Cardiovascular, biochemical and hormonal changes during food-induced hypotension in chronic autonomic failure.

The cardiovascular, biochemical and hormonal responses to a standard test meal have been investigated in patients with chronic autonomic failure and normal subjects. In autonomic failure there was a rapid (within 15 min), substantial and prolonged fall in blood pressure after the meal. A marked fall in blood pressure also occurred after a liquid meal of similar composition and caloric content, with no change in blood pressure in age-matched subjects with normal autonomic function. In autonomic failure after the test meal the blood pressure reached its nadir (45% fall) after 60 min, and had not returned to pre-meal levels after 3 h. There were no changes in cutaneous and forearm blood flow. In the normal subjects there were no changes in blood pressure after the meal; forearm blood flow fell and cardiac output increased. In autonomic failure there were no changes in plasma noradrenaline levels, unlike the normal subjects. Plasma adrenaline levels were unchanged in both groups. There was a similar rise in levels of plasma renin activity in both groups. The haematocrit and plasma osmolality did not change in either group. Changes in plasma glucose and plasma insulin levels were similar in both groups. The responses of 3 pancreatic gut peptides, neurotensin, pancreatic polypeptide and enteroglucagon, were greater in autonomic failure. Basal levels and responses of vasoactive intestinal polypeptide, cholecystokinin-8 and somatostatin were similar in both groups. The motilin response was greater in normal subjects. We conclude that in patients with autonomic failure there was a rapid, substantial and prolonged fall in blood pressure after a meal. This reduction in blood pressure was not counteracted by an increase in sympathetic nervous activity and other compensatory changes, as occur normally. It was unlikely that osmotic effects of the meal or gut secretions resulted in a significant loss of intravascular fluid into the gut. The fall in blood pressure probably results from vasodilatation within the splanchnic circulation, to which pancreatic and gastrointestinal hormones with vasodilatory actions may contribute.

Unmasking of the cardiovascular effects of carbohydrate in subjects with sympathetic denervation.

The cardiovascular, biochemical and hormonal effects of a standard meal and two differing carbohydrates have been studied in normal subjects and in patients with autonomic failure (AF) and impaired cardiovascular reflexes. In the normal subjects blood pressure (BP) was unchanged after a meal and oral glucose. In AF patients, however, there was a marked and prolonged fall in BP after the meal. A similar fall occurred after oral glucose with only a small fall after oral xylose. In normal subjects, the meal and glucose raised plasma noradrenaline levels, unlike in AF patients, in whom noradrenaline and adrenaline levels were unchanged. In normal subjects with intact autonomic reflexes there are minimal cardiovascular effects induced by a meal or glucose. In AF subjects neural mechanisms are impaired, which probably unmasks the primary effects of food ingestion. The ability of glucose, but not xylose, to induce a similar degree of hypotension suggests that insulin may play an important role in postcibal hypotension.

Naloxone does not affect the cardiovascular, sedative or neurohormonal effects of clonidine in normal and hypertensive man.

The possibility that some of the cardiovascular, sedative or neurohormonal effects of clonidine are mediated by opiate receptors was investigated in normotensive and hypertensive subjects. In normal subjects intravenous (i.v.) clonidine lowered blood pressure, increased sedation and raised levels of plasma renin activity and growth hormone. Levels of other anterior pituitary hormones (prolactin, luteinizing hormone and follicle stimulating hormone) and of arginine vasopressin were unchanged. The effects of clonidine were similar after the administration of naloxone. In patients with essential hypertension clonidine lowered blood pressure, increased sedation and reduced plasma noradrenaline levels. There was an insignificant fall in levels of plasma renin activity. Prior administration of naloxone did not influence the effects of clonidine. It is concluded that the cardiovascular, sedative and neurohormonal effects of acutely administered clonidine are not dependent on opiate receptor activation in either normal or hypertensive man.

Growth hormone response to clonidine is impaired in patients with central sympathetic degeneration.

Serum growth hormone (GH) levels before and after intravenous clonidine (1.5 mcg/Kg) were measured in normal subjects and patients with chronic idiopathic autonomic failure (AF) due to central sympathetic degeneration. Normal subjects showed a rise in plasma GH from 2 +/- 1 mU/l to 27 +/- 12 mU/l. Basal levels were similar but there was no rise in GH levels in the AF patients. There was no difference in sedation in the two groups, indicating similar central nervous system penetration of the drug. Systolic blood pressure fell in both groups. Diastolic blood pressure fell significantly in normals but not in the AF patients. Clonidine-induced growth hormone release may be a potentially useful neuroendocrine marker indicating derangement of certain components of the central alpha-adrenergic system in man.

The effect of desmopressin on nocturnal polyuria, overnight weight loss, and morning postural hypotension in patients with autonomic failure.

Day and night urine volume, morning and evening body weight, and supine and sitting blood pressure were measured in five patients with chronic autonomic failure who were not receiving treatment with drugs. All had nocturnal polyuria, overnight weight loss, and a pronounced postural fall in blood pressure, with lowest levels in the morning. Desmopressin (2-4 micrograms given intramuscularly at 8 pm) reduced nocturnal polyuria, diminished overnight weight loss, raised supine blood pressure, and reduced the postural fall, especially in the morning, when patients were often at their worst. Desmopressin may be a useful alternative to, or may supplement, other forms of treatment in some patients with autonomic failure.

Hypotensive and sedative effects of insulin in autonomic failure.

The haemodynamic responses to intravenous insulin (0.15 units/kg) were measured in five patients with chronic autonomic failure who were not receiving drug treatment. After the administration of insulin supine blood pressure fell steadily, with a substantial reduction even before the onset of hypoglycaemia. None of the patients showed the usual range of neuroglycopenic symptoms, but they all became drowsy, with increasing sedation as the blood glucose concentration fell. In four other patients with autonomic dysfunction intravenous injection of 25-50 ml of 50% glucose alone caused a striking, although transient, fall in blood pressure. Hypoglycaemia was reversed by a 10 minute intravenous infusion of 100 ml of 25% glucose; this did not lower blood pressure further and rapidly restored previous levels of alertness. Consideration must be given to the hypotensive potential of insulin in patients with autonomic failure during an insulin stress test. The inability of these patients to show the usual manifestations of hypoglycaemia, plus the short lived, though pronounced, reduction in blood pressure after intravenous administration of 50% glucose, may further increase the risks of this procedure.

Atrial demand pacing to protect against vagal overactivity in sympathetic autonomic neuropathy.

The clinical features, investigation and management of a patient with a subacute autonomic neuropathy are described. A series of physiological and biochemical studies indicated severe but selective sympathetic cardiovascular dysfunction, associated with bradycardia. The bradycardia was enhanced by raising blood pressure but there was no other evidence either of cardiac vagal impairment or hyperreactivity. Oral atropine prevented the bradycardia but had to be withdrawn because of intolerable side effects. An atrial demand pacemaker was implanted to elevate basal heart rate and prevent bradycardia. The pacemaker alone did not improve postural hypotension but it enabled the blood pressure to be readily and safely controlled by a combination of drugs.

Differential blood pressure and hormonal effects after glucose and xylose ingestion in chronic autonomic failure.

1. To investigate whether carbohydrate contributes to postprandial hypotension in autonomic failure, the cardiovascular, biochemical and hormonal effects of oral glucose and an iso-osmotic solution of oral xylose were studied on separate occasions in six patients with chronic autonomic failure. The effects of oral glucose were also studied in eight normal subjects. 2. In the patients oral glucose lowered blood pressure substantially (-34 +/- 7% at 60 min, area under curve -24.9 +/- 3.5%, P less than 0.001) and for a prolonged period (-25 +/- 4% at 120 min). Plasma noradrenaline levels did not change. In the normal subjects blood pressure was unchanged and plasma noradrenaline rose, suggesting a compensatory increase in sympathetic nervous activity. 3. In the patients xylose caused a smaller and more transient fall in blood pressure (-15 +/- 6% at 90 min, area under curve -8.9 +/- 4%, P less than 0.05) with a non-significant elevation in packed cell volume (36.7 +/- 1.8 to 38.2 +/- 1.8). It was therefore unclear if xylose was exerting osmotic effects within the bowel which contributed to the small blood pressure fall. Packed cell volume did not change in either the patients or normal subjects after glucose. 4. In the patients and normal subjects plasma insulin rose after glucose. Insulin levels were unchanged after xylose. Levels of pancreatic polypeptide and neurotensin, a potential vasodilator, rose in the patients only. The latter rose to a similar extent after both glucose and xylose, making it unlikely that neurotensin alone accounted for the hypotension. 5. These studies indicate that the carbohydrate components of a meal, and in particular those causing insulin release, contribute to postprandial hypotension in patients with autonomic failure.