Conversion of MHPG to vanillylmandelic acid. Implications for the importance of urinary MHPG.

Deuterium-labelled 4-hydroxy-3-methoxyphenylglycol (MHPG), when administered intravenously, is rapidly converted to 4-hydroxy-3-methoxymandelic acid (or vanillylmandelic acid [VMA]) or conjugates of MHPG. Since over half of either racemic D,L-MHPG or the natural D-MHPG is converted to VMA and since about half of urinary VMA is derived from MHPG, estimates of the proportion of urinary MHPG derived from the brain must be revised. The results indicate that only about one fifth of urinary MHPG is derived from the brain, and clearly urinary MHPG cannot be used as a valid index of brain norepinephrine metabolism. While these observations do not alter the value of urinary MHPG as a predictor of therapeutic response or in subclassifying affective disorders, it is clear that new research questions must be formulated and appropriate investigations completed before the relationship of urinary MHPG to affective disorders is understood.

Hydrocortisone-induced hypertension in humans: pressor responsiveness and sympathetic function.

Oral hydrocortisone increases blood pressure and enhances pressor responsiveness in normal human subjects. We studied the effects of 1 week of oral hydrocortisone (200 mg/day) on blood pressure, cardiac output, total peripheral resistance, forearm vascular resistance, and norepinephrine spillover to plasma in eight healthy male volunteers. Although diastolic blood pressure remained unchanged, systolic blood pressure increased from 119 to 135 mm Hg (SED +/- 3.4, p less than 0.01), associated with an increased cardiac output (5.85-7.73 l/min, SED +/- 0.46, p less than 0.01). Total peripheral vascular resistance fell from 15.1 to 12.2 mm Hg/l/min (SED +/- 1.03, p less than 0.05). Resting forearm vascular resistance remained unchanged, but the reflex response to the cold pressor test was accentuated, the rise in resistance increasing from 10.5 mm Hg/ml/100 ml/min (R units) before treatment to 32.6 R units after treatment (SED +/- 6.4, p less than 0.025). The rise in forearm vascular resistance accompanying intra-arterial norepinephrine (25, 50, and 100 ng/min) was also significantly greater after hydrocortisone, increasing from an average of 14.9 +/- 2.4 R units before treatment to 35.1 +/- 5.5 R units after hydrocortisone (SED +/- 6.0, p less than 0.05). A shift to the left in the dose-response relation and fall in threshold suggested increased sensitivity to norepinephrine after treatment. Measurement of resting norepinephrine spillover rate to plasma and norepinephrine uptake indicated that overall resting sympathetic nervous system activity was not increased. The rise in resting blood pressure with hydrocortisone is associated with an increased cardiac output (presumably due to increased blood volume).(ABSTRACT TRUNCATED AT 250 WORDS)

Variations in endothelial function and arterial compliance during the menstrual cycle.

Female sex hormones have been implicated in the cardioprotection of premenopausal women. However, the cardiovascular actions of these hormones and the effects of their natural fluctuations during the menstrual cycle are not fully understood. We studied changes in vascular function during the menstrual cycle in 15 healthy premenopausal women. Four noninvasive procedures were performed during the early follicular (EF), late follicular (LF), early luteal (EL), and late luteal (LL) phases: flow-mediated dilatation (FMD) of the brachial artery during reactive hyperemia, laser Doppler velocimetry (LDV) with direct current iontophoresis of acetylcholine (ACh) and nitroprusside, whole body arterial compliance (WBAC), and pulse wave velocity. Hormone levels were consistent with predicted cycle phase and showed that all subjects ovulated during the cycle studied. FMD, LDV with ACh, and WBAC varied cyclically, with significant increases from the F to LF phase, sharp falls in the EL phase, and significant recoveries in the LL phase. These changes were most marked for FMD [EF, 8.8 +/- 0.6% (mean +/- SEM); LF, 10.0 +/- 0.7; EL, 4.2 +/- 0.6; LL, 8.6 +/- 0.9] and the LDV response to ACh (EF, 2.7 +/- 0.2 V/min; LF, 3.3 +/- 0.4; EL, 1.8 +/- 0.3; LL, 2.7 +/- 0.4). WBAC changed similarly (EF, 0.58 +/- 0.08 arbitrary units; LF, 0.84 +/- 0.06; EL, 0.65 +/- 0.05; LL, 0.68 +/- 0.06). Sodium nitroprusside-induced vasodilatation decreased significantly from EF to EL, with no other significant difference, and pulse wave velocity did not vary significantly over the four time points. Conductance and resistance artery endothelial reactivity and smooth muscle sensitivity to nitric oxide and arterial compliance are modulated significantly in response to the changing hormonal patterns of the menstrual cycle. These findings emphasize the importance of menstrual phase in the interpretation of data on endothelial function and may provide insights into the mechanisms underlying sex differences in cardiovascular risk and other disease processes in premenopausal women.

Intermittent claudication. An update on management.

The mainstay of treatment for claudication is reversal of risk factors, especially smoking, and the use of antiplatelet drugs and possibly pentoxifylline. A major factor in the long term management is atherosclerotic involvement in other parts of the circulation resulting in a shortened life span. Treatment should be directed at the disease in general, rather than in the legs alone. Patients disabled by claudication may gain symptomatic relief with relatively low risk using balloon angioplasty or vascular reconstructive procedures.

Action of propranolol on arterial pressure and on cardiovascular reflexes.

In the rabbit, administration of 500 mug (+/-) propranolol into the lateral cerebral ventricle resulted in rapid leakage of drug into the blood. The drug produced a small reduction in blood pressure at 2 and 4 hours after injection but because of the rapid leakage, this could have been due to its peripheral actions. To investigate possible central mechanisms of action which were independent of peripheral effects, we tested the action of intravenously administered propranolol on the reflex rise in TPR evoked in rabbits by graded Valsalva-like manoeuvres. This was performed in unanaesthetised rabbits with Doppler flowmeters for measuring cardiac output. Graded expiratory pressures (EP) were applied to the inlet and outlet tubes of the tracheotomised animal's respiratory valve and to the cuff around their thorax and abdomen. Administration of propranolol at two levels (168 +/- 35 ng/ml, and 240 +/- 33 ng/ml) for 1 hour had no effect on slope and threshold of the EP-TPR relationship. By contrast to the minimal effects on the reflex with propranolol, the EP-related rise in TPR was attenuated by clonidine. We conclude that propranolol does not lower blood pressure in the rabbit by attenuating sympathetic constrictor activity.

The role of coronary artery disease in complications of abdominal aortic aneurysm surgery.

Coronary artery disease (CAD) is a major cause of morbidity and mortality after elective surgical repair of abdominal aortic aneurysm (AAA). The aim of this study was to determine the relationship between the extent of CAD observed in coronary angiograms (more than 50% stenosis) and the frequency of postoperative myocardial ischemic complications in a consecutive series of 84 patients who underwent elective AAA repair. Ninety-four percent of the patients with clinical evidence of CAD had significant disease as observed in coronary angiograms and eight patients had left main CAD. Seventy-two patients underwent AAA repair with a mortality rate of 1.4%; five patients had preliminary myocardial revascularization, and AAA surgery was not recommended for four patients because of severe cardiac disease. Postoperative myocardial ischemic complications occurred in 13.4% of the patients who had undergone surgery--almost exclusively in patients with clinical evidence of CAD. Both myocardial ischemia and preoperative intervention were more frequent in patients with double- or triple-vessel disease than in patients with less extensive disease. Patients with symptoms and with double- or triple-vessel CAD have a high risk of developing myocardial ischemia after AAA surgery. Preliminary myocardial revascularization may be beneficial in this group of patients.

Safety studies with the University of Melbourne multichannel electrotactile speech processor.

Results of safety investigations conducted as an integral part of the development of a multichannel electrotactile speech processor (Tickle Talker) are reported. Electrical parameters of the stimulus waveform, design of the electrode handset and cabling, and the electrical circuitry of the speech processor/stimulator and programming interface have been analyzed for potential risks. Constant current biphasic square pulses delivered to electrodes positioned on the skin surface over the digital nerve bundles were chosen to optimize the safety, comfort, and function of the electrotactile stimulus. The device was battery-powered, and the user circuit was isolated from earth-referenced sources. Each electrode was isolated by capacitive coupling, preventing DC leakage of current to the user circuit. Studies of finger temperature showed slight cooling of the skin on the fingers of both stimulated and unstimulated hands for individual subjects following electrotactile stimulation through the Tickle Talker. Subsequent analysis of finger and hand vascular circulation in five subjects showed slight reductions in hand blood flow in some individuals. The results did not demonstrate a significant mean decrease in hand or finger blood flow following electrotactile stimulation. No evidence of sympathetic involvement was found, nor were any changes in vascular structure of the hand such as those associated with Raynaud's disease found. Evidence suggests that the decrease in temperature found in the initial study may be due to a change in the ratio of blood flow between arteriovenous anastomoses and nutritive capillary beds. Studies of: 1) changes in mean threshold and comfortable pulse widths over time; and, 2) changes in tactual sensitivity as measured by hot/cold, sharp/dull, and two-point difference limen discrimination, did not detect any systematic change in peripheral nervous system function following electrotactile stimulation. Analysis of electroencephalogram (EEG) recordings taken during electrotactile stimulation, and after relatively long periods of experience with the device did not show any pathological changes which might be associated with epileptic foci. In summary, no contraindications to long-term use of the Tickle Talker were detected in the studies performed.

A review of reflex sympathetic dystrophy.

Reflex sympathetic dystrophy, or as it is now known, complex regional pain syndrome, Type 1, is an unusual complication of a variety of injuries whose development should be suspected in the presence of disproportionate pain coupled with autonomic disturbance. Early recognition and treatment with multimodality therapy offer a high probability of recovery.

Cardiac and pulmonary norepinephrine release and removal in the dog.

Norepinephrine extraction and spillover rates were determined in the heart and lungs of anesthetized dogs under resting conditions, during sympathetic stimulation, and during epicardial pacing. The fractional extraction of norepinephrine across the coronary and pulmonary vascular beds was measured from the venoarterial difference in tritiated norepinephrine after infusion of a tracer dose to a steady state level. Cardiac extraction averaged 0.299 +/- 0.03 and pulmonary extraction averaged 0.215 +/- 0.014; extraction was unaffected by sympathetic stimulation or pacing. Norepinephrine spillover from sympathetic nerve terminals in the heart and lungs was measured from the venoarterial difference in endogenous norepinephrine and plasma flow after correction for the extraction component. Cardiac norepinephrine spillover increased linearly with increasing frequency of sympathetic stimulation to 7.44 times resting levels at 2 Hz. During pacing, there was no change in cardiac norepinephrine spillover despite marked changes in heart rate. Norepinephrine spillover was demonstrated under resting conditions in the lung and was greater than observed in the heart. Pulmonary norepinephrine spillover increased with sympathetic stimulation to 4.15 times resting levels at 2 Hz. It is possible to separate the contributions of norepinephrine extraction and spillover to measured venoarterial differences of norepinephrine under physiological conditions in the dog.

Relative contributions of aortic and carotid sinus baroreceptors to the baroreceptor-heart rate reflex of the conscious rabbit.

Conscious rabbits with previously implanted perivascular balloons for altering blood pressure were studied before and 6 days after: (i) sham-operation (n = 6); (ii) section of carotid sinus nerves alone (n = 7); (iii) section of aortic nerves alone (n = 5); and (iv) combined sino-aortic denervation (n = 5). Sigmoid mean arterial pressure (MAP)-heart period (HP) baroreflex curves were derived and were characterized by: (i) the HP range (HPR) between upper and lower plateau levels; (ii) the median blood pressure (BP50); and (iii) the average gain (G). Resting MAP and HP and the 3 baroreflex parameters were not altered significantly 6 days after sham-operation. After section of the carotid sinus nerves alone resting MAP and BP50 rose by 18 +/- 2.6 mm Hg, resting HP fell by 31 +/- 4.2 msec, whilst HPR and G fell to about 45% and 20 % respectively of initial preoperative control. After cutting the aortic nerves alone there was a similar fall in resting HP as after carotid denervation. However, the rises in resting MAP and BP50 were only about half of those observed after carotid denervation (P < 0.05) and the changes in HPR and G to 65% and 58% of control respectively were also less marked (P ¿ 0.01). The aortic baroreceptor zone also exerted smaller effects on the sympathetic efferent component of the baroreflex HP response. Despite the different effects exerted by each zone on the reflex parameters there was little difference in threshold pressure for producing cardiac slowing. After combined sino-aortic denervation there was a similar rise in resting MAP (19 mm Hg) as after carotid sinus denervation alone, but there was more marked tachycardia, with a fall in resting HP of 82 msec (P < 0.001) and both resting and baroreflex-mediated vagal tones were completely abolished. The small residual pressure-determined HP changes of about 8 msec were entirely sympathetic and probably mediated through cardiopulmonary baroreceptors.

Role of aortic and carotid sinus baroreceptors on Valsalva-like vasoconstrictor and heart rate reflexes in the conscious rabbit.

Graded 30 s manoeuvers were used to elicit cardiovascular responses in conscious instrumented rabbits by applying pressures from 2.5 to 20 mm Hg (Valsalva Pressure, VP) to the animal's respiratory valve and to a sphygmomanometer cuff wrapped around its thorax and abdomen. In normal rabbits the Valsalva-like manoeuvers elicited VP-related rises in total peripheral resistance (TPR), heart rate and in right atrial pressure (RAP), VP-related fall in cardiac output (CO) and no change in mean arterial pressure (MAP). The rises in TPR and heart rate and the maintenance of MAP were reflexly mediated, whilst the CO and RAP changes were largely a mechanical consequence of the manoeuver as assessed from the responses after autonomic effector blockade. In rabbits with selective section of the carotid sinus nerves the reflex responses were little altered from normal, but after selective section of the aortic nerves there was significant attenuation of the TPR response, indicating that the input from the aortic baroreceptors was more important for this response than that from the carotid receptors. After combined denervation of the aortic and carotid baroreceptor zones (but with the vagi intact) the reflex TPR and heart rate changes were completely abolished, with the responses the same as after autonomic effector block. The results indicate that the arterial baroreceptor zones make a major contribution to the reflex cardiovascular responses to the Valsalva manoeuver in the rabbit and that any reflex effects of cardiopulmonary baroreceptor stimulation are only expressed in the presence of an intact arterial baroreceptor input.

Effect of ketamine, althesin, and thiopentone on the Valsalva-constrictor and heart rate reflexes of the rabbit.

The circulatory effects of Valsalva-like manoeuvers were studied before and during i.v. infusions of either ketamine, Althesin and thiopentone given in doses that produced similar levels of light anesthesia. The Valsalva-like manoeuvers were of 30 s duration and consisted of applying Valsalva pressures (VP) from 2.5 to 20 mm Hg to the animal's respiratory valve and to a cuff placed around its thorax and abdomen. In the conscious rabbit the major reflex responses to the Valsalva-like manoeuver were VP-related rises in total peripheral resistance (TPR) and in heart rate which were mainly mediated through intrathoracic baroreceptors and were completely abolished by sino-aortic denervation. Ketamine depressed the Valsalva-TPR response by about 30-40% but Althesin and thiopentone were without effect. Ketamine and thiopentone produced marked depression of the Valsalva-heart rate reflex, but Althesin had relatively little effect. We concluded that ketamine produces greater impairment of blood pressure homeostasis mediated through constrictor and heart rate reflexes evoked through arterial and cardiopulmonary baroreceptors than the other two anesthetics.

Valsalva vasoconstrictor reflex in human hypertension in after beta-adrenoreceptor blockade in conscious rabbits.

1. A Valsalva-like manoeuvre was used to elicit graded rises in total peripheral resistance (TPR) in conscious rabbits. The rises were reflex and mediated through sympathetic constrictors. Propranolol infused at different rates reaching plasma concentrations up to 240 (SEM 33) ng/ml had no effect on this reflex but reduced mean arterial pressure. However, the response was attenuated by clonidine in a dose-dependent manner. 2. Valsalva manoeuvres were used to elicit graded sympathetically mediated rises in TPR index in twenty-nine subjects with mean arterial pressure ranging from 75 to 165 mmHg. Absolute sensitivity of the constrictor response increased with rising resting TPR index, resulting in some enhancement of constrictor responses in the hypertensive subjects. It seems likely that non-autonomic factors (e.g. vessel structure) rather than hyperactive neural constrictor effects are involved in the enhanced constrictor responses in essential hypertension.

The use of regional, low dose streptokinase in recently thrombosed arterial grafts.

Between August 1983 and January 1985, 20 patients aged 33-77 years, with occluded lower limb bypass grafts, were on 23 occasions treated with streptokinase via intra-arterial infusion. Streptokinase (5000 units/h) was effective in clearing occluded grafts in 15 patients on 16 occasions. The median duration of occlusion in these patients was 5 days and the median duration of streptokinase infusions was 24 h. Completion angiography following streptokinase thrombolysis revealed five graft stenoses and 12 outflow stenoses or occlusions. In two grafts no cause for graft failure could be identified. These results permitted the surgeon to make an accurate pre-operative assessment of the definitive therapy required to ensure graft patency.