Establishing principles for migraine management in primary care.

Published guidelines for the management of migraine in primary care were evaluated by an international advisory board of headache specialists, to establish evidence-based principles of migraine management that could be recommended for international use. Twelve principles of migraine management were identified, covering screening, diagnosis, management and treatments: Almost all headaches are benign/primary and can be managed by all practising clinicians. Use questions/a questionnaire to assess the impact on daily living and everyday activities, for diagnostic screening and to aid management decisions. Share migraine management between the clinician and the patient. Provide individualised care for migraine and encourage patients to manage their migraine. Follow up patients, preferably with migraine calendars or diaries. Regularly re-evaluate the success of therapy using specific outcome measures and monitor the use of acute and prophylactic medications regularly. Adapt migraine management to changes that occur in the illness and its presentation over the years. Provide acute medication to all migraine patients and recommend it is taken at the appropriate time, during the attack. Provide rescue medication/symptomatic treatment for when the initial therapy fails. Offer to prescribe prophylactic medications, as well as lifestyle changes, to patients who have four or more migraine attacks per month or who are resistant to acute medications. Consider concurrent co-morbidities in the choice of appropriate prophylactic medication. Work with the patient to achieve comfort with mutually agreed upon treatment and ensure that it is practical for their lifestyle and headache presentation. Using these principles, practising clinicians can screen and diagnose their headache patients effectively and manage their migraine patients over the long-term natural history of the migraine process. In this way, the majority of migraine patients can be well treated in primary care, ensuring a structured and individualised approach to headache management, and conserving valuable healthcare resources.

Physical impairments in cervicogenic headache: traumatic vs. nontraumatic onset.

In order to quantify the physical impairments associated with different types of headache, 77 subjects belonging to four different groups (postmotor vehicle accident cervicogenic headache subjects, cervicogenic headache subjects nontraumatic, migraine patients and control subjects) were evaluated using the following variables: posture, cervical range of motion, strength of the neck flexors and extensors, endurance of the short neck flexors, manual segmental mobility, proprioception of the neck, and pain (McGill Pain Questionnaire and the skin roll test). The results of this study showed that postmotor vehicle accident cervicogenic patients have significantly limited active cervical range of motion (in flexion/extension and rotations), present decreased strength and endurance of neck flexors and decreased strength of the extensor muscles. Our results suggest that there are enough differences between the postmotor vehicle accident and nontraumatic cervicogenic headache subjects to warrant caution when analysing the data of these two subgroups together, as several studies have done in the past. The onset of headache is therefore an important variable that should be controlled for when attempting to characterize the physical impairments associated with cervicogenic headache.

Reduced capacity of cardiac efferent sympathetic neurons to release noradrenaline and modify cardiac function in tachycardia-induced canine heart failure.

To investigate the capacity of efferent sympathetic neurons to modulate the failing heart, stellate ganglion stimulation was performed in dogs with biventricular heart failure induced by rapid ventricular pacing (240 beats/min) for 4-6 weeks. Less noradrenaline was released from cardiac myoneural junctions into coronary sinus blood in response to left stellate ganglion stimulation in anesthetized failing heart preparations (582 pg/mL, lower and upper 95% confidence intervals of 288 and 1174 pg/mL, n = 19) compared with healthy heart preparations (6391 pg/mL, 95% confidence intervals of 4180 and 9770 pg/mL, n = 14; p < 0.001). There was substantial adrenaline extraction by failing hearts (49 +/- 6%), although it was slightly lower than in healthy heart preparations (65 +/- 9%, p = 0.055). In contrast with healthy heart preparations, no net release of adrenaline occurred during stellate ganglion stimulation in any of the failing heart preparations, and ventricular tissue levels of adrenaline fell below the sensitivity limit of the HPLC technique. In failing heart preparations, maximal electrical stimulation of right or left stellate ganglia resulted in minimal augmentation of left ventricular intramyocardial (17%) and chamber (12%) systolic pressures. These indices were augmented by 145 and 97%, respectively, following exogenous noradrenaline administration. Thus, the cardiac efferent sympathetic neurons' reduced capacity to release noradrenaline and modify cardiac function can contribute to reduction of sympathetic support to the failing heart.

Effect of changes in myocardial epinephrine stores on plasma norepinephrine gradient across the dog heart.

Plasma norepinephrine (NE) concentration ([NE]) gradient across the heart was measured under electrical stimulation of the left stellate ganglion (LSG; 4 Hz, 4 V, 2 ms pulse width, 1 min) in control (Ctrl) and in adrenalectomized (Adrx) dogs, without and with a 10-min epinephrine (Epi) infusion (92 ng.kg-1.min-1), which partly restored myocardial Epi stores in Adrx dogs (2.9 +/- 0.7 ng/g vs. 6.4 +/- 0.7 ng/g in Ctrl dogs) and slightly increased tissue Epi stores in Ctrl dogs (10.5 +/- 1.3 pg/g). Compared with Ctrl dogs (1,069 +/- 172 pg/ml), the [NE] gradient across the heart under stimulation of the LSG was not modified 1 wk after bilateral adrenalectomy (1,190 +/- 122 pg/ml) or after Epi infusion in Ctrl (1,134 +/- 276 pg/ml) and Adrx (1,259 +/- 279 pg/ml) dogs. The beta 2-antagonist ICI-118,551 significantly reduced the stimulation-induced [NE] gradient across the heart in Ctrl dogs (621 +/- 190 and 603 +/- 86 pg/ml without and with a 10-min Epi infusion, respectively) but not in Adrx dogs deprived of tissue Epi (1,345 +/- 345 pg/ml). Partial repletion of myocardial Epi stores in Adrx dogs restored the effect of ICI-118,551 on the stimulation-induced [NE] gradient (776 +/- 121 pg/ml). These results provide direct support of the hypothesis that tissue Epi, which originates from the adrenal medulla and which is released locally along with NE, is the endogenous agonist for presynaptic beta 2-receptors and potentiates NE release.

Minimal modification of canine ventricular myocyte cell surface beta adrenoceptors despite desensitisation of ventricular function during exogenous beta adrenoceptor challenge.

OBJECTIVE: The aim was to determine whether a 120 min exposure of ventricular myocytes to beta agonist challenge alters ventricular cell surface beta adrenergic receptors concomitant with desensitisation of ventricular function. METHODS: Supramaximal doses of isoprenaline (1 microgram.kg-1.min-1 intravenously) were given continuously to anaesthetised dogs for 15 (n = 6), 60 (n = 2), and 120 (n = 6) min. Changes induced during beta adrenoceptor challenge in right and left ventricular systolic pressures were correlated with right and left ventricular myocyte beta adrenoceptor number and affinity. RESULTS: Isoprenaline initiated early augmentation in right [23(SEM 3)-78(10) mm Hg] and left [82(6)-186(11) mm Hg] ventricular intramyocardial systolic pressures. After 5 min of continuous exogenous beta agonist challenge these pressures were reduced to 42(4) mm Hg and 104(16) mm Hg, respectively, even though the agonist challenge persisted. Throughout the subsequent 115 min exposure period these pressures remained relatively similar. Despite these inotropic effects the number (Bmax) and affinity (Kd) of ventricular myocyte beta adrenergic cell surface receptors, as determined by the tissue slice technique, were similar before and after 15, 60, and 120 min exposure to isoprenaline. CONCLUSIONS: (1) After the desensitisation of the initial enhancement of ventricular inotropism that occurs during the first 5 min of a beta agonist challenge, inotropism remains relatively constant for the next 115 min exposure. (2) Desensitisation of ventricular inotropism elicited during 2 h exposure of the in situ heart to a beta agonist challenge is not primarily due to altered myocyte cell surface beta adrenergic receptor number or affinity.

Effect of increases in myocardial epinephrine content on epinephrine release from the dog heart.

The effect of short-term (10 min) and prolonged (180 min) epinephrine (E) infusion (92.5 ng.kg-1.min-1) on E content of the myocardium and on the subsequent release of E from the heart during stimulation of the left stellate ganglion (4 and 10 Hz, 4 V, 2 ms, 1 min) was studied in anesthetized dogs. The E content in the free wall of the left ventricle significantly increased 1.7- and 4.2-fold following short-term and prolonged E infusion, respectively, compared with a control group infused with saline. Tissue norepinephrine (NE) content was not modified by E infusion. The plasma E concentration gradient across the heart indicated a significant release of E during electrical stimulation of the left stellate ganglion, which was related to the amount of E stored in the tissue (e.g., control, 126 +/- 60; 10-min infusion, 279 +/- 105; 180-min infusion, 1487 +/- 287 pg.mL-1; at 10 Hz). NE release from the heart also tended to increase with the amount of E stored in the myocardium and released upon electrical stimulation of the left stellate ganglion, although the difference did not reach statistical significance. These results provide further direct evidence that blood-borne E can be taken up and stored in sympathetic nerve endings and can be released as a cotransmitter with NE. Locally released E could favor NE release.

Presynaptic effects of epinephrine on norepinephrine release from cardiac sympathetic nerves in dogs.

The possible functional role of tissue epinephrine in the modulation of norepinephrine release from cardiac sympathetic nerve endings in anesthetized dog was investigated. Observations were carried out under control conditions and after a short- (10 min) and long-term (180 min) epinephrine infusion (92 ng.kg-1.min-1). An increase in the stimulation-induced release of norepinephrine after intravenous administration of a selective beta 2-agonist (fenoterol, 0.5 micrograms/kg) indicated the presence of the beta 2-facilitatory mechanism. Furthermore, the facilitatory effect of fenoterol was inhibited by intravenous administration of a selective beta 2-antagonist (ICI 118551, 1 mg/kg). Short-term epinephrine infusion did not facilitate the stimulation-induced release of norepinephrine, when tissue epinephrine content in the left ventricle was increased 1.5-fold, without, as well as with, alpha 2-blockade (yohimbine, 0.3 mg/kg). However, stimulation-induced release of norepinephrine from the myocardium was significantly potentiated in animals in which tissue epinephrine in the left ventricle was greatly increased (5.6-fold) by a prolonged infusion of epinephrine (180 min). It is concluded that a facilitatory mechanism mediated by presynaptic beta 2-adrenoceptors is present in cardiac sympathetic nerve endings of the dog. Some of our observations support the hypothesis that this mechanism may be influenced by locally released epinephrine and, thus, by tissue epinephrine content.

Psychophysiological profiles in response to various challenges during recovery from acute aerobic exercise.

Cardiovascular and sympathetic profiles in response to a series of physical and mental challenges were examined during recovery from an acute bout of aerobic exercise performed at 60% VO2,max for 30 min. 9 healthy men were tested on two occasions, once under an experimental (exercise) and once under a control (video watching) condition, in a counter-balanced order, one week apart. Although no differences in blood pressure were found in the two conditions, heart rate and plasma catecholamine concentrations were higher in the exercise than in the control session. These findings were partly attributed to elevated physiological levels 'carried over' from exercise. State anxiety and anger-hostility, however, were lower in the post-experimental period than in the pre-experimental period. The results are discussed in terms of their relevance to exercise and stress psychophysiology.

Beta 1- and beta 2-adrenoceptor subtypes in canine intrathoracic efferent sympathetic nervous system regulating the heart.

The augmentation of cardiac inotropism induced by electrical stimulation of acutely decentralized efferent preganglionic sympathetic axons is reduced after the administration of timolol into the major ipsilateral intrathoracic ganglia. Thus it has been proposed that, in addition to nicotinic synapses, beta-adrenergic ones exist in intrathoracic ganglia that are involved in the efferent sympathetic regulation of the mammalian heart. Whether these are beta 1- as opposed to beta 2-adrenoceptor subtypes is unknown. In the present series of experiments, acutely decentralized canine efferent preganglionic sympathetic axons were stimulated before and after the administration of beta 1 (atenolol)- or beta 2 (ICI 118551)-selective adrenoceptor antagonists into the ipsilateral stellate and middle cervical ganglia to determine whether beta 1- or beta 2-adrenoceptors exist in intrathoracic ganglia that are involved in cardiac regulation. Augmentations of right and left ventricular inotropism induced by efferent preganglionic sympathetic axon stimulation were attenuated when either agent was administered into the major ipsilateral intrathoracic sympathetic ganglia. Myocardial liberation of norepinephrine evoked by these stimulations was also reduced after intraganglionic administration of either agent. These data indicate that canine intrathoracic neurons contain beta 1- and beta 2-adrenoceptors that are involved in the efferent sympathetic regulation of the heart.

Epinephrine release from the heart during left stellate ganglion stimulation in dogs.

Plasma epinephrine (E) and norepinephrine (NE) concentrations were measured (radioenzymatic assay) in blood samples simultaneously withdrawn from the aorta (Ao) and coronary sinus (CS) on 10 anesthetized dogs immediately before and during a 1-min period of electrical stimulation of the left stellate ganglion (4 V, 4 ms, 10 Hz). Heart rate and systolic blood pressure significantly increased in response to electrical stimulation (152 +/- 8 to 180 +/- 15 beats/min and 128 +/- 12 to 149 +/- 12 mmHg, mean +/- SE; P less than 0.05). Plasma NE concentrations were not significantly different in the Ao and the CS (432 +/- 110 and 319 +/- 67 pg/ml) before the stimulation, whereas a net removal of E was present across the myocardium (Ao, 172 +/- 61; CS, 71 +/- 22 pg/ml). A large NE spillover in the CS was observed during the stimulation (Ao, 1,555 +/- 513; CS, 10,583 +/- 3,753 pg/ml). A significant output of E from the myocardium was also present (Ao, 165 +/- 42; CS, 291 +/- 74 pg/ml) during the stimulation. Determination of NE and E concentrations by high-performance liquid chromatography in five of the dogs confirmed the observation made with the radioenzymatic assay, i.e., a significant uptake (66%) of blood-borne E was present across the myocardium in the control situation (Ao, 320 +/- 97; CS, 110 +/- 23 pg/ml), whereas plasma E concentrations in the CS (280 +/- 61 pg/ml) were 1.5 times the values found in Ao (184 +/- 56 pg/ml) under electrical stimulation. These observations give further support to the hypothesis that endogenous tissue E can act as a cotransmitter of sympathetic fibers.

Regional plasma catecholamine removal and release at rest and exercise in dogs.

Dynamics of circulating catecholamines (CA) were studied at rest (heart rate = 104 +/- 3 beats/min) and during mild treadmill exercise (heart rate = 168 +/- 5 beats/min) in 60 dogs. Plasma epinephrine (E) and norepinephrine (NE) removal from circulation and release into circulation were estimated from plasma CA arteriovenous differences across the regional vascular beds studied (pulmonary, myocardial, hepatosplanchnic, renal, and skeletal muscle vascular beds) and from regional blood flows. Regional plasma E fractional extraction (PEFE) was used as an index of NE removal from plasma. Arterial plasma CA increased significantly from rest to exercise (P less than 0.05). A significant PEFE was observed at rest and exercise across all studied vascular beds but the pulmonary bed. When plasma flow was taken into account, the largest contributors to plasma CA removal were the hepatosplanchnic vascular bed at rest and skeletal muscle vascular beds during exercise. At rest, the hepatosplanchnic vascular bed was a major contributor to the plasma NE pool. During exercise, main contributors to NE release into plasma were skeletal muscle vascular beds. Circulating CA kinetics did not appear to vary from rest to exercise. Clearance and apparent distribution space were estimated to be, respectively, 1.5 l/min and 2 liters for circulating E and 2 l/min and 5 liters for NE at rest and exercise. Circulating E and NE half times were estimated to be approximately 1 and 1.8 min, respectively.

Effects of yohimbine and desipramine on cardiac noradrenaline release and ventricular arrhythmias during acute coronary artery occlusion and reperfusion in anesthetized dogs.

Effects of yohimbine (YHMB, an alpha 2-antagonist) and desipramine (DMI, a neuronal uptake inhibitor) were compared on cardiac noradrenaline (NA) release either upon left ansa subclavia nerve stimulation during acute occlusion of the left anterior descending coronary artery (LAD) or upon subsequent LAD reperfusion without stimulation in anesthetized dogs. In control dogs, before LAD occlusion, coronary sinus (CS) NA output increased from 5.4 +/- 1.0 to 26.8 +/- 4.0 ng/min (p less than 0.05) upon stimulation (2 Hz, 30 s). The response to stimulation remained unchanged 25 min after LAD occlusion. During reperfusion 60 min after occlusion, the output of CS-NA and lactate increased from 6.1 +/- 0.8 to 51.3 +/- 19.4 ng/min (p less than 0.05) and from 2.7 +/- 0.5 to 6.7 +/- 1.3 mg/min (p less than 0.05), respectively. In dogs treated with YHMB, the stimulation-induced increase in NA output was potentiated at least fourfold (p less than 0.05) either before or during LAD occlusion, but not during reperfusion. In dogs receiving DMI, stimulation-induced CS-NA output was enhanced to a similar extent (approximately twofold, p less than 0.05) either before or during occlusion, while reperfusion-induced NA output was markedly potentiated by approximately ninefold (p less than 0.05). Maximum dP/dt of left ventricular pressure remained unchanged upon reperfusion in all groups. The total arrhythmic ratio in the drug-treated groups did not significantly differ from the ratio in control dogs upon either stimulation or reperfusion. The data suggest that an abrupt increase in NA output upon reperfusion may result from a washout of NA locally accumulated in the ischemic and (or) peri-ischemic region during the preceding occlusion period, and that NA thus released does not have substantial hemodynamic effects. The results indicate that in the presence of YHMB or DMI, the potentiated increase in NA release in response to either nerve stimulation during LAD occlusion or to reperfusion without stimulation did not aggravate ventricular arrhythmia, most probably owing to the antiarrhythmic properties of these substances.