Micro-electrode multi-unit recordings of muscle nerve sympathetic activity (MSA) involved in cardiovascular homeostasis or skin nerve sympathetic activity (SSA) involved in thermoregulation were made in the right peroneal nerve of 48 healthy volunteers during performance of the cold pressor test, i.e. immersion of one hand in ice water (2 +/- 0.5 degrees C) for 1 min. Eleven subjects underwent the same procedure on a second MSA recording occasion. As a rule, immersion evoked an increase in MSA, with a gradual decrease on emersion. The response showed a wide range of variation between and within subjects; the intra-individual difference between first and second immersion on the same recording occasion was up to sevenfold, and from first to second recording up to fivefold. The increase in MSA correlated with the degree of discomfort from the ice water. In nine subjects with a large increase in MSA on ice water immersion, intracutaneous painful electrical stimulation to a level equalling the discomfort from the ice water was added, but it was not accompanied by any change in MSA. The increase in MSA was accompanied by and correlated quite well with an increase in blood pressure. Intra-arterial blood pressure recordings showed that MSA occurred at pressure levels normally associated with total inhibition of MSA, and that an inverse linear relationship between diastolic blood pressure and MSA at rest was abolished during the ice water immersion. SSA showed no consistent change with ice water immersion. It is concluded that the cold pressor test is a powerful activator of MSA, i.e. baroreceptor-governed vasoconstrictor outflow; that MSA contributes to the blood pressure elevation with this manoeuvre; that MSA operates at another blood pressure level during the manoeuvre and that the baroreflex inhibitory level consequently is changed; and that the response is not a reaction to pain only.

Microneurographic recordings of muscle nerve sympathetic activity, which is governed by baroreceptors and involved in blood pressure regulation, were made in the peroneal nerve in 16 healthy volunteers during physiological bladder distension. When the urge to urinate was pronounced, sympathetic outflow increased from a baseline level of 16.3 +/- 1.7 to 23.2 +/- 1.9 bursts/min (mean +/- SEM, p less than 0.01). There was a concomitant significant rise in both systolic and diastolic blood pressure, from 125 +/- 2/74 +/- 2 to 140 +/- 4/84 +/- 3 mm Hg. After micturition, sympathetic activity and blood pressure returned toward initial values. It is concluded that 1) increased sympathetic outflow contributed to the rise in blood pressure, 2) there is a vesicovascular response mediated by sympathetic vasoconstrictor neurons in humans corresponding to mechanisms observed in animals, and 3) the described functional relation between bladder distension and sympathetic vasoconstrictor activity probably plays a role in clinical conditions such as autonomic dysreflexia in humans with cervical spinal cord lesions and nocturnal micturition syncope.

Nalmefene appears to be effective and safe in reducing heavy drinking, even when accompanied by minimal psychosocial support.

Background Specific and selective alpha2-adrenergic drugs are widely exploited in veterinary anesthesiology. Because alpha2-agonists are also being introduced to human practice, the authors studied reversal of a clinically relevant dexmedetomidine dose with atipamezole, an alpha2-antagonist, in healthy persons. Methods The study consisted of two parts. In an open dose-finding study (part 1), the intravenous dose of atipamezole to reverse the sedative effects of 2.5 microg/kg of dexmedetomidine given intramuscularly was determined (n = 6). Part 2 was a placebo-controlled, double-blinded, randomized cross-over study in which three doses of atipamezole (15, 50, and 150 microg/kg given intravenously in 2 min) or saline were administered 1 h after dexmedetomidine at 1-week intervals (n = 8). Subjective vigilance and anxiety, psychomotor performance, hemodynamics, and saliva secretion were determined, and plasma catecholamines and serum drug concentrations were measured for 7 h. Results The mean +/- SD atipamezole dose needed in part 1 was 104+/-44 microg/kg. In part 2, dexmedetomidine induced clear impairments of vigilance and psychomotor performance that were dose dependently reversed by atipamezole (P < 0.001). Complete resolution of sedation was evident after the highest (150 microg/kg) dose, and the degree of vigilance remained high for 7 h. Atipamezole dose dependently reversed the reductions in blood pressure (P < 0.001) and heart rate (P = 0.009). Changes in saliva secretion and plasma catecholamines were similarly biphasic (i.e., they decreased after dexmedetomidine followed by dose-dependent restoration after atipamezole). Plasma norepinephrine levels were, however, increased considerably after the 150 microg/kg dose of atipamezole. The pharmacokinetics of atipamezole were linear, and elimination half-lives for both drugs were approximately 2 h. Atipamezole did not affect the disposition of dexmedetomidine. One person had symptomatic sinus arrest, and another had transient bradycardia approximately 3 h after receiving dexmedetomidine. Conclusions The sedative and sympatholytic effects of intramuscular dexmedetomidine were dose dependently antagonized by intravenous atipamezole. The applied infusion rate (75 microg x kg(-1) x min(-1)) for the highest atipamezole dose was, however, too fast, as evident by transient sympathoactivation. Similar elimination half-lives of these two drugs are a clear advantage considering the possible clinical applications.

The opioid antagonist nalmefene offers an alternative to traditional pharmacological treatments for alcoholism. The present study was designed to investigate the relationship between nalmefene plasma concentration and central m-opioid receptor occupancy after a clinically effective dose (20 mg, orally). Pharmacokinetics and m-opioid receptor occupancy of nalmefene after single and repeated dosing over 7 days was studied in 12 healthy subjects. Serial blood samples were obtained after both dosings, and pharmacokinetic parameters for nalmefene and main metabolites were determined. Central m-opioid receptor occupancy of nalmefene was measured with positron emission tomography (PET) and [ 11 C]carfentanil at four time points (3, 26, 50, 74 h) after both dosings. Nalmefene was rapidly absorbed in all subjects. The mean t 1/2 of nalmefene was 13.4 h after single and repeated dosing. The accumulation of nalmefene and its main metabolites in plasma during the repeated dosing period was as expected for a drug with linear pharmacokinetics, and steady-state was reached for all analytes. Both nalmefene dosings resulted in a very high occupancy at m-opioid receptors (87-100%), and the decline in the occupancy was similar after both dosings but clearly slower than the decline in the plasma concentration of nalmefene or metabolites. High nalmefene occupancy (83-100%) persisted at 26 h after the dosings. The prolonged m-opioid receptor occupancy by nalmefene indicates slow dissociation of the drug from m-opioid receptors. These results support the rational of administering nalmefene when needed before alcohol drinking, and they additionally suggest that a high m-opioid receptor occupancy can be maintained when nalmefene is taken once daily.