MODULATION OF RENAL NORADRENALINE RELEASE BY PREJUNCTIONAL RECEPTOR SYSTEMS IN VITRO

1. The amount of noradrenaline released per nerve impulse from renal sympathetic nerves can be modulated through specific prejunctional receptors. 2. Under in vitro conditions activation of alpha 1-, alpha 2-, prostaglandin, adenosine, dopamine and serotonin receptors inhibits noradrenaline release from the kidney. 3. Stimulation of prejunctional beta-adrenoceptors, probably of the beta 2-subtype, as well as stimulation of prejunctional angiotensin II receptors facilitates noradrenaline release. Moreover, neuronally released noradrenaline inhibits its own release through activation of both prejunctional alpha 1- and alpha 2-adrenoceptors. 4. Locally produced PGE2, which is formed and released via stimulation of postjunctional alpha 1-adrenoceptors, as well as adenosine, released from postjunctional sites by renal nerve stimulation (RNS), seems to inhibit noradrenaline release through their specific prejunctional receptor systems.     

HYPERTENSION THROUGH ADRENALINE ACTIVATION OF PREJUNCTIONAL β-ADRENOCEPTORS

1. Adrenaline can enhance the stimulation-induced release of transmitter noradrenaline in sympathetically innervated tissues by activating prejunctional beta-adrenoceptors. 2. Adrenaline incorporated into sympathetic transmitter stores by neuronal uptake can be subsequently released as a co-transmitter and can then activate prejunctional beta-adrenoceptors, thus completing a facilitatory feedback loop. 3. Rats chronically treated with adrenaline develop elevated blood pressures compared to control rats. beta-Adrenoceptor blockade prevents the rise in blood pressure. 4. Activation by adrenaline of facilitatory prejunctional beta-adrenoceptors of sympathetic nerves innervating cardiovascular effector tissues may explain adrenaline-induced rises in blood pressure.     

FACILITATION OF SYMPATHETIC TRANSMISSION BY PREJUNCTIONAL β-ADRENOCEPTORS IN CARDIAC AND VASCULAR TISSUES

1. In rat isolated tail arteries and atria in which transmitter stores are labelled with (3H)-noradrenaline, isoprenaline in low concentrations facilitates the stimulation-induced efflux of tritium. 2. This effect is dependent on the frequency and duration of electrical stimulation, being observed only at low frequency (2 Hz) and short duration (10 s in atria and 30 s in arteries) or at high frequency (5 Hz) and long duration (1 min in atria and 4 min in arteries). 3. In atria, phenotlamine enchances tritium efflux with stimulation at 5 Hz for 1 min but not at 2 Hz for 10 s. Conversely, propranolol reduces tritium efflux with stimulation at 2 Hz for 10 s but not at 4 Hz for 1 min. 4. The results can be interpreted in terms of the selective operation, depending on the frequency and duration of electrical stimulation, of inhibitory and facilitatory feedback loops for transmitter release involving prejunctional alpha -and beta-adrenoceptors, respectively.     

DUAL EFFECTS OF CLONIDINE ON RAT PREJUNCTIONAL α-ADRENOCEPTORS

1. The effects of clonidine (1.0 mumol/l) and phentolamine (3.0 mumol/l) on the stimulation-induced efflux of radioactivity were assessed in rat isolated atria and tail arteries in which transmitter stores had been labelled with (3H)-noradrenaline. 2. In atria, clonidine did not affect transmitter release when stimulation was for 10 s periods at frequencies of 1, 2 or 5 Hz, whereas at 10 Hz there was a significant 1.2-fold enhancement of release. Phentolamine enhanced release with stimulation at 5 Hz and 10 Hz by 1.5- and 2.5-fold respectively. 3. In tail arteries, clonidine reduced release when stimulation was for 30 s periods at a frequency of 1 Hz, but did not affect release at 2 Hz or 5 Hz. Phentolamine in each case produced an approximately 1.5-fold enhancement of release. 4. In the pithed rat, spinal stimulation of cardioaccelerator fibres produced a tachycardia, the magnitude of which depended on the frequency and duration of stimulation. Clonidine (10 micrograms/kg, i.v.) caused either a reduction or an enhancement of the response depending on the frequency and duration of stimulation; in the presence of phentolamine (2 mg/kg, i.v.), clonidine had no effect. 5. The results are consistent with partial agonistic actions of clonidine at prejunctional alpha-adrenoceptors in the rat cardiovascular system; such effects may be of relevance to the mechanism of the clonidine withdrawal syndrome.     

DEMONSTRATION OF PROXIMAL TUBULAR α-ADRENOCEPTORS IN VIVO

Receptors for parathyroid hormone (PTH) in the renal tubule are coupled to adenylate cyclase stimulation. PTH causes a rise in urinary cAMP by leakage from adenylate cyclase stimulation. PTH causes a rise in urinary cAMP by leakage from cells of the proximal convoluted tubule. The effects of alpha-adrenergic agonists and antagonists on the urinary cAMP response to PTH were investigated in anaesthetized rats in vivo. Injection of PTH (15 u/kg i.v.) produced an increase in urinary cAMP from 1.7 (s.e.m. = 0.3, n = 6) to 7.47 (s.e.m. = 0.7, n = 6) nmol cAMP/mumol creatinine in 30 min urine samples. Infusion of the alpha 2-adrenoceptor agonist clonidine at 1 microgram/kg per min caused a decrease in the cAMP response to PTH to 3.6 (s.e.m. = 0.5, n = 12) nmol cAMP/mumol creatinine. Infusion of the alpha 2-selective catecholamine alpha-methylnoradrenaline (1 microgram/kg per min) caused a similar reduction in urinary cAMP response to that observed with clonidine. The alpha-adrenoceptor antagonist phentolamine (100 micrograms/kg per min) enhanced the cAMP response to PTH and reversed the decreased response caused by clonidine. These results demonstrate the presence of alpha-receptors in the rat proximal convoluted tubule which oppose the actions of PTH in vivo.     

PERTUSSIS TOXIN ATTENUATES ANGIOTENSIN II BUT NOT β-ADRENOCEPTOR FACILITATION OF NORADRENALINE RELEASE FROM RAT KIDNEY CORTEX

1. Angiotensin II (AII; 0.01 and 0.1 μmol/L), angiotensin I (AI, 0.1 μmol/L) and the β-adrenoceptor agonist isoprenaline (0.1 μmol/L) all facilitated the stimulation-induced outflow of radioactivity from slices of rat kidney cortex incubated in [³H]-noradrenaline. 2. Treatment of rats with pertussis toxin (25 and 50 μg/kg i.v.) to inactivate G-proteins attenuated the facilitation caused by AII and AI, but not that caused by isoprenaline. 3. The hypothesis that isoprenaline enhances noradrenaline release by generating AII to activate facilitatory prejunctional AII receptors is not supported by the present study. The hypothesis predicts that pertussis toxin, by inactivating the G-proteins associated with AII receptors, should have inhibited the facilitatory effect of isoprenaline. This did not occur.     

HUMAN VASCULAR α-ADRENOCEPTORS: THE RELEVANCE OF SUBTYPES

1. The post-receptor mechanisms of alpha 1 and alpha 2-adrenoceptor subtypes in guinea-pig aorta and human digital arteries have been explored. 2. Nifedipine antagonized contractile responses of human digital arteries to TL99 and methoxamine to a similar degree, thus suggesting that neither the alpha 1 nor the alpha 2 receptor is preferentially linked to calcium entry through voltage-operated channels of the cell membrane. 3. In the guinea-pig aorta, which contains only alpha 1-adrenoceptors, methoxamine-stimulated inositol phosphate (IP) production at similar concentrations was required to produce contractile responses. 4. In the human digital artery, noradrenaline also produced a significant increase in IP formation, but preliminary experiments have suggested that both TL99 and methoxamine stimulate IP production. 5. Thus, the present authors have been unable as yet to confirm, in a tissue which contains both alpha 1- and alpha 2-adrenoceptors, that the post-receptor mechanisms of the alpha subtypes are different.     

TIME COURSE OF RECOVERY OF β- AND α1-ADRENOCEPTORS IN EXPERIMENTAL ASTHMA

1. The time course of recovery of reduced beta-adrenoceptors caused by ovalbumin (OA) challenge was investigated using guinea-pigs. 2. The effects of prednisolone on the recovery time course were also evaluated. 3. beta- and alpha 1-receptor assays were performed using lung membranes. Adenylate cyclase activity was also measured. 4. OA challenge reduced the number of beta-adrenoceptors by 35%, and a significant decrease (13%) persisted for 7 days. The number of beta-adrenoceptor recovered after 14 days. 5. OA challenge elevated the number of alpha 1-adrenoceptors. A significant increase (24%) was observed after 7 days, and it took a further 7 days for the recovery. 6. After OA challenge there was a significant decrease in adenylate cyclase activity after 7 days, which recovered after a further 7 days. 7. Inhalation of prednisolone accelerated the recovery of beta-adrenergic responsiveness, though it did not affect the recovery of the number of alpha 1-adrenoceptors. Prednisolone inhalation also elevated beta-adrenergic responsiveness in non-asthmatic subjects. 8. It is concluded that reduced beta-adrenergic responsiveness caused by OA challenge persisted for 7 days and recovered after a further 7 days. Steroid hormone increased beta-adrenoceptors.     

SPECTROPHOTOMETRIC STUDY OF α-ADRENOCEPTORS AFFECTING MICROCIRCULATION OF RAT SKIN

1. To determine the α-adrenergic receptor subtypes that affect the microcirculation of skin, the relative absorption (RA) spectra of the skin on the backs of rats were measured using reflectance spectrophotometric methods. We injected α-adrenergic agonists, noradrenaline (NA), phenylephrine (PE) and clonidine (CL), intravenously and determined changes in the RA value at 569 nm, one of the isosbestic points of the oxyhaemoglobin and deoxyhaemoglobin absorption. 2. NA reduced the RA value and the reduction was inhibited significantly by pretreatment with phenoxybenzamine (PBZ; P<0.01). These findings suggested that the haemoglobin content in the skin tissue decreased as a result of vasoconstriction through α-adrenoceptors. 3. NA, PE and CL produced dose-dependent reductions in RA. CL and NA produced virtually equipotent reductions except at the highest dose used. PE produced smaller effects. The potency of these drugs in terms of changes in RA did not correlate with their potency in terms of rises in systemic blood pressure (NA ≤ PE ≥ CL). 4. Yohimbine (YO) inhibited the NA-induced reduction in RA to a greater degree than bunazosin (BU). Midaglizole, a specific α₂-adrenergic antagonist, significantly and dose dependently inhibited the NA-induced reduction in RA. 5. Although BU inhibited NA-induced reduction in RA only slightly, the effect was significant (P<0.05). BU significantly inhibited PE-induced reduction (P<0.01), but did not inhibit CL-induced reduction. 6. These observations suggest that the microcirculation of the skin of the rat is affected mainly by α₂-adrenoceptor mediated vasoconstriction. However, α₁-adrenoceptor mediated vasoconstriction also has some effect.     

DIFFERENTIAL BLOCKING EFFECTS OF PRAZOSIN AND YOHIMBINE ON PRESSOR RESPONSES TO NEURONALLY RELEASED AND EXOGENOUSLY ADMINISTERED NORADRENALINE IN THE PITHED RAT

The effects of prazosin and yohimbine on pressor responses to sympathetic nerve stimulation and intravenous injections of noradrenaline, phenylephrine and clonidine were examined in pithed rats to determine the postjunctional location of alpha 2-adrenoceptors in the vascular smooth muscle. Prazosin antagonized the pressor responses to phenylephrine and to sympathetic nerve stimulation more effectively than the responses to noradrenaline and to clonidine. Yohimbine antagonized the pressor responses to noradrenaline and to clonidine more effectively than the responses to sympathetic nerve stimulation and to phenylephrine. These results suggest that alpha 2-adrenoceptors as well as alpha 1-adrenoceptors produce vasoconstriction in the rat vasculature and support the hypothesis that alpha 1-adrenoceptors are predominantly located within the neuroeffector junction in contrast to an extrajunctional location of alpha 2-adrenoceptors.     

RILMENIDINE ACTS AS A PARTIAL AGONIST AT PREJUNCTIONAL α2-ADRENOCEPTORS IN GUINEA-PIG ATRIA

1. The present study was carried out to determine whether rilmenidine, a recently introduced antihypertensive agent which acts on alpha 2-adrenoceptors, has partial agonist activity on prejunctional alpha 2-adrenoceptors in guinea-pig atria. 2. Isolated preparations of guinea-pig atria were incubated with [3H]-noradrenaline and the efflux of radioactivity induced by stimulation of intramural sympathetic nerves was used as an index of release of transmitter noradrenaline. 3. Rilmenidine (1 mumol/l) inhibited noradrenaline release evoked by short trains (five, 20 and 50 pulses) of sympathetic nerve stimulation and this inhibitory effect of rilmenidine was antagonized by the alpha 2-adrenoceptor antagonists, idazoxan (0.1 and 0.3 mumol/l) and rauwolscine (0.3 mumol/l) whereas it was not affected by the alpha 1-adrenoceptor antagonist prazosin (0.1 mumol/l). 4. On the other hand, rilmenidine (1 mumol/l) enhanced noradrenaline release evoked by long trains (150 and 300 pulses) of stimulation and this effect was also abolished by idazoxan (0.1 mumol/l). 5. These findings suggest that the effects of rilmenidine on transmitter release depend on the degree of auto-inhibition: when the concentration of noradrenaline in the biophase of the prejunctional alpha 2-adrenoceptors is low, rilmenidine acts as an agonist, but when the concentration is high it acts as an antagonist. Thus, rilmenidine, like clonidine, is a partial agonist on prejunctional alpha 2-adrenoceptors in guinea-pig atria.     

CENTRAL α-ADRENOCEPTORS AND BLOOD PRESSURE REGULATION IN THE RAT

1. Radioligand binding studies using [³H]-prazosin (α₁) and [³H]-yohimbine (α₂) were undertaken to characterize central α-adrenoceptors in regions involved in blood pressure regulation. 2. Both α₁- and α₂-adrenoceptors were identified in the anterior and posterior hypothalamus and dorsal midline area of the caudal medulla oblongata of the rat. 3. The α₁- or α₂-adrenergic pharmacological specificity of the adrenoceptors was similar in each region, although their concentrations were different. 4. The concentration of α₂-adrenoceptors in the anterior hypothalamus was decreased following sino-aortic denervation suggesting that some hypothalamic α₂-adrenoceptors are associated with neurones of the baroreflex arc.     

DECREASED CARDIAC β-ADRENOCEPTORS IN HYPERTENSIVE RATS

1. β-Adrenoceptors have been investigated in cardiac and renal cell membranes from hypertensive and normal rats. 2. The ¹²⁵I-labelled β-adrenoceptor antagonist l-(4-iodophenoxy)-3-isopropyl-aminopropan-2-ol was used to measure directly the number and affinity of receptors. 3. Cardiac membranes from hypertensive rats had a lower concentration of β-adrenoceptors than membranes from control normotensive animals, but the affinities of the receptors remained unchanged. Receptor concentration decreased by half and was similar in each of the three models of experimental hypertension investigated. 4. In contrast, kidney membranes from hypertensive animals had the same β-adrenoceptor concentration and affinity as membranes from normotensive rats. 5. The decrease in cardiac β-adrenoceptor concentration may reflect an increase in cardiac sympathetic drive in these experimental hypertensive models.     

α1- AND α2-ADRENOCEPTORS OF THE CIRCULAR MYOMETRIUM FROM THE DIOESTROUS GUINEA-PIG

1. In order to investigate the nature of the alpha-adrenoceptors mediating contraction of circular myometrium from dioestrous guinea-pigs, the effects of several adrenoceptor antagonists upon log concentration curves to noradrenaline and phenylephrine have been examined. 2. In the presence of ICI 118,551 and nisoxetine both phenylephrine and noradrenaline produced concentration-dependent contractures of circular myometrium from virgin dioestrous guinea-pigs. Noradrenaline was the more potent and produced larger maximal contractions. Indomethacin (1 mumol/l) decreased the maximum effects of phenylephrine but not those of noradrenaline. Xylazine produced indomethacin-sensitive contractions which were not dose-related and which never exceeded 40% of those evoked by noradrenaline. Responses to xylazine and to noradrenaline, but not those to phenylephrine, were reduced in a low calcium solution. 3. Prazosin produced competitive antagonism of the effects of phenylephrine upon preparations of circular myometrium from virgin and parous dioestrous animals; pA2 values were both 8.1. Phentolamine also competitively antagonized the effects of phenylephrine (virgin animals, pA2=7.7). 4. Both prazosin and phentolamine antagonized the effects of noradrenaline upon preparations from virgin dioestrous animals, however, Schild plot analysis did not indicate a simple bimolecular interaction between agonist and receptors. In the presence of prazosin the alpha 2-adrenoceptor antagonist idazoxan produced dose-dependent parallel shifts in the positions of the log concentration-response curves to noradrenaline; the pA2 was 7.7. In the presence of idazoxan or of indomethacin prazosin competitively antagonized the effects of noradrenaline; the pA2 values were 8.5 and 8.2 respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

EXCITATORY AND INHIBITORY EFFECTS OF NORADRENALINE ON THE ISOLATED GUINEA-PIG VAS DEFERENS

SUMMARY 1. Contractions of guinea-pig isolated vasa deferentia produced by noradrenaline were found to consist of several phases. The sustained part of the contraction was very small compared with maximal contractions produced by stimulation of the postganglionic nerves. The sustained phase was usually preceded by a rapid phasic contraction and in some experiments was followed by contraction on washing out the noradrenaline.
2. Contractions in response to noradrenaline were blocked by the α-adrenoceptor antagonist, phentolamine.
3. Noradrenaline-induced contractions were inhibited in the presence of low conditioning doses of noradrenaline, phenylephrine, oxymetazoline or methoxamine. This effect may provide an explanation for the observation that noradrenaline inhibits contractions produced by sympathetic nerve stimulation. Although it was presumably mediated via α-adrenoceptors the inhibitory effect was not due to depolarization alone since it could not be reproduced by increasing the potassium concentration of the Krebs solution.
4. The α-receptor agonists inhibited responses to noradrenaline or phenylephrine, but augmented potassium and acetylcholine contractions. This specificity of action eliminates the possibility that a distinct group of α-receptors solely mediating a relaxant effect were activated in these experiments but suggests receptor desensitization.
5. Receptor-specific desensitization was also found to be a property of the acetylcholine receptors in the vas.     

INVOLVEMENT OF α1-ADRENOCEPTORS IN CHRONOTROPIC RESPONSES TO ENDOGENOUSLY RELEASED AMINES IN THE PITHED RAT

1. In pithed rats, yohimbine (1 mg/kg i.v.) enhanced the positive chronotropic responses to spinal stimulation of cardiac sympathetic nerves with eight pulses delivered at 2 or 4 Hz, indicating that auto-inhibition was operating, but did not increase responses to shorter lengths of trains of 8 pulses at 8, 16 or 32 Hz which did not allow sufficient time for auto-inhibition to come into effect. 2. The positive chronotropic response to cardiac sympathetic nerve stimulation with eight pulses at 8 Hz of about 60 beats/min was not affected by prazosin (1 mg/kg) or diltiazem (0.2 mg/kg), but was reduced to about 20% of the control value by propranolol (1 mg/kg). 3. In the presence of propranolol, the residual positive chronotropic responses to cardiac sympathetic nerve stimulation were virtually abolished by prazosin (1 mg/kg) or diltiazem (0.2 mg/kg). 4. The positive chronotropic response to tyramine (0.1 mg/kg i.v.) was reduced from 100 to 12 beats/min by propranolol (1 mg/kg), and the residual response was abolished by prazosin. 5. The findings indicate that noradrenaline released from cardiac sympathetic terminals by nerve stimulation or by tyramine acts on alpha 1-adrenoceptors to produce a positive chronotropic response that is revealed when beta-adrenoceptors are blocked.     

FUNCTIONAL ASSESSMENT OF α1-ADRENOCEPTOR SUBTYPES IN PORCINE CORONARY ARTERY

1.α₁-Adrenoceptors are known to play an important role in vasoconstriction in response to adrenergic stimulation. However, the functional importance of α₁-adrenoceptor subtypes at the epicardial coronary artery remains unclear. We examined α-adrenoceptor subtypes by comparing functional affinities for α-adrenoceptor antagonists on noradrenaline (NA)-induced vasoconstriction in porcine denuded right coronary arteries. 2. Noradrenaline induced a dose-dependent vasoconstriction in incubated vessel rings. Prazosin and phentolamine were potent and competitive antagonists for NA-induced contraction (pA₂ 10.27 and 9.03, respectively). In contrast, the selective α₂-adrenoceptor antagonist yohimbine had a low affinity (pA₂ 6.13). Two selective α_1A-adrenoceptor antagonists, WB 4101 and 5-methyl urapidil, were potent and competitive antagonists of α₁-adrenoceptor-induced contraction (pA₂ 10.67 and 8.90, respectively) and the selective α_1D-adrenoceptor antagonist BMY 7378 had a low affinity (pA₂ 6.06). Noradrenaline-induced contraction was insensitive to the alkylating effects of chlorethyl-clonidine. These observations indicate that the vasoconstriction is predominantly mediated by the α_1A-adrenoceptor subtype. This was also supported by a good correlation between pA₂ values from the present study and reported binding affinities (pK_i) of various α-adrenoceptor antagonists with cloned human α_1A-adrenoceptors (r= 0.98), but not for α_1B- or α_1D-adreno-ceptor subtypes (r= 0.77 and 0.41, respectively). 3. Our results indicate that the α_1A-adrenoceptor is the main functional receptor subtype in porcine denuded coronary arteries.     

EVIDENCE FOR DIRECT INTERACTION OF KETAMINE WITH α- AND β2-ADRENOCEPTORS

1. Ketamine has a number of effects that suggest that it may interact with α- and β-adrenoceptors. To date, the experimental evidence for this has been indirect and has been based on physiological studies using competitive blocking agents. In the present study we sought to determine from receptor binding studies whether ketamine binds directly to α- and β-adrenoceptors. 2. Membrane preparations o. α₁- and β₂-adrenergic binding sites were obtained from urinary bladder and urethrae of sheep. These binding sites were characterized by saturation analyses using [³H]-prazosin for α₁-adrenoceptor binding sites and [¹²⁵I]-cyanopindolol (CYP) for the β₂-adrenoceptor binding sites. The receptors were further characterized by displacement studies using selective and non-selective antagonists. 3. Studies in which ketamine was used to displac. [³H]-prazosin revealed a K_d of 3.40±1.23× 10^?3 mol/L for ketamine binding to ai-adrenoceptors. Displacement studies of [¹²⁵I]-CYP by ketamine showed a K_d of 0.35±0.03× 10^?3 mol/L for ketamine binding to β₂-adrenoceptors. 4. We conclude that ketamine interacts directly with both ai- an. β₂-adrenoceptors and that such interactions probably explain the reported effects of this agent on the vasculature and the bronchial tree.     

HETEROGENEITY OF VASCULAR SMOOTH MUSCLE α-ADRENOCEPTORS IN CANINE BLOOD VESSELS

1. For the past decade, using radioligand binding, contractility and immunohistochemical techniques, we have been characterizing vascular smooth muscle (VSM) adrenoceptors in four functionally different canine blood vessels, namely the dog aorta (DAO), dog mesenteric artery (DMA), dog mesenteric vein (DMV) and dog saphenous vein (DSV). 2. This communication briefly reviews our findings (with a special emphasis on alpha-adrenoceptor subtypes), which showed that none of the four canine vessels showed the same complement of alpha-adrenoceptor subtypes. 3. All four vessels elicited alpha 1-adrenoceptor contractile responses (antagonized by prazosin), but alpha 2-adrenoceptor responses (sensitive to rauwolscine), were found only in DMV and DSV. 4. Pharmacological characterization using alpha 1-adrenoceptor subtype-selective antagonists showed that DAO contains mainly alpha 1B-adrenoceptors (some alpha 1D-adrenoceptors) and DMA has primarily alpha 1A/1L-adrenoceptors, alpha 1-Adrenoceptors in DMV are primarily of the alpha 1D subtype, but either a new or unusual alpha 1-adrenoceptor subtype was revealed in the DSV.     

EFFECTS OF THE α2-ADRENOCEPTOR AGONIST UK14304 ON PRESSOR RESPONSES IN PITHED RATS

1. Intravenous infusions of UK14304 (0.3-10 micrograms/kg per min) in pithed rat produced dose-dependent pressor responses which were not affected by prazosin (10 micrograms/kg) but were reduced by yohimbine (0.3 mg/kg). 2. Pressor responses to noradrenaline (0.1 micrograms/kg), phenylephrine (1 micrograms/kg) and vasopressin (10 mU/kg) were enhanced during infusions of UK14304 (0.03-1 micrograms/kg per min). Likewise, pressor responses to spinal sympathetic stimulation were enhanced during infusions of low concentrations of UK14304 (0.03-0.3 microgram/kg per min) but were reduced during infusion of a higher concentration of UK14304 (10 micrograms/kg per min). 3. After administration of yohimbine (0.3 mg/kg) or the calcium channel blocking drug diltiazem (infused at 50 micrograms/kg per min), pressor responses to noradrenaline and UK14304 were reduced, and responses to noradrenaline during infusion of UK14304 were not enhanced. 4. Prazosin (10 micrograms/kg) revealed a secondary depressor component in the response to sympathetic stimulation which is due to beta-adrenoceptor activation, since it was abolished by ICI 118551 (0.3 mg/kg). In the presence of ICI 118551 plus prazosin, pressor responses to sympathetic stimulation were enhanced during infusions of UK14304. 5. The depressor response to nitroprusside and the depressor component of responses to sympathetic stimulation after prazosin were enhanced during infusions of UK14304 at concentrations that increased the blood pressure. 6. The findings show that alpha 2-adrenoceptor activation enhanced the pressor responses to sympathetic nerve stimulation, noradrenaline, phenylephrine and vasopressin in the pithed rat and beta-adrenoceptor activation produced depressor responses which increased with increasing blood pressure.