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Biomedical subjects

A M Heagerty

Publications and source records attributed to A M Heagerty.

At least 109 records · Page 6Linked to original sources
PubMed1988

Acute inotropic effects of intravenous nifedipine and its vehicle compared with saline: a double-blind study of systolic time intervals in normal subjects.

1. The inotropic effects of intravenous nifedipine and its vehicle were studied noninvasively in a double-blind placebo controlled crossover fashion using systolic time intervals in 12 normal subjects. 2. Nifedipine caused vasodilation, a fall in systolic and diastolic blood pressure, and increased heart rate. The vehicle alone caused vasodilation and decreased systolic blood pressure, without a change in heart rate. 3. Nifedipine increased left ventricular ejection time (LVET) and decreased pre-ejection period (PEP) and the ratio PEP/LVET, whereas the vehicle alone had the opposite effect. Neither treatment affected the total duration of electromechanical systole. 4. These results suggest that the vehicle has a negative inotropic effect, which is overcome by the indirect positive inotropic effect of nifedipine when they are administered together systemically.

Adult↗
PubMed1988

Noradrenaline stimulation of the phosphoinositide system: evidence for a novel hydrophobic inositol-containing compound in resistance arterioles.

1. Five inositol phosphates were extracted from adult rat resistance arterioles and separated by ion-exchange high performance liquid chromatography. 2. By use of this technique, inositol phosphates liberated were identified as inositol 1-phosphate, inositol 1,4-bisphosphate, inositol 1,3,4-trisphosphate, inositol 1,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate. Stimulation of phosphoinositide hydrolysis with noradrenaline produced increases in inositol phosphate production. 3. Three inositol-containing phospholipids extracted from resistance arterioles were measured as their glycerol esters following deacylation, thereby permitting an analysis of both membrane and cytosolic components of the phosphoinositide signalling system. 4. A substantial agonist-sensitive pool of a previously undescribed inositol but not glycerol-containing lipid extract component was also identified in this tissue. 5. These experiments for the first time allow a precise description of phosphoinositide metabolism in resting and agonist-stimulated resistance arterioles and provide data on a novel compound possibly similar to that recently described in other tissues.

Animals↗
PubMed1988

Dietary changes in membrane lipids and leucocyte calcium.

It has been postulated that changes in the fatty acid component of cell membrane phospholipids play an important role in cell membrane ion handling. To test this hypothesis, we have administered the polyunsaturated fatty acid linoleic acid (as 4 g daily of safflower oil) to 25 normotensive volunteers in a double-blind crossover trial for 4 weeks. There was a significant decrease in leucocyte ionised calcium at the end of active treatment compared with the end of placebo period. There was no difference in subjects with and without a family history of hypertension and there was no significant effect upon blood pressure. It is concluded that cell membrane fatty acids play a role in the regulation of intracellular calcium in the leucocyte, and perhaps therefore in other tissues.

Adult↗
PubMed1988

The haemodynamic effects of intravenous nifedipine in normotensive and hypertensive subjects.

The antihypertensive effects of intravenous nifedipine, given by bolus and 2 hour infusion, were studied at two dose levels in seven hypertensive (mean BP 178/114 mmHg) and five age-matched normotensive controls (mean BP 128/81 mmHg). Nifedipine significantly reduced systolic and diastolic blood pressure in the hypertensive patients by approximately 20%, but not in the normotensive controls. Similar changes in heart rate and forearm blood flow were seen after bolus injection in both groups, but these were not sustained during infusion. Intravenous nifedipine may be a useful acute treatment for hypertensive emergencies.

Adult↗
PubMed1987

Nifedipine infusion in acute myocardial infarction: experience in twelve patients.

Studies of nifedipine have not shown that it reduces myocardial infarct size in humans. These studies did not consider the pharmacokinetics and dynamics of nifedipine. Oral doses of nifedipine cause high plasma concentrations and possibly harmful hemodynamic changes. Intravenous nifedipine infusion can rapidly achieve and maintain a steady concentration without repeated hemodynamic upsets. We studied 24-h intravenous nifedipine infusion in 12 patients with acute myocardial infarct, starting within 6 (mean 4.0 +/- 0.7) h of onset of pain, to determine its safety, pharmacokinetics, and dynamics. An intravenous nifedipine bolus of 15 micrograms/kg was followed by an infusion of 0.9 mg/h for 24 h. After the bolus, pulse rate rose 12.5 +/- 8.0 p less than 0.01) and blood pressure fell (systolic by 20 +/- 34, p less than 0.05, and diastolic by 7.5 +/- 15.6, p less than 0.05). There were similar but lesser changes during the infusion. Myocardial oxygen requirements, as measured by the rate-pressure product, did not increase. The mean nifedipine concentration at steady state was 17.2 +/- 4.2 ng/ml and mean elimination T 1/2 3.57 +/- 2.70 h. Nifedipine was discontinued in 3 patients because of hypotension (SBP less than 90), rapid atrial fibrillation, and complete heart block in one patient each. Seven patients developed thrombophlebitis. Large studies of this preparation examining infarct size limitation and mortality are feasible, although in view of the problems of thrombophlebitis in peripheral veins, shorter infusion times or infusion via central lines would be more acceptable.

Administration, Oral↗
PubMed1987

Erythrocyte phosphoinositide metabolism in essential hypertensive patients and their normotensive offspring.

The metabolism of phosphoinositides was investigated in erythrocyte membranes of essential hypertensive patients, normotensive offspring of hypertensive patients and matched controls. Measurement of 32P-labelling of phosphatidylinositol 4-phosphate and phosphatidylinositol 4,5-bisphosphate revealed no differences in the rate of incorporation of the isotope in essential hypertensive patients compared with controls. In the normotensive offspring of essential hypertensive patients there was a highly significant increase in the rate of 32P incorporation (P less than 0.01), compared with matched controls, indicating a higher rate of metabolic turnover in these subjects. These data demonstrate that phosphoinositide metabolism is enhanced in subjects genetically at risk of hypertension, before the blood pressure has risen, but once the blood pressure is established, it is no different from control values. Abnormal phosphoinositide metabolism may be a further manifestation of a genetically determined defect of membrane physicochemical function underlying essential hypertension.

Erythrocyte Membrane↗
PubMed1987

Vascular renin-angiotensin system: the unanswered questions.

Study of the vascular renin-angiotensin system can be approached in a number of ways. The capacity of the blood vessel to generate angiotensin II, when exposed to angiotensinogen, immunocytochemical demonstration of renin, the presence of renin mRNA and functional changes attributable to local generation of angiotensin have all been used. Although each of these techniques requires careful and critical examination from the standpoint of specificity and sensitivity, there is now strong evidence for a functionally important system in the arterial wall. The relative importance of uptake and local synthesis and the physiological role of this system, as distinct from the renal renin system, still remains to be elucidated.

Animals↗
PubMed1987

Membrane handling of calcium in essential hypertension.

Several abnormalities have been described in the blood-cell handling of calcium in patients with hypertension and rats with genetic hypertension. We have suggested elsewhere that the multiple abnormalities of monovalent and divalent ion handling by blood cells in hypertension, which are loosely and variably associated with blood pressure, reflect a global variability of cell membrane lipids. In the light of this suggestion we tested the relevance of decreased membrane binding of calcium by examining basal and maximal calcium binding in hypertensive patients and in normotensive subjects with and without a family history of hypertension. Calcium binding was reduced to a similar degree in both hypertensive subjects and those with a family history of hypertension. To examine the role of membrane lipids we examined calcium binding in relation to erythrocyte membrane composition, and found a negative correlation between the palmitic:linoleic acid ratio and calcium binding. This is consistent with the observation of a reduction in the unsaturated fatty acid, linoleic acid, in the erythrocyte membrane of hypertensive subjects, and this may therefore be of functional significance. In further studies, although there was no net difference in leucocyte cytosolic calcium between essential hypertensive subjects and normotensive controls, there was a positive relationship between leucocyte calcium and membrane palmitic:linoleic acid ratio only in normotensives. To test further the role of membrane lipids in calcium handling we administered linoleic acid (4 g daily safflower seed oil) to 13 normotensive volunteers in a double-blind crossover trial. Four weeks of administration of the linoleic acid produced a significant decrease in leucocyte calcium (P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Pharmacokinetics and pharmacodynamics of nifedipine infusion in normal volunteers.

Two studies of the pharmacokinetics and pharmacodynamics of intravenous nifedipine infusion were performed: the first, a randomised double-blind crossover study of nifedipine and its vehicle in eight subjects, the second a dose ranging study in nine subjects. Nifedipine pharmacokinetics did not vary with dose or duration of infusion up to 8 h, and are similar to those reported for other nifedipine preparations. Nifedipine increased heart rate and forearm blood flow and decreased blood pressure after bolus injection but not during prolonged infusion. The vehicle decreased blood pressure and increased forearm blood flow after bolus injection but not during prolonged infusion. It did not affect heart rate. The vehicle's haemodynamic activity has not been previously recognised and is of potential importance in the study of this and similar preparations of calcium antagonists.

Adult↗
PubMed1987

Effect of cold pressor test-induced stress on leukocyte sodium transport and norepinephrine.

The effects of stress on leukocyte membrane sodium efflux rate constant and plasma norepinephrine levels were studied before and during cold pressor test in normotensive subjects with and without a family history of hypertension. After 20 minutes of supine rest, no significant differences in total, ouabain-resistant or ouabain-sensitive sodium efflux rate constants were apparent between the two groups. In normotensive subjects with no family history, there was no significant change in any efflux rate constant during cold pressor test, although there was a highly significant negative correlation between change in total efflux rate constant and change in norepinephrine levels (r = -0.82, p less than 0.01, n = 12). During cold pressor test in subjects with a family history of hypertension, there was a significant rise in the ouabain-resistant efflux rate constant (1.5 +/- 0.1 vs 1.0 +/- 0.1 hr-1; p less than 0.01, n = 10); this level was also significantly higher than that in control subjects (p less than 0.002). In this group, the ouabain-sensitive efflux rate constant fell slightly but not significantly (1.8 +/- 0.2 vs 2.1 +/- 0.2 hr-1; n = 10). These results suggest that stress in the form of a cold stimulus produces qualitative differences in leukocyte cation transport in normotensive offspring of hypertensive patients as compared with subjects without such a family history.

Adult↗
PubMed1987

Studies of isolated resistance vessels from offspring of essential hypertensive patients.

In order to investigate whether functional and morphological changes are present in the resistance vasculature before hypertension is established, isolated subcutaneous resistance vessels were studied from 21 young normotensive subjects with a family history of hypertension and 22 controls matched for age, sex, and weight. The vessels from the offspring of hypertensive patients displayed no morphological changes or differences in reactivity or sensitivity to the vasoconstrictor agonists norepinephrine, angiotensin II, serotonin, and vasopressin. In the presence of cocaine, however, vessels from offspring showed a significantly greater shift in sensitivity to norepinephrine, a phenomenon also observed in previous studies of vessels from hypertensive patients. The results suggest that in essential hypertension, while morphological and functional abnormalities of the resistance vasculature may develop as the blood pressure rises, a defect in neuroeffector activity is present before hypertension is established and may be a manifestation of abnormal sympathetic nervous system activity underlying the disease.

Adult↗
PubMed1987

Evidence for increased media thickness, increased neuronal amine uptake, and depressed excitation--contraction coupling in isolated resistance vessels from essential hypertensives.

The functional and morphologic characteristics of isolated subcutaneous resistance vessels (about 170 micron i.d.) from 15 untreated subjects with essential hypertension and 15 matched controls were examined. The vessels from the hypertensives had a 29% increase in the media-thickness-to-lumen-diameter ratio. The maximal force development to noradrenaline (NA) expressed as active pressure (an estimate of the pressure the vessels could have contracted against in vivo) was 30% higher in vessels from the hypertensives, while active media stress (force per square unit of smooth muscle) and sensitivity to NA was not significantly different. Increased active pressure, as well as unaltered active media stress and sensitivity, was seen for vasopressin, serotonin, angiotensin II, and K+. There was, however, an enhanced leftward shift of the NA sensitivity with cocaine (an inhibitor of the neuronal amine pump) in vessels from the hypertensives [pD2(+cocaine) and pD2(-cocaine) were 0.185 +/- 0.53) and 0.040 +/- 0.044, hypertensives and normotensives, respectively, p less than 0.05] suggesting an abnormality of presynaptic function in essential hypertension. Furthermore, the calcium sensitivity was depressed (pD2 was 4.197 +/- 0.050 and 4.381 +/- 0.068, hypertensives and normotensives, respectively, p less than 0.05), and the rate of relaxation was faster (p less than 0.05) in vessels from hypertensives, suggesting that excitation-contraction coupling might be depressed. The results suggest that the increased pressor response in essential hypertension can, to a large extent, be explained by altered vascular structure, while smooth muscle function is either unchanged or possibly depressed.

Arteries↗
PubMed1987

Nifedipine substituted for minoxidil in the treatment of refractory hypertension.

Nifedipine slow release tablets were substituted for minoxidil in the treatment of 13 patients with hypertension refractory to conventional therapy. In 12 patients substitution was associated with continuing control of blood pressure (BP), although 11 required maximum dose of 120 mg daily and one 80 mg daily. BP control remained satisfactory in nine patients for at least one year after substitution and in all, loop diuretics previously required with minoxidil to control fluid retention, were discontinued. Three patients (23%) however had to be withdrawn because of side effects; one within days of starting therapy and two after three months: one patient died after sustaining myocardial infarction. There was no evidence of deterioration in renal function in those patients continuing on nifedipine. This drug in combination with other antihypertensive agents provides an alternative approach to the management of patients with refractory hypertension, avoiding the severe side effects of the potent vasodilators.

Adrenergic beta-Antagonists↗
PubMed1987

The combination of verapamil and captopril in the treatment of essential hypertension.

A single-blind trial was carried out in 18 patients with moderately severe hypertension to investigate the efficacy of the angiotensin-converting enzyme inhibitor captopril in combination with the calcium antagonist verapamil after treatment with captopril alone had failed to achieve satisfactory control. For the first 2 weeks of the study, patients received 50 mg captopril twice daily, then 50 mg captopril plus 160 mg verapamil twice daily for 4 weeks, followed by 160 mg verapamil twice daily for a further 4 weeks. The double-dummy technique was used with placebo tablets given during the first and last treatment periods. Blood pressure and heart rate measurements in the supine and standing position were made at 2-week intervals throughout the study. Analysis of the results from the 13 patients who completed the trial protocol showed that the two drugs in combination produced significant reductions (p less than 0.01) in both supine and standing blood pressures compared with captopril alone, but a significant reduction (p less than 0.02) only in diastolic blood pressure compared with verapamil alone. Heart rate was not changed significantly throughout the study. Only 1 patient was withdrawn because of side-effects, although on questioning constipation, in particular, proved to be a problem in many.

Captopril↗
PubMed1987

Effects of manipulation of sodium balance on erythrocyte sodium transport.

The effects of changing sodium balance on blood pressure (BP) and erythrocyte sodium transport were investigated in normotensive first-degree relatives of hypertensive patients and control subjects randomised to receive low and high salt diets for two weeks, separated by a two week washout period. Changing from high to low salt intake produced a significant fall in standing diastolic pressure (DBP) in control subjects but not in the offspring of hypertensive patients. In both groups erythrocyte sodium efflux was not changed significantly by either manoeuvre, but the relatives had a significantly higher ouabain insensitive sodium efflux rate constant on both the low and the high salt diet compared to the controls (P less than 0.05). These results are not in keeping with the hypothesis which suggests the release of a humoral sodium pump inhibitor in response to sodium loading but lend support to the view that there is a disturbance of membrane permeability to sodium in subjects genetically prone to hypertension.

Adult↗