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PubMed1997

Inhibition of sympathetic outflow by the angiotensin II receptor antagonist, eprosartan, but not by losartan, valsartan or irbesartan: relationship to differences in prejunctional angiotensin II receptor blockade.

It is well established that angiotensin II can enhance sympathetic nervous system function by activating prejunctional angiotensin II type I (AT1) receptors located on sympathetic nerve terminals. Stimulation of these receptors enhances stimulus-evoked norepinephrine release, leading to increased activation of vascular alpha 1-adrenoceptors and consequently to enhanced vasoconstriction. In the present study, the effects of several chemically distinct nonpeptide angiotensin II receptor antagonists were evaluated on pressor responses evoked by activation of sympathetic outflow through spinal cord stimulation in the pithed rat. Stimulation of thoracolumbar sympathetic outflow in pithed rats produced frequency-dependent pressor responses. Infusion of sub-pressor doses of angiotensin II (40 ng/kg/min) shifted leftward the frequency-response curves for increases in blood pressure, indicating augmented sympathetic outflow. Furthermore, pressor responses resulting in spinal cord stimulation were inhibited by the peptide angiotensin II receptor antagonist, Sar1, Ile8 [angiotensin II] (10 micrograms/kg/min). These results confirm the existence of prejunctional angiotensin II receptors at the vascular neuroeffector junction that facilitate release of norepinephrine. The nonpeptide angiotensin II receptor antagonist, eprosartan (0.3 mg/kg i.v.), inhibited the pressor response induced by spinal cord stimulation in a manner similar to that observed with the peptide antagonist, Sar1, Ile8[angiotensin II]. In contrast, equivalent doses (0.3 mg/kg i.v.) of other nonpeptide angiotensin II receptor antagonists, such as losartan, valsartan, and irbesartan, had no effect on spinal cord stimulation of sympathetic outflow in the pithed rat. Although the mechanism by which eprosartan, but not the other nonpeptide angiotensin II receptor antagonists, inhibits sympathetic outflow in the pithed rat is unknown, one possibility is that eprosartan is a more effective antagonist of prejunctional angiotensin II receptors that augment neurotransmitter release. Because eprosartan is more effective in inhibiting sympathetic nervous system activity compared to other chemically distinct nonpeptide angiotensin II receptor antagonists, eprosartan may be more effective in lowering systolic blood pressure and in treating isolated systolic hypertension.

Acrylates↗

PubMed1994

Nitric oxide--a novel autonomic neurotransmitter.

Considerable evidence suggests that nitric oxide (NO) acts as a nonadrenergic noncholinergic (NANC) transmitter at autonomic neuroeffector junctions. NO is generated enzymatically from L-arginine by a constitutive, cytosolic, Ca2+/calmodulin-activated NO synthase (NOS): NADPH- and tetrahydrobiopterin-dependent cytochrome P-450-type hemoprotein. Electrophysiological and pharmacological data indicate that NO fulfils most of the criteria for a neurotransmitter. It is released from axon terminals when invaded by action potentials and mimics the effect of nerve stimulation. The changes in the mechanical and/or electrical activity of smooth muscle preparations in response to transmural stimulation of NANC nerves are antagonized by inhibitors of NO synthesis or oxyhemoglobin, an NO scavenger. NO acts principally by stimulating soluble guanylate cyclase. Studies on the histochemical localization of NOS point to the involvement of the neural L-arginine-NO pathway in the regulation of vascular tone and of several aspects of respiratory, gastrointestinal, and genitourinary tract functions.

Animals↗

PubMed1987

Substance P and calcitonin gene-related peptide: effects on mast cells and in human skin.

Mast cells are found in close association with blood vessels, and histamine is known to be a potent vasodilator in humans. It is now clear that mast cells form neuroeffector junctions and that one of the types of nerve involved is the peptide-containing primary afferent neurone (C fibre). Nerve stimulation produces vasodilation which is blocked by antihistamines or by depletion of mast cell histamine with compound 48/80. Nerve stimulation also releases histamine and degranulates mast cells. Substance P and other neuropeptides release histamine from isolated rat and human skin mast cells. The actions of substance P and calcitonin gene-related peptide in human skin are compatible with a role for these two peptides in neurogenic inflammation. The inflammatory effects of substance P in human skin are inhibited by antihistamines. The possible role of the mast cell in neurogenic inflammation is discussed.

Animals↗

PubMed1994

Mechanisms responsible for sympathetic activation by cigarette smoking in humans.

BACKGROUND: The pressor and tachycardic effects of cigarette smoking are associated with an increase in plasma catecholamines, suggesting the dependence of these effects on adrenergic stimulation. Whether the stimulation occurs at a central or a peripheral level and whether reflex mechanisms are involved is unknown. METHODS AND RESULTS: In nine normotensive healthy subjects (age, 33.0 +/- 3.5 years, mean +/- SEM), we measured blood pressure (Finapres device), heart rate (ECG), calf blood flow and vascular resistance (venous occlusion plethysmography), plasma norepinephrine and epinephrine (high-performance liquid chromatography assay), and postganglionic muscle sympathetic nerve activity (microneurography from the peroneal nerve) while subjects were smoking a filter cigarette (nicotine content, 1.1 mg) or were in control condition. Cigarette smoking (which raised plasma nicotine measured by high-performance liquid chromatography from 1.0 +/- 0.9 to 44.2 +/- 7.1 ng/mL) markedly and significantly increased mean arterial pressure (+13.2 +/- 2.3%), heart rate (+30.3 +/- 4.7%), calf vascular resistance (+12.1 +/- 4.9%), plasma norepinephrine (+34.8 +/- 7.0%), and plasma epinephrine (+90.5 +/- 39.0%). In contrast, muscle sympathetic nerve activity showed a marked reduction (integrated activity -31.8 +/- 5.1%, P < .01). The reduction was inversely related to the increase in mean arterial pressure (r = -.67, P < .05), but the slope of the relation was markedly less (-54.1 +/- 7.5%, P < .05) than that obtained by intravenous infusion of phenylephrine in absence of smoking. The hemodynamic and neurohumoral changes were still visible 30 minutes after smoking and occurred again on smoking a second cigarette. Sham smoking was devoid of any hemodynamic and neurohumoral effect. CONCLUSIONS: These data support the hypothesis that in humans the sympathetic activation induced by smoking depends on an increased release and/or a reduced clearance of catecholamines at the neuroeffector junctions. Central sympathetic activity is inhibited by smoking, presumably via a baroreceptor stimulation triggered by the smoking-related pressor response. The baroreflex is impaired by smoking, however, indicating that partial inability to reflexly counteract the effect of sympathetic activation is also responsible for the pressor response.

Adult↗

PubMed1997

Increased cardiac adrenergic drive precedes generalized sympathetic activation in human heart failure.

BACKGROUND: Previous studies with radiotracer methods have indicated increases in cardiac norepinephrine (NE) and renal NE spillover in patients with severe congestive heart failure (CHF). However, data on the regional sympathetic profile in early stages of CHF are limited. In this study, sympathetic function in the heart, kidneys, and skeletal muscle was evaluated in patients with mild-to-moderate CHF and compared with that in patients with severe CHF and healthy subjects. METHODS AND RESULTS: Total body and regional NE spillover from the heart and kidney was assessed with isotope dilution with steady state infusions of [3H]NE. Sympathetic nerve traffic to the skeletal muscle vascular bed (MSA) was recorded intraneurally. Cardiac NE spillover in patients with mild-to-moderate CHF (n = 21) was increased threefold versus that in healthy subjects (n = 12, P < .05), whereas total body and renal NE spillover and MSA did not differ from those in healthy subjects. In the severe CHF group (n = 12), cardiac NE spillover was increased fourfold (P < .05), and total body and renal NE spillover and MSA were high compared with both mild-to-moderate CHF subjects and healthy subjects (P < .05 for both). Fractional extraction of [3H]NE across the heart was reduced by approximately 40% in both CHF groups versus control subjects (P < .05). CONCLUSIONS: These results indicate a selective increase in cardiac adrenergic drive (increased amounts of transmitter available at neuroeffector junctions) in patients with mild-to-moderate CHF. This increase appears to precede the augmented sympathetic outflow to the kidneys and skeletal muscle found in advanced CHF.

Adult↗

PubMed1993

Increased dietary salt sensitizes vasomotor neurons of the rostral ventrolateral medulla.

Excess dietary sodium is a major contributing factor to the incidence and severity of hypertension. However, the precise mechanism or mechanisms by which salt contributes to the severity of hypertension are unknown. The region of the rostral ventrolateral medulla (RVLM) is a principal brain stem locus critical for the regulation of arterial blood pressure by the sympathetic nervous system. The purpose of this study was to determine if excess dietary sodium chloride might alter the function or responsiveness of neurons in the RVLM. Male Sprague-Dawley rats were given either tap water or 0.9% sodium chloride solution to drink for 10 to 14 days. Excess sodium chloride did not affect baseline blood pressure. However, when neurons of the RVLM were stimulated by microinjections of L-glutamate, evoked increases in arterial pressure were potentiated in rats given sodium chloride. Augmented pressor responses could not be accounted for by increased vascular reactivity because both groups responded similarly to intravenously administered phenylephrine and norepinephrine. Additionally, electrical stimulation of descending spinal sympathoexcitatory axons produced identical pressor responses in both groups, indicating that altered synaptic transmission at central or peripheral neuroeffector junctions distal to the RVLM could not explain enhanced pressor responses produced by direct stimulation of RVLM cell somata. Finally, impaired arterial baroreceptor reflexes could not account for augmented RVLM pressor responses, as depressor and bradycardic responses produced by electrical stimulation of aortic baroreceptor afferents were not reduced in rats given excess dietary sodium chloride.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of Variance↗

PubMed1987

Changes in hemodynamics and myocardial contractility during chronic sodium depletion in conscious dogs.

Chronic sodium depletion has been reported to decrease ejection fraction in anesthetized dogs. We tested the hypothesis that this reduction in cardiac performance is due to either hemodynamic or humoral factors. Seven mongrel dogs were fed a low sodium diet (less than 2 mEq Na+ per day) for 5 weeks. Echocardiographic and radionuclide techniques were used to monitor cardiac function. There was a gradual but significant (p less than 0.01) decrease in ejection fraction from 61 +/- 7% (SD) at baseline to 47 +/- 8% after 5 weeks of sodium depletion in association with a fall in left ventricular end-diastolic volume. Ejection fraction did not change in five control dogs fed 55 mEq Na+ per day throughout the 5-week follow-up period. Myocardial contractility did not change in either salt-depleted or control dogs. Plasma norepinephrine levels in the coronary sinus were twice as high in salt-depleted as in control dogs, but there were no significant differences in arterial norepinephrine concentration between the two groups. Therefore, we concluded that reduced ejection fraction during sodium depletion resulted from hemodynamic changes (decreased preload). The excess available norepinephrine failed to increase myocardial contractility, suggesting a dysfunction at the cardiac adrenergic neuroeffector junction.

Animals↗

PubMed1989

Mathematical model of the changes in heart rate elicited by vagal stimulation.

We developed a mathematical model of the underlying cellular mechanisms responsible for the changes in sinus cycle length (SCL) elicited by vagal stimulation in intact animals. The model incorporated a stimulation-mediated depletion of the releasable pool of acetylcholine (ACh) in the nerve endings, the in vitro reaction kinetics of acetylcholinesterase, and the electrical activity of a pacemaker cell with six membrane ionic currents. SCL increased linearly with the frequency of simulated vagal stimulation, as it does in animal experiments, because the concentration of ACh in the neuroeffector junction [( ACh]) saturated as the frequency of stimulation was increased and because SCL increased geometrically in response to increases in [ACh]. The dependence of SCL on the timing of vagal stimulation in the cardiac cycle resulted, in part, from the dependence of [ACh] on SCL. Simulated vagal stimulation entrained the sinus node because the rate of activation and inactivation of ACh-activated K+ channels depended only weakly on membrane potential during diastolic depolarization. SCL increased geometrically with [ACh], because 1) during diastolic depolarization, the amplitude of the ACh-activated K+ current was approximately equal to the amplitude of the sum of the other ionic currents, 2) [ACh] was low enough to saturate neither acetylcholinesterase nor the cellular system that activates the ACh-activated K+ channels, 3) the pacemaker cell membrane behaved electrotonically like a capacitor, and 4) the sum of all the ionic currents increased linearly with the amplitude of the ACh-activated K+ current.

Acetylcholine↗

PubMed1987

Angiotensin II-noradrenergic interactions in renovascular hypertensive rats.

This study tested the hypothesis that interactions of endogenous angiotensin II (AII) with the noradrenergic neuroeffector junction are important in renin-dependent hypertension. In the in situ blood-perfused rat mesentery, in normal rats exogenous AII potentiated mesenteric vascular responses to periarterial (sympathetic) nerve stimulation (PNS) more than vascular responses to exogenous norepinephrine (NE). In 2-kidney-1-clip (2K-1C) rats with renovascular hypertension mesenteric vascular responses to PNS and NE were greater than in sham-operated rats, and renovascular hypertension mimicked the effects of exogenous AII with respect to enhancing responses to PNS more than responses to NE. In 2K-1C rats, but not in sham-operated rats, 1-Sar-8-Ile-AII markedly suppressed vascular responses to PNS, without influencing responses to NE. Finally, 1-Sar-8-Ile-AII attenuated sympathetic nerve stimulation-induced neuronal spillover of NE in 2K-1C rats, but not in sham-operated rats. These data indicate that renovascular hypertension enhances noradrenergic neurotransmission, and that this enhancement is mediated in part by AII-induced facilitation of NE release.

Angiotensin I↗

PubMed1999

Extended angiotensin converting enzyme inhibition changes the innervation of renal glomerular afferent arterioles.

Chronic inhibition of the angiotensin I converting enzyme (ACE) with enalapril, results in a phenotypic change of the medial cells of renal afferent arterioles from contractile smooth muscle cells to renin containing epithelioid cells. In normal animals, the density of the innervation of the juxtaglomerular renin containing epithelioid cells is much lower compared to the contractile cells. The effector tissues are known to play an important role in determining the pattern and density of their innervation. In this study, we tested the hypothesis that the density of the innervation of the afferent arteriole smooth muscle cells decreases when they change their phenotype from contractile to renin containing epithelioid cells. The results show that the density of the innervation had significantly increased and the association of the terminals with the smooth muscle cells had changed. There were significantly more varicosities around renal afferent arterioles from rabbits treated with enalapril (10 microg/kg/h) for 6 weeks (mean +/- SEM = 634 +/- 175 x 10(3)/mm2 vessel surface, cf. 329 +/- 69 x 10(3)/mm2 vessel surface in untreated rabbits, P = 0.05), with the number of neuroeffector junctions remaining the same (124 +/- 14 and 164 +/- 32 x 10(3)/mm2 vessel surface) and significantly more non-contacting varicosities (i.e. lying > 100 nm from the medial cells) (74 +/- 5% and 25 +/- 7%, respectively; P = 0.003). Thus, there was no reduction in the innervation of afferent arterioles in which the smooth muscle cells had changed phenotype in response to enalapril treatment as hypothesised. Instead, it would appear that proliferation of the innervation had occurred, with the formation of additional varicosities but these varicosities failed to form neuromuscular junctions. This study has identified a form of neural plasticity in the kidney that has not previously been described.

Journal Article↗

PubMed2002

Role of antioxidants in the protection of the nitrergic neurotransmitter.

There is now compelling evidence that the L-arginine/nitric oxide (NO) pathway generates the non-adrenergic non-cholinergic (NANC) neurotransmitter which mediates smooth muscle relaxation in a variety of nitrergically-innervated tissues. However, one strange aspect of this nitrergic neurotransmission process is that certain drugs (i.e. superoxide generators and NO-scavengers) powerfully inhibit relaxations to exogenous NO, but have little or no effect on relaxations to electrical field stimulation. This thesis examined the possibility that in the nitrergically-innervated gastric fundus of the pig tissue antioxidants present in the neuroeffector junction might protect the endogenous nitrergic neurotransmitter (free radical NO) from attack by superoxide anions and scavenging activity, while exogenous NO would still be vulnerable before it reaches the nitrergic synapses within the tissue. We found that several antioxidants (in casu Cu/Zn superoxide dismutase, reduced glutathione, bilirubin) exerted a partial or complete protection of the relaxation induced by exogenous NO against the differentiating drugs under investigation. A close interrelationship between the endogenous nitrergic neurotransmitter and the antioxidants Cu/Zn superoxide dismutase and bilirubin (produced by the heme oxygenase/biliverdin reductase system) was corroborated by immunohistochemical data showing the presence of these latter defense systems in all nitrergic neurons. Pharmacological depletion further established a role for Cu/Zn superoxide dismutase in peripheral nitrergic neurotransmission. For glutathione, only a partial depletion could be obtained and this did not influence nitrergic neurotransmission.

Animals↗

PubMed1992

Possible location and function of neuropeptide Y receptor subtypes in the rat mesenteric arterial bed.

Earlier investigation of the vascular actions of Neuropeptide Y (NPY) led us to propose that distinct receptors mediated the prejunctional inhibition of periarterial nerve-stimulated norepinephrine (NE) release and the postjunctional potentiation of the increase in perfusion pressure elicited by vasoconstrictors. These receptors were designated Y2 and Y1, respectively, based on the ability of C-terminal fragments to mimic the former action. The present study investigates further the involvement of these putative receptor subtypes in the isolated and perfused mesenteric arterial bed. [Leu31Pro34]NPY, a novel analog with specificity at the Y1 receptors, potentiated the increase in perfusion pressure elicited by exogenously administered NE and arginine vasopressin, confirming the existence of this NPY subtype postjunctionally. This immediate and prolonged potentiation was abolished by phentolamine, attenuated by benextramine and the reputed NPY antagonist, PYX1. [11-36]NPY also produced a concentration-dependent potentiation of NE-stimulated increase in perfusion pressure suggesting that the Y2 receptor subtype may also be present postjunctionally in this model of the vascular neuroeffector junction. The finding that the profile of this potentiation differed from that elicited by [Leu31Pro34]NPY and, in contrast to the latter, was not attenuated by PYX1, intimates the existence of both distinct subtypes postjunctionally. [Leu31Pro34]NPY also reduced periarterial nerve-stimulated release of NE with a concomitant reduction in perfusion pressure indicating, in addition to the Y2 subtype, the presence of the Y1 receptor prejunctionally in the rat mesenteric arterial bed.

Adrenergic alpha-Antagonists↗

PubMed2004

[Tiotropium as a controller of bronchoconstriction].

Cholinergic nerve fibres arise in the nucleus ambiguus and the dorsal motor nucleus of the vagus nerve in the brainstem. They travel down as the vagus nerve to parasympathetic ganglia placed in the walls of the airways. From these ganglia, short postganglionic fibres innervate airway smooth muscle and the submucosal glands in the lung. Activation of vagal nerve releases acetylcholine at the neuroeffector junctions, where it binds to postsynaptic receptors, resulting in bronchoconstrictions. The resting bronchomotor tone in normal airways has a cholinergic component mediated via muscarinic cholinergic receptors. The human airways have five subtypes of muscarinic cholinergic receptors: the M1 and M3 mediate bronchoconstriction and stimulation of mucus secretion, while M2 control the release of acetylcholine from M1 and M3 receptors through a negative-feedback mechanism. Anticholinergic bronchodilators act by blocking muscarinic receptors. Tiotropium bromide is cutting age anticholinergic bronchodilator. It dissociates more slowly from M1 and M3 than from M2 receptors and subsequently has a long and safety duration of action. In COPD patients tiotropium comparing to placebo, ipratropium and long acting beta agonists significantly improves lung function. It is an effective bronchodilator that reduces dyspnea, COPD exacerbations frequency and improves health status. This suggests that tiotropium will make an important contribution to chronic pulmonary disease therapy.

Bronchi↗

PubMed1990

The effect of sodium intake on ventricular performance in healthy men.

We analyzed the effects of acute sodium intake on left ventricular performance in 11 healthy normotensive men using Doppler echocardiography. For 2 weeks, they took 2,700-kcal diets containing 6 g and 24 g sodium chloride per day in the low sodium phase (5 days) and in the high sodium phase (5 days), respectively. Blood pressure, urine, hematocrit, and echocardiographic values were measured every day throughout this study. Although a decrease in the serum norepinephrine concentration and an increase in the ejection fraction were noticed in the low sodium phase, there was no significant change in the relation between end-systolic stress and mean velocity of circumference shortening. All subjects also performed a cold pressor test in both phases, and we analyzed the end-systolic stress-volume relation (modified Emax). Modified Emax of the high sodium phase was significantly larger than that of the low sodium phase. As published in previous research on dogs, we consider that this discrepancy at rest may be caused by a dysfunction at the cardiac adrenergic neuroeffector junction in humans, too, and that sodium intake may enhance the change in ventricular contractility by a cold pressor test.

Adult↗

PubMed1990

Autoradiographic localization of dopamine DA-2 receptor sites in rat mesenteric vascular tree.

By using combined in vitro radioreceptor binding and autoradiographic techniques and [3H]spiroperidol (in the presence of the 5-hydroxytryptamine-2 receptor blocker ketanserin) as a ligand, the pharmacological properties and the anatomical localization of dopamine (DA) DA-2 receptors sites in rat mesenteric vascular tree were analyzed. [3H]Spiroperidol was bound by sections of rat mesentery in a manner consistent with the labeling of DA-2 receptors, with a Kd value of 2.48 nM and with a maximum binding value of 159 fmol/mg of protein. Light microscopic autoradiography revealed specific [3H]spiroperidol binding sites primarily in the adventitial layer and in the adventitial-medial border as well as in the intimal layer. Adventitial and adventitial-medial binding sites disappeared after 6-hydroxydopamine sympathectomy. In contrast, chemical sympathectomy was without effect on intimal [3H]spiroperidol binding sites. The density of adventitial and adventitial-medial binding sites was higher in medium and small sized vessels than in larger ones. These findings are indicative of the existence of DA-2 receptors sites located both prejunctionally (6-hydroxydopamine-sensitive) and in the intimal layer. Prejunctional mesenteric DA-2 receptors may be involved in the inhibition of noradrenaline release from sympathetic neuroeffector junctions. The functional significance of intimal [3H]spiroperidol binding sites, if any, should be established in future studies.

Animals↗

PubMed1990

Effects of clonidine on renal sympathetic nerve activity and norepinephrine spillover.

The antihypertensive action of clonidine (CLO) depends mainly on decreased release of the sympathetic neurotransmitter, norepinephrine (NE), at vascular neuroeffector junctions. The decreased release can be due to stimulation of alpha-2 adrenoceptors or other receptors in the brain or due to stimulation of presynaptic inhibitory alpha-2 adrenoceptors on sympathetic nerve endings. To compare central and peripheral contributions to the depressor action of CLO, renal sympathetic nerve activity (RSNA) and renal spillover of NE (RNEs) were measured at baseline and during reflexive increases in RSNA evoked by nitroprusside-induced hypotension (27, 50 and 105 micrograms/kg/min) before and after CLO treatment in adrenal-demedullated, anesthetized rats. Administration of CLO decreased RSNA by 52 +/- 8% and RNEs by 32 +/- 13% (means +/- S.E.M.). At levels of RSNA less than 50% above control, there were no significant changes in RNEs; above this level of activity RNEs increased, regardless of CLO treatment. CLO treatment did not alter significantly the relationship between increases in RSNA and in RNEs during nitroprusside-induced hypotension. The results suggest that in neurologically intact, anesthetized animals, CLO decreases renal NE release mainly by inhibiting sympathetic outflow, with little if any peripheral presynaptic action.

Adrenal Medulla↗

PubMed1978

Metabolic modulation of neurotransmitter release--adenosine, adenine nucleotides, potassium, hyperosmolarity, and hydrogen ion.

Evidence has accumulated that several factors, which have been proposed as mediators of exercise hyperemia, can modulate adrenergic neurotransmission in blood vessels. Adenosine and the adenine nucleotides depress the response of isolated blood vessels of the dog to nerve stimulation more than that to exogenous norepinephrine; this difference is explained by a decreased release of the neurotransmitter. Potassium, hyperosmolarity, and acidosis also depress adrenergic neurotransmission in isolated veins. These results are consistent with the hypothesis that metabolic changes in the vicinity of the adrenergic neuroeffector junction are capable of decreasing the output of neurotransmitter to the blood vessels in the exercising muscle.

Adenine Nucleotides↗

PubMed1985

Pharmacologic and therapeutic significance of alpha-adrenoceptor subtypes.

The concept that neurotransmitters can modulate their own release through presynaptic inhibitory autoreceptors is well established. The presynaptic inhibitory autoreceptors involved in a negative feedback mechanism that modulates the release of norepinephrine are of the alpha 2-subtype. Stimulation of central alpha 2-adrenoceptors by drugs like clonidine, guanfacine, and guanabenz produces an antihypertensive and bradycardiac effect through a decrease in sympathetic tone. In vascular smooth muscle, the alpha 1-adrenoceptor subtype predominates and mediates vasoconstriction although alpha 2-adrenoceptors mediating vasoconstriction are also present in some vascular beds. Phenylephrine preferentially stimulates alpha 1-adrenoceptors and guanabenz preferentially stimulates alpha 2-adrenoceptors in vascular smooth muscle, whereas norepinephrine is an agonist at both alpha 1- and alpha 2-subtypes. The pressor response to phenylephrine was markedly reduced by prazosin. In contrast, the response to norepinephrine was relatively resistant to blockade, and that to guanabenz, totally resistant to blockade by prazosin. Inhibition of neuronal uptake by cocaine or desipramine and pretreatment of cats with 6-hydroxydopamine increased the effectiveness of prazosin in blocking the pressor responses to norepinephrine, but not to guanabenz or phenylephrine. These results support the proposal that postsynaptic alpha 1-adrenoceptors are preferentially innervated (i.e., within the neuroeffector junction), while the postsynaptic alpha 2-adrenoceptors are in extrasynaptic locations. The subclassification of alpha-adrenoceptors into alpha 1- and alpha 2-subtypes opens the possibility of designing selective drugs to act as agonists or antagonists on these receptor subtypes. These compounds have useful therapeutic applications, and in the case of selective alpha 2-adrenoceptor antagonists, novel potential uses may exist, both at the level of the central nervous system and in the periphery.

Adrenergic alpha-Agonists↗