These data provide important information on the brain and plasma exposure of new phytocannabinoids and guidance for the most efficacious administration route and time points for determination of drug effects under in vivo conditions.

SUMMARY1. Muscle sympathetic nerve activity (MSA) was recorded in the peroneal nerve at the knee by microneurography in ten healthy subjects and determinations were made simultaneously of intra-arterial blood pressure, and whole-body and cardiac noradrenaline spillover to plasma. Measurements were made at rest, during isometric handgrip at 30% of maximum power and during stress induced by forced mental arithmetic.2. At rest there were significant positive correlations between spontaneous MSA (expressed as number of sympathetic bursts min-) and both spillover of noradrenaline from the heart and concentration of noradrenaline in coronary sinus venous plasma.3. Both isometric handgrip and mental arithmetic led to sustained increases of blood pressure, heart rate and MSA. Plasma concentrations of noradrenaline and spillover of noradrenaline (total body and cardiac) increased. In general the effects were more pronounced during handgrip than during stress. 4. When comparing effects during handgrip and stress the ratio between the fractional increases of MSA and cardiac noradrenaline spillover were significantly greater during handgrip.5. The data suggest (a) that there are proportional interindividual differences in the strength of resting sympathetic activity to heart and skeletal muscle which are determined by a common mechanism and (b) that handgrip and mental stress are associated with differences in balance between sympathetic outflows to heart and skeletal muscle.

Curves relating renal sympathetic nerve activity and mean arterial pressure were derived in conscious rabbits during ramp changes in mean arterial pressure, elicited by perivascular balloon inflation. The renal sympathetic nerve activity-mean arterial pressure relationship consisted of a high-gain sigmoidal region about resting, where renal sympathetic nerve activity rose or fell in response to moderate falls and rises of mean arterial pressure. With larger pressure rises, renal sympathetic nerve activity first fell to a lower plateau and then reversed at even higher mean arterial pressure. When mean arterial pressure was lowered below resting, renal sympathetic nerve activity rose to an upper plateau and then reversed abruptly toward resting at low mean arterial pressure. Both arterial and cardiac baroreceptors exerted substantial inhibitory influences on renal sympathetic nerve activity at all pressure levels. These effects appeared additive over the central high gain region of the curve, but beyond this region there were non-additive interactions. The latter were affected considerably by alfathesin anesthesia. In other experiments, we studied the effects of sustained alterations in resting mean arterial pressure induced by infusing nitroprusside and phenylephrine, which produced rapid resetting of the renal baroreflex. The latter could be accounted for, in part, by resetting of the threshold of the arterial baroreceptors and in part by contributions from other afferents, probably the cardiac receptors. During resetting associated with nitroprusside-induced falls in resting blood pressure, high-gain reflex adjustments in renal sympathetic nerve activity to moderate changes in mean arterial pressure were preserved, but during resetting associated with phenylephrine-induced rises in resting mean mean arterial pressure, the resting renal sympathetic nerve activity lay on the lower curve plateau, resulting in reduction in the apparent gain of the reflex renal sympathetic nerve activity response to moderate changes in mean arterial pressure.

In isolated organs, or when given in low dose intra-arterially, tricyclic antidepressant drugs are known to block reuptake of norepinephrine into sympathetic nerve varicosities, with a resultant increased norepinephrine washout. On the other hand, systemic administration of such drugs in humans reduces norepinephrine spillover to plasma. To clarify these seemingly contradictory findings, we have measured concurrently muscle sympathetic activity in the peroneal nerve (microneurography) and rates of norepinephrine spillover to plasma for the body as a whole and for the heart, the kidneys, and the forearm (radiotracer technique), both before and after intravenous infusion of desipramine, 0.5 mg/kg. Desipramine lowered the overflow of norepinephrine to plasma for the body as a whole and from the forearm and the kidneys (by 30-50%) but increased cardiac norepinephrine spillover by 25%. Both the number of sympathetic bursts per min in the peroneal nerve and their mean voltage amplitudes were markedly reduced after desipramine; total activity (bursts/min x mean burst amplitude) fell by approximately 90%. The effects of desipramine on norepinephrine spillover are explicable in terms of inhibition of central sympathetic outflow, balanced against the local blockade of transmitter reuptake. In most sites, the predominant effect is a reduction of norepinephrine overflow. For the heart, where reuptake is so important in transmitter disposition, the net effect is increased overflow.

SUMMARY.We studied the effects of sustained changes in resting mean arterial pressures (MAP) on arterial baroreceptor properties in anesthetized rabbits and on the baroreceptor-heart rate reflex in conscious animals. The rabbits had balloons implanted round their aorta and vena cava, for producing transient changes in MAP about the resting MAP. Aortic baroreceptor function curves were obtained at different resting MAP by relating balloon-induced changes in MAP to either (1) integrated aortic nerve activity or (2) unit baroreceptor activity. Any sustained change in resting MAP reset the unit function curves in the same direction within 15 minutes by altering their threshold without affecting gain. The effect was reversible and independent of starting pressure. It was the same whether resting MAP was altered by vasoactive drugs (nitroprusside, phenylephrine) or was changed by withdrawing or infusing blood in sympathetically blocked rabbits. We studied baroreflex function in conscious rabbits by deriving MAP-heart period (HP) curves at different resting MAP. Nitroprusside lowered baroreflex threshold for evoking bradycardia, whereas phenylephrine increased threshold. From our analysis, the resting MAP-mediated changes in receptor threshold accounted for the reflex threshold changes. Altered baroreceptor properties did not account for changes in baroreflex HP range produced by both drugs, and in reflex gain; these were probably due to afferent interactions in the CNS. Because of rapid arterial baroreceptor resetting, transient changes (of about 30 seconds or less) in MAP of moderate magnitude evoked normal reflex heart rate responses at each resting MAP. After changes in resting MAP sustained for 15 minutes or longer, reflex changes in resting heart rate were considerably smaller than in the absence of resetting. Therefore the arterial baroreceptors provide the baroreflex with a "floating" rather than a fixed set point, determined by the prevailing MAP. {Cue Res 50: 428-439, 1982)

SUMMARY1. We investigated the effects of the opiate antagonist naloxone on changes in renal nerve activity and the renal sympathetic baroreflex during haemorrhage and whether they could be mimicked by blocking afferent input from cardiac receptors.2. Renal nerve activity, arterial pressure and heart rate were recorded in conscious rabbits during blood loss of either 18 or 34-40 % of the blood volume. The renal sympathetic baroreflex was elicited by perivascular balloon-induced changes in arterial pressure, before and at the end of haemorrhage. The experiment was repeated during intravenous naloxone infusion (4 mg kg-', then 0X12 mg kg-' min-'), and after blocking afferent input from cardiac receptors (5 % intra-pericardial procaine).3. Moderate haemorrhage elicited a rise in renal nerve activity and modest inhibition of the range of the renal sympathetic baroreflex. Severe haemorrhage triggered an abrupt fall in nerve activity and arterial pressure which was accompanied by strong inhibition of the baroreflex range and other curve parameters. There were minimal changes in the baroreceptor-heart rate reflex.4. Intravenous naloxone and pericardial procaine prevented the falls in renal nerve activity and pressure triggered by severe blood loss but did not affect the increase in activity elicited by moderate haemorrhage. Both drugs produced similar enhancement of the normovolaemic renal sympathetic baroreflex. Naloxone prevented the baroreflex inhibition elicited by both levels of haemorrhage while pericardial procaine prevented most (but not all) of the baroreflex inhibition seen during severe haemorrhage without affecting that found during moderate haemorrhage.5. We conclude that cardiac receptors (probably ventricular baroreceptors) but not arterial baroreceptors have an opiate synapse on their reflex pathways to the renal nerve. A major part of the action of naloxone during haemorrhage can be explained by blockade of this type of synapse on baroreflex pathways to renal and probably other sympathetic vasoconstrictors. The presence of procaine-resistant but naloxone-sensitive effects during haemorrhage suggests a role for extra-cardiac baroreceptors with opioid central nervous connections.

Peripheral- and central nervous system (CNS)-mediated effects of desipramine (Des) on sympathetic nerves and the contribution of alpha 2-adrenoceptors to these effects were studied in conscious rabbits. Blood pressure, renal sympathetic nerve activity (SNA), and norepinephrine (NE) reuptake and spillover into plasma were measured before and after intracisternal (ic) or intravenous (i.v.) administration of Des. In other animals, NE spillover responses to i.v. Des were examined before and after alpha 2-adrenoceptor blockade with i.v. idazoxan. Treatment with i.v. Des blocked neuronal reuptake and decreased renal SNA but did not alter blood pressure or NE spillover. Decreased NE release by sympathetic nerves after i.v. Des was reflected by a decrease in the combined rate of NE reuptake and spillover. Treatment with ic Des (at 1.7% of the i.v. dose) decreased blood pressure and renal SNA and produced equivalent falls in NE reuptake and spillover, indicating little peripheral effect of centrally administered Des on the efficiency of neuronal reuptake. Thus Des had two distinct actions: the drug blocked neuronal reuptake by direct actions on nerve endings and reduced SNA by actions within the CNS. After ic Des, decreased SNA produced parallel falls in NE reuptake, spillover, and blood pressure. After i.v. Des, blockade of neurotransmitter reuptake increased NE concentrations at sympathoeffector junctions offsetting the fall in SNA, so that there was little change in NE spillover or blood pressure. However, after alpha 2-adrenoceptor blockade with i.v. idazoxan, NE spillover increased in response to i.v. Des. Thus the Des-induced decrease in NE release was partly mediated by an action of raised intrasynaptic NE concentrations on inhibitory alpha 2-adrenoceptors.

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