1 Increased renal vascular resistance is one renal functional abnormality that contributes to hypertension, and alpha(1)-adrenoceptors play a pivotal role in modulating this renal vascular resistance. This study investigates the functional contribution of alpha(1)-adrenoceptor subtypes in the renal cortical vasculature of Wistar-Kyoto rats on a normal sodium diet (WKYNNa) compared with those given saline to drink for 6 weeks (WKYHNa). 2 The renal cortical vascular responses to the adrenergic agonists noradrenaline (NA), methoxamine (ME) and phenylephrine (PE) were measured in WKYHNa and WKYNNa rats either in the absence (the control phase) or presence of chloroethylclonidine (CEC), an alpha(1B)-adrenoceptor antagonist, 5-methylurapidil (5-MeU), an alpha(1A) antagonist, or BMY7378, an alpha(1D) antagonist. 3 Results showed a greater renal cortical vascular sensitivity to NA, PE and ME in the WKYHNa compared with WKYNNa rats (P < 0.05). Moreover, 5-MeU and BMY7378 attenuated adrenergically induced renal cortical vasoconstriction in WKYHNa and WKYNNa rats; this response was largely blunted in CEC-treated WKYHNa rats (all P < 0.05) but not in CEC-treated WKYNNa rats. 4 The data suggest that irrespective of dietary sodium content, in Wistar-Kyoto rats alpha(1A)- and alpha(1D)-subtypes are the major alpha(1)-adrenoceptors in renal cortical vasculature; however, there appears to be a functional involvement of alpha(1B)-adrenoceptors in the WKYHNa rats.

Clonidine, an antihypertensive drug, binds to alpha 2-adrenergic and imidazoline receptors. The endogenous ligand for imidazoline receptors may be a clonidine-displacing substance, a small molecule isolated from bovine brain. This clonidine-displacing substance was purified and determined by mass spectroscopy to be agmatine (decarboxylated arginine), heretofore not detected in brain. Agmatine binds to alpha 2-adrenergic and imidazoline receptors and stimulates release of catecholamines from adrenal chromaffin cells. Its biosynthetic enzyme, arginine decarboxylase, is present in brain. Agmatine, locally synthesized, is an endogenous agonist at imidazoline receptors, a noncatecholamine ligand at alpha 2-adrenergic receptors and may act as a neurotransmitter.

The rostral ventrolateral medulla is the primary site of action for clonidine, a centrally acting antihypertensive. In the rostral ventrolateral medulla, clonidine binds not only to alpha-2 adrenergic receptors but also to specific imidazole sites. In order to determine whether a putative imidazole receptor mediates the hypotensive action of clonidine, a series of compounds was tested 1) in vitro for binding affinity at imidazole and alpha-2 sites and 2) in vivo for ability to lower arterial pressure and heart rate when microinjected directly into the rostral ventrolateral medulla. Hypotensive potency was correlated with affinity at imidazole sites (r = 0.84), but not with alpha-2 affinity (r =-0.05). The bradycardia elicited by this series of compounds also correlated with affinity at imidazole receptors (r = 0.89), but not with alpha-2 affinity (r = 0.10). Furthermore, the imidazole idazoxan selectively reversed the fall in arterial pressure elicited by clonidine, whereas SKF-86466, an alpha-2 antagonist which is not an imidazole, failed to attenuate clonidine's action. An imidazole receptor in the rostral ventrolateral medulla appears to mediate the central hypotensive actions of clonidine and related centrally acting imidazoles and may participate in the regulation of arterial pressure and heart rate.

Cessation of drug use in chronic opiate abusers produces a severe withdrawal syndrome that is highly aversive, and avoidance of withdrawal or associated stimuli is a major factor contributing to opiate abuse. Increased noradrenaline in the brain has long been implicated in opiate withdrawal, but it has not been clear which noradrenergic systems are involved. Here we show that microinjection of beta-noradrenergic-receptor antagonists, or of an alpha2-receptor agonist, into the bed nucleus of the stria terminalis (BNST) in rats markedly attenuates opiate-withdrawal-induced conditioned place aversion. Immunohistochemical studies revealed that numerous BNST-projecting cells in the A1 and A2 noradrenergic cell groups of the caudal medulla were activated during withdrawal. Lesion of these ascending medullary projections also greatly reduced opiate-withdrawal-induced place aversion, whereas lesion of locus coeruleus noradrenergic projections had no effect on opiate-withdrawal behaviour. We conclude that noradrenergic inputs to the BNST from the caudal medulla are critically involved in the aversiveness of opiate withdrawal.

1. ZENECA ZD7288 (4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino) pyridinium chloride) is a sinoatrial node (SAN) modulating agent which produces a selective slowing of the heart rate. Its effects have been studied in single, freshly dissociated guinea-pig SAN cells, by standard patch clamp procedures. 2. Whole-cell inward currents were evoked by hyperpolarizing voltage clamp steps from a holding potential of -40 mV. ZD7288 inhibited the hyperpolarization activated cationic current (If) in a concentration-dependent manner. The 'selective bradycardic agents' alinidine and UL-FS 49 (zatebradine) both also inhibited If. 3. The activation of If was investigated by measuring tail current amplitudes at +20 mV after hyperpolarizing steps to different potentials to activate the current. The reduction in If resulted from both a shift in the If current activation curve in the negative direction on the voltage axis, and also a reduction in the activation curve amplitude. 4. ZD7288 did not affect the ion selectivity of the If channel, since the tail current reversal potential was unchanged in the presence of the drug. 5. With ZD7288 the inhibition of If was not use-dependent, whereas UL-FS 49 displayed use-dependence in the block of the If current. 6. Whereas ZD7288 had no significant effect on the delayed rectifier current (Ik) in these cells, both alinidine and UL-FS 49 significantly reduced Ik at the same concentrations which reduced If. 7. The data show that ZD7288 reduces If by affecting the activation characteristics of the If current; this inhibition may account for this agent's selective bradycardiac properties.

[3H]WB-4101 and p-[3H]aminoclonidine were used for light microscopic autoradiographic localization of alpha 1 and alpha 2 adrenergic receptors, respectively, in the rat brain. The binding of these ligands to slide-mounted tissue sections had all of the characteristics associated with alpha 1 and alpha 2 receptors. It was saturable with appropriate kinetic constants and was blocked only by other alpha-adrenergic drugs with the appropriate potency. Autoradiographic studies revealed a distribution of alpha-adrenergic receptors throughout the nervous system. Certain areas had elevated levels. These included parts of the olfactory bulb and nucleus, parts of the cerebral cortex and dentate gyrus, the more medial portions of the hypothalamus and thalamus, the locus ceruleus and nucleus tractus solitarii, and parts of the spinal cord. In certain areas, the distribution of alpha 1 and alpha 2 receptors was markedly different. These results provide some rational basis for the observed actions of alpha-adrenergic drugs on the central nervous system. For example, the finding of high densities of alpha 2 receptors in the nucleus tractus solitarii is most likely related to its antihypertensive action. The observed codistribution of alpha 2 receptors with opiate receptors would provide an explanation of the observation that alpha 2 agonists block opiate withdrawal. The results are also discussed in relationship to the anatomy of catecholamine systems in the brain.

Neuropeptide Y (NPY) is a 36-amino-acid, C-terminal amidated peptide that is found in bulbospinal pathways and can inhibit the release of the primary afferent C-fiber neurotransmitter, substance P. Based on these observations, the present studies examined the possible antinociceptive effects of this peptide and several NPY fragments after intrathecal administration in rats prepared with chronic intrathecal catheters. In the 52 degrees C hot plate test, NPY produced a dose-dependent elevation in the nociceptive threshold with a median effective dose of 1.1 nmol. The ordering of fragments' activity was: NPY greater than NPY16-36 greater than or equal to NPY19-36 greater than or equal to NPY14-36 greater than or equal to NPY18-36 much greater than NPY1-36-OH = NPY18-36-OH = 0. In the paw pressure test, NPY was not active, even at the highest doses examined (median effective dose greater than 20 nmol), whereas the C-terminal fragments retained their potency and produced significant increases in the pressure required to evoke escape (NPY18-36: median effective dose = 18.7 nmol). The rank ordering of activity in the paw pressure test was: NPY19-36 greater than or equal to NPY14-36 greater than or equal to NPY18-36 greater than or equal to NPY16-36 much greater than NPY = NPY18-36-OH = 0. Peptide YY, human pancreatic polypeptide and avian pancreatic polypeptide behave similarly to NPY.(ABSTRACT TRUNCATED AT 250 WORDS)

This symposium is concerned with the treatment of spasticity and, in particular, with results from studies of tizanidine as a treatment for patients with MS and spinal cord injury. In this article, the definitions and pathophysiologies of spasticity are reviewed, and the issue of when and if to treat spasticity is evaluated. The merits of newer pharmacologic and invasive therapies are discussed relative to reduction of patient discomfort and the possibility of restored function.

We have attempted to define the alpha adrenoceptor subtype(s) on which intrathecally applied alpha adrenergic agonists act to produce their antinociceptive effect. The potencies of intrathecal (i.t.) prazosin or i.t. yohimbine to antagonize the elevations of thermal nociceptive threshold induced by i.t. 2-[2,6-diethylphenylamino]-2-imidazoline (ST-91), methoxamine or norepinephrine (NE) were determined in the rat. Tail-flick and hot plate tests were used to determine thermal nociceptive threshold. At the ID50 level, the alpha-2 selective antagonist yohimbine was significantly more potent than the alpha-1 selective antagonist prazosin at blocking the analgesia produced by the alpha-2 selective agonist ST-91, whereas prazosin was significantly more potent than yohimbine at antagonizing the analgesia produced by the alpha-1 selective agonist methoxamine or by the nonselective alpha agonist NE. Analgesic doses of methoxamine evoked a readily observable disturbance of motor and autonomic function, whereas such effects were not observed after analgesic doses of ST-91 or NE. Both i.t. methoxamine and i.t. ST-91 elevated thermal nociceptive threshold in rats depleted of lumbar spinal cord NE by pretreatment 7 days before with i.t. 6-hydroxydopamine. Our results suggest that stimulation of either one of two separate populations of postsynaptic spinal alpha adrenoceptors will inhibit spinal nociceptive transmission. One of these populations appears to be composed of alpha-2 adrenoceptors. The subtype classification of the alpha adrenoceptors composing the other population remains unclear.

1. We examined whether alpha 1-adrenoceptors in various blood vessels can be divided into subtypes by antagonist affinity or by susceptibility to chloroethylclonidine or nifedipine. 2. Noradrenaline or phenylephrine produced concentration-dependent contractions in all the tissues tested, which were competitively inhibited by phentolamine, yohimbine, prazosin, WB4101 and HV723. However, there were large differences between the tissues in the pA2 values for all the antagonists except phentolamine. 3. The blood vessels could be classified into three groups (I, II and III) on the basis of their affinity variation. In group I (dog mesenteric artery and vein, saphenous vein), the pA2 values for HV723 were greater than 9, and those for HV723 and WB4101 were approximately 1 log unit higher than for prazosin. This rank order of affinity reversed in group II (dog carotid artery and rat thoracic aorta), where prazosin was more potent (pA2 values greater than 9.5) than HV723 or WB4101. In group III (rabbit mesenteric artery, thoracic aorta and carotid artery and guinea-pig thoracic aorta), on the other hand, prazosin, HV723 and WB4101 inhibited the noradrenaline response with a similar affinity (pA2 values ranging from 8 to 9). 4. Yohimbine inhibited the responses to noradrenaline and phenylephrine with a lower affinity than prazosin, HV723 or WB4101. The pA2 values for yohimbine were similar in groups I and II (the values greater than 6.5), which were greater than those in group III (values less than 6.4).(ABSTRACT TRUNCATED AT 250 WORDS)

Intraspinal administration of alpha 2 adrenergic agonists produces analgesia, but clinical application of these agents is limited by dose-dependent sedation and hypotension. Recently, neostigmine has been demonstrated to counteract hypotension in sheep and enhance antinociception to tail flick in rats from spinally administered alpha 2 adrenergic agonists. We investigated this spinal interaction further in chronically prepared, conscious sheep, testing antinociception with a mechanical pressure stimulus on the forelimb. Clonidine produced dose-dependent antinociception which was antagonized by idazoxan and enhanced by neostigmine, although it was unaltered by methylatropine. Clonidine increased acetylcholine in cerebrospinal fluid, an effect potentiated by physostigmine and blocked by idazoxan. The highly lipid-soluble alpha 2 adrenergic agonists dexmedetomidine and clonidine produced antinociception, whereas the poorly lipid-soluble ST-91 (2,[2,6-diethylphenylamino]-2-imidazoline) produced antinociception only at much larger doses and did not affect cerebrospinal fluid levels of acetylcholine. In human volunteers, epidurally administered clonidine increased cerebrospinal fluid acetylcholine levels at the time of peak analgesia. These results support the existence of an interaction between alpha 2 adrenergic and cholinergic mechanisms of analgesia at the spinal level and underscore the importance of lipid solubility in the actions of spinally administered drugs in sheep.