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Biomedical subjects

A M Heagerty

Publications and source records attributed to A M Heagerty.

At least 73 records · Page 4Linked to original sources
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↗
PubMed1993

Cardioreparation and the concept of modulating cardiovascular structure and function.

Hypertension and atherosclerotic cardiovascular disease represent major global health problems. Practising physicians are challenged daily by patients suffering adverse cardiovascular events, such as myocardial infarction, stroke, heart failure and sudden cardiac death. Major risk factors have been identified of which the most important is left ventricular hypertrophy. In recent years, growth factors, regulatory peptides and effector hormones of the renin-angiotensin-aldosterone system have been identified as important modulators of cell growth and behaviour. It therefore follows that a major emphasis has been placed on the importance of abnormalities in organ structure as the primary basis for impaired function of the heart and vasculature, including large and medium sized arteries and resistance vessels, or arterioles. The concept of reparation recognizes the importance of abnormalities in tissue structure to the functional basis of disease. It suggests that the structurally remodelled heart and vasculature can be restored to, or toward, normal structure and function by suitable therapy. Experimental and clinical trials which address this premise are reviewed herein.

Animals↗
PubMed1992

The phosphoinositide signaling system and hypertension.

The phosphoinositide signaling system is common to many vasoconstrictor agents and as such is influential in the regulation of blood pressure. Recently, there have been major advances in our understanding of these lipids and their metabolism. Characterization of the phospholipase C isozymes and protein kinase C isozymes involved in transmembrane signaling has progressed rapidly. The role of diacylglycerol kinase as a regulator of protein kinase C activity has been established, and phosphatidic acid has been recognized as a cellular messenger. Studies in the spontaneously hypertensive rat have shown abnormalities of phospholipase C that could result in enhanced activity and explain changes in sensitivity reported in rats with this disease. During agonist activation of inositol lipid hydrolysis, levels of inositol 1,4,5-trisphosphate and 1,2-diacylglycerol are elevated in spontaneously hypertensive rats compared with Wistar-Kyoto control rats. These changes are observed early, prior to blood pressure stabilization, and may be downregulated once hypertension is established. In addition, there is evidence for reduced diacylglycerol kinase activity and enhanced protein kinase C activity in the spontaneously hypertensive rat. These data provide evidence for hyperresponsiveness of the phosphoinositide signaling system in the developmental stages of hypertension. However, confirmatory experiments in nongenetic animal models of hypertension and in human tissues are needed to establish that this is not just a phenotypic phenomenon of the spontaneously hypertensive rat.

Animals↗
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

Primate vascular responses to octimibate, a non-prostanoid agonist at the prostacyclin receptor.

1. Octimibate is a potent inhibitor of human platelet aggregation, and appears to act (at least in part) through the prostacyclin receptor, as described in the preceding paper. Here, the vascular effects, both in vitro and in vivo, of octimibate have been compared to those of the stable prostacyclin (PGI2) mimetic, iloprost. Since octimibate shows extensive species variation and is potent at inhibiting platelet aggregation in primates, all of the experiments reported here have been carried out with primate tissue or in vivo in cynomolgus monkeys. 2. Activation of adenylyl cyclase in human lung membranes appears to involve stimulation of the vascular PGI2 receptor. Octimibate, as well as iloprost, stimulates adenylyl cyclase in this preparation. The EC50 values for iloprost and octimibate are 50 nM and 340 nM respectively. These values are similar to those seen with human platelet membranes. As with platelets, the maximal activation achievable with octimibate is 60% of that seen with iloprost. This result suggests that octimibate is a partial agonist for stimulation of adenylyl cyclase. 3. Iloprost (10-100 nM) relaxes human coronary and mesenteric artery precontracted with KCl, and also relaxes cynomolgus monkey aorta precontracted with phenylephrine. Octimibate appears to be a partial agonist for relaxation of human coronary artery precontracted with KCl; the intrinsic activity of octimibate (10 microM) is 0.15 compared to iloprost, and octimibate surmountably antagonizes the relaxant effects of iloprost with a Kp of 200 nM. Octimibate (up to 10 microM) evokes only weak relaxation of human mesenteric artery (precontracted with KCl) and cynomolgus monkey aorta (precontracted with phenylephrine). 4. The effects of iloprost and octimibate were compared in vivo in cynomolgus monkeys. In addition to inhibiting ex vivo platelet aggregation, both compounds cause hypotension with little effect on heart rate. The dose-response curves for inhibition of ex vivo platelet aggregation and a fall in mean arterial blood pressure were compared. The dose-separation (i.e., the relative differences in effective concentrations) for the two responses is similar with both iloprost and octimibate. 5. Since the pern; beral resistance vessels are intimately involved in regulation of systemic arterial blood pressure, the effects of both agents were tested on human peripheral resistance vessels (150-400pm diameter) in vitro. These vessels are relaxed by both iloprost and octimibate following precontraction with KCI. The IC50 value for iloprost is 44nM, and 1.7 microM octimibate evokes 50% of the maximal relaxation obtained with iloprost. Thus, the relative potencies of the two compounds in relaxing human subcutaneous resistance vessels are similar to their relative potencies in inhibiting platelet responses. This result correlates with the lack of platelet versus vascular selectivity seen with the in vivo monkey studies. 6. These results suggest that octimibate, a partial agonist at the prostacyclin receptor, is unable to discriminate between platelet and vascular prostacyclin receptors in primates.

15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5↗
PubMed1991

Functional and structural effects of ACE inhibitors on the cardiovascular system.

There is considerable interest in the ability of angiotensin-converting enzyme (ACE) inhibitors not only to lower blood pressure, but also to reverse hypertension-induced remodelling of the circulation. Recently published data would suggest that treatment of spontaneously hypertensive rats from an early age with ACE inhibitors will prevent the development of the expected changes in the resistance vessels as the animals age and that withdrawal of treatment is followed by a lag period before the blood pressure rises. Such findings appear to be contrary to those obtained with other hypertensive drugs where morphological changes are not as effectively attenuated and blood pressure rises rapidly after withdrawal of treatment. There is some evidence for a relationship between the efficacy of ACE inhibitors in this area and lipid solubility. This raises the possibility that the mechanism at work is related to the inhibition of tissue-located renin-angiotensin systems both in vascular smooth muscle and elsewhere, possibly in the central nervous system. An overall review of the literature indicates that treatment of spontaneously hypertensive rats with ACE inhibitors can result in prolonged reduction of blood pressure, even after treatment is withdrawn. Comparisons with other treatments suggest that it is easier to reduce blood pressure than to reverse vascular structure. However, achieving a reversal in morphological changes in resistance vessels as well as controlling blood pressure may be important for reducing the mortality from ischaemic heart disease. ACE inhibitors may have a direct effect on reversal of vascular structure, but other sites of action may also be important in this aspect of their action.

Angiotensin-Converting Enzyme Inhibitors↗
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

Arterial neuroeffector responses in early and mature spontaneously hypertensive rats.

Intramural sympathetic neuroeffector responses and presynaptic regulation of neurotransmission by amine uptake and alpha 2-adrenergic receptors were examined in young (5-week-old) and mature (12-week-old) spontaneously hypertensive rats (SHR) and were compared with those of age-matched Wistar-Kyoto (WKY) control rats. Electrical field stimulation (20 V, 0.2-msec pulse width, 3-second pulse train each minute, 5-100 Hz) elicited contractile responses from isolated mesenteric arteries mounted in a myograph. There was a significant difference between the sensitivity of arteries to electrical field stimulation in the two age groups, with arteries from 12-week-old rats being more sensitive than arteries from 5-week-old animals. Also, there was a significant age-strain interaction: the sensitivity of arteries from SHR to electrical field stimulation increased dramatically with age compared with that of WKY rat arteries. Cocaine significantly increased the sensitivity to electrical field stimulation after inhibition of presynaptic alpha 2-adrenergic receptors, and had a significantly greater effect in arteries from 5-week-old SHR compared with WKY controls. This would reflect an overactive neuronal amine uptake mechanism in young SHR. At 12 weeks there was no significant interstrain difference in the effect of cocaine. Yohimbine increased the sensitivity to electrical field stimulation both before and after inhibition of neuronal amine uptake, but there was no difference in its effect with age or strain. Therefore, although sensitivity to sympathetic nerve stimulation varies with age in the SHR, there is no evidence that this can be ascribed to alpha 2-adrenergic receptor function.

Animals↗
PubMed1991

Effects of protection from pressure on resistance artery morphology and reactivity in spontaneously hypertensive and Wistar-Kyoto rats.

The effects of regional hypotension on femoral resistance artery reactivity and morphology were investigated in spontaneously hypertensive rats (SHR) and control Wistar-Kyoto (WKY) rats. A partially constricting ligature (0.4 mm i.d.) was placed around the left external iliac artery at 5 weeks, which resulted in significantly reduced femoral mean arterial pressures distal to the ligature at 12 and 24 weeks. The femoral mean arterial pressure distal to the ligature in SHR was similar to that in WKY unprotected hind limbs. Resistance arteries (approximately 200 microns i.d.) were taken from unligatured and protected hind limbs and mounted in a myograph for reactivity and morphological measurements. Each experiment therefore utilized one artery distal to a ligature and one from the control hind limb. Histological examination revealed that nuclear density differed neither between strains nor between arteries from protected and unprotected femoral beds. Media thickness, media cross-sectional area, and media/lumen ratios were reduced in arteries from the hypotensive hind limb in SHR and WKY rats at 12 and 24 weeks. Arteries from the protected hind limbs of SHR were structurally indistinguishable from those from the normally perfused WKY vasculature. It is concluded that the medial content and maximal contractile responses of femoral resistance arteries from SHR and WKY rats are mainly determined by the local perfusion pressure and that normalization of perfusion pressure in SHR normalizes resistance artery structure.

Age Factors↗
PubMed1991

Angiotensin II: vasoconstrictor or growth factor?

The consequence of a sustained rise in blood pressure is an adaptive change in the structure of the heart and the vasculature. In humans, the left ventricle, aorta, and medium-sized arteries undergo hypertrophy whereas the changes in resistance vessels are unclear at present. Recent studies suggest that left ventricular hypertrophy is a better predictor of stroke or cardiac risk than age or blood pressure. Therefore, the cellular mechanisms that bring about these structural alterations to the circulation in hypertension are the subject of intense research at this time. The main factor was assumed to be the pressure load imposed on the wall of the left ventricle and the arteries. However, recent work has suggested that pressor hormones can act as growth factors in vascular tissues by pressure-independent actions. This article examines the cellular mechanisms activated by angiotensin II that could be involved in producing growth and the evidence available that this nonpressor role is important in vitro and in vivo.

Angiotensin II↗
PubMed1991

Does treated essential hypertension result in renal impairment? A cohort study.

To determine how frequently essential hypertension results in significant renal impairment we undertook a follow-up study of 176 patients with well documented essential hypertension first seen in 1975-1977. Six patients were Asian, two Negro, and the remainder Europid. Follow-up was achieved in 92% of the cohort at five years and in 87% at 12-14 years. At five years 13 (7%) patients had moved away or were lost, and 15 (9%) patients had died (11 cardiovascular deaths). Treated blood pressure was greater than 160/95 mmHg in 60/148 patients and greater than 200/100 mmHg in 16 patients. Despite this, no significant change in serum creatinine was detected in the group as a whole. Increments in serum creatinine of at least 35 mumol/l occurred in six patients. Over the ensuing 6-9 years serum creatinine had returned to normal in three of these patients and stabilized in two; the sixth patient died from myocardial infarction. No patient reached end-stage renal failure. We conclude that progressive deterioration in renal function in essential hypertension is rarely a significant problem in Caucasian patients. A decline in renal function should prompt a search for underlying primary renal disease.

Adult↗
PubMed1991

Salt restriction, a sceptic's viewpoint.

In the light of the proposal that dietary salt intake should be reduced as a community health care measure designed to lower blood pressure and consequently mortality and morbidity from stroke and heart disease, the evidence that there is a link between salt intake and blood pressure is reviewed. In addition the effects of salt restriction on mild hypertension are surveyed as is the feasibility of sustaining a community-based campaign to reduce salt intake. It is concluded that whilst it would be possible to mount a concerted health care programme directed towards lowering the salt intake of the general population the benefits in terms of blood pressure would be extremely small. The impact on stroke and heart disease is unknown and possible adverse effects have not been examined.

Blood Pressure↗
PubMed1991

Changes in vascular morphology in essential hypertension.

Hypertension has emerged as an important risk factor in cardiovascular diseases. However, the success of antihypertensive treatment in reducing cardiac mortality is limited. It is becoming clear that structural changes in the resistance vessels and, indeed, other vascular changes such as hypertrophy in the aorta and left ventricle increase the risk of premature cardiac events. Future therapy for hypertension must be directed at not only lowering blood pressure but also reversing structural alterations in the vasculature.

Antihypertensive Agents↗
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↗