Comparison of the effects of sleep, exercise and autonomic drugs on ventricular extrasystoles, using ambulatory monitoring of electrocardiogram and electroencephalogram.

Ambulatory monitoring of the electrocardiogram (ECG) and the electroencephalogram (EEG) in 12 untreated patients with frequent ventricular extrasystoles showed a significant decrease in both ventricular extrasystoles and heart rate during sleep. The decrease in ventricular extrasystoles correlated more closely with the change in heart rate than with the level of arousal. During wakefulness, similar changes in ventricular extrasystoles and heart rate could be produced by the intravenous administration of propranolol and, to a lesser extent, by phenylephrine. Exercise produced an initial increase in ventricular extrasystoles, with suppression at higher levels in most patients. Thus, the frequency of ventricular extrasystoles is usually reduced at both extremes of heart rate, and the changes that occur during sleep can be explained by autonomic mediation, with the sympathetic limb of the autonomic nervous system having a greater effect than the vagus.

The effects of changes in diet on lipid levels and platelet thrombus formation in living blood vessels.

The work reported here describes an in vivo study over several days in each animal, of the formation and behaviour of platelet thrombi in injured living blood vessels in response to topically applied adenosine diphosphate (ADP) in rabbits fed initially on normal diets, then on experimental "saturated" or "polyunsaturated" diets. The effects of these diets on triglyceride fatty acids and on cholesterol and triglyceride levels are reported. It may be of significance that in each experiment the "polyunsaturated" and "saturated" diets appeared to be associated with an increased sensitivity to ADP greater than observed in rabbits on a normal diet or in normal animals in other studies.

Serum lipids in treated diabetic children and their families.

Fasting lipid concentrations have been measured in fifty treated juvenile diabetics, their siblings and parents to determine which types of hyperlipoproteinaemia co-exist with juvenile diabetes and whether the abnormalities relate to diabetic control, or represent familial disorders. Lipid concentrations amongst the parents did not differ from adult control. Triglyceride concentrations were significantly higher in those diabetic children with fasting blood glucose concentrations greater than 10 mmol/l than those with concentrations less than 10 mmol/l. The latter group had similar triglyceride levels to non-diabetic siblings. Cholesterol concentrations were not related to fasting blood glucose and were similar in diabetic and sibling controls. Hyperlipoproteinaemia (types IIa, IIb and IV) was present in ten of the diabetic patients. Six of the nine diabetic patients with raised cholesterol had at least one parent with cholesterol in the highest quintile for the control population, whereas only six of the forty-one with lower levels had parents in this category. A similar trend for cholesterol was apparent amongst the non-diabetic siblings. However, no association was apparent between the triglyceride levels of diabetics (or their siblings) and parents. Thus although hyperlipidaemia associated with juvenile diabetes appears to be largely due to inadequate control, raised cholesterol concentrations frequently occur.

The effects of treatment with aspirin and an antithrombotic agent SH1117 upon platelet thrombus formation in living blood vessels.

The work reported here describes an in vivo study, over several days in each animal, of the formation and behaviour of platelet thrombi in injured living blood vessels in response to topically applied adenosine diphosphate in rabbits which have been treated with oral doses of SH1117 alone or together with acetyl-salicylic (ASA) before and after i.v. injection of alloxan. These two substances SH1117 and ASA when given together display a synergism which is similar to that described for dipyridamole and ASA, but the antithrombotic action of SH1117 and ASA seems to be more profound. It may be of significance that oral SH1117 given alone appears to confer a degree of insensitivity of the injured vessel in its response to ADP, as such an effect is not displayed by dipyridamole.

A simple method of measuring tremor using a variable-capacitance transducer.

A simple, inexpensive method of recording tremor, using a variable-capacitance transducer, is described. Technical details of the transducer are given, along with examples of tremor traces illustrating the transducer's ability to monitor parkinsonian patients during drug therapy.

The synergistic effect of aspirin and dipyridamole upon platelet thrombi in living blood vessels.

In rabbits previously injected i.v. with alloxan, serial observations of platelet thrombus formation in response to topical adenosine diphosphate (ADP) at sites of electrical injuries in pial arteries have been made. Using this model we have studied the effects of oral daily doses of dipyridamole (Persantin) and acetyl salicylic acid (ASA) upon platelet thrombus formation. Oral daily doses of 42 mg of ASA and 6 mg dipyridamole given separately in alloxan-treated rabbits are without effect. When given together orally, 42 mg and 6 mg respectively reduced the level of sensitivity to ADP for producing platelet thrombi to that established for the rabbits before the injection of alloxan. But withdrawal of these combined doses of dipyridamole and ASA caused the sensitivity of ADP for platelet thrombus formation to be raised to the much increased level present in rabbits soon after they are given i.v. alloxan. This apparent synergistic behaviour displayed by dipyridamole and ASA in these rabbits results in antithrombotic effects which are clearly absent when these two agents are given separately. It is of interest that the dose levels used here are equivalent, an a body weight ratio, to those being used in man in the current Persantin-Aspirin Reinfarction Study.

Clinical trial of the beta-adrenoreceptor-blocking agent tolamolol with the use of 24 hour blood pressure recordings.

1. The average blood pressure over 24 h and its variability were measured in eight unrestricted subjects before and after commencing therapy with a new beta-adrenoreceptor-blocking agent, tolamolol. 2. The drug caused a fall of 15 +/- 6 mgHg in mean arterial pressure and heart rate fell by 13 beats/min. The variation in blood pressure and heart rate over 24 h was unchanged after treatment.

Blood pressure variability in patients on beta-blockers.

The direct arterial blood pressure was monitored over 24 hours in unrestricted untreated patients in order to obtain the average pressure and standard deviation over 24 hours. The standard deviation was taken as the index of variability of pressure. In eight subjects the study was repeated three months after commencement of treatment with a beta-adrenergic blocking agent (tolamolol, 300 mg/day). In these subjects tolamolol resulted in a fall in mean blood pressure from 107 to 92 mmHg (P less than 0-05) and a fall in heart rate from 82 to 70 beats per minute (P less than 0-01). The variability in blood pressure, however, was unaffected by treatment.

The reversibility by dipyridamole of the increased sensitivity of in vivo platelet aggregation in rabbits after alloxan.

Rabbits hyperglycaemic after previous intravenous injection with alloxan show an increased sensitivity of the aggregation of platelets to adenosine diphosphate applied topically to injured arteries. This increased sensitivity is completely reversed by treatment with oral dipyridamole but returns if the dipyridamole is withdrawn.

Increased sensitivity of in vivo platelet aggregation in rabbits after alloxan or streptozotocin.

In 14 rabbits previously injected intravenously with alloxan (dose 75-150 mg/kg) with subsequent hyperglycaemia, intra-arteriolar aggregation of platelets at the sites of small standardized electrical injuries to cerebral cortical vessels showed an increased sensitivity (P is less than 0.001) to application of adenosine diphosphate (ADP) in animals anaesthetized with either urethane or Pentothal. Intravenous injection of streptozotocin (10 rabbits, dose 30-200 mg/kg) was not followed so regularly by hyperglycaemia but even so many of these animals also showed increased sensitivity to ADP. After neither alloxan nor streptozotocin did the increased sensitivity correlate with the dose of agent used, the time between its injection and ADP testing, or changes in the rabbit's body weight. Again, ADP sensitivity did not correlate with the degree of hyperglycaemia, hyperketonaemia or hyperlactacidaemia. There was no rapid change in ADP sensitivity after i.v. injection of glucose to produce hyperglycaemia in normal rabbits, nor after parenteral or topical administration of insulin. Use of a removable skull capsule allowed serial observations on individual animals and these, together with observations on rabbits injected first with alloxan and later with daily insulin, showed reversibility of the increased ADP sensitivity by regular insulin injection for at least 5 days; this effect did not depend upon return of blood glucose levels to normal. In cross-perfusion experiments the increased ADP sensitivity was found to be dependent upon a blood factor for such sensitivity was shown by the head of a normal rabbit perfused with blood from a diabetic trunk. The results did not exclude a contribution of a mural factor to the results in intact animals after alloxan. The results are in keeping with in vitro observations of increased sensitivity to ADP of platelet aggregation in diabetic patients and demonstrate that such an effect holds within living blood vessels, as well as providing a model for further experiment.

Sleep and blood pressure.

Direct arterial pressure was recorded continuously over 24 hours in 18 totally unrestricted people (six normotensives, four untreated hypertensives, and eight treated hypertensives). There was an almost equal fall of about 20% in both systolic and diastolic blood pressure during sleep in the three groups when compared with their waking pressures. This fall in pressure was greater than that observed previously in patients sleeping in a laboratory or hospital. Furthermore, it suggests that hypertensive subjects do not have a higher centrally-induced vasoactive component and that hypotensive drugs do not alter the pattern of blood pressure behaviour induced by sleep.

Continuous recording of direct arterial pressure in unrestricted patients. Its role in the diagnosis and management of high blood pressure.

We have compared casual indirect measurements of arterial pressure obtained 1) by the general practitioner (GP) and 2) in the outpatient clinic (OPC) with 24 hour continuous recording of direct arterial pressure in two selected group of unrestricted patients. 1) Eight asymptomatic, untreated patients with suspected hypertension. 2) Eight asymptomatic, treated patients whose indirect pressure readings seemed inappropriately high when considered against a general absence of target organ damage. Both groups showed that usually there was good agreement between arterial pressure recorded indirectly by GP and OPC while continuous recording showed wide variability of systolic and diastolic pressures over 24 hours and a significant fall during sleep. The first groups with suspected hypertension showed that the indirect measurements were not significantly different from the 24 hour direct recording. The second group of patients on treatment for hypertension showed a discrepancy, the direct readings being significantly lower than the indirect. This difference (approixmately 30 mm Hg mean arterial pressure) would explain the lack of target organ damage and may have been due to the effect of exercise augmenting the hypotensive action of drugs or due to a well developed defense reflex which biased the indirect readings.

Direct arterial pressure, heart rate, and electrocardiogram during cigarette smoking in unrestricted patients.

Direct arterial pressure, heart rate, and ECG have been recorded over a 24-hour period in nine individuals who were completely unrestricted throughout the study. Forty-nine separate cigarette smoking episodes were clearly indicated and analyzed. The results of our study confirm a significant increase in arterial pressure five minutes after smoking a cigarette. The systolic rise in pressure (mean 10.7 mm. Hg, P less than 0.001) was approximately twice that of the diastolic rise (5.3 mm. Hg, P less than 0.001) and was present under different conditions of everyday life with notable exception of lying in bed before sleep, We found no quantitative difference between normotensive and hypertensive subjects. There was no certain change in heart rate (mean increase +0.8 beats per minute, t equals 0.59, NS) in the group as a whole. Smoking also had a short-term action consisting of a brief fall in arterial pressure and heart rate occuring over eight to ten heart beats following immediately after the first inhalation of tobacco smoke, followed by a rebound rise in arterial pressure to a level greater than the presmoking level; this is probably a vagal effect. Cigarette smoking caused angina pectoris in one individual and the records showed ST-segment depression in the ECG before the subjective appreciation of pain.