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Biomedical subjects

L G Howes

Publications and source records attributed to L G Howes.

At least 73 records · Page 4Linked to original sources
PubMed1992

Pressor dose responses and baroreflex sensitivity in quadriplegic spinal cord injury patients.

OBJECTIVE: To assess the relative contribution of impaired baroreceptor reflexes and enhanced cardiovascular reactivity to the exaggerated blood pressure rises which occur in quadriplegic spinal cord injury patients with automatic hyperreflexia. DESIGN: Pressor dose responsiveness was evaluated by determining the steady-state dose of phenylephrine, alpha-methylnoradrenaline and angiotensin II required to achieve a blood pressure rise of 20 mmHg and the steady-state dose of isoprenaline required to increase heart rate by 20 beats/min in eight quadriplegic spinal cord injury patients and eight control subjects. RESULTS: The dose of phenylephrine alpha-methylnoradrenaline and angiotensin II to achieve a rise in blood pressure of 20 mmHg was significantly reduced in the spinal cord injury group, whilst the dose of isoprenaline required to raise heart rate by 20 beats/min did not differ significantly from the control group. Baroreceptor sensitivity, assessed by straight line regression of change in heart period with change in blood pressure during steady-state infusions of phenylephrine, did not differ statistically between the two groups, but the results could not exclude some evidence of impairment in the spinal cord injury patients. Baroreceptor sensitivity was much less variable in spinal cord injury patients than in controls. CONCLUSIONS: These findings suggest that quadriplegic patients with spinal cord injury have exaggerated pressor responses with significantly less variability in baroreflex sensitivity. The former probably contributes to the autonomic hyperreflexia seen in these patients. The latter provides some support to the suggestion that centrally mediated psychogenic responses contribute to the variability in baroreceptor sensitivity seen in normal subjects.

Adult↗
PubMed1992

Steady-state pharmacokinetics and pharmacodynamics of cilazapril in the presence and absence of cyclopenthiazide.

Twenty-two patients with essential hypertension received a single dose of 2.5 mg cilazapril and were then randomised into a double-blind parallel group study to receive either placebo, 1.25 mg cilazapril + 0.5 mg cyclopenthiazide (CPTZ), 2.5 mg cilazapril + 0.5 mg CPTZ, or 2.5 mg cilazapril alone for 1 month. After oral administration of a single dose of 2.5 mg cilazapril, the active diacid cilazaprilat appeared rapidly in the plasma (Tmax 2.0 +/- 0.2 h). With the radioinhibitor assay used in this study, a single elimination phase of cilazaprilat was evident, with a half-life (t1/2) of 2-3 h. At steady state, the pharmacokinetics of cilazaprilat were similar to single-dose administration and were not altered by CPTZ. The Cmax and area under the curve (AUC) of cilazaprilat were directly proportional to dose. Cilazapril administration in the dose range of 1.25-2.5 mg produced a dose-proportional inhibition of angiotensin-converting enzyme (ACE) activity that was maximum 2 h after drug administration. The degree of ACE inhibition correlated with the plasma concentration-time profile of cilazaprilat and the maximum decrease in blood pressure (BP). The EC50 for ACE inhibition by cilazaprilat was 7.7 ng/ml after acute treatment and was not significantly altered during chronic administration or by concomitant administration of CPTZ. There was no evidence of a dose-related antihypertensive effect of cilazapril at steady state and, with the small numbers of subjects used in this study, there was no evidence of 24-h BP control with monotherapy.

Aged↗
PubMed1992

Comparison of the pharmacokinetics and pharmacodynamics of perindopril, cilazapril and enalapril.

1. The pharmacokinetic and pharmacodynamic responses to enalapril, perindopril and cilazapril have been studied in essential hypertensives (2, 4 and 8 mg perindopril and 2.5 mg cilazapril, single dose and steady state) and normotensive volunteers (10 mg enalapril, single dose). 2. Plasma levels of the active diacid compounds reached similar peaks after single dose administration of the drugs. However, perindoprilat levels persisted for 5 days whereas cilazaprilat levels were not detectable beyond 12 h. 3. The higher levels of perindoprilat were associated with a greater inhibition of plasma angiotensin-converting enzyme (ACE) activity in both acute and steady state studies. 4. The potency of the active diacids in inhibiting plasma ACE activity was perindoprilat greater than cilazaprilat greater than enalaprilat. 5. There was a close relationship between plasma concentration, ACE inhibition and blood pressure decrease. Although both cilazapril and perindopril administration reduced blood pressure in hypertensive subjects, only perindopril exerted 24 h blood pressure control at the doses used.

Adult↗
PubMed1991

Cardiac risk factor management. Experience of an outpatient hypertension clinic.

OBJECTIVE: To describe the outcome of the management of cardiovascular risk factors in the hypertension clinic of a teaching hospital over a five-year period. DESIGN: Retrospective analysis of risk factor data (blood pressure, plasma cholesterol level, body weight, smoking and drinking habits) obtained from computerised hypertension clinic progress report forms. SETTING: Public teaching hospital. PATIENTS: One hundred and thirty-one patients referred to the clinic from both general practice and from within the hospital who attended the clinic regularly during the five-year study period. INTERVENTION: Long term management of hypertension and coexisting coronary risk factors by dietary, medical and lifestyle intervention. RESULTS: There was a significant improvement in diastolic blood pressure control in 1990 versus 1986 in both men and women, while systolic blood pressure improved in women only. The number of patients controlled with monotherapy increased from 38% in 1986 to 45% in 1990. Eighty-nine per cent of the men and 85% of women remained above their maximum desirable weight. Reported levels of alcohol consumption were low and the proportion of smokers was below that of the general population. A significant decline in plasma total cholesterol levels was observed in the women. Despite dietary advice and a limited use of lipid lowering drugs, 53.2% of the men and 66.1% of the women continued to have total plasma cholesterol levels above 5.5 mmol/L in 1990. High density lipoprotein levels increased significantly in the women only. CONCLUSION: A high proportion of our clinic patients have well controlled hypertension, but the clinic program produced little evidence of improvement in risk factors in men stabilised by long term therapy. More intensive methods of achieving lifestyle modification and a wider use of lipid lowering drugs may be needed if we are to achieve satisfactory body weights and lipid profiles in hypertensive patients.

Ambulatory Care Facilities↗
PubMed1991

Comparative effects of angiotensin converting enzyme inhibition (perindopril) or diuretic therapy on cardiac hypertrophy and sympathetic activity following myocardial infarction in rats.

The long-term effects of perindopril or chlorothiazide therapy were studied in rats after the induction of myocardial infarction by coronary artery ligation. Rats with infarction developed marked cardiomegaly, indicating the presence of chronic left ventricular dysfunction. The ratio of the norepinephrine metabolite, 3,4-dihydroxyphenylethylene glycol (DHPG) to norepinephrine (NE) was elevated in the right ventricle of rats with infarction, suggesting a chronic increase in cardiac sympathetic activity. Perindopril therapy commenced either immediately following infarction or 4 weeks following infarction reduced DHPG/NE ratios toward normal levels, and prevented or reversed cardiac hypertrophy. In contrast, chlorothiazide therapy significantly reduced DHPG/NE ratios but did not decrease cardiac hypertrophy. Perindopril reverses or prevents cardiac hypertrophy and chronic cardiac sympathetic hyperactivity following myocardial infarction, while chlorothiazide reduces cardiac sympathetic activity without influencing cardiomegaly.

Angiotensin-Converting Enzyme Inhibitors↗
PubMed1991

Diurnal blood pressure variation in quadriplegic chronic spinal cord injury patients.

1. Measurement of blood pressure and heart rate over a 24 h period was performed in 10 quadriplegic spinal cord injury patients and 10 immobilized, neurologically intact orthopaedic subjects by using the Spacelabs 90207 automated ambulatory monitoring system. 2. Systolic and diastolic blood pressure fell significantly at night in orthopaedic subjects but not in quadriplegic patients, and night-time blood pressures were similar in both groups. 3. Cumulative summation of differences from a reference value (cusum analysis) confirmed a markedly diminished diurnal blood pressure variation in the quadriplegic patients. 4. These findings could not be accounted for on the basis of blood pressure variations during chronic postural change. 5. Heart rate fell significantly at night in both groups. 6. The findings suggest that the increase in blood pressure during waking hours in neurologically intact subjects is a consequence of a diurnal variation in sympathetic activity (absent in quadriplegic patients with sympathetic decentralization) which is independent of changes in physical activity.

Adult↗
PubMed1991

Altered alpha 1-adrenoceptor-mediated responses in atria of rats with chronic left ventricular infarction.

Phosphoinositide (PI) turnover, chronotropic and inotropic responses to alpha 1-adrenoceptor activation, and alpha 1-adrenoceptor density were studied in atria from rats with left ventricular myocardial infarction (LVMI) and noninfarcted rats. LVMI was produced after surgical ligation of the left coronary artery in 8-week-old Wistar rats. Rats were killed 4 weeks after this operation when rats with LVMI had developed significant hypertrophy of both ventricles and atria. Phenylephrine 0.1 mM to 1 mM, with propranolol 0.3 mM, produced a concentration-dependent increase in heart rate (HR) in right atria from noninfarcted rat hearts, and this response was significantly reduced in rats with LVMI. In electrically driven left atria, the concentration-dependent, phenylephrine-induced positive inotropic responses observed with propranolol added were also significantly impaired in rats with LVMI as compared with those of noninfarcted rats. In contrast, neither PI turnover in response to phenylephrine in the presence of propranolol nor alpha 1-adrenoceptor density was reduced in rats with LVMI. These results suggest that the impaired alpha 1-adrenoceptor-induced chronotropic and inotropic responses in atria from rats with LVMI are not due to downregulation of alpha 1-adrenoceptors or to impaired activation of PI turnover after alpha 1-adrenoceptor stimulation, but to impairment of one or more biochemical responses distal to PI hydrolysis or changes in coupling mechanisms other than hydrolysis of PIs.

Animals↗
PubMed1991

Plasma noradrenaline in cirrhosis: a study of kinetics and temporal relationship to ascites formation.

The kinetics of plasma noradrenaline (NA) were studied in 14 patients with cirrhosis and ascites and 13 normal subjects. [3H]noradrenaline ([3H] NA) was infused intravenously to steady state and the spillover of NA into plasma and its clearance from plasma calculated. The increase in plasma NA in the cirrhotic patients was due to an increase in NA spillover (14.5 vs 3.9 nmol min-1m-2; P less than 0.001). NA plasma clearance was also increased in the cirrhotic patients (3.5 vs 2.11 min-1m-2; P less than 0.01). Plasma NA and dihydroxyphenylglycol (DHPG), a metabolite of NA of which a portion is formed after re-uptake of NA into sympathetic nerve endings, were then measured in 23 patients with cirrhosis and ascites, 17 patients with cirrhosis who had never had ascites, and 34 normal subjects. Both plasma NA and DHPG were significantly increased in the patients with ascites (NA 4.7, DHPG 14.7 nmol l-1 and in the patients with cirrhosis but no ascites (NA 3.8, DHPG 12.0 nmol l-1) compared with normal subjects (NA 1.9, DHPG 8.8 nmol 1-1). Therefore, the increase in plasma NA in cirrhosis is due to increased activity of the sympathetic nervous system rather than interference with the metabolism of NA or impaired neuronal uptake of NA. This increase appears to precede the development of ascites.

Adult↗
PubMed1991

Acute effects of exercise on plasma lipids, noradrenaline levels and plasma volume.

1. Total plasma cholesterol, high-density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), noradrenaline, haematocrit, haemoglobin and heart rate were measured in blood sampled from an antecubital vein in nine volunteers after 1 min standing and at intervals up to 1 h following 5 min of vigorous bicycle exercise. 2. Heart rates and plasma noradrenaline levels rose substantially immediately following exercise and gradually returned toward baseline levels 60 min post-exercise. 3. Total plasma cholesterol levels rose by 24% immediately post-exercise and slowly returned to baseline levels 60 min post-exercise. Similar changes were observed for LDL-C (20.2%) and HDL-C (27.7%). As a result, LDL:HDL ratios did not alter. 4. These changes in total plasma cholesterol, HDL-C and LDL-C were explained by changes in plasma volume that occurred as a consequence of vigorous exercise. 5. Changes in plasma volume may be a mechanism by which some environmental factors such as stress are associated with elevated plasma cholesterol levels.

Adult↗
PubMed1990

Role of metabolic risk factors in cardiovascular prognosis of systemic hypertension.

There is an increasing awareness of the need to manage multiple risk factors in hypertensive patients, and of possible adverse metabolic effects of antihypertensive drugs which may counteract their ability to reduce the risk of cardiovascular disease. Data collected from the Austin Hospital Hypertension Clinic support previous observations that the incidence of cardiovascular risk factors such as plasma lipid abnormalities are high in hypertensive patients, and although it is becoming easier to control blood pressure in these patients, modification of other risk factors is difficult. The use of diuretics in doses lower than those conventionally prescribed has been advocated as a means of reducing the adverse metabolic effects. However, data from this study suggest that although low-dose hydrochlorothiazide therapy (25 to 50 mg/day) may be as effective as conventional doses of captopril in reducing blood pressure, adverse metabolic effects on plasma potassium, glucose and uric acid levels remain a problem. Indapamide, a relatively new diuretic when used at a fixed dose (2.5 mg/day), appears to be devoid of significant adverse metabolic effects and is a useful alternative to thiazide diuretics. An integrated approach to the management of multiple cardiovascular risk factors is important in hypertensive patients and should include non-pharmacologic methods and the selection of antihypertensive drugs that do not have adverse metabolic effects.

Antihypertensive Agents↗
PubMed1990

The effects of a single dose of dilevalol on [3H]-noradrenaline plasma kinetics and plasma lipoprotein cholesterol concentrations.

1. A single oral dose of dilevalol (200 mg or 400 mg) or placebo was administered to 15 normal male volunteers in a double-blind, random order crossover study. 2. Dilevalol had no significant effect on supine blood pressures or heart rates, but caused a significant fall in systolic blood pressure 1 and 30 min following standing, and attenuated the rise in diastolic blood pressure and heart rate that accompanies standing. 3. Dilevalol caused a dose dependent increase in plasma noradrenaline levels from arterialized blood which was due to an increase in noradrenaline spillover with no change in clearance. 4. Dilevalol increased plasma levels of the noradrenaline metabolite 3,4-dihydroxyphenylethylene glycol (DHPG) (which is formed in sympathetic nerves following neuronal uptake of noradrenaline), indicating that the increase in noradrenaline spillover was not due to the blockade of neuronal uptake. 5. Acute dilevalol administration had no effect on total plasma cholesterol, HDL-cholesterol or LDL-cholesterol levels.

Adult↗
PubMed1990

Effects of regular alcohol consumption on 24 hour ambulatory blood pressure recordings.

1. Regular consumption of 1 g/kg of alcohol for 4 days did not significantly alter mean 24 h blood pressures compared with a similar period when dextrose was consumed to match caloric intake. 2. In contrast, the variability of diastolic blood pressure was increased by regular alcohol consumption. 3. Increased blood pressure variability in response to the stress of blood pressure measurement may contribute to the observed association between hypertension and alcohol consumption.

Adolescent↗
PubMed1990

Steady state plasma [3H]-noradrenaline kinetics in quadriplegic chronic spinal cord injury patients.

1. Steady state plasma noradrenaline kinetics were measured in eight male quadriplegic patients and in eight age and sex matched controls. 2. Plasma noradrenaline levels were significantly lower in quadriplegic patients compared to controls. Noradrenaline spillover rate was markedly reduced in quadriplegics compared to controls while noradrenaline clearance was similar in both groups. 3. Noradrenaline kinetics in quadriplegic patients differ from peripheral autonomic neuropathy patients where reductions in both the spillover and clearance of noradrenaline are present.

Adult↗
PubMed1990

Genealogy of the spontaneously hypertensive rat and Wistar-Kyoto rat strains: implications for studies of inherited hypertension.

The spontaneously hypertensive rat (SHR) is the most commonly used animal model of hypertension. For many years, it has been widely accepted that the most appropriate control strain is the Wistar-Kyoto (WKY) rat to which SHR rats are genetically related. However, recent concerns have been raised about genetic differences between the various colonies of SHRs and, in particular, genetic differences between colonies of WKY rats. It has been further emphasized that the only way to establish that a genetic trait is an etiological factor in the development of hypertension is through studies of F2 backcrosses between SHR and WKY rats. The present article details the history of the SHR and WKY strains and demonstrates why there is high likelihood of genetic variability between rats of both strains from different colonies around the world. It suggests that the WKY strain is not the most suitable for backcross studies because of the incidence of spontaneous hypertension and the somewhat higher levels of blood pressure in these rats. A central reference strain is proposed using SHRs inbred at Kyoto University, where brother/sister inbreeding has continued for more than 80 generations.

Animals↗
PubMed1989

Pharmacokinetics and antihypertensive effects of low dose clonidine during chronic therapy.

Using a sensitive and specific radioimmunoassay the pharmacokinetic disposition of clonidine was determined in hypertensive patients after a single dose and then after 5, 28 and 56 days of chronic dosing with 75 micrograms bd. Following a single dose of clonidine maximal plasma concentrations of 0.34 +/- 0.06 ng/ml were achieved after 3.6 +/- 1.2 hours. After 5 days of repetitive dosing the maximal concentration was significantly higher, 0.66 +/- 0.06 ng/ml and remained so throughout chronic therapy (P = 0.018). The AUC, Tmax and T1/2 did not differ significantly between the acute dose and the chronic dosing pharmacokinetic studies. Clonidine also produced a significant fall in blood pressure. Supine diastolic blood pressure fell from 106 +/- 5 mmHg predose to 99 +/- 6 mmHg 2 hours after the first dose (P less than 0.05). The corresponding values after cyclopenthiazide alone were 108 +/- 8 and 105 +/- 8 mmHg (P = 0.13). Similar falls in blood pressure were produced during chronic therapy.

Adult↗