Plasma catecholamine modulation of alpha 2 adrenoreceptor agonist affinity and sensitivity in normotensive and hypertensive human platelets.

We measured alpha 2-adrenoreceptor density as well as affinity for and sensitivity to agonist on intact platelets of normotensive and hypertensive subjects before and after physiological increases in plasma catecholamines. In normotensives, posture-induced rises in plasma catecholamines correlated with reduced alpha 2-adrenoreceptor agonist affinity and fewer high affinity state receptors. Platelet aggregation and inhibition of adenylate cyclase by L-epinephrine also was reduced. Hypertensive subjects had similar rises in plasma catecholamines with upright posture, but showed no change in receptor affinity or sensitivity. No change in platelet alpha 2-adrenoreceptor number occurred in these studies. In vitro incubation with L-epinephrine revealed that platelets from hypertensives had slower desensitization than those from normotensives. Binding studies at different temperatures and with varying sodium concentrations found no thermodynamic or sodium-dependent differences between normotensive and hypertensive groups. These studies demonstrate that platelets from hypertensive subjects exhibit a defect in the ability of physiological concentrations of agonist to desensitize the alpha 2-adrenoreceptor.

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)

Sodium loading and posture modulate human atrial natriuretic factor plasma levels.

Atrial natriuretic factor is postulated to act through atrial stretch receptors as a volume regulatory hormone that stimulates diuresis and natriuresis in response to increased atrial pressure. To characterize the stimuli associated with the release of atrial natriuretic factor in humans, we studied 14 normal subjects, both in the supine position and after 10 minutes in an upright posture, while they were on a regular diet (Day 0) and during 3 days of supplemental sodium chloride intake (8 g/day). Radioimmunoassay of plasma atrial natriuretic factor was performed with rabbit antibody to the human hormone amino acids (102-126). Urinary sodium excretion increased from 111 +/- 13 mEq/day (mean +/- SEM) on Day 0 to 275 +/- 15 mEq/day by the third day (Day 3) of high sodium intake. The level of atrial natriuretic factor in the supine position rose from 17 +/- 4 pg/ml (Day 0) to 76 +/- 13 pg/ml on Day 3 (p less than 0.001) and after 10 minutes in an upright posture on Day 3, the level fell to 32 +/- 10 (p less than 0.005). Plasma concentrations of atrial natriuretic factor correlated positively with spot and 24-hour urinary sodium excretion and weight gain, and correlated negatively with plasma aldosterone and renin activity. We conclude that the response of atrial natriuretic factor to sodium loading and posture change in humans is appropriate for a volume regulatory hormone.

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 less than 0.001). Intravenous theophylline (4.3 mg/kg) reduced LPF by 15% from 550 +/- 50 to 470 +/- 90 ml/min (P less than 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.

Oral yohimbine in human autonomic failure.

Yohimbine is an alpha 2-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 less than 0.01), mean diastolic BP by 16 mm Hg from 77 +/- 9 to a maximum of 93 +/- 15 mm Hg (p less than 0.01), and mean heart rate (HR) by 10 beats per minute (BPM) from 68 +/- 12 to a maximum of 78 +/- 17 BPM (p less than 0.01). Plasma norepinephrine (NE) increased from 104 +/- 71 to a maximum of 196 +/- 182 pg/ml (p less than 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 less than 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 patient's own sympathetic system.

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.

Hypercalcemia associated with cancer of prostate without bony metastases.

Although hypercalcemia is sometimes found in carcinoma of the prostate with osseous metastases, it is rarely seen as a paraneoplastic manifestation of this neoplasm. We present a patient with such a tumor in whom severe hypercalcemia developed in the absence of detectable osseous metastases.

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.

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.

Carbon monoxide in the urban atmosphere: hazards to the pedestrian and the street-worker.

The carbon monoxide (CO) concentrations encountered by pedestrians and workers in the streets of a large metropolis were monitored by a reliable and sensitive portable detector (the Ecolyzer). Up to 1,000 observations per day were collected for several months during the summer and fall of 1973. The CO levels ranged from 10 to 50 ppm (varying with wind speed and direction, atmospheric stability, traffic density, and the height of nearby buildings). Much higher average concentrations were found in such adverse sites as poorly ventilated underpasses and underground garages. Street closures for a pedestrian mall reduced levels on the mall to around the general urban background withoug large increases in readings on adjoining streets. Many street-workers have little medical supervision, and for this reason the urban eight-hour CO ceilings may be a more appropriate air quality target than the usual industrial figure of 50 ppm. However, even the latter is sometimes exceeded on busy city streets.

Hypertension in the elderly. The benefits of therapy.

Because of the growing number of elderly in the population, hypertension in this age-group is becoming an increasingly important issue. Hypertension carries greater risk in the elderly, and the benefits of treatment of diastolic hypertension appear to be at least as great in this age-group as in younger populations. The benefits of treating systolic hypertension remain to be determined. On the basis of available information, hypertension in the elderly should be treated in a fashion similar in general to that used in younger patients. However, great care must be taken to minimize side effects, postural hypotension in particular. Special consideration of the physiologic, pharmacologic, behavioral, and socioeconomic factors in the elderly will help guide therapy design.

[Alpha 2-adrenoreceptor regulation in the human body]. / Reguliatsiia al'fa 2-adrenoretseptorov v organizme cheloveka.

The affinity of platelet alpha-2-adrenoreceptors for adrenaline is decreased in vivo and in vitro exposure of platelets to catecholamines at physiological concentrations in normal subjects. The direction of these alterations is consistent with the direction of the desensitization phenomena observed in the intact platelet. Hypertensive subjects display an abnormality characterized by an inability to reduce the affinity of their platelet alpha-2-adrenoreceptors in response to increased circulating levels of catecholamines. The potential importance of this defect in the etiology and clinical manifestations of essential hypertension remains to be ascertained.

Hypertension and the J-curve. How low should you go?

Recent analyses of treated blood pressure versus events suggest that drug treatment might result in an increase in coronary events or mortality at treated diastolic pressures below 80 mm Hg (the "J-curve"). However, this contention is highly controversial. Both sides of the argument are examined and a balanced approach for target blood pressure goals on treatment is outlined.

The potent pressor effect of phenylpropanolamine in patients with autonomic impairment.

We determined the pressor effect of phenylpropanolamine hydrochloride, a widely used sympathomimetic agent, in 14 patients with autonomic failure and orthostatic hypotension. Blood pressure was monitored every five minutes in the sitting position with an automated device. Oral administration of 25 mg of phenylpropanolamine hydrochloride in nine patients produced significant increases in systolic (32 mm Hg), diastolic (15 mm Hg), and mean (21 mm Hg) blood pressures. The pressor effect appeared within the first 60 minutes and was still present at 105 minutes. There was no change in heart rate. Blood pressure was also significantly raised by administration of 12.5 mg of oral phenylpropanolamine hydrochloride in five additional patients. We conclude that administration of 25 mg of phenylpropanolamine hydrochloride elicits a potent pressor response in patients with orthostatic hypotension and that significant hypertension may result.

Anaesthesia for phaeochromocytoma in pregnancy.

PURPOSE: Phaeochromocytoma in pregnancy is a rare occurrence. Details of the anaesthetic are even more rarely reported. Our purpose is to describe our management with reference to previous reports. CLINICAL FEATURES: A 31-yr-old woman underwent resection of a phaeochromocytoma at seven weeks gestation. Preoperative preparation included 2 mg prazosin p.o. bid and 40 mg propranolol p.o. bid. A balanced anaesthetic technique including 5 mg midazolam, 1500 micrograms alfentanil, 35 micrograms sufentanil, nitrous oxide and isoflurane was used. Blood pressure was controlled with 3.4 g magnesium and 2437 micrograms nitroglycerin. There were no episodes of hypertension intraoperatively. The patient made an uneventful recovery and delivered a normal baby at 37 wk gestation by caesarean section. CONCLUSION: Anaesthesia for resection of a phaeochromocytoma in early pregnancy can be successfully managed with preoperative alpha and beta sympathetic blockade and a balanced anaesthetic technique using magnesium as the main intraoperative hypotensive agent.

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.

Postjunctional vascular smooth muscle alpha-2 adrenoreceptors in human autonomic failure.

Animal studies have suggested that vasoconstrictor alpha-2 adrenoreceptors exist on vascular smooth muscle cells. We tested this hypothesis in a patient with severe autonomic failure who demonstrated a pressor response to oral clonidine (a selective alpha-2 adrenoreceptor partial agonist). After clonidine 0.8 mg orally, mean arterial pressure rose by 54 mm Hg. After pretreatment with prazosin (a selective alpha-1 adrenoreceptor antagonist) and confirmation of alpha-1 blockade, clonidine 0.8 mg still raised mean arterial pressure by 43 mm Hg. After pretreatment with yohimbine (a selective alpha-2 adrenoreceptor antagonist), clonidine 0.8 mg elevated mean arterial pressure by 13 mm Hg. Since alpha-1 antagonism does not block, and alpha-2 antagonism does not block the pressor effect of clonidine, we conclude that clonidine raised blood pressure in this severely affected autonomic failure patient by vascular alpha-2 adrenoreceptor stimulation. Thus, this provides pharmacological evidence that postjunctional vascular smooth muscle alpha-2 adrenoreceptors exist in man and can modulate blood pressure.

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.