Abrogation of alpha-adrenergic vasoactivity in chronically inflamed rat knee joints

It has previously been shown that chronic inflammation causes a reduction in sympathetic nerve-mediated vasoconstriction in rat knees. To determine whether this phenomenon is due to an alteration in smooth muscle adrenoceptor function, the present study compared the alpha-adrenoceptor profile of blood vessels supplying the anteromedial capsule of normal and chronically inflamed rat knee joints. While the rats were under urethan anesthesia, the alpha(1)-adrenoceptor agonists methoxamine and phenylephrine and the alpha(2)-adrenoceptor agonist clonidine (0.1-ml bolus; dose range 10(-12)-10(-7) mol) were applied to exposed normal rat knees, resulting in a dose-dependent fall in capsular perfusion. Comparison of drug potencies indicated that alpha(2)-adrenergic effects > alpha(1)-vasoactivity. One week after intra-articular injection of Freund's complete adjuvant to induce chronic joint inflammation, the vasoconstrictor effects of methoxamine, phenylephrine, and clonidine were all significantly attenuated compared with normal controls. These findings show that the preponderance of sympathetic adrenergic vasoconstriction in the anteromedial capsule of the rat is carried out by postjunctional alpha(2)-adrenoceptors. Chronic joint inflammation compromises alpha(1)- and alpha(2)-adrenoceptor function, and this change in alpha-adrenergic responsiveness may help explain the perfusion changes commonly associated with inflammatory arthritis.     

Adrenoceptors modulate depressor responses of endothelin-1 into the superior colliculus of rats

Endothelin-1 (ET-1) (10 pmol) microinjected into the superficial layer of superior colliculus induces decreases in blood pressure (control, 108 +/- 5 mmHg, n=6; ET-1, 71 +/- 4 mmHg, n=5). The effects on blood pressure induced by endothelin-1 were significantly (p<0.05) reduced by pre-administration into the superior colliculus of the alpha1-adrenoceptor agonist phenylephrine (1 nmol) (46 +/- 5%, n=5), beta1-adrenoceptor antagonist acebutolol (5 nmol) (51 +/- 6%, n=5) or beta1/beta2-adrenoceptor antagonist propranolol (3.4 nmol) (51 +/- 11%, n=5). In contrast, endothelin-1-induced effects were increased (p<0.05) by microinjections into the superior colliculus of prazosin (2.4 nmol) (49 +/- 7%, n=5), an alpha1-adrenoceptor antagonist; dobutamine (4 nmol) (51 +/- 9%, n=5), a beta1-adrenoceptor agonist or isoprenaline (1 nmol) (49 +/- 6%, n=5), a beta1/beta2-adrenoceptor agonist. No involvement of alpha2- or beta2-adrenoceptors has been detected. Therefore, ET-1 induces decreases in blood pressure with selective involvement of alpha1- and beta1-adrenoceptors.     

Clonidine-induced coronary vasodilatation in isolated guinea pig heart is not mediated by endothelial alpha2 adrenoceptors.

Functional role of endothelial alpha(2)-adrenoceptor in coronary circulation remains unclear. Clonidine, an agonist of alpha(2)-adrenoceptors, was reported to induce coronary vasodilatation via stimulation of endothelial alpha(2)-adrenoceptors or coronary vasoconstriction involving vascular smooth muscle alpha(2)-adrenoceptors. Moreover, H(2) receptor-dependent responses to clonidine were described. Here, we reassess the contribution of endothelial alpha(2)-adrenoceptor and H(2) receptors to coronary flow and contractility responses induced by clonidine in the isolated guinea pig heart. We found that clonidine (10(-9) - 10(-6) M) produced concentration-dependent coronary vasoconstriction without a significant change in contractility. This response was inhibited by the alpha(1)/alpha(2)-adrenoceptor antagonist - phentolamine (10(-5) M) and the selective alpha(2)-adrenoceptor antagonist yohimbine (10(-6) M), but it was not changed by the selective alpha(1)-adrenoceptor antagonist prazosin (10(-6) M). In the presence of nitric oxide synthase inhibitor, L-NAME (10(-4) M) the clonidine-induced vasoconstriction was potentiated. Clonidine at high concentrations of 10(-5) - 3 x 10(-5) M produced coronary vasodilatation, and an increase in myocardial contractility. These responses were abolished by a selective H(2)-receptor antagonist, ranitidine (10(-5) M), but not by phentolamine (10(-5) M). We conclude that in the isolated guinea pig heart, clonidine-induced vasoconstriction is mediated by activation of smooth muscle alpha(2)-adrenoceptors whereas clonidine-induced coronary vasodilatation is mediated by activation of vascular H(2) histaminergic receptors. Accordingly, endothelial alpha(2)-adrenoceptors does not seem to play a major role in coronary flow response induced by clonidine.     

Evidence against the role of alpha 1-adrenoceptor reserve in buffering the inhibitory effect of nifedipine on the contractility of canine vascular smooth muscle

The relationship between the postsynaptic alpha 1-adrenoceptor reserve and the sensitivity of vasoconstriction induced by alpha-adrenoceptor agonists to the dihydropyridine Ca2+ entry blocker nifedipine was investigated in isolated muscle strips of dog mesenteric artery (DMA) and saphenous vein (DSV). The amplitudes of the contractile responses of DMA induced by phenylephrine were the same as those in DSV in the presence and in the absence of extracellular Ca2+. The use of 3 x 10(-9) M phenoxybenzamine to irreversibly block the alpha 1-adrenoceptors revealed a marked difference in the size of the alpha 1-adrenoceptor reserve between DMA (40%) and DSV (7%). In spite of a larger receptor reserve, the contractile responses induced by phenylephrine in DMA were more sensitive to nifedipine compared with those in DSV. These results suggest that the postsynaptic alpha 1-adrenoceptor reserve in vascular smooth muscle, at least in DMA and DSV, does not play an important role in buffering the inhibitory effect of nifedipine on the contractile response to a full agonist of alpha 1-adrenoceptors. Other factors, such as the difference in the membrane depolarizing effect, the ability to utilize intracellular Ca2+ for contraction, and the possible existence of alpha 1-adrenoceptor subtypes, may contribute to the different inhibitory effects of nifedipine on these blood vessels.     

Nature of alpha 1 and postjunctional alpha 2 adrenoceptors in the pulmonary vascular bed

The subtypes of postjunctional alpha adrenoceptors in the feline pulmonary vascular bed were studied by using selective alpha-adrenoceptor agonists and antagonists. Under conditions of controlled pulmonary blood flow and constant left atrial pressure, intralobar injections of the alpha 1 agonists phenylephrine and methoxamine, and the alpha 2 agonists UK 14,304 and B-HT 933, increased lobar arterial pressure in a dose-related manner. Prazosin, an alpha 1-adrenoceptor antagonist, reduced responses to phenylephrine and methoxamine to a greater extent than responses to UK 14,304 and B-HT 933. Yohimbine, an alpha 2 blocker, decreased responses to UK 14,304 and B-HT 933 without altering responses to phenylephrine or methoxamine. The same pattern of blockade was observed in animals pretreated with 6-hydroxydopamine, an adrenergic neuronal blocking agent. However, in propranolol-treated animals, prazosin antagonized responses to phenylephrine and methoxamine without altering responses to UK 14,304 or B-HT 933, and the selectivity of the blocking effects of yohimbine were preserved. Responses to intralobar injections of norepinephrine (NE) were markedly decreased by prazosin, whereas yohimbine had only a small effect. These data suggest the presence of both postjunctional alpha 1 and alpha 2 adrenoceptors mediating vasoconstriction in the pulmonary vascular bed. These results also indicate that the vasoconstrictor responses to injected NE in the cat pulmonary vascular bed result mainly from activation of alpha 1 adrenoceptors.     

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.     

Adrenergic control of lipogenesis and lipolysis in the chicken in vitro

The adrenergic inhibition of lipogenesis and stimulation of lipolysis in the avian has been examined using chicken hepatocytes and adipose tissue explants in vitro. Lipogenesis was inhibited by adrenergic agonists: epinephrine (alpha + beta) greater than isoproterenol (beta 1/beta 2) greater than norepinephrine (alpha 1/alpha 2, beta 1) greater than metaproterenol (beta 2), phenylephrine (alpha 1). Dobutamine (beta 1 agonist) and dopamine (dopaminergic agonist) did not significantly affect [14C]acetate incorporation into lipid, while clonidine and para-aminoclonidine (alpha 2 agonists) were slightly stimulatory. Lipolysis in young and adult chicken adipose tissue was stimulated by epinephrine, isoproterenol, phenylephrine, dobutamine and metaproterenol, but was inhibited by clonidine and para-aminoclonidine. Both the antilipogenic and lipolytic effects of epinephrine were partially blocked by phentolamine (alpha 1 = alpha 2 antagonist) or propranolol (beta 1 = beta 2 antagonist), but completely inhibited by phentolamine and propranolol administered together.     

Characterization of postjunctional adrenoceptor subtypes in isolated rat myocardial cells in culture

The effects of agonists and antagonists, specific for the different adrenoceptor subtypes on the automaticity of cultured ventricular cells from postnatal rat, were studied. Chronotropic responses were assessed by recording monophasic action potentials using intracellular microelectrodes. Contraction was assessed by an electro-optical procedure. (-)-Isoproterenol, salbutamol, (-)-phenylephrine, and methoxamine increased the spontaneous rate in a dose-dependent manner, but the stimulatory potencies of alpha-adrenoceptor agonists were weaker than those of the beta-alternates. The frequency response to (-)-isoproterenol was inhibited by atenolol but not by butoxamine. Atenolol was also more effective than butoxamine in antagonizing the rate acceleration by salbutamol. The chronotropic effects of phenylephrine and methoxamine were inhibited by prazosin. In contrast, neither clonidine nor yohimbine displayed any chronotropic action. These findings suggest that the postjunctional adrenoceptors present in the sarcolemma of the isolated cardiac muscle cells, which mediate automaticity responses to catecholamines, are of beta 1, beta 2, and alpha 1 types, the physiological contribution of the beta 1-adrenoceptors being predominant. Applicability of these conclusions to the in situ myocardiocytes is discussed with respect to the level of functional differentiation achieved by the rat myocardial cells in culture.     

Effect of adrenergic agonists on human chorionic gonadotropin release by human trophoblast cells obtained from first trimester placenta

The cultured syncytiotrophoblast cells from human first trimester placenta were used to determine the effect of adrenergic agonists on human chorionic gonadotropin (hCG) production in vitro. Beta-adrenergic agonists isoproterenol, ritodrine and isoxsuprine increased the hCG release during the 2 h incubation period, however, alpha-agonists norepinephrine and phenylephrine and a beta 1-agonist dobutamine had no effect. The effect of isoproterenol was blocked by propranolol and butoxamine, but less efficiently by phentolamine and atenolol. These results indicate that placental hCG production can be modulated by stimulation of beta-, possibly beta 2-adrenoceptors but not by alpha-adrenoceptors.     

Endothelial dysfunction and decreased vascular responsiveness in the anterior cruciate ligament-deficient model of osteoarthritis.

Chronic inflammation associated with osteoarthritis (OA) may alter normal vascular responses and contribute to joint degradation. Vascular responses to vasoactive mediators were evaluated in the medial collateral ligament (MCL) of the anterior cruciate ligament (ACL)-deficient knee. Chronic joint instability and progressive OA were induced in rabbit knees by surgical transection of the ACL. Under halothane anesthesia, laser speckle perfusion imaging (LSPI) was used to measure MCL blood flow in unoperated control (n = 12) and 6-wk ACL-transected knees (n = 12). ACh, bradykinin, histamine, substance P (SP), and prostaglandin E(2) (PGE(2)) were applied to the MCL vasculature in topical boluses of 100 microl (dose range 10(-14) to 10(-8) mol). In normal joints, ACh, bradykinin, histamine, and PGE(2) evoked a dilatory response. Substance P caused a biphasic response that was dilatory from 10(-14) to 10(-11) mol and constricting at higher doses. In ACL-deficient knees, ACh, bradykinin, histamine, and SP decreased perfusion, whereas PGE(2) had a biphasic response that decreased perfusion at 10(-14) to 10(-11) mol and was dilatory at higher concentrations. Sodium nitroprusside increased perfusion in resting and phenylephrine-precontracted vessels with no significant differences between ACL-transected and control knees. Femoral artery occlusion and release increased perfusion by 74.3 +/- 11.1% in control knees but only by 25.8 +/- 4.4% in ACL-deficient knees. The altered responsiveness of the MCL vasculature to these inflammatory mediators may indicate endothelial dysfunction in the MCL, which may contribute to the progression and severity of OA and to the adaptation of the joint in an altered mechanical environment.     

Beta-adrenoceptor agonists do not stimulate daytime melatonin secretion in healthy subjects a double blind placebo controlled study

Noradrenergic stimulation of pineal β-adrenoceptors results in melatonin secretion.To investigate β-adrenoceptor mediated plasma melatonin responses in humans, ritodrine, salbutamol (β2-adrenoceptor agonists) and dobutamine (β1-adrenoceptor agonist) were infused from 0900 to 1200 h to 8 healthy subjects (four men and four women) in a double blind, crossover, placebo controlled study. Ritodrine and salbutamol significantly increased plasma cyclic AMP and decreased serum potassium concentrations indicating the presence of β2-adrenoceptor stimulation. Dobutamine substantially increased systolic blood pressure corresponding to its β1-adrenoceptor agonist propriety. However, neither β2- nor β1-adrenoceptor stimulation modified plasma melatonin concentration. These results show that β-adrenoceptor agonists do not increase daytime plasma melatonin concentration     

Contractile responses to adrenergic nerve stimulation are enhanced with removal of endothelium in rat caudal artery

Removal of the endothelium from isolated perfused rat caudal arteries produced a two fold increase in the contractile response to transmural nerve stimulation. Pretreatment with 6-hydroxydopamine eliminated the contractile response to adrenergic nerve stimulation but failed to uncover any vasodilatory effect of electrical stimulation, either directly on smooth muscle or via non-adrenergic nerves. Endothelial removal also produced two and four fold enhancement of the contractile responses to the selective alpha 1- and alpha 2-adrenoceptor agonists methoxamine and B-HT 920. However, pKB values for prazosin and yohimbine versus both agonists indicate that both methoxamine and B-HT 920 are acting primarily at alpha 1-adrenoceptors in this tissue. These results provide evidence that endothelial factors released either at basal levels or by the stimulation of agonists play a significant physiological role in modifying the contractile responses of blood vessels.     

Desensitization of the vascular contractile response to cumulative doses of alpha 2-adrenoceptor agonists

Contractile responses to single or cumulative doses of alpha-adrenoceptor agonists were compared in the tail artery and the saphenous vein of the rat. In the rat tail artery, there were no differences in the dose-response relationships to noradrenaline, methoxamine, and KCl whether the agonists were applied as single or cumulative doses. However, the responses to single doses of clonidine and B-HT 920 were significantly larger than similar doses applied cumulatively. In the rat saphenous vein, responses to single doses of noradrenaline, clonidine, and B-HT 920 were also significantly larger than the corresponding cumulative doses. However, there was no difference in the responses to KCl. It was suggested that desensitization of alpha 2-adrenoceptors in these vessels may result in the diminished responses to cumulative doses of the agonists. Desensitization appeared to be specific to alpha 2-adrenoceptors, since the effect was not observed in responses mediated by the alpha 1-adrenoceptors and KCl.     

Roles of alpha and beta adrenergic receptors in control of glucose oxidation in hamster epididymal adipocytes.

Oxidation of [14C] glucose in isolated epididymal adipocytes from Golden hamsters was stimulated by isoproterenol, epinephrine and norepinephrine, which all interact with beta-adrenergic receptors and by adrenocorticotrophic hormone. In contrast alpha-receptor agonists, such as phenylephrine, methoxamine or clonidine did not increase basal glucose oxidation. The beta-adrenergic blocking drug propranolol inhibited both lipolysis and glucose oxidation when these had been stimulated by isoproterenol, epinephrine or norepinephrine. Conversely, the alpha-adrenergic blocking drugs phentolamine and phenoxybenzamine did not influence lipolysis or glucose oxidation when isoproterenol provided the stimulus and increased both lipolysis and glucose metabolism in the present of either epinephrine or norepinephrine. All alpha-adrenergic agonists tested (phenylephrine, methoxamine and clonidine) lowered lipolysis and glucose oxidation isolated adipocytes exposed to isoproterenol. However, when adrenocorticotropin provided the stimulus for glucose oxidation and lipolysis, only clonidine produced a significant reduction in lipolysis and glucose oxidation. None of the alpha-agonists influenced glucose metabolism which had been increased by insulin. These data confirm the presence of both alpha and beta adrenergic receptors on hamster epididymal adipocytes and suggest that they exert antagonistic influences on lipolysis and glucose oxidation. These data are also consistent with the view that adrenergic stimulation of glucose oxidation and lipolysis in adipocytes are both mediated through beta receptors.     

The effect of alpha-adrenergic agonists on the membrane potential of fat-cell mitochondria in situ.

1. The accumulation of [3H]methyltriphenylphosphonium by isolated fat-cells was used to estimate the membrane potential of mitochondria in situ. 2. An alpha-adrenergic receptor-mediated decrease in the apparent accumulation of [3H]methyltriphenylphosphonium was observed. Methoxamine, clonidine and low concentrations of phenylephrine decreased the calculated mitochrondrial membrane potential without significantly raising cyclic AMP levels, adenylate cyclase activity or stimulating lipolysis. The agonist potency order was phenylephrine greater than methoxamine greater than clonidine. 3. The decrease in the calculated mitochondrial membrane potential caused by phenylephrine, clonidine and methoxamine was blocked by the alpha-adrenergic antagonist prazosin but not by yohimbine nor by the beta-antagonist propranolol. This suggests that the effect on the calculated mitochondrial membrane potential may be mediated by alpha 1-like receptors.     

Selective alpha2-adrenergic properties of dexmedetomidine over clonidine in the human forearm.

We tested the hypothesis that dexmedetomidine (Dex) has greater alpha(2)- vs. alpha(1) selectivity than clonidine and causes more alpha(2)-selective vasoconstriction in the human forearm. After local beta-adrenergic blockade with propranolol, forearm blood flow (plethysmography) responses to brachial artery administration of Dex, clonidine, and phenylephrine (alpha(1)-agonist) were determined in healthy young adults before and after alpha(2)-blockade with yohimbine (n = 10) or alpha(1)-blockade with prazosin (n = 9). Yohimbine had no effect on phenylephrine-mediated vasoconstriction but blunted Dex-mediated vasoconstriction (mean +/- SE: -41 +/- 5 vs. -11 +/- 2%; before vs. after yohimbine) more than clonidine-mediated vasoconstriction (-39 +/- 5 vs. -28 +/- 4%; before vs. after yohimbine) (P < 0.02). Prazosin blunted phenylephrine-mediated vasoconstriction (-39 +/- 4 vs. -8 +/- 2%; before vs. after prazosin) but had similar effects on both Dex- (-30 +/- 4 vs. -39 +/- 6%; before vs. after prazosin) and clonidine-mediated vasoconstriction (-29 +/- 3 vs. -41 +/- 7%; before vs. after prazosin) (P > 0.7). Both Dex and clonidine reduced deep forearm venous norepinephrine concentrations to a similar extent (-59 +/- 12 vs. -55 +/- 10 pg/ml; Dex vs. clonidine, P > 0.6); this effect was abolished by yohimbine and blunted by prazosin. These results suggest that Dex causes more alpha(2)-selective vasoconstriction in the forearm than clonidine. The similar vasoconstrictor responses to both drugs after prazosin might be explained by the presynaptic effects on norepinephrine release.     

ACL deficiency impairs the vasoconstrictive efficacy of neuropeptide Y and phenylephrine in articular tissues: a laser speckle perfusion imaging study.

Sympathetic-derived neuropeptide Y (NPY) helps regulate inflammatory responses in injury and disease, is a vasoconstrictor, and stimulates angiogenesis. Rupture of the anterior cruciate ligament (ACL) is a common clinical presentation that results in tissue inflammation, hyperemia, and angiogenesis in the intact medial collateral ligament (MCL). This study is the first to examine the vasoregulatory role of NPY in ACL-deficient knee joints by using the newly developed technique of laser speckle perfusion imaging (LSPI). MCL blood flow was measured in two groups of adult rabbits: unoperated control (n = 6), and 6-wk ACL transected (n = 5). Under anesthesia, the MCL was surgically exposed and tissue blood flow was imaged at high resolution using LSPI. NPY was applied to the MCL vasculature in topical boluses of 100 mul (dose range 10(-14) to 10(-9) mol), and the alpha-adrenoceptor agonist phenylephrine was applied in doses of 10(-14), 10(-10), and 10(-7) mol. In control rabbits, topical administration of NPY or phenylephrine produced dose-dependent vasopressor responses (maximal effect at 10(-9) mol NPY and 10(-7) mol phenylephrine). In ACL-transected knees, there was little or no vasoconstrictive response to NPY at any dose. The response to phenylephrine was significantly reduced compared with control ligaments. Possible causes of the reduced vasoconstrictive response to NPY in the MCL after 6 wk of ACL deficiency include development of tolerance to the peptide due to a prolonged increase in sympathetic nerve activity or change in the distribution or functionality of the NPY Y(1) receptors. Chronic ACL deficiency leads to profound and protracted hyperemia in associated articular tissues. Abrogation of a vasoconstrictor response to both NPY and phenylephrine in the MCL indicates that ACL deficiency induces major changes in the vascular physiological homeostasis.     

Characteristics of the central adrenergic mechanisms regulating arterial pressure in rats with hereditary arterial hypertension

Adrenergic mechanisms of blood pressure regulation were studied in a newly developed strain of rats with inherited stress-provoked arterial hypertension, spontaneously hypertensive rats (SHR) and normotensive Wistar rats. A number of adrenergic agonists (noradrenaline, adrenaline, phenylephrine, clonidine, naphazoline, isoproterenol, dobutamine, Alupent) were infused into the lateral brain ventricle under nembutal anesthesia and the reaction of the peripheral blood pressure was measured. It was shown that blood pressure reactions were similar in rats with inherited stress-provoked arterial hypertension and in SHR but significantly differed from those of normotensive Wistar rats. The data obtained suggest that the development of inherited hypertension was accompanied by changes in alpha 1 to alpha 2 adrenoreceptor ratio in pressor and depressor brain regions. A decrease in the depressor effect after stimulation of beta 1 and beta 2 receptors has been also observed.     

Exogenous NO administration and alpha-adrenergic vasoconstriction in human limbs.

Nitric oxide (NO) is capable of blunting alpha-adrenergic vasoconstriction in contracting skeletal muscles of experimental animals (functional sympatholysis). We therefore tested the hypothesis that exogenous NO administration can blunt alpha-adrenergic vasoconstriction in resting human limbs by measuring forearm blood flow (FBF; Doppler ultrasound) and blood pressure in eight healthy males during brachial artery infusions of three alpha-adrenergic constrictors (tyramine, which evokes endogenous norepinephrine release; phenylephrine, an alpha1-agonist; and clonidine, an alpha2-agonist). To simulate exercise hyperemia, the vasoconstriction caused by the alpha-agonists was compared during adenosine-mediated (>50% NO independent) and sodium nitroprusside-mediated (SNP; NO donor) vasodilation of the forearm. Both adenosine and SNP increased FBF from approximately 35-40 to approximately 200-250 ml/min. All three alpha-adrenergic constrictor drugs caused marked reductions in FBF and calculated forearm vascular conductance (P < 0.05). The relative reductions in forearm vascular conductance caused by the alpha-adrenergic constrictors during SNP infusion were similar (tyramine, -74 +/- 3 vs. -65 +/- 2%; clonidine, -44 +/- 6 vs. -44 +/- 6%; P > 0.05) or slightly greater (phenylephrine, -47 +/- 6 vs. -33 +/- 6%; P < 0.05) compared with the responses during adenosine. In conclusion, these results indicate that exogenous NO sufficient to raise blood flow to levels simulating those seen during exercise does not blunt alpha-adrenergic vasoconstriction in the resting human forearm.     

Lack of functional antilipolytic alpha 2-adrenoceptor in rat fat cell:comparison with hamster adipocyte

1. The small population of [3H]clonidine binding sites in rat fat cell membranes do not have the characteristics of typical alpha 2-adrenoceptors. 2. Clonidine (an alpha 2-adrenoceptor agonist) has no antilipolytic effect on rat fat cells stimulated by theophylline. 3. In contrast to the rat, [3H]clonidine labels an alpha 2-adrenoceptor in hamster fat cell membranes and clonidine exerts a strong antilipolytic effect on theophylline-stimulated lipolysis.