Studies on the functional role of alpha-adrenoceptors in the cardiac sympathetic ganglia of the dog.

Inhibitory alpha-adrenoceptors were studied in cardiac ganglia of pentobarbital-anesthetized dogs. Blockade of alpha 1- or alpha 2-adrenoceptors augmented preganglionic nerve stimulation induced tachycardia without altering the response to postganglionic nerve stimulation. The effect produced by blockade of ganglionic alpha 1-adrenoceptors with terazosin had different frequency-response characteristics from, was of smaller magnitude than, and was additive with the effect produced by blockade of ganglionic alpha 2-adrenoceptors with rauwolscine. The response to activation of ganglionic nicotinic cholinergic receptors in the absence of electrical stimulation of the preganglionic nerve was not affected by blockade of either alpha 1- or alpha 2-adrenoceptors. The response to nicotinic cholinergic receptor activation during periods of continuous preganglionic nerve stimulation was augmented following blockade of alpha 2-adrenoceptors but unaffected by alpha 1-adrenoceptor blockade. These results suggest that there are two different inhibitory pathways involving alpha-adrenoceptors in mammalian sympathetic ganglia and provide evidence that these inhibitory pathways are operative under the experimental conditions of ganglionic transmission.     

Heterogeneity of vascular alpha-adrenoceptors in man

The knowledge on alpha-adrenoceptors has expanded enormously in the last decade, mostly as a result of in vitro and in vivo animal experiments. In the face of considerable species differences we have tested several of the newly developed concepts on alpha-adrenoceptors in the circulation of the human forearm. In this model we were able to show the presence of postsynaptic alpha 1- and alpha 2-adrenoceptors, both contributing to resting vascular tone. Although adrenaline and noradrenaline were shown to have affinity for each alpha-adrenoceptor subtype, noradrenaline seems to be the natural agonist for both receptors. Evidence is presented for an intrasynaptic location of the alpha 1-adrenoceptor and an extrasynaptic location of the alpha 2-adrenoceptor and also for a functional presynaptic alpha 2-adrenoceptor in the human forearm circulation. Selective hyperresponsiveness to alpha 1- or alpha 2-adrenoceptor stimulation in hypertensive patients could not be established. Calcium entry blockers were shown to attenuate the vasoconstriction induced by selective alpha 2-adrenoceptor stimulation but not by selective alpha 1-adrenoceptor stimulation. These data support the physiological and pharmacological relevance of the new concepts on alpha-adrenoceptors for the situation in man.     

Evidence for and against heterogeneity of alpha 1-adrenoceptors

Recent experimental evidence has suggested that the alpha 1 adrenoceptor may need to be further subdivided. It can no longer be stated categorically that alpha 1-adrenoceptors are present only at postjunctional sites, in view of several reports of alpha 1-mediated modulation of adrenergic and cholinergic neurotransmission. Furthermore, comparison of the pharmacologic characteristics of the alpha 1-adrenoceptor in different species and/or tissues can show clear differences in sensitivity to selective agonists and antagonists, and differences in the degree of dependence on extracellular calcium. However, in other cases, alpha 1-adrenoceptors at diverse sites have been found to have identical characteristics. Furthermore, the subcategories identified by the various selective agents do not fall into the same discrete groups, in contrast to division of alpha-adrenoceptors into alpha 1 and alpha 2-adrenoceptors. Therefore, at this time it seems premature to subdivide the alpha 1-adrenoceptor further.     

Benzo(alpha)pyrene-induced up-regulation of CYP1A2 gene expression: role of adrenoceptor-linked signaling pathways

CYP1A2, a principal catalyst for metabolism of various therapeutic drugs and carcinogens, among others, is in part regulated by the stress response. This study was designed to assess whether catecholamines and in particular adrenergic receptor-dependent pathways, modulate benzo(alpha)pyrene (B(alpha)P)-induced hepatic CYP1A2. To distinguish between the role of central and peripheral catecholamines in the regulation of CYP1A2 induction, the effect of central and peripheral catecholamine depletion using reserpine was compared to that of peripheral catecholamine depletion using guanethidine. The effects of peripheral adrenaline and L-DOPA administration were also assessed. The results suggest that alterations in central catecholamines modulate 7-methoxyresorufin O-demethylase activity (MROD), CYP1A2 mRNA and protein levels in the B(alpha)P-induced state. In particular, central catecholamine depletion, dexmedetomidine-induced inhibition of noradrenaline release and blockade of alpha(1)-adrenoceptors with prazosin, up-regulated CYP1A2 expression. Phenylephrine and dexmedetomidine-induced up-regulation may be mediated, in part, via peripheral alpha(1)- and alpha(2)-adrenoceptors, respectively. On the other hand, the L-DOPA-induced increase in central dopaminergic activity was not followed by any change in the up-regulation of CYP1A2 expression by B(alpha)P. Central noradrenergic systems appeared to counteract up-regulating factors, most likely via alpha(1)- and alpha(2)-adrenoceptors. In contrast, peripheral alpha- and beta-adrenoceptor-related signaling pathways are linked to up-regulating processes. The findings suggest that drugs that bind to adrenoceptors or affect central noradrenergic neurotransmission, as well as factors that challenge the adrenoceptor-linked signaling pathways may deregulate CYP1A2 induction. This, in turn, may result in drug-therapy and drug-toxicity complications.     

Mechanism of the radioprotective effect of catecholamine receptor agonists. Inclusion in the radioprotective effect of both subtypes of alpha-adrenoreceptors

alpha-Adrenoceptor agonists of both main groups, i. e. arylalkylamines and imidazolines, have a pronounced radioprotective effect. Their chemical analogs, which fail to stimulate alpha-adrenoceptors, do not protect mice. The effect of phenylephrine, adrenaline, and noradrenaline comes into play via alpha 1-adrenoceptors and that of clonidine, via alpha 2-adrenoceptors and also via alpha 1-adrenoceptors. Adrenoceptor agonists can probably manifest their radioprotective action via both subtypes of alpha-adrenoceptors. Possible intracellular mechanisms of the radioprotective action are discussed.     

Comparative studies on nerve- and noradrenaline-induced melanosome aggregation within different species of fish

1. The aggregation of melanosomes within melanophores of the cuckoo wrasse (Labrus ossifagus; belonging to the family Labridae) has, on pharmacological grounds, been shown to be mediated by postsynaptic alpha 2-adrenoceptors which in turn act via an inhibitory control of adenylate cyclase. 2. In the present paper we have investigated some American species belonging to the Labridae, Haemulidae, Embiotocidae, Clinidae and Pleuronectidae. 3. In all instances, except in the case of sargo (Haemulidae), we could demonstrate that melanosome aggregation probably was mediated by postsynaptic alpha 2-adrenoceptors which mediate their effect by inhibiting the adenylate cyclase of the melanophores. 4. Although these receptors apparently, on pharmacological grounds, may be classified as alpha 2-adrenoceptors it was also concluded that there is a phylogenetic divergence among these receptors.     

GYKI-12743 a new postsynaptic vascular alpha-adrenoceptor antagonist.

Using the pithed rat preparation it has been proven that GYKI-12743 exerted its alpha-adrenergic blocking action only at the postsynaptic vascular level in the cardiovascular system. This new molecule failed to antagonize the presynaptic alpha 2-adrenoceptors of the cardiac sympathetic nerve endings. Thereby it was possible to demonstrate the first vasoselective postsynaptic adrenoceptor antagonist which potentially might be interesting in the cardiovascular therapy.     

Metabolic regulation by alpha 1- and alpha 2-adrenoceptors.

The role of alpha-adrenoceptors in the mediation of autonomic function, particularly in the control of the cardiovascular system, is widely known. However, alpha-adrenoceptors are also important in the regulation of a variety of metabolic processes that occur in the body either through direct action or by stimulation of the release of other mediators that control metabolic function. Thus, alpha 2-adrenoceptor activation by circulating or neuronally released catecholamines inhibits the release of insulin from pancreatic islet beta-cells and, by inhibiting this response, alpha 2-adrenoceptor antagonists have been shown to have an antihyperglycemic effect. The alpha-adrenoceptor-mediated regulation of the release of pituitary hormones is indirect, with alpha-adrenoceptors being located on peptidergic neurons in the hypothalamus that secrete releasing hormones into the hypophysial portal system to regulate the secretion of hormones from the anterior pituitary gland. Thus, the increase in cortisol secretion from the adrenal glands following a meal is produced, at least in part, by an alpha 1-adrenoceptor-mediated increase in vasopressin and CRF-41 secretion from neurons on the hypothalamus that stimulate the release of adrenocorticotrophic hormone secretion from the pituitary gland, which subsequently stimulates the synthesis and release of cortisol from the adrenal medulla. In addition to metabolic regulation by alpha 1- and alpha 2-adrenoceptors within the endocrine system, alpha-adrenoceptors are also a component of the system that regulates certain aspects of metabolism within autonomic effector cells, such as the control of smooth muscle cell division and growth during periods of continued alpha-adrenoceptor activation as a result of activation of second messenger systems.     

Calcium handling in vasoconstriction to stimulation of alpha 1- and alpha 2-adrenoceptors

Vasoconstriction to stimulation of postsynaptic alpha 1- and alpha 2-adrenoceptors involves different mechanisms of Ca2+ mobilization. Alpha 2-adrenoceptor-mediated vasoconstriction in vivo as well as in vitro is invariably and effectively antagonized by Ca2+ channel blockers, such as nifedipine or verapamil, and is therefore primarily carried by influx of extracellular Ca2+. On the other hand, alpha 1-adrenoceptor stimulation has been linked to both influx of extracellular Ca2+ and release of Ca2+ from intracellular stores. The sensitivity of alpha 1-adrenoceptor-mediated vasoconstriction to blockade by Ca2+ channel antagonists depends on how much both mechanisms of Ca2+ mobilization contribute to the contraction process, and varies between vascular tissues and alpha 1-adrenoceptor agonists. The experimental evidence for the differential utilization of Ca2+ in vasoconstriction to alpha 1- and alpha 2-adrenoceptor stimulation is reviewed.     

Synergistic effects in theα 1- andβ 1-adrenergic regulations of intracellular calcium levels in striatal astrocytes

1. Using indo-1 as a calcium fluorescent probe, we have observed the following in striatal astrocytes in primary culture. 2. The stimulation of alpha-adrenoceptors induces a rapid rise in cytosolic calcium resulting from an internal calcium mobilization followed by an external calcium influx (4-min duration). 3. The stimulation of beta 1-adrenoceptors evokes only a slight internal calcium mobilization (90-sec duration). 4. The simultaneous stimulation of beta 1- and alpha 1-adrenoceptors induces a more prolonged calcium influx (10 min). The latter phenomenon could explain the calcium-dependent synergistic effects of alpha 1 and beta stimulation on cAMP production already described in the brain.     

Correlations between central hypotensive and peripheral hypertensive effects of structurally dissimilar alpha-adrenoceptor agonists

The possible similarity between peripheral (vascular) and central α-adrenoceptors was investigated. For 12 structurally dissimilar α-adrenoceptor agonists, including clonidine, a correlation study is described between the adrenergic effects mediated by both types of α-adrenoceptors, i.e. hypotensive and hypertensive efficacies. Hypotensive activity was quantified by means of a pC₂₅, calculated from log dose-response curves determined after intravenous administration to anaesthetized, normotensive rats. Accordingly, hypertensive potency was expressed as a pC₆₀, established in pithed, normotensive rats. Apparent partition coefficients (log P′) were measured between octanol and buffer (pH=7.4; 37°C) to account for the difference in accessibility to both classes of α-adrenoceptors. A most significant, positive relationship was derived between pC₂₅ and a linear combination of pC₆₀ and log P′. This finding indicates a resemblance among the central and peripheral α-adrenoceptors excited by the drugs. The results are discussed and explained in the light of the recent identification of distinct populations of postsynaptic α₁- as well as α₂-adrenoceptors in peripheral vascular smooth muscle, both involved in drug-induced vasoconstriction.     

Partial agonist properties of a new derivative of dihydrobenzofuran, S 9871, and its stereoisomers in pithed rats

In the pithed rat, (imidazolinyl-2)-2 dihydro 2,3 benzofuran or S 9871 and its stereoisomers were found to block alpha-adrenoceptors. In the present investigation the agonistic effect were studied in pithed rats. With (+/-) and (+) S 9871 this effect is compatible with a stimulation of alpha 1-adrenoceptors and the effect of (-) stereoisomer with a stimulation of alpha 1 and alpha 2 adrenoceptors.     

D2-receptor-linked signaling pathways regulate the expression of hepatic CYP2E1

This study investigated the role of catecholamine-related signaling pathways in the regulation of hepatic cytochrome P450 (CYP2E1). Central and peripheral catecholamine depletion with reserpine down-regulated CYP2E1. On the other hand, selective peripheral catecholamine depletion with guanethidine increased CYP2E1 apoprotein levels. Enrichment of peripheral catecholamines with adrenaline suppressed p-nitrophenol hydroxylase activity (PNP). PNP activity was also markedly suppressed by l-DOPA. Stimulation of D(2)-receptors with bromocriptine up-regulated CYP2E1, as assessed by enzyme activity and protein levels, whereas blockade of D(2)-dopaminergic receptors with sulpiride down-regulated this isozyme. These findings indicate that central and peripheral catecholamines have different effects on CYP2E1. Central catecholamines appear related to the up-regulation, whereas the role of peripheral catecholamines is clearly related to the type and location of adrenoceptors involved. D(2)-receptor-linked signaling pathways have an up-regulating effect on CYP2E1, while D(1)-receptor pathways may down-regulate this isozyme. It is worth noting that the widespread environmental pollutant benzo(alpha)pyrene (B(alpha)P) altered the modulating effect of catecholaminergic systems on CYP2E1 regulation. In particular, whereas stimulation or blockade of adrenoceptors had no effect on constitutive PNP activity, exposure to B(alpha)P modified the impact of central and peripheral catecholamines and alpha(2)-adrenoceptors on CYP2E1 expression. It appears that under the influence of B(alpha)P, alpha(2)-adrenergic receptor-linked signaling pathways increased CYP2E1 apoprotein levels. Given that a wide range of xenobiotics and clinically used drugs are activated by CYP2E1 to toxic metabolites, including the production of reactive oxygen species (ROS), it is possible that therapies challenging dopaminergic receptor- and/or alpha(2)-adrenoceptor-linked signaling pathways may alter the expression of CYP2E1, thus affecting the progress and development of several pathologies.     

Structure--activity relationships among novel phenoxybenzamine-related beta-chloroethylamines

A series of beta-chloroethylamines 5--18, structurally related to the irreversible alpha(1)-adrenoceptor antagonist phenoxybenzamine [PB, N-benzyl-N-(2-chloroethyl)-N-(1-methyl-2-phenoxyethyl)amine hydrochloride, 1] and the competitive antagonist WB4101 [N-(2,3-dihydro-1,4-benzodioxin-2-ylmethyl)-N-[2-(2,6-dimethoxyphenoxy)ethyl]amine hydrochloride, 2], were synthesized and evaluated for their activity at alpha-adrenoceptors of the epididymal and the prostatic portion of young CD rat vas deferens. All compounds displayed irreversible antagonist activity. Most of them showed similar antagonism at both alpha(1)- and alpha(2)-adrenoceptors, whereas compounds 13 and 18, lacking substituents on both the phenoxy group and the oxyamino carbon chain, displayed a moderate alpha(1)-adrenoceptor selectivity (10--35 times), which was comparable to that of PB. Compounds 14 and 15, belonging to the benzyl series and bearing, respectively, a 2-ethoxyphenoxy and a 2-i-propoxyphenoxy moiety, were the most potent alpha(1)-adrenoceptor antagonists with an affinity value similar to that of PB (pIC(50) values of 7.17 and 7.06 versus 7.27). Interestingly, several compounds were able to distinguish two alpha(1)-adrenoceptor subtypes in the epididymal tissue, as revealed by the discontinuity of their inhibition curves. A mean ratio of 24:76 for these alpha(1)-adrenoceptors was determined from compounds 8--10, 12, and 15--17. Furthermore, compounds 9, 10, 12, 16a, and 16b showed higher affinity towards the minor population of receptors, whereas compounds 8, 15, and 17 preferentially inhibited the major population of alpha(1)-adrenoceptors. In addition, selected pharmacological experiments demonstrated the complementary antagonism of the two series of compounds and their different, preferential affinity for one of the two alpha(1)-adrenoceptor subtypes. In conclusion, we found beta-chloroethylamines that demonstrate a multiplicity of alpha(1)-adrenoceptors in the epididymal portion of young CD rat vas deferens and, as a consequence, they are possible useful tools for alpha(1)-adrenoceptor characterization.     

Presynaptic alpha-adrenoceptors in median preoptic nucleus modulate inhibitory neurotransmission from subfornical organ and organum vasculosum lamina terminalis

The median preoptic nucleus (MnPO) in the lamina terminalis receives a prominent catecholaminergic innervation from the dorsomedial and ventrolateral medulla. The present investigation used whole cell patch-clamp recordings in rat brain slice preparations to evaluate the hypothesis that presynaptic adrenoceptors could modulate GABAergic inputs to MnPO neurons. Bath applications of norepinephrine (NE; 20-50 microM) induced a prolonged and reversible suppression of inhibitory postsynaptic currents (IPSCs) and reduced paired-pulse depression evoked by stimulation in the subfornical organ and organum vasculosum lamina terminalis. These events were not correlated with any observed changes in membrane conductance arising from NE activity at postsynaptic alpha(1)- or alpha(2)-adrenoceptors. Consistent with a role for presynaptic alpha(2)-adrenoceptors, responses were selectively mimicked by an alpha(2)-adrenoceptor agonist (UK-14304) and blockable with an alpha(2)-adrenoceptor antagonist (idazoxan). Although the alpha(1)-adrenoceptor agonist cirazoline and the alpha(1)-adrenoceptor antagonist prazosin were without effect on these evoked IPSCs, NE was noted to increase (via alpha(1)-adrenoceptors) or decrease (via alpha(2)-adrenoceptors) the frequency of spontaneous and tetrodotoxin-resistant miniature IPSCs. Collectively, these observations imply that both presynaptic and postsynaptic alpha(1)- and alpha(2)-adrenoceptors in MnPO are capable of selective modulation of rapid GABA(A) receptor-mediated inhibitory synaptic transmission along the lamina terminalis and therefore likely to exert a prominent influence in regulating cell excitability within the MnPO.     

Vascular adrenergic interactions during hemorrhagic shock

The objective of this paper is to review the sequence of vascular events that follows severe hemorrhage. The initial cardiovascular imbalance is a fall in the volume/vascular capacity relationship that leads to reductions in cardiac output and mean arterial pressure (MAP). Peripheral sensors detect the fall in MAP and changes in blood chemistry that cause withdrawal of the normal inhibitory tone from the cardiovascular control centers in the central nervous system. The resulting increased sympathetic activity initiates a series of events that include stimulation of peripheral adrenergic nerves and the adrenal medulla. The magnitude of the compensatory vasoconstriction that follows is the net result of the interaction of the epinephrine (E) from the adrenal medulla and norepinephrine (NE) from the peripheral nerves on the peripheral vascular adrenoreceptors as well as other nonadrenergic mechanisms not discussed here (i.e., angiotensin endogenous opiates). By using pharmacological blocking agents, these adrenoreceptors have been subclassified as: innervated postsynaptic alpha 1; presynaptic alpha 2 (Ps alpha 2); and extrasynaptic alpha 2 (Es alpha 2) adrenoreceptors. The action of E and NE on the alpha 1 and Es alpha 2 receptors initiates the compensatory vasoconstriction, whereas action of these catecholamines on the Ps alpha 2 located on the presynaptic membrane inhibits further release of NE from peripheral nerve terminals, thereby reducing the effect of the innervated alpha 1 receptors. This autoinhibition together with a similar action by prostaglandin E on NE release is thought to be, at least in part, responsible for the vascular decompensation known to occur in the skeletal muscle after hemorrhage. Thus, one of the factors determining survival after hemorrhage may be related to the relative dominance of alpha 1 and Es alpha 2 receptors during the initial compensatory response.     

Analysis of responses to sympathetic nerve stimulation in the feline pulmonary vascular bed

The adrenergic receptor subtypes mediating the response to sympathetic nerve stimulation in the pulmonary vascular bed of the cat were investigated under conditions of controlled blood flow and constant left atrial pressure. The increase in lobar vascular resistance in response to sympathetic nerve stimulation was reduced by prazosin and to a lesser extent by yohimbine, the respective alpha 1- and alpha 2-adrenoceptor antagonists. Moreover, in animals pretreated with a beta-adrenoceptor antagonist to prevent an interaction between alpha- and beta 2-adrenoceptors, responses to nerve stimulation were reduced by prazosin, but yohimbine had no significant effect. On the other hand, in animals pretreated with a beta-adrenoceptor antagonist, yohimbine had an inhibitory effect on responses to tyramine and to norepinephrine. Propranolol had no significant effect on the response to nerve stimulation, whereas ICI 118551, a selective beta 2-adrenoceptor antagonist, enhanced responses to nerve stimulation and injected norepinephrine. The present data suggest that neuronally released norepinephrine increases pulmonary vascular resistance in the cat by acting mainly on alpha 1-adrenoceptors and to a lesser extent on postjunctional alpha 2-adrenoceptors but that this effect is counteracted by an action on presynaptic alpha 2-receptors. The present studies also suggest that neuronally released norepinephrine acts on beta 2-adrenoceptors and that the response to sympathetic nerve stimulation represents the net effect of the adrenergic transmitter on alpha 1-, alpha 2-, and beta 2-adrenoceptors in the pulmonary vascular bed.     

Photoaffinity labeling of human platelet and rabbit kidney alpha 2-adrenoceptors with [3H]SKF 102229

A newly developed alpha 2-adrenergic photoaffinity ligand, 3-methyl-6-chloro-9-azido-1H-2,3,4,5-tetrahydro-3-benzazepine (SKF 102229), has been radiolabeled with tritium to a specific activity of approximately 80 Ci/mmol. Using membranes prepared from human platelets and from rabbit kidney, alpha 2-adrenoceptors have been covalently labeled following photolysis in the presence of [3H]SKF 102229. As determined by SDS-PAGE, the apparent molecular weight of alpha 2-adrenoceptors from both of these tissues was 64,000. The yield of covalent insertion of [3H]SKF 102229 into the alpha 2-adrenoceptor was very good. Thus, following photolysis up to 90% of the alpha 2-adrenoceptors could be irreversibly labeled with [3H]SKF 102229.     

Postsynaptic alpha-adrenoceptor characterization and Ca2+ channel antagonist and activator actions in rat tail arteries from normotensive and hypertensive animals

Postsynaptic alpha-adrenoceptors in the rat tail artery have been examined by determining the pA2 values for antagonists against several alpha-adrenoceptor agonists. In this tissue the alpha-adrenoceptor agonists all produce concentration-dependent mechanical responses with the following rank order of potency: clonidine greater than norepinephrine greater than phenylephrine greater than UK 14304 greater than B-HT 920. Antagonism by prazosin and yohimbine of phenylephrine, norepinephrine, and clonidine responses does not reveal the anticipated discrimination between alpha 1- and alpha 2-adrenoceptors. Thus, pA2 values for prazosin (9.1-9.5), yohimbine (7.2-7.4), and corynanthine (7.0-7.1) and idazoxan (7.6) do not show large differences between these receptor agonists and suggests the predominance of alpha 1-adrenoceptor mediated contractile responses in this preparation. Significant differences between antagonist activities (pA2 values) in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR) artery preparations have not been observed. The sensitivity sequence of alpha-adrenoceptor agonist-induced responses to nifedipine and D 600 is B-HT 920 greater than clonidine greater than phenylephrine greater than norepinephrine. Dependence of agonist response upon extracellular Ca2+ parallels the sensitivity to Ca2+ channel antagonists. Sensitivity to D 600 of phenylephrine responses increased with decreasing concentration of phenylephrine or with receptor blockade by phenoxybenzamine: sensitivity of responses to B-HT 920 was not affected by these procedures. Tail artery strips from WKY and SHR do not exhibit major differences in sensitivity to D 600 or to Ca2+ depletion. Bay k 8644, a Ca2+ channel activator, produces concentration-dependent mechanical responses in the tail artery in the presence of modestly elevated K+ concentrations (10-15 mM): these actions of elevated K+ can be mimicked by both alpha 1- and alpha 2-adrenoceptor agonists including methoxamine, St 587, UK 14304, and clonidine. These studies do not provide clear evidence for the existence of discrete postsynaptic alpha 1- and alpha 2-adrenoceptor populations in rat tail artery as indicated by pA2 values or Ca2+ dependence of response.     

Spontaneously hypertensive rats exhibit an enhanced mydriatic response to clonidine. Evidence for enhanced sensitivity of central alpha 2-adrenoceptors

Comparisons among spontaneously hypertensive (SHR), Kyoto Wistar (KW), and Wistar (W) rats were made of the functional states of central nervous system (CNS) alpha 2-adrenoceptors (clonidine-induced mydriasis) and nonvascular peripheral presynaptic alpha 2-adrenoceptors (clonidine-induced inhibition of the neurogenic twitch of the isolated vas deferens). While there were no differences among the strains of rats in the concentration of clonidine required to produce a 50% inhibition of the electrically evoked contractile response of the vas deferens, there was a significant reduction in the mean effective concentration (ED50) of clonidine to induce mydriasis in SHR as compared with KW and W rats. These observations indicate that CNS alpha 2-adrenoceptors may be functionally more sensitive in SHR. The data also suggest that the sensitivity of nonvascular presynaptic alpha 2-adrenoceptors, at least in the vas deferens, is not altered in hypertensive animals.