Endothelin-induced contraction of human peripheral resistance vessels is partly dependent on stimulation of sodium-hydrogen exchange.
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Amiloride↗
Biomedical subjects
A M Heagerty
Publications and source records attributed to A M Heagerty.
Resistance artery phosphoinositide metabolism in genetic hypertension.
Precapillary resistance arteries from spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive rats (WKY) were found to contain three inositol lipids and to produce five inositol phosphate peaks. These were assessed by a highly sensitive procedure which involved the separation of radiolabelled inositol-containing components by anion-exchange high-performance liquid chromatography. Basal levels of radiolabelled inositol lipids were found to be significantly increased in SHR at 5 weeks of age, and also increased at 12 weeks, although this was only statistically significant for glycerophosphoinositol. At 5 weeks of age, exposure to a maximal concentration of noradrenaline brought about a significant increase in lipid radioactivity in WKY and in glycerophosphoinositol and glycerophosphoinositol 4-phosphate in SHR. The levels of these lipids remained significantly raised in the SHR at this time. At 12 weeks of age, exposure to noradrenaline produced reductions in radioactivity associated with inositol lipids. These new levels were elevated in SHR and significant for glycerophosphoinositol 4-phosphate. Basal levels of four inositol phosphates were not different between the two rat strains at 5 weeks of age. Inositol 1,3,4-trisphosphate was only present at minute levels and could not be measured. At 12 weeks of age, basal radiolabelling of inositol phosphates was not different between the two strains. The application of noradrenaline caused age-dependent changes in arterial inositol-containing compounds in both strains, which resulted in increased levels of inositol 1,4,5-trisphosphate in young SHR and also in adult rats in which the blood pressure level had become established.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
The effect of short chain fatty acid supplementation on membrane electrolyte transport and blood pressure.
Eleven normotensive subjects with no family history of essential hypertension took part in a double-blind randomized placebo-controlled crossover study to examine the effects of supplementing a normal omnivore diet with miglyol. This resulted in a fall in diastolic blood pressure in both the supine and standing positions, achieving statistical significance for the standing diastolic pressures, following miglyol treatment. Miglyol is rich in caprylic (8:0) and capric acids (10:0), both short chain saturated fatty acids, and supplementation with this produced a significant fall in erythrocyte membrane oleic and linoleic acid (P less than 0.01 compared to placebo for each fatty acid), as well as a fall in the saturated fat palmitic acid (16:0) (P less than 0.01). These changes were not associated with any alterations in total erythrocyte sodium influx, bumetanide sensitive influx or sodium red cell intracellular or potassium content. In addition, body weight and urinary excretion of sodium and potassium did not change. These data indicate that this dietetic manipulation with an oil rich in short chain saturated fatty acids lowers diastolic blood pressure but not as a result of changes in membrane sodium handling. It is possible that the short chain fats displace the longer carbon chain fatty acids which are metabolically important to cellular integrity and it is in this way that blood pressure falls.
1-Deoxynojirimycin↗
Nifedipine and/or atenolol for mild to moderate hypertension: a general practice study.
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Atenolol↗
Evidence for a decreased noradrenaline sensitivity in mesenteric resistance vessels from rats with chemical renal medullectomy.
1. Chemical renal medullectomy was performed in Wistar rats by intraperitoneal injection of 2-bromoethylamine hydrobromide (200 mg/kg body weight). The effect of this treatment upon blood pressure and mesenteric vascular reactivity and morphology was studied 3 weeks after treatment. 2. Blood pressure was significantly raised in medullectomized rats. The indirect systolic pressures (means +/- SEM) were 112 +/- 2.4 mmHg (14.9 +/- 0.32 kPa) and 123 +/- 3.5 mmHg (16.4 +/- 0.5 kPa) (P less than 0.02) for control (n = 12) and medullectomized (n = 12) rats, respectively. However, there were no significant changes in the morphology of the mesenteric resistance vessels. 3. Maximum pressor responses and Ca2+ sensitivities were unchanged in these vessels compared with controls, but the sensitivity to noradrenaline was significantly reduced. Noradrenaline pD2 (= -log ED50) values (means +/- SEM) were 5.87 +/- 0.03 and 5.69 +/- 0.08 (P less than 0.05) for control (n = 12) and medullectomized (n = 12) rats, respectively. 4. This study demonstrates that in this model of hypertension the noradrenaline sensitivity is reduced in mesenteric resistance vessels, but there are no detectable morphological changes associated with the rise in blood pressure.
Animals↗
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↗
A double-blind randomized cross-over study of the efficacy and tolerability of nifedipine and nitrendipine in the treatment of mild to moderate hypertension.
1. In order to examine whether nitrendipine was superior to slow release nifedipine as monotherapy in the treatment of mild to moderate essential hypertension, the two agents were administered to 22 patients in a double-blind randomized cross-over study, incorporating low and titrated dose regimes. 2. Six patients failed to complete the study because of vasodilator side-effects such as headache, flushing and ankle swelling. Three were taking nitrendipine and three took nifedipine and all withdrawals occurred at the introduction of the drug. 3. Both agents reduced blood pressure in the 16 patients who completed the study, and neither agent was superior to the other; mean blood pressure after the placebo phase was 177 +/- 5.5/100 +/- 2.6 mm Hg supine and 175 +/- 5.3/113 +/- 2.4 mm Hg standing. At the end of therapy with nifedipine pressures were 160 +/- 4.0/91 +/- 3.0 mm Hg supine and 158 +/- 4.6/103 +/- 2.7 mm Hg standing. After 8 weeks treatment with nitrendipine blood pressures were 162 +/- 4.4/90 +/- 2.9 mm Hg supine and 161 +/- 6.2/104 +/- 2.7 mm Hg standing. Comparisons of these attained blood pressures on both agents showed no statistically significant differences. 4. Nitrendipine did not appear to be effective on a once daily basis.
Adult↗
The contractile effects of porcine tetradecapeptide renin substrate in human resistance vessels: evidence of activation by vascular wall renin and serine proteases.
In order to test the hypothesis that the contraction induced in human resistance arterioles by porcine tetradecapeptide renin substrate (TDP) is mediated by enzymes specific to the renin-angiotensin cascade, human resistance vessels from skin and subcutaneous fat were mounted in a myograph and exposed to TDP in the presence and absence of the human renin inhibitor H261, the serine protease inhibitor aprotinin, a polyclonal anti-human renin antibody and captopril. TDP induced a dose-dependent contraction that could be abolished by saralasin. The sensitivity to TDP was significantly attenuated by H261, aprotinin and combinations of captopril with aprotinin and captopril plus aprotinin and H261, as indicated by a significant reduction in pD2 (-log10ED50 [mmol/l]) for TDP. However, captopril alone was ineffective. It was concluded that at physiological pH, porcine TDP induces contraction in human resistance vessels by the action of enzymes not specific to the renin-angiotensin cascade. Whilst a clear inhibitory effect of H261 was demonstrated, a significant comparable inhibition by captopril and a polyclonal renin antibody was not observed. This may reflect the difficulty with which these inhibitors gain access to their intracellularly located substrates.
Electric Stimulation↗
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↗
The effect of dietary linoleic acid on blood pressure and erythrocyte sodium transport.
The influence of an increase in the polyunsaturated fat linoleic acid on blood pressure and erythrocyte membrane sodium transport was investigated in normotensive first degree relatives of hypertensive patients and controls by the double blind administration of safflower oil or paraffin oil (placebo) capsules for four weeks separated by a four week washout period. Systolic blood pressure fell in the controls with linoleic acid supplementation but there was no significant change in total sodium efflux rate constant. When the pattern of response was compared the changes in supine systolic blood pressure, plasma renin activity, total and ouabain-sensitive sodium efflux rate constant were significantly different in the controls compared to the relatives. These results show that dietary linoleic acid supplementation may have effects on ionic fluxes across cell membranes and cause a modest fall in blood pressure. In addition, since the response to the change in fat intake was different in the relatives and the controls, this provides further evidence of differences in the physicochemical structure of the plasma membrane in hypertensive subjects and their offspring.
Adult↗
Linoleic acid supplementation, membrane lipids and leucocyte sodium transport in normotensive humans.
Ten normotensive subjects had their omnivore diet supplemented with increasing doses of linoleic acid in the form of safflower seed oil in order to examine the effects of this polyunsaturated fat upon leucocyte sodium transport. Increasing the dose ingested to the limits of tolerance produced a significant decrease in ouabain resistant sodium efflux (P less than 0.05) but no significant change in total or ouabain-sensitive sodium extrusion. Intraleucocytic sodium content was correlated with erythrocyte membrane oleic acid % (r = 0.368, P less than 0.05); leucocyte ouabain resistant flux was correlated with oleic acid % (r = 0.453, P less than 0.01) and linoleic acid % (r = -0.319, P less than 0.05). No such associations were observed with ouabain sensitive sodium extrusion. No changes in body weight or urinary electrolyte excretion were observed. It is concluded that, at physiological concentrations, membrane linoleic acid content influences transmembrane sodium fluxes but not through modulation of sodium pump activity. Furthermore, the beneficial effect of this dietary manoeuvre, observed previously with small increments of safflower seed oil, was not seen in this experiment so the hypotensive activity of this manipulation must be regarded as limited.
Adult↗
Effects of drug treatment on human resistance arteriole morphology in essential hypertension: direct evidence for structural remodelling of resistance vessels.
To examine whether effective drug treatment would reverse the morphological changes in resistance arterioles which characterise untreated essential hypertension, the vessels' media thickness and contractility were measured before and after long-term treatment. Nine patients underwent skin biopsy before and after a mean 13 months of antihypertensive treatment (range 4-24 months). Subcutaneous resistance arterioles were dissected and mounted in a myograph. Treatment did not affect the shift in sensitivity to noradrenaline in the presence of cocaine, sensitivity to exogenously administered calcium, and the rate of relaxation after withdrawal of vasoconstrictor stimuli. The media/lumen ratio fell significantly (p = 0.011) owing to a significant regression in media thickness (p = 0.0195), but this was not complete. Thus, effective antihypertensive treatment can reverse some of the structural change observed in the untreated state, although it apparently does not affect calcium sensitivity or relaxation rate; these features are thought to be consequences of the disease after it has become established.
Antihypertensive Agents↗
Blood vessels and human essential hypertension.
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Antihypertensive Agents↗
Dietary fat in relation to fatty acid composition of red cells and adipose tissue in colorectal cancer.
Fatty acids were determined in erthrocytes in 49 patients with colorectal cancer and compared with age and sex-matched controls. Marginally increased levels of stearic acid (P = 0.057) and oleic acid (P = 0.064) and decreased arachidonic acid (P = 0.043) occurred in cancer patients. There was no difference in the stearic to oleic acid ratio between the two groups. Dietary intake, assessed by dietary recall and adipose tissue analysis was also not different. In control subjects the polyunsaturated:saturated (P:S) fatty acid ratio correlated between diet and adipose tissue (P less than 0.01, at least). In contrast cancer patients showed different correlations; in particular dietary and erythrocyte P:S fatty acid ratios correlated (P less than 0.01). These findings may indicate disturbed fat metabolism in cancer patients. The erythrocyte stearic to oleic acid ratio is of no diagnostic value.
Adenocarcinoma↗
31P nuclear magnetic resonance measurement of free erythrocyte magnesium concentration in man and its relation to blood pressure.
1. 31P n.m.r. spectroscopy was used to measure the dissociation constant of MgATP under simulated intracellular conditions and to measure erythrocyte free magnesium concentration. 2. In a group of 40 subjects, the relationship between erythrocyte free magnesium and blood pressure, age and sex was examined by univariate and multivariate regression analysis. 3. A weak positive association was found between erythrocyte free magnesium and mean blood pressure. This association was lost in a multivariate regression analysis including both age and sex. 4. No significant relationship was found between erythrocyte free magnesium and age, sex, family history of hypertension or use of the combined oral contraceptive pill in the sample studied.
Adult↗
Vasopressin-mediated contractions in mesenteric arteries from spontaneously hypertensive rats: differences in response compared with Wistar-Kyoto animals.
1. The sensitivity of mesenteric resistance arterioles to [arginine]vasopressin (AVP) was investigated in spontaneously hypertensive rats (SHR) and control Wistar-Kyoto rats (WKY). No difference in pAVP (-log dose of AVP producing 50% of the maximum response) was observed [SHR 0.21 +/- 0.03 m-units/ml (n = 10) vs WKY 0.15 +/- 0.06 m-units/ml (n = 9)], although SHR vessels exhibited greater absolute tension development. 2. Both strains of rat displayed tachyphylaxis to repeated stimulation with AVP, and oscillatory tension changes were observed in all vessels from SHR and rarely in WKY vessels at activating concentrations of AVP. 3. AVP did not elicit a contractile response after noradrenaline-induced calcium depletion. 4. After vessels were depleted of calcium by using a combination of calcium-free media and noradrenaline stimulation, restoration of calcium in the presence of AVP elicited a greater contractile response in SHR vessels. 5. The results therefore provide evidence for an increased calcium response to AVP in SHR resistance vessels, although this was only demonstrable by calcium recovery experiments.
Animals↗
Recent advances in therapy for hypertension.
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Alcohol Drinking↗
The effects of coarctation hypertension upon vascular inositol phospholipid hydrolysis in Wistar rats.
In order to examine the effects of imposing an acute pressure load upon vascular structure and phosphoinositide hydrolysis, aortic medial thickness, cross-sectional area, cell nuclear counts and inositol phosphate accumulation were measured in Wistar rats with experimental coarctation and sham-operated controls at 3, 9 and 20 days after surgery. Compared to sham-operated animals, rats with coarctation had significantly higher carotid artery pressures throughout the study. Below the ligature, femoral arterial pressure was significantly lower in animals with coarctation. Proximal to the coarctation, there was an increase in aortic medial cross-sectional area and medial thickness but no increase in nuclear counts, suggesting the induction of hypertrophy; statistically significant changes were present at 9 and 20 days. Distal to the ligature only small structural changes were observed indicating some atrophy had occurred. Inositol phosphate accumulation had increased slightly at 3 days in proximal aortae from ligatured rats, and was significantly raised at 9 and 20 days; no such changes were recorded below the coarctation. These data indicate that the increased load upon the proximal aorta initiates increased inositol phosphate production through local mechanisms. Whilst a causal link has not been conclusively established between phosphoinositide turnover and hypertrophy, the association between the two in these studies is consistent with the hypothesis that the induction of increased cell phosphoinositide metabolism contributes, at least in part, to the proximal aortic structural changes observed in this model.
Angiotensin II↗