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Biomedical subjects

T O Morgan

Publications and source records attributed to T O Morgan.

At least 55 records · Page 3Linked to original sources
PubMed1992

Spontaneous and propagated calcium release in isolated cardiac myocytes viewed by confocal microscopy.

Laser scanning confocal microscopy of the Ca(2+)-sensitive fluorophore fluo-3 has been used to investigate spontaneous and propagated calcium release at high temporal and spatial resolution in enzymatically dispersed rat cardiomyocytes. Waves of fluorescence which propagated throughout the cytosol were evident in spontaneously contracting cardiac cells containing fluo-3, but not in cells containing Ca(2+)-insensitive fluorophores [2',7'-bis (carboxyethyl)-5,6-carboxyfluorescein, SNARF-1, rhodamine-123, or tetramethylrhodamine-labeled dextran]. These waves represent localized areas of elevated [Ca2+] [975 +/- 13 (SE) nM, range 800-1,500 nM; n = 16 cells]. Ca2+ waves were initiated by the spontaneous release of Ca2+ from the sarcoplasmic reticulum (SR) and propagated through cells at rates of 50-150 microns/s. Ca2+ waves were usually initiated at the cell ends, but multiple and variable initiation foci were observed in some cells. Where waves intersected within a single cell there was extinction of wave propagation, confirming the SR as the direct source of Ca2+ and revealing a refractory period in SR Ca2+ release. In some cells high-frequency Ca2+ waves lead to synchronized elevation of [Ca2+] throughout the entire cytosol and within the time period associated with cell depolarization. These observations support the hypothesis that some cardiac arrhythmias are initiated by spontaneous and propagated Ca2+ release and involve subsequent depolarization, global elevation of intracellular [Ca2+], and cell contraction.

Aniline Compounds↗
PubMed1992

Hemodynamic comparisons of enalapril and felodipine and their combination.

Thirty-six patients (33 male, 3 female) with a mean age of 67 years and a diastolic blood pressure between 95 and 115 mm Hg, after a four-week placebo run-in period entered a double-blind crossover study comparing felodipine 5 and 10 mg with enalapril 5 and 10 mg and their combination (enalapril 5 mg + felodipine 5 mg). Combined therapy caused a fall in blood pressure of 24/16 mm Hg at trough level that was greater than the falls with the higher doses of monotherapy. The fall with felodipine was greater than with enalapril. Similar patients responded to felodipine and enalapril but more patients achieved blood pressure control with felodipine. When patients not controlled with enalapril 5 mg had felodipine 5 mg or enalapril 5 mg added, felodipine was more effective at lowering blood pressure than the increase in enalapril dosage. A similar effect occurred in those not controlled with felodipine 5 mg. Adverse effects occurred in 22 patients on felodipine, 14 patients on enalapril and 8 on combined therapy. The lipoprotein profile was not altered significantly. Glomerular filtration rates as assessed by 24-hour creatinine clearance were 90 ml/min at randomization, 125 ml/min on felodipine, 108 ml/min on enalapril and 120 ml/min on the combination. Felodipine and enalapril in low doses are effective antihypertensive agents in elderly people. Felodipine monotherapy is more effective than enalapril monotherapy but a greater blood pressure lowering effect can be obtained with the combination of low doses of enalapril and felodipine. This has the advantage that the number of side effects is less.

Aged↗
PubMed1991

The use of non-invasive blood pressure measurements to measure pressor responses in rats during air stress.

1. A non-invasive tail cuff method was validated against direct intra-arterial blood pressure measurements (r2 greater than 0.9) and then used to measure the systolic blood pressure (SBP) responses to air-jet stimulation in mature conscious Sprague-Dawley (SD) and spontaneously hypertensive rats (SHR). The experiments with the SHR were conducted in parallel with age matched SD rats. 2. All rats were trained to remain in perspex holders and when their SBP had stabilized, a jet of air of 10 min duration was directed at the rat's nose via rubber tubing. The blood pressure was measured during the first, fifth and tenth minute. 3. The maximum SBP response normally occurred during the first min of air-jet stimulation and averaged +30 mmHg in the SHR and +21 mmHg in the SD. Although of higher magnitude in the SHR, when expressed as a percentage of the control SBP, the rise was similar for both strains, 13% and 14%, respectively. 4. The pressor response of three SD rats stimulated daily for up to 12 days did not show any evidence of habituation to the stimulus. 5. The pressor responses to air-jet stimulation were abolished in anaesthetized rats, suggesting that they are primarily higher centre responses.

Air↗
PubMed1991

Calcium transport in the proximal convoluted tubule and loop of Henle of rats made diabetic with streptozotocin.

In-vivo microperfusion was used to localize the reabsorptive defect responsible for the hypercalciuria of diabetes mellitus and to investigate possible causative factors. Unidirectional proximal calcium absorption was not significantly different in rats made diabetic with streptozotocin compared with controls, providing evidence against the involvement of this nephron segment in the phenomenon. Calcium absorption by the loop of Henle, was however, significantly (P less than 0.01) lower in diabetic animals (32.1 +/- 1.2 vs 40.4 +/- 0.6 pmol/min). Based on our knowledge of calcium movements within the loop, it is likely that the reabsorptive defect residues within the thick ascending limb. The calcium lesion was found to be independent of acute changes in intraluminal glucose concentration and could not be corrected by acute insulin treatment. The study also provides new information on the relationship between intratubular glucose and fluid movements in the rat nephron. In diabetic rats a proximal perfusate containing 30 mmol glucose/l resulted in fluid absorption comparable with that seen in control rats perfused with 5 mmol glucose/l. However, intraluminal glucose had a stimulatory effect on fluid absorption in the loop of Henle of diabetic rats (10.7 +/- 0.5 vs 7.9 +/- 0.4 nl/min; P less than 0.01).

Absorption↗
PubMed1990

A superfusion bath for single-cell recording with high-precision optical depth control, temperature regulation, and rapid solution switching.

A superfusion system for isolated cell recording, which uses a novel optical technique for feedback control of solution depth (+/- 5 microns), is described. A retroreflective optosensor senses the distance between itself and a white hydrophobic plastic float, supported by surface tension on the surface of the solution. The combination of optical depth sensing with stepper-motor-driven pumps, pneumatic ("noise-free") solution switching and Peltier-effect solution heating/cooling provides a high degree of control over the cell superfusion environment. The solution flow rate to the bath is selected over the range 0.08-5.00 (+/- 0.01) ml min-1 with provision for solution recirculation. The temperature control range of the Peltier element is 4.0 degrees-70.0 degrees C. At temperatures selected over the range 16.0 degrees-36.0 degrees C, and at flow 3.00 ml min-1 the temperature gradient through the central working position of the bath is not more than 0.2 degrees C. At this flow, bath solution exchange on valve actuation is 90% complete within 0.7 s. This superfusion system is particularly suited to conventional and fluorescence imaging techniques where accurate control of the solution level ensures constant optical conditions. In electrophysiological experiments this apparatus will also provide stabilization of electrode capacitance with adjustment of solution depth. The robust and compact design of the system allows it to be carried between different applications.

Cell Physiological Phenomena↗
PubMed1990

The use of carvedilol in elderly hypertensive patients.

Carvedilol, a beta-blocking drug with vasodilator activity, has been used in 4 studies in 107 elderly patients with essential hypertension and has reduced blood pressure effectively. In the first study the pharmacokinetics and clinical response were compared between 21 patients greater than 65 years of age and 8 patients aged 35-50 years). The peak blood levels, time to maximal concentration, area under the curve, half-life and trough level of the drug with chronic administration did not differ. The clinical responses to the drug were similar, with a greater fall in systolic blood pressure in the older group. However the initial systolic blood pressure in the older group was higher. Carvedilol was compared with metoprolol, pindolol and nitrendipine in elderly patients. The responses to carvedilol were at least equal to those obtained with the other drugs. Control was achieved in the three studies with once-daily therapy. There was no significant postural hypotensive effect. A feature of all studies was the large number of patients who responded to carvedilol. The side-effect profile of the drug was acceptable; headache and dizziness were more common than with placebo or the comparison drugs and were frequently associated. There were no adverse biochemical effects and the lipid profile was not altered. Carvedilol is an effective antihypertensive drug that lowers blood pressure equally well in the young and the old.

Adrenergic beta-Antagonists↗
PubMed1990

Altered responsiveness of proximal tubule fluid reabsorption of peritubular angiotensin II in spontaneously hypertensive rats.

Stimulation of proximal tubular fluid reabsorption by peritubular angiotensin II (Ang II) was examined by split-drop micropuncture in 5- and 12-week-old spontaneously hypertensive rats (SHR) and age-matched normotensive Wistar-Kyoto rats (WKY). In WKY, the maximum stimulation occurred at 10(-11) mol/l and the response did not vary with age. In 5-week-old SHR, the dose-response relationship was similar in shape and in the extent of the maximum response but was shifted one half-logarithmic step to the right, indicating decreased sensitivity to Ang II. In contrast, the dose-response relationship was shifted one half-logarithmic step to the left in 12-week-old SHR compared with WKY. Alterations in the responsiveness of the proximal tubule to Ang II in young SHR could contribute to sodium retention observed during development of hypertension in these rats.

Angiotensin II↗
PubMed1990

A review of the antihypertensive effects of felodipine alone or in combination.

Felodipine is a dihydropyridine that blocks the slow entry channel for calcium. It is highly vascular selective and reduces blood pressure (BP) by dilatation of peripheral arterioles. It reduces BP in mild, moderate, and severe hypertension, and the fall in BP depends upon the initial level. It has been compared with a variety of other drugs as monotherapy or as add-on therapy. In these studies, felodipine (10-40 mg/day) has caused a similar or greater fall in BP and a similar or greater percentage of patients have achieved a diastolic BP less than or equal to 90 mm Hg. The plain tablet of felodipine needs to be given twice a day but an extended-release form can be given once daily. Some patients respond to 5 mg/day and most patients respond to a daily dose of 20 mg or less. The adverse effects are few except for a constellation of symptoms related to the vasodilator ability of the drug. These include palpitations, flushing, fatigue, dizziness, and headaches. These occur, if at all, usually within the first 2 weeks and diminish as the drug is continued. They can be limited by starting on a small dose of felodipine (5 mg/day). People who have these adverse effects usually have a good response to the drug. Another adverse effect, which is the most frequent reason for drug withdrawal, is ankle edema. This is more common on the higher doses of the drug. It is due to dilatation of the precapillary resistance vessels rather than sodium and water retention. Felodipine is a useful and effective antihypertensive drug and can be used as monotherapy or added to other antihypertensive drugs. It is effective in people with all grades of hypertension.

Animals↗
PubMed1990

Prevalence of left ventricular hypertrophy in elderly patients with well controlled hypertension.

1. Left ventricular hypertrophy (LVH) was measured by echocardiography in 154 patients, mostly males, aged 55 years or more, with hypertension who had been well controlled for at least 2 years. 2. Satisfactory studies with no other cardiac lesions were available for 103 patients; 52% had LVH and 48% had normal left ventricular dimensions. 3. In patients with well controlled hypertension there was a high prevalence of LVH despite adequate control for at least 2 years. Neither the level of control nor the drugs used appeared to predict the outcome. 4. Consideration needs to be given to earlier treatment, greater lowering of blood pressure, or different drugs to reduce this high prevalence of LVH.

Aged↗
PubMed1990

Prognosis of male patients with treated hypertension followed over 15 years.

1. Male patients aged 50-75 years on treatment for hypertension in 1973 have been followed for 15 years. 2. Overall mortality in the 271 patients was 63% and 41% died of vascular disease. 3. Coronary artery disease or sudden death occurred in 44% of the patients who died and was between 2 and 6 times more common than in the general population. 4. Treatment of hypertension has improved overall prognosis but mortality from coronary artery disease is more common than in the general population.

Aged↗
PubMed1990

Perinatal salt intake alters blood pressure and salt balance in hypertensive rats.

Blood pressure and the rate of excretion of an oral salt load were examined in spontaneously hypertensive rats of the Okamoto strain after exposure in utero and during suckling to a high salt (3% NaCl, wt/wt), low salt (0.1%), control salt (0.8%), or high potassium (2.2% KCl, wt/wt) [corrected] maternal diet. After weaning, all offspring were given a diet containing 0.8% NaCl. There were small but significant differences in growth rate among offspring groups over the 60 weeks of observation, with rats exposed to perinatal low salt and high salt diet being lighter than those given control or high potassium diet. There were positive, significant correlations between body weight and blood pressure in all dietary groups at 8 weeks of age but not 16 or 24 weeks. Rats exposed to perinatal low salt diet had significantly lower blood pressures than the other three groups, which had similar blood pressures. Low salt rats also exhibited an exaggerated natriuresis after a single, oral salt load (0.15 M saline, 1% body weight) compared with the other three diet groups, which were not different from each other. High potassium rats had a reduced kaliuresis and diuresis after the salt load when compared with the other three groups. At 60 weeks of age, rats that received perinatal low salt diet had significantly heavier adrenal glands when compared with the other groups, and the high potassium group had significantly elevated plasma renin concentrations. Thus, maternal electrolyte intake during the perinatal phase may alter body fluid homeostasis in genetically susceptible individuals at maturity.

Animals↗
PubMed1990

Metabolic effects of various antihypertensive agents.

Mortality resulting from coronary artery disease and sudden death has not been significantly reduced by the use of antihypertensive medications in patients with hypertension, despite evidence that hypertension is a major risk factor for myocardial infarction. One possible reason is that the drugs used may have adverse metabolic effects that negate the beneficial effect of lowering blood pressure. Diuretics and beta-blocking agents produce a wide range of biochemical or metabolic alterations-e.g., changes in plasma potassium and in lipoprotein profiles. In general, fewer or less marked alterations are associated with the use of angiotensin-converting enzyme inhibitors, alpha-adrenergic blockers, and slow calcium channel blocking drugs. The effects of these agents alone and in combination and their potential relationship with coronary adverse events are reviewed. Although the clinical relevance of these alterations has yet to be fully determined, it is rational to suggest that given or current knowledge, the antihypertensive agent selected for use should be an effective, well-tolerated drug with a minimum of adverse biochemical or metabolic effects.

Antihypertensive Agents↗
PubMed1990

Granular juxtaglomerular cells and prorenin synthesis in mice treated with enalapril.

The short-term and long-term effects (for up to 98 days) of the angiotensin converting enzyme inhibitor enalapril were investigated in male and female BALB/c mice. In control animals, separate antisera to renin and its prosequence produced an identical pattern of staining in granular cells of the juxtaglomerular apparatus (JGA) a short distance from the glomerulus. After 1 day of the enalapril treatment there was a decrease in the number of JGA granular cells immunostained with antisera to both renin and its prosequence. Electron microscopy revealed degranulation of mature granules from JGA granular cells. Fusion of granules with the cell membrane was not observed, but numerous membrane-like structures (myelin figures) were identified in the cytoplasm and extracellular space, indicating possible secretion. In addition, the volume proportion of granulated cells in relation to the glomerular volume was decreased, as was renal renin content. With continuing enalapril treatment, separate antisera to renin and its prosequence stained the same granulated JGA cells with equal intensity. The cells so stained increased in number, extending down the wall of the afferent arteriole to cortical radial arteries (interlobular arteries) upstream from the glomerulus. Ultrastructural studies revealed a progressive development of cytoplasmic granulation in JGA granular cells and in smooth muscle cells extending into cortical radial arteries. Furthermore, the volume proportion of granulated cells in relation to the glomerular volume was significantly increased, as was renal renin content. Thus, short-term enalapril treatment in mice provoked rapid secretion of renin via degranulation of mature granules from JGA granular cells. In contrast, long-term enalapril treatment produced a continuing stimulus for renin synthesis, secretion and storage, resulting in an increased thickness of the afferent arteriolar wall. The mechanism for this change appears to be hypertrophy and hypergranulation of granular JGA cells and neogranulation of smooth muscle cells upstream from the glomerulus. Identification of the intrarenal mediators that induce these phenotypic changes presents an interesting challenge.

Animals↗
PubMed1989

Efficacy of cilazapril compared with hydrochlorothiazide in the treatment of mild-to-moderate essential hypertension. Multicentre Study Group.

The effect of cilazapril, a new inhibitor of angiotensin-converting enzyme, in a dosage of 2.5 or 5 mg once daily, was compared with that of hydrochlorothiazide 25 or 50 mg in 169 patients with mild to moderate hypertension. Blood pressure at entry was 158/103 mm Hg (cilazapril) and 160/103 mm Hg (hydrochlorothiazide). Cilazapril 2.5 mg caused a decrease in blood pressure of 14.7 +/- 2.3/12.6 +/- 1.2 mm Hg compared with a decrease of 12.6 +/- 2.2/10.2 +/- 1.2 mm Hg with hydrochlorothiazide 25 mg. Those patients who required an increase of dosage to the higher level then showed decreases of 15.0 +/- 2.1/14.3 +/- 1.2 (cilazapril) and 19.7 +/- 1.9/13.3 +/- 1.2 hydrochlorothiazide. All decreases in blood pressure were statistically significant but were not statistically different from each other. Fifty-one percent of patients reached a sitting diastolic blood pressure of 90 mm Hg or less receiving 2.5 mg of cilazapril and an additional 28 percent of patients reached this goal receiving 5 mg. The figures for patients receiving hydrochlorothiazide were comparable: 36 and 35 percent. Twenty-one adverse events remotely, possibly, or probably related to therapy were reported with cilazapril and 32 with hydrochlorothiazide. Three patients withdrew from cilazapril because of mild angioedema, headaches, and chest pain, respectively, and three patients withdrew from hydrochlorothiazide treatment because of fatigue, dizziness, and gastric hemorrhage. Hydrochlorothiazide caused a decrease in potassium levels and an increase in levels of cholesterol, uric acid, urea and - gamma cilazapril had no adverse biochemical effects. Cilazapril lowered blood pressure to the same extent as hydrochlorothiazide. Young patients had better responses to cilazapril than to hydrochlorothiazide. It is concluded that cilazapril is an effective and safe drug for patients with mild to moderate hypertension.

Adolescent↗
PubMed1989

Exercise tolerance in the heat on low and normal salt intakes.

1. Salt restriction is recommended in the treatment of hypertension and is included in national dietary guidelines, but its effect on exercise in hot conditions has not been extensively studied. 2. The effects of 2 weeks on two levels of salt intake (50 and 150 mmol/day) on the ability to exercise (60% of maximal oxygen uptake) in a hot environment (35 degrees C) were studied in eight healthy normotensive subjects. 3. All subjects were able to complete the exercise load on the two levels of salt intake. No differences in mean oxygen uptake, heart rate or rectal temperature during exercise were observed between the two salt intakes. 4. Plasma sodium, potassium and osmolality were similar on the two salt intakes both before and during exercise. Plasma renin activity and aldosterone concentration were elevated after 2 weeks on the reduced salt intake and remained so during exercise. 5. The estimated sweat rate during exercise was similar on the two salt intakes but the loss of sodium was less on the low salt intake. 6. On the basis of these results it is concluded that moderate salt restriction does not impair the ability to exercise in a hot environment.

Adult↗
PubMed1989

Characterization of single heart cell contractility by rapid imaging.

1. A rapid imaging technique with temporal resolution of about 1 ms was employed to describe cell-length changes during the isotonic contraction cycle of adult rat ventricular myocytes at 22 degrees C. 2. Parameters of cell contraction and relaxation were defined and values obtained under control conditions and after treatment with 5 mumol/L verapamil. 3. Over 15 min, verapamil dramatically reduced the maximum shortening attained. This was associated with delay in both excitation-contraction coupling latency and the time at which maximum rate of shortening occurred. However, peak shortening was recorded earlier in the contraction cycle. Total cell-cycle time was abbreviated under the influence of verapamil and maximum rates of shortening and lengthening were depressed in a similar manner. 4. The results highlight the value of improved temporal precision in describing myocyte contractility and validate the use of the parameters defined in the single-cell model for the study of the mechanisms of action of cardiotonic agents.

Animals↗