, thus excluding the NO pathway in this abnormality. Impaired flow-dependent dilatation may contribute to the increased peripheral resistance in hypertension.

Animals↗
PubMed1996

Myogenic tone in mesenteric arteries from spontaneously hypertensive rats.

To investigate myogenic tone during the developmental and established phases of hypertension, segments of distal (6th order) mesenteric arteries from spontaneously hypertensive rats (SHR) at 5 and 20 wk were isolated and pressurized in vitro and compared with vessels from age-matched Wistar-Kyoto (WKY) control animals. At 5 wk, tone was significantly enhanced in the SHR. At 20 wk tone was no longer significantly increased over a wide pressure range, although arteries from the SHR were able to maintain diameter at all pressures studied, whereas vessels from the WKY exhibited forced distension at 180 and 200 mmHg. From the relative slope of the pressure-diameter relationship (myogenic index), no increase in peak myogenic responsiveness was observed in arteries from the SHR at either time point. Passive lumen diameters were significantly decreased in arteries from SHR at both time points. From the total and passive midwall circumference-tension relationships, total tension was observed at a reduced midwall circumference in the SHR, but increased absolute levels of total tension were not observed. The normalized midwall circumference-tension relationships in the two strains revealed increased total tension due to active tension development at a reduced normalized circumference at 5 wk in the SHR. At 20 wk the normalized midwall circumference-tension relationships in the two strains were identical. These results demonstrate that myogenic tone in mesenteric arteries is enhanced during the development of hypertension but not when it is established, except at high intraluminal pressures.

Aging↗
PubMed1996

Increased wall-lumen ratio of mesenteric vessels from the spontaneously hypertensive rat is not associated with increased contractility under isobaric conditions.

We investigated the morphological (wall-lumen ratio) and contractile characteristics of distal mesenteric arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) controls at a distending pressure of 63% of the mean aortic pressure of each rat using a pressure arteriograph. The wall-lumen ratios obtained were compared with those obtained at a pressure of 100 mm Hg. Experiments were carried out at 5 and 20 weeks. Mean aortic pressure of SHR was significantly increased at 5 weeks compared with that of WKY and was further increased by 20 weeks. At 63% of mean aortic pressure, no difference in the wall-lumen ratio of the arteries was observed between strains at 5 weeks; at 20 weeks, the wall-lumen ratio of SHR arteries was significantly increased compared that in WKY arteries. The wall-lumen ratio of SHR vessels did not differ at 63% mean aortic pressure compared with 100 mm Hg at either 5 or 20 weeks, whereas this parameter was significantly reduced in WKY vessels at 100 mm Hg compared with 63% mean aortic pressure at 5 and 20 weeks. In the presence of spontaneous myogenic tone, there was a borderline reduction in the lumen diameter of SHR vessels compared with WKY vessels and with increasing norepinephrine concentrations at 5 weeks. At 20 weeks, lumen diameter between strains did not differ in the presence of myogenic tone nor with increasing norepinephrine concentrations. Similar results were obtained when vessels from both rat strains were pressurized to 80 mm Hg. Thus, the increased wall-lumen ratio in the distal mesenteric arteries from adult SHR compared with those from WKY is not associated with an increased contractility under isobaric conditions when studied at physiological distending pressure.

Animals↗
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↗
PubMed1993

Histology of subcutaneous small arteries from patients with essential hypertension.

The purpose of the present study was to determine the cellular basis for the increased ratio of media thickness to lumen diameter (media-lumen ratio) consistently found in the peripheral resistance arteries from patients with essential hypertension using an unbiased stereological principle (the "disector"). Segments of subcutaneous resistance arteries (approximately 200 microns internal diameter) were isolated from gluteal biopsies of skin and subcutaneous fat taken from 16 untreated patients with essential hypertension and 16 age- and sex-matched normotensive control subjects. Measured under standardized conditions (ie, relaxed and under controlled mechanical conditions) on an isometric myograph, vessels from hypertensive patients had a significant (P < .05) reduction in lumen diameter and an increase in media-lumen ratio (P < .05) compared with vessels from normotensive control subjects. These changes were not associated with alterations in the estimated media volume per segment length. After these measurements had been made, the arteries were fixed, serial sectioned, and stained. The volume fraction of smooth muscle cells within the media was estimated by point counting on photomicrographs of the vessels. Using the disector principle, we determined the numerical density (number per unit volume) of smooth muscle cells within the media of each vessel and calculated the average smooth muscle cell volume (1775 +/- 122 [mean +/- SEM] and 1532 +/- 112 microns 3, hypertensive and normotensive, respectively, P > .05) on the basis of these measurements.(ABSTRACT TRUNCATED AT 250 WORDS)

Adipose Tissue↗
PubMed1991

Intracellular pH in rat resistance arteries during the development of experimental hypertension.

1. In order to examine the effects of experimental hypertension on intracellular pH in mesenteric resistance arteries, intracellular pH was measured in mesenteric resistance arteries from rats with coarctation 72 h, 9 days and 28 days after the aorta was partially constricted between the origins of the renal arteries. Carotid arterial pressure was significantly raised at all time points. 2. Second-order mesenteric resistance arteries were mounted in a myograph and were loaded with the acetoxymethyl ester of the pH-sensitive dye 2',7'-bis(carboxyethyl)-5,6-carboxyfluorescein. Morphological measurements demonstrated that arteries from rats with coarctation had an increased media volume at 9 days and at 28 days compared with vessels from sham-operated control animals, but this was only statistically significant at 28 days. 3. Resting intracellular pH was not significantly different at any time point in arteries from rats with coarctation compared with control animals, although there was a rise in intracellular pH in both groups of rats between 72 h and 9 days. The application of 4,4-di-isothiocyanatostilbene-2,2'-disulphonic acid produced a fall in intracellular pH which was significantly greater in the sham-operated rats at 9 days; this difference was not found at 28 days. Blockade of Na+/H+ exchange with 60 mumol/l ethylisopropylamiloride led to a similar fall in intracellular pH in both groups of rats at 9 days but a significantly greater fall in intracellular pH in arteries of rats with coarctation at 28 days. Activation with noradrenaline (10 mumol/l) induced acid changes in intracellular pH that were similar in both groups of rats.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Intracellular pH in human resistance arteries in essential hypertension.

To investigate intracellular pH (pHi) in human resistance arteries in essential hypertension, vessels were obtained from small biopsies of skin and subcutaneous fat from 14 untreated patients, and the results were compared with those from 14 matched normotensive control volunteers. Segments of isolated resistance arteries were mounted in a myograph and loaded with the pH-sensitive fluorescent dye 2',7'-bis(2-carboxyethyl)-5(6)-carboxyfluorescein. Fluorescence signals were monitored using a series of barrier filters and chromatic beam splitters. In this way both resting pHi and the changes in pHi observed during isometric contractions initiated by agonists could be recorded. Resting pHi was not different in vessels from hypertensive patients (hypertensive, 7.24 +/- 0.06 versus control, 7.25 +/- 0.04 pH units). The application of ethylisopropylamiloride (EIPA) and 4,4'-diisothiocyanatostilbene-2,2'-disulfonic acid (DIDS) demonstrated that both Na(+)-H+ exchange and bicarbonate-dependent membrane mechanisms contributed to pHi homeostasis but that neither system was overactive in hypertension (pHi change with EIPA in vessels from hypertensive versus control subjects was -0.11 +/- 0.02 and 0.13 +/- 0.03 pH units, respectively, and pHi change with DIDS in vessels from hypertensive versus control subjects was -0.097 +/- 0.05 and -0.091 +/- 0.03 pH units, respectively). The application of norepinephrine or 125 mM K+ solution induced contraction in the arterial segments with an accompanying fall in pHi. With norepinephrine this fall was significantly attenuated in vessels from hypertensive patients. These results fail to provide evidence for raised pHi in resistance arteries in human essential hypertension, and contrary to previous reports in circulating blood cells, Na(+)-H+ exchange is not overactive in the vessels of such patients.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1991

Long-term structural changes in human hypertensive vessels.

Indirect assessments of the haemodynamics of the circulation in human essential hypertension demonstrate that when the disease is established there is an increase in peripheral vascular resistance and a normal cardiac output. The resistance to blood flow is maintained by an adaptive alteration in the geometry of precapillary vessels which is brought about as a result of the pressure excess; the change is manifested as an increased wall-to-lumen ratio. How this is achieved is the subject of intense research at this time, but in addition, there is some controversy as to the exact nature of the cellular alterations to the vascular architecture at the level of the resistance artery. The purpose of this work is to address problems that have arisen in trying to solve this question, and to identify therapeutic implications for future management of hypertension, and for reducing the number of cardiac events.

Animals↗
PubMed1989

Resting intracellular pH in mesenteric resistance arteries from spontaneously hypertensive and Wistar-Kyoto rats: effects of amiloride and 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid.

In order to investigate the membrane-located mechanisms that control intracellular pH in resistance arteries, mesenteric vessels from spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) at 5 weeks of age were mounted in a myograph and loaded with 2',7'-bis(carboxyethyl)5,6-carboxyfluorescein (BCECF). Resting intracellular pH was studied over 10 min in the presence of amiloride (1 mmol/l), or 4,4'-diisothiocyanatostilbene-2,2'-disulphonic acid (DIDS; 0.2 mmol/l). In the presence of DIDS, there was no significant difference in the resulting fall in intracellular pH over 10 min between rat strains. However, in the presence of amiloride there was a significantly greater fall in intracellular pH in SHR (P less than 0.001). These data indicate that in the resting state Na(+)-H+ exchange is increased in SHR resistance arteries at the time when blood pressure is rising and vascular remodelling is taking place.

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed1989

The measurement of internal pH in resistance arterioles: evidence that intracellular pH is more alkaline in SHR than WKY animals.

In order to investigate whether resistance arterioles from spontaneously hypertensive rats (SHR) were more alkaline than those from Wistar-Kyoto rats (WKY), mesenteric arterioles were mounted in a myograph and loaded with the pH-sensitive dye 2',7'-bis (carboxyethyl)5,6-carboxyfluorescein (BCECF). At 5 weeks of age the arterioles from SHR were significantly more alkaline compared with WKY vessels, at a time when the blood pressure was rising and media:lumen ratio was increasing in the hypertension-prone animals. At 12 weeks this difference was not present due to a non-significant rise in intracellular pH in WKY arterioles. Activation of the vessels with high K+ depolarizing solution or noradrenaline induced an acid change in pH but no subsequent alkalinization was apparent. These results suggest that resistance arterioles from SHR are more alkaline than WKY vessels when the blood pressure is rising and their structural architecture is being modified, and the alkaline cytoplasmic pH may be contributing to the generation of the structural excess seen in these vessels in established hypertension.

Animals↗
PubMedDate not supplied

Effect of experimental hypertension on phosphoinositide hydrolysis and proto-oncogene expression in cardiovascular tissues.

Products of inositol lipid hydrolysis and levels of c-myc, c-fos and H-ras mRNAs were measured in rat left ventricle and vascular tissues 72 h and 9 days after the induction of aortic coarctation in order to examine inositol phosphate and proto-oncogene signals during the development of pressure-related cardiac and vascular structural changes. There was a significant increase in left ventricular and proximal aortic mass at both time points but no change in mesenteric resistance artery morphology in rats with coarctation. At 72 h there was a significant increase in c-myc, c-fos and H-ras mRNAs in the left ventricle of rats with coarctation, and this was accompanied by increased levels of inositol (1,4,5)-trisphosphate. Similar results were obtained in the proximal but not the distal aorta. In resistance arteries inositol phosphate production and proto-oncogene mRNA expression were unchanged. The results indicate that at 72 h aortic coarctation induced structural thickening in the left ventricle and proximal aorta and was associated with increased inositol phosphate production and stimulation of specific proto-oncogene mRNAs. By 9 days following surgery much of the structural change in these tissues was completed, and these raised cellular signals were no longer observed. The results suggest that both increased inositol lipid hydrolysis and a rise in the expression of these proto-oncogenes are important processes in the development of vascular hypertrophy seen in this model of hypertension.

Animals↗
PubMedDate not supplied

Myogenic tone in coronary arteries from spontaneously hypertensive rats.

The aims of this study were to investigate myogenic tone in cannulated coronary arteries from SHR (spontaneously hypertensive rats) and WKY (Wistar-Kyoto rats) at 5 and 20 weeks of age under pressurised no-flow conditions. Pressure-diameter relationships (20-200 mm Hg) were determined in the presence (active) and absence (passive) of calcium and myogenic tone at each pressure was calculated. Active, but not passive diameter-pressure relationships were significantly different between strains at both ages. Active diameters were similar between strains at pressures up to 140 mm Hg at 5 and 20 weeks. At higher pressures SHR arteries generated more tone. Maximum myogenic tone was similar between strains in spite of increased wall thickness in the SHR at both ages. Endothelium denudation increased myogenic tone to a greater extent in the SHR at both ages. Active diameters of endothelium-denuded SHR arteries were smaller than those of WKY in the range 20-120 mm Hg at 5 week and 20-80 and 160-180 mm Hg at 20 weeks. These results demonstrate that during both the developmental and established phases of hypertension, myogenic tone is not enhanced in intact SHR coronary arteries, except at the highest pressures. Following endothelium removal SHR arteries generated greater myogenic tone also at lower pressures. These data demonstrate a greater endothelium-mediated antagonism of myogenic tone in SHR coronary arteries.

Age Factors↗