Jack Onrot

Isolated Failure of Autonomic Noradrenergic Neurotransmission

AUTONOMIC disorders are usually characterized by widespread abnormalities in both the sympathetic and the parasympathetic systems; this is true whether the autonomic disorder is associated with cen...

Hemodynamic and humoral effects of caffeine in autonomic failure. Therapeutic implications for postprandial hypotension.

We examined the effects of caffeine and meals on blood pressure and heart rate in 12 patients with autonomic failure. The influence of caffeine on plasma norepinephrine, epinephrine, and renin activity was also studied. Caffeine 250 mg, raised blood pressure by 12/6 mm Hg, from 129 +/- 25/78 +/- 12 (mean +/- S.D.) to a maximum of 141 +/- 30/84 +/- 16 mm Hg at 45 minutes (P less than 0.01), but did not change heart rate, levels of norepinephrine, or epinephrine, or plasma renin activity. Blood pressure fell by 28/18 mm Hg after a standardized meal, from 133 +/- 32/80 +/- 15 to a minimum of 105 +/- 21/62 +/- 12 mm Hg at 60 minutes (P less than 0.01). After pretreatment with 250 mg of caffeine, the standardized meal induced a fall of only 11/10 mm Hg, from 140 +/- 33/79 +/- 7 to 129 +/- 31/69 +/- 13 mm Hg at 60 minutes (P less than 0.05 vs. values after the control per day for seven days) in five patients, postprandial blood pressures remained higher after caffeine than after placebo (P less than 0.05). We conclude that caffeine is a pressor agent and attenuates postprandial hypotension in autonomic failure, and that this effect is not primarily due to elevations in sympathoadrenal activity or activation of the renin-angiotensin system. Caffeine may be useful in the treatment of orthostatic hypotension due to autonomic failure, especially in the postprandial state.

Oral yohimbine in human autonomic failure

Yohimbine is an α2-adrenoreceptor antagonist that acts to enhance sympathetic nervous system discharge and potentiate sympathetically mediated cardiovascular reflex responses. We therefore assessed the ability of yohimbine to increase sympathoadrenal discharge and raise blood pressure (BP) in patients with autonomic failure characterized by profound orthostatic hypotension. Yohimbine 5 mg orally in eight seated patients significantly elevated mean systolic BP by 33 mm Hg from 136 ± 15 (mean ± SD) to a maximum of 169 ± 23 mm Hg (p < 0.01), mean diastolic BP by 16 mm Hg from 77 ± 9 to a maximum of 93 ± 15 mm Hg (p < 0.01), and mean heart rate (HR) by 10 beats per minute (BPM) from 68 ± 12 to a maximum of 781 17 BPM (p < 0.01). Plasma norepinephrine (NE) increased from 104 ± 71 to a maximum of 196 ± 182pg/ml(p < 0.05), but plasma epinephrine (E) did not increase significantly (31 ± 18 versus a maximum of 39 ± 21 pg/ml). In five patients given yohimbine 2.5 mg orally, BP, HR, NE, and E tended to increase, but the changes were not significant. Plasma yohimbine levels correlated significantly with the changes in mean arterial pressure (r = 0.61, p < 0.01). Yohimbine raises BP and HR in patients with autonomic failure. These effects are dose- and concentration-dependent and mediated through increased sympathetic discharge. Yohimbine may be useful in the treatment of orthostatic hypotension associated with autonomic failure. It is unique among current modes of therapy for this disorder in that it enhances discharge of the patients own sympathetic system.

Cardiovascular effects of adenosine infusion in man and their modulation by dipyridamole

In man, intravenous infusion of adenosine has been useful in inducing sustained hypotension during anesthesia. Bolus injections terminate supraventricular tachyarrhythmias by delaying AV node conduction. It has been proposed that some of its cardiovascular effects are related to inhibition of noradrenergic neurotransmission. We assessed the cardiovascular and sympathoadrenal effects of intravenous infusion of adenosine (10 to 140 micrograms/kg/min) in 7 conscious normal subjects. At the highest infusion rate achieved, adenosine increased heart rate by 33 bpm (p less than 0.005), increased systolic blood pressure by 13 mm Hg (p less than 0.02) and decreased diastolic blood pressure by 8 mm Hg (p less than 0.02). Plasma norepinephrine and epinephrine increased 44% and 213% respectively. Basal plasma renin activity was 0.7 +/- 0.09 ng AI/ml/hr and remained unchanged. Higher doses were not given due to the appearance of subjective side effects (headache, nervousness, flushing and an urge to breathe deeply). During dipyridamole administration, 4-fold lower doses were required to produce equivalent cardiovascular effects. We conclude that in conscious man, intravenous infusion of adenosine is associated with activation rather than inhibition of the sympathoadrenal system. The possible mechanisms of this sympathetic activation are discussed.

Management of chronic orthostatic hypotension

Chronic orthostatic hypotension is characterized by recurrent symptoms of cerebral hypoperfusion due to low upright blood pressure levels. The initial approach should be to identify and correct reversible causes. Persistence of orthostatic hypotension suggests autonomic failure. The goal of management is to minimize symptoms and maximize functional capacity; therefore the magnitude of blood pressure fall is not as important as the advent of symptoms. Therapy is based upon the underlying pathophysiology and the risk/benefit ratio of interventions. Patient education and nondrug measures form the cornerstone of management. Drug therapy is often limited by unacceptable supine hypertension. Rational drug use can be governed by individualized trials of therapy. Patients with moderate or severe orthostatic hypotension are difficult to treat, but can be helped toward resumption of a normal life.

Enhanced Left Ventricular Contractility in Autonomic Failure: Assessment Using Pressure-Volume Relations

Severe autonomic failure is usually characterized by both supine hypertension and orthostatic hypotension. Inadequate preload reserve, insufficient arterial resistance and abnormal cardiac performance have been postulated to contribute to the hypotension. To clarify these mechanisms, left ventricular performance and contractility were assessed using radionuclide ventriculography and systolic pressure-volume relations when supine and with graded head-up tilt in 11 patients with autonomic failure. Results were compared with those of 12 normal subjects, using phenylephrine infusion for pharmacologic afterload augmentation after autonomic blockade with atropine and propranolol. In a subset of four patients with autonomic failure, systolic pressure-volume relations were similar by both the tilt and phenylephrine methods. In autonomic failure, end-diastolic volume, end-systolic volume and stroke volume decreased with progressive degrees of tilt (p less than or equal to 0.007 for each). The supine radionuclide ejection fraction and cardiac output were similar to those of normal subjects (69% versus 68% and 5.4 versus 4.9 liters/min, respectively, p = NS). However, the slopes of the pressure-volume relations and the supine pressure/volume ratio in autonomic failure were much greater than normal (8.8 versus 2.5, and 6.3 versus 3.6 mm Hg/ml, respectively, p less than or equal to 0.04 for both). The baseline total peripheral resistance was greater than normal (24.9 versus 17.4 mm Hg.min-1/liter, p = 0.01), but the resistance at maximal tilt failed to increase (20.8 +/- 6.1 units). Plasma norepinephrine concentrations were lower than normal. Thus, patients with autonomic failure had hypercontractile left ventricular performance when assessed by pressure-volume relations, and their hearts were well matched to the elevated peripheral resistance.(ABSTRACT TRUNCATED AT 250 WORDS)

Direct Vasodilator Effect of Hyperventilation-Induced Hypocarbia in Autonomic Failure Patients

Hyperventilation produces small decreases in blood pressure in normal subjects and larger decreases in patients with autonomic failure. The authors studied the mechanism for this observation by measuring mean arterial pressure (MAP) and arterial blood gas (ABG) changes in eight patients with severe primary autonomic failure after various maneuvers designed to alter PaCO2, PaO2, and pH. Maneuvers included voluntary hyperventilation, breathing a 5% CO2/95% O2 mixture, breathing 12% O2, breathing through a 1 meter tube to increase dead space, breathing 100% O2, and infusion of 120 mEq NaHCO3 over 30 minutes. All maneuvers led to expected changes in ABGs. Voluntary hyperventilation lowered MAP by 23 +/- 4 (p less than 0.01) mmHg but MAP was raised 11 +/- 3 and 7 +/- 1 mmHg by hyperventilation resulting from increasing breathing dead space or from breathing 5% CO2, respectively. Breathing 100% O2 or 12% O2 had no significant effect on MAP, and NaHCO3 infusion raised MAP by 8 +/- 4 (p less than 0.05) mmHg. With all maneuvers, change in MAP correlated with change in PaCO2 (r = 0.72, p less than 0.001) and change in pH (r = -0.57, p less than 0.01) but not with PaO2. Multiple regression analysis showed that only changes in PaCO2 predicted the change in MAP for all maneuvers. The authors conclude that a decrease in PaCO2 causes the observed decreases in MAP with hyperventilation. This most likely represents a direct peripheral vasodilator effect of hypocarbia rather than a reflex or centrally-mediated mechanism since our patient population is characterized by inadequate or absent autonomic cardiovascular reflex responses.

Reduction of liver plasma flow by caffeine and theophylline

Caffeine and theophylline block the vasodilating effects of adenosine and may act to enhance sympathoadrenal discharge and activate the renin‐angiotensin system. To determine if these methylxanthines might thereby have effects on regional blood flow, we studied the influence of caffeine and theophylline on apparent liver plasma flow (LPF) in normal subjects as assessed by indocyanine green clearance. Oral caffeine, 250 mg, reduced LPF by 19% from 630 ± 150 to 510 ± 120 ml/min (P < 0.001). Intravenous theophylline (4.3 mg/kg) reduced LPF by 15% from 550 ± 50 to 470 ± 90 ml/min (P < 0.05). These methylxanthine‐induced falls in LPF may alter the disposition of concomitantly administered drugs. Because of their widespread use in Western society, caffeine and theophylline may be major determinants of liver blood flow in the general population. They may therefore prolong the t1/2 and increase steady‐state levels of hepatically eliminated drugs.

Neck tumour with syncope due to paroxysmal sympathetic withdrawal.

A patient with recurrent squamous carcinoma metastatic to the neck after radical neck dissection and high dose radiation therapy developed paroxysmal hypotensive episodes that were severe, spontaneous and characterised by suppressed sympathetic but not enhanced parasympathetic activity. Intravenous pressors were successful in treating acute episodes but neither drug therapy nor surgical neck exploration reliably prevented syncopal attacks. Glossopharyngeal and/or vagal nerve infiltration by tumour with episodic activation of the afferent limb of the baroreflex arc producing vasodilatation primarily due to sympathetic withdrawal is the likely mechanism of life threatening syncope in this patient.