Influence of angiotensin II, alpha- and beta-adrenoceptors on peripheral noradrenergic neurotransmission in canine gracilis muscle in vivo.

Interactions between angiotensin II and adrenoceptor-mediated effects on peripheral sympathetic neurotransmission were investigated in constant flow blood-perfused canine gracilis muscle in situ, without and with pretreatment by non-competitive alpha-adrenoceptor blockade. Angiotensin converting enzyme (ACE)-inhibition by benazeprilat increased nerve stimulation (2 Hz, 4 min)-evoked noradrenaline (NA) overflow (+ 21 +/- 5%) with alpha-adrenoceptors intact, but reduced NA overflow (- 18 +/- 6%) when alpha-adrenoceptors were blocked. Vasoconstrictor responses were slightly reduced by benazeprilat. Subsequent infusion of angiotensin II (Ang II, 20 and 500 ng kg-1 min-1 i.v., raising arterial concentrations from 0.6 +/- 0.2 pM to 1390 +/- 240 and 25,110 +/- 3980 pM, respectively) failed to increase NA overflow or to enhance stimulation-evoked vasoconstriction. Adrenaline (0.4 nmol kg-1 min-1 i.v.) did not change evoked NA overflow before or after benazeprilat, either with or without alpha-adrenoceptor blockade, despite high concentrations (approximately 10 nM) in arterial plasma. Following benazeprilat, propranolol reduced NA overflow (- 24 +/- 3%) only if the alpha-adrenoceptors were blocked. In conclusion, benazeprilat reduced evoked NA overflow in the presence of alpha-adrenoceptor blockade to a similar degree as previously shown in the presence of neuronal uptake inhibition in this model. However, contrasting to our previous findings, benazeprilat enhanced NA overflow and reduced the post-junctional response to nerve stimulation in the absence of alpha-adrenoceptor blockade. This could be related to bradykinin accumulation during ACE-inhibition, in addition to the reduction of Ang II generation. Our data are not compatible with facilitation of NA release by circulating Ang II even at pharmacological dose levels. Although activation of prejunctional beta-adrenoceptors may facilitate evoked NA overflow in this model, circulating adrenaline is ineffective under physiological conditions even after alpha-adrenoceptor blockade. Also, beta-adrenoceptor-mediated prejunctional effects do not seem to involve Ang II in canine skeletal muscle in vivo.     

Prejunctional β2-adrenoreceptor blockade reduces nerve stimulation evoked release of endogenous noradrenaline in skeletal muscle in situ

Prejunctional β-adrenoceptor-mediated modulation of endogenous noradrenaline (NA) overflow elicited by sympathetic nerve stimulation was studied in blood-perfused canine gracilis muscle in situ. An attempt was made to subclassify these β-adrenoceptors by comparing the effects of β₁-selective (metoprolol) and non-selective (propranolol) β-adrenoceptor blockade. Animals were pre-treated with desipramine and phenoxybenzamine in order to counteract possible influences of neuronal uptake and stimulation-evoked changes in vascular resistance on the diffusion of NA into the blood stream. Metoprolol did not decrease stimulation-evoked NA overflow, as compared with control experiments (?10 and ?8 %, respectively). However, propranolol reduced stimulation-evoked NA overflow by 30% in metoprolol pre-treated animals (P < 0.05 vs. control experiments). Both antagonists elevated basal perfusion pressure, suggesting that vascular post-junctional β₁-as well as β₂-adrenoceptors are present. Propranolol increased stimulation-evoked vasoconstriction in metoprolol pre-treated animals, indicating that neuronally released NA may activate postjunctional β₂-adrenoceptors under these experimental conditions. In conclusion, our findings suggest that NA release can be enhanced by activation of prejunctional β₂-adrenoceptors in vivo.     

Pharmacological properties of prejunctional α-adrenoceptors in isolated feline middle cerebral arteries; comparison with the postjunctional α-adrenoceptors

In cat middle cerebral arteries (CMCA) preincubated with ³H-noradrenaline (NA), the outflow of tritium evoked by electrical stimulation was reduced to 32% by α-adrenoceptor (α-receptor) stimulation with oxymetazoline, and increased to 487% by α-receptor blockade with HEAT. The relative order of potency for α-receptor agonists on prejunctional receptors was: clonidine ≥ oxymetazoline > phenylephrine, and the antagonist rauwolscine was more potent than prazosin. This indicates that the prejunctional α-receptors are mainly of α₂-type. Rauwolscine was more potent than prazosin in inhibiting the contractions induced by NA, indicating a predominance of α₂-receptors postjunctionally. Apart from clonidine having higher intrinsic activity pre- than postjunctionally, all drugs examined (oxymetazoline, phenylephrine, rauwolscine, HEAT (BE2254), and prazosin) had similar concentration-effect curves on the pre- and postjunctional receptors. Furthermore, the ratios of EC₅₀-values pre- and postjunctionally of rauwolscine, oxymetazoline, and clonidine were all close to unity. These results indicate that pre- and postjunctional α₂-receptors in the CMCA have similar pharmacological characteristics and cannot be influenced separately by the presently used drugs.     

Blockade of central β-adrenoceptors attenuates tremor induced by 5-hydroxytryptamine (5-HT)-receptor activation in rats

The effect of β-adrenoceptor antagonists, varying in lipophilicity and receptor selectivity, were studied on tremor elicited by l -5-hydroxytryptophan (L-5-HTP) in rats pretreated with a peripherally acting decarboxylase inhibitor and a monoamine oxidase inhibitor, or by the directly acting 5-HT agonist s-methoxy-N,N-dimethyltryptamine (5-MeODMT). Plasma levels of the β-adrenoceptor antagonists were determined simultaneously. The non-selective lipophilic adrenoceptor antagonist propranolol was found to dose-dependently reduce tremor intensity, whereas the non-selective hydrophilic adrenoceptor antagonist sotalol had no effect, indicating a central site of action. Furthermore, β₁-selective blockade with the adrenoceptor antagonist metoprolol had no effect on tremor intensity, whereas the β₂-selective antagonist ICI 118,551 dose-dependently suppressed tremor intensity, suggesting that the β-adrenoceptor subtype involved is of the β₂-type. These results suggest that blockade of centrally located β₂-adrenoceptors are able to attenuate the tremor response following 5-hydroxytryptamine receptor activation.     

Effects of nimodipine,Bay K 8644 and pinacidil on α1- and α2-adrenoceptor-mediated vasoconstriction in human hand veins

The effects of nimodipine, Bay K 8644 and pinacidil, three drugs interfering with transmembrane Ca²⁺ fluxes in different ways, were investigated in isolated human hand veins. Their ability to influence the concentration-response relationship for noradrenaline (NA) was assessed in the absence and presence of prazosin or rauwolscine. The contractile response to NA was almost abolished in Ca²⁺-free medium. Nimodipine and pinacidil depressed the NA concentration-response curve both in the absence and presence of α-adrenoceptor blockers. The NA response was only partially inhibited by nimodipine, indicating that NA may activate nimodipine-insensitive influx pathways, presumably receptor-operated calcium channels. Pinacidil inhibited the contractile response to 124 mM K⁺ and reduced the NA-induced contraction in the presence of nimodipine, suggesting that pinacidil has actions other than the opening of potassium channels and subsequent membrane hyperpolarization. Bay K 8644 increased the NA potency fourfold in the presence of rauwolscine, whereas it had no effect on the NA response in the presence of prazosin and in the absence of α-adrenoceptor blockade. Such an action of Bay K 8644 can be reconciled with α-adrenoceptor activation causing membrane depolarization and opening of potential-operated calcium channels. It may be concluded that both α₁- and α₂-adrenoceptor-mediated contractions in human hand veins are highly dependent on Ca²⁺ influx, although the mechanisms utilized to bring about this influx partly differ between the two receptor subtypes.     

Pharmacological characterization of postjunctional α-adrenoceptors in isolated human omental arteries and veins

The α-adrenoceptors in human omental arteries and veins were characterized and compared. In the arteries both prazosin (pA₂ 9.48) and rauwolscine (pA₂ 7.19) displaced the noradrenaline (NA) concentration-response (cr) curve towards higher concentrations without reduction of maximum. Neither clonidine, nor oxymetazoline had any consistent contractile effects. Phenylephrine had a lower potency than NA, but a similar intrinsic activity. In the veins, both prazosin (pA₂ 9.72) and rauwolscine (pA₂ 8.11) displaced the NA cr-curve towards higher concentrations, but also significantly depressed maximum. Clonidine and oxymetazoline contracted veins from 3 out of 7 and 4 out of 6 patients, respectively. Their pD₂-values were similar to that of NA, but their intrinsic activities were significantly lower. NA was more potent than phenylephrine in these vessels, and there was no significant difference in intrinsic activity. The results suggest that in human omental arteries, the postjunctional a-adrenoceptors are mainly of the α₁-type, even if a small population of α₂-adrenoceptors cannot be excluded. In omental veins, there seems to be a functionally important population of postjunctional α₂-adrenoceptors occurring together with a population of α₁-adrenoceptors.     

Influence of extracellular calcium and nifedipine on α1-and α2-adrenoceptor-mediated contractile responses in isolated rat and cat cerebral and mesenteric arteries

The influence of extracellular Ca²⁺ and nifedipine on contractile responses to 10 μM noradrenaline (NA) was investigated in isolated rat and cat middle cerebral (RCA, CCA) and mesenteric (RMA, CMA) arteries. In the CCA (containing predominantly α₂-adrenoceptors), the NA-induced contractions developed considerably more slowly than in the RCA, RMA (containing mainly α₁-adrenoceptors) and CMA (sensitive to both at,- and α₂-adrenoceptor selective antagonists). The tonic component of the NA-induced contraction in the four types of artery was substantially suppressed after only short periods in Ca²⁺-free solution. In each type of artery, excluding the CCA, the contractile response to 124 mM K⁺ was more sensitive to Ca²⁺ deprivation than that to NA. This suggests that NA, besides mobilizing extracellular Ca²⁺, can also release Ca²⁺ from an intracellular pool in the RCA, RMA and CMA, but not in the CCA. Thus, α₁-adrenoceptor-mediated contractions in the RCA and RMA seem to depend on both Ca²⁺ influx and intracellular Ca²⁺ release, whereas α₂-adrenoceptor-mediated contractile responses in the CCA appear to rely almost entirely on Ca²⁺ influx. Both the maximum response and the tonic component of the NA-induced contraction were significantly more sensitive to nifedipine in the CCA than in the RCA. In comparison with the NA-induced contractions in these arteries, those in the RMA and CMA were relatively resistant to nifedipine. In the CCA exposed to NA in Ca²⁺-free medium, nifedipine almost abolished the contraction induced by re-addition of Ca²⁺, whereas in the other types of artery, Ca²⁺ re-application evoked a significant contraction also in the presence of the drug. The differential effects of nifedipine presumably reflect differences between the arteries, not only in the relative contribution of Ca²⁺ influx and intracellular Ca²⁺ release to the contractile activation, but also in the nifedipine sensitivity of the Ca²⁺ entry pathways utilized by NA. It is concluded that the mechanisms through which NA induces contraction seem to be related both to the subtype of α-adrenoceptor stimulated by NA and to the type of vessel studied.     

α 2 –Adrenoceptor activation may trigger the increased production of endothelium–derived nitric oxide in skeletal muscle during acute haemorrhage

Our previous studies indicated that acute haemorrhage leads to a pronounced increase in the release of endothelium-derived nitric oxide (EDNO) graded in relation to the magnitude of the blood loss. The EDNO-induced vasodilatation, confined selectively to the arterial `feeder' vessels, attenuates the concomitant reflex adrenergic constriction and thereby prevents deleterious reduction of blood flow. The present study aimed at investigating whether the reflex release of blood-borne catecholamines might trigger this EDNO release via activation of endothelial α₂-adrenoceptors. The study was performed on the sympathectomized vascular bed of cat skeletal muscle with a technique permitting quantitative recordings of resistance (tone) in consecutive vascular sections. Selective α₂-adrenoceptor blockade with idazoxan applied at steady state vasoconstriction after a 35% blood loss evoked an initial generalized dilator response (attributable to inhibition of post-synaptic smooth muscle α₂-adrenoceptors), followed by a constrictor response selectively in the arterial feeder vessels, the latter compatible with the hypothesis of reduced EDNO release by α₂-adrenoceptor blockade. More direct evidence for the hypothesis was obtained from studies of the vascular response to EDNO blockade ( L -NAME) after haemorrhage in the presence and absence of α₂-adrenoceptor blockade. The constrictor response to EDNO blockade, which is a measure of the pre-existing EDNO dilator influence (EDNO production), was significantly smaller (P < 0.01) in the presence than absence of α₂-adrenoceptor blockade. The results indicate that blood-borne catecholamines, via activation of endothelial α₂-adrenoceptors, trigger the increase in the EDNO release in acute haemorrhage, implying a functionally important negative feedback in the integrated control of vascular tone in bleeding.     

Modulation of oxotremorine-induced tremor by central β-adrenoceptors

The muscarinic agonist oxotremorine was used to induce tremor in rats pretreated with methylatropine. An objective assessment of tremor intensity was accomplished by means of an accelerometer-based recording system. The non-selective, lipophilic β-adrenoceptor antagonist propranolol dose-dependently suppressed tremor intensity, whereas the r -isomer of propranolol was without effect, verifying β-adrenoceptor involvement. Since the hydrophilic, non-selective β-antagonist nadolol was ineffective, the effect appears to be located inside the blood-brain barrier. The β₂-selective antagonist ICI 118, 551 dose-dependently reduced tremor intensity, whereas selective blockade of β₁-adrenoceptors with metoprolol had no effect, indicating the participation of a β₂-adrenoceptor. On the other hand, the lipophilic β₂-agonist clenbuterol dose-dependently enhanced tremor induced by oxotremorine. Determination of circulating plasma catecholamine concentrations revealed that the effect of β-antagonists on tremor was not secondary to an effect on the oxotremorine-induced rise in catecholamine levels. Thus, the results suggest that β₂-adrenocpetors located inside the blood-brain barrier are able to modulate oxotremorine-induced tremor in rats.     

VIP inhibition of vascular smooth muscle: complementary to β2-adrenoceptor mediated relaxation in the isolated rat portal vein

Exogenous VIP caused a concentration dependent inhibition of the spontaneous mechanical activity in the isolated rat mesenteric-portal vein preparation via a mechanism which was completely independent of the propranolol-blocked β-adrenoceptor, of high K⁺ in the medium and of exogenous bovine pancreatic polypeptide, neurotensin and opioids. The potency of VIP ((pD₂=7.52±0.18, n=6) was about 30 times higher than that of isoprenaline in the atropine and phentolamine-blocked preparation. The isoprenaline inhibition was mediated via a β₂-type of adrenoceptor with low apparent affinity for noradrenaline (intrinsic activity (a) = 0.27±0.01, n=8). Opposite effects of exogenous VIP and noradrenaline were on the other hand observed in the atropinized and β-blocked preparation. These results suggest that in the rat portal vein neuronal VIP and circulating adrenaline may be complementary in their antagonism of the α-adrenoceptor mediated increase in contractility.     

Postjunctional α1- and α2-adrenoceptors mediating contraction in isolated human groin arteries and veins

By means of selective agonists and antagonists for α₁- and α₂-receptors, the α-receptor subtypes in human groin arteries and veins were characterized and compared. In the arteries the α₁-receptor blocker prazosin caused a concentration-dependent parallel displacement of the noradrenaline (NA) concentration-response (cr) curve without reduction of maximum (pA₂=9.86); the selective α₂-receptor antagonist rauwolscine in the concentration 10^-8 M caused a right-ward shift of the NA cr-curve without reduction of E_max, but 10^-7 M and 10^-6 M caused little or no further shift. In the veins, the two antagonists had the opposite effects. Rauwolscine caused a concentration-dependent right-ward shift of the NA cr-curve without depression of maximum (pA₂=9.03); prazosin 10^-9 M significantly displaced the NA cr-curve, whereas 10^-8 M and 10^-7 M caused little or no further shift. The responses to the α₂-receptor agonist clonidine in the arteries were too small to allow calculations of pEC50 values; in the veins contractions were elicited in all vessel segments investigated (pEC₅₀=6.24). Phenylephrine, selective for α₁-receptors, was significantly more potent in arteries than in veins. NA was significantly more potent in veins than in arteries. It is concluded that in human groin vessels, there is a functional predominance of arreceptors in the arteries and of a2-receptors in the veins.     

Decreased responsiveness of vascular postjunctional α1-, α2-adrenoceptors and neuropeptide Y1 receptors in rats with heart failure

Heart failure is associated with increased sympathetic nerve activity. We hypothesized that chronic sympathetic stimulation in heart failure resulted in decreased vascular sympathetic responsiveness. A pithed rat model was employed to evaluate peripheral vascular α-adrenoceptor and neuropeptide Y (NPY) receptor responsiveness. Heart failure was induced in Sprague–Dawley rats by coronary artery ligation. Sham operated rats (Sham) served as controls. Two months after this surgical procedure, both heart failure (n= 30) and Sham (n= 30) rats underwent standard pithing procedure. Pressor responses to preganglionic sympathetic nerve stimulation (PNS) and activation of postjunctional α₁- and α₂-adrenoceptors as well as Y1 receptors were studied. In response to PNS, cardiac index was similar between heart failure and sham rats (P= n.s.). Mean arterial pressure (MAP) increased in a frequency-dependent fashion after PNS in heart failure rats as well as in control rats. All the agonists used, i.e. the α₁-adrenoceptor agonist phenylephrine, the α₂-adrenoceptor agonists clonidine and BHT933 as well as NPY, induced dose-dependent increases in MAP in heart failure and in sham rats. However, in rats with heart failure, the response to all the agonists studied was significantly decreased and the dose response curves were shifted to the right (P < 0.01). We conclude that in vivo vascular response to postjunctional α₁- and α₂-adrenoceptors as well as Y1 receptors are decreased in rats with heart failure.     

Increased β1-adrenoceptor density after 6-hydroxydopamine pretreatment in rat colon and lung

Estimation of β-adrenoceptor-binding sites with ¹²⁵I-(-)-pindolol in rat colon show a proportion of 30%β₁,-adrenoceptors and 70%β₂-adrenoceptors. Studies on the isolated colon strip have revealed a neuronal β-adrenoceptor involved in the inhibitory response of colon motility to β-adrenoceptor stimulation. In order to further characterize the β-adrenoceptors in the colon, acute and chronic treatments with 6-hydroxydopamine were made. Both acute pretreatment of rats with 6-hydroxydopamine for 8 and 24 h (one intravenous injection) and chronic treatment for 3 days (implanted osmotic mini-pumps), reduced the noradrenaline tissue content by 90%, and successively increased the β-adrenoceptor-binding sites from 14.3 to 21.7 fmol mg^_1 P^_1 in colon and from 158 to 240 fmol mg^-1 P^_1 in lung membranes. Displacement of the radiolabelled ligand by the selective β-adrenoceptor antagonists, pafenolol and ICI 118.551 showed that the density of β₁,-adrenoceptor binding sites was more than doubled, whereas the density of β₂-adrenoceptor-binding sites was only marginally increased by chronic treatment with 6-hydroxydopamine. Thus sympathetic denervation by 6-hydroxydopamine treatment produced a selective increase in β₁-adrenoceptors in the rat colon. These results may indicate that stimulation of β₁-adrenoceptors in both colon and lung have a neuronal linkage.     

Regional distribution of α-adrenoceptor subtypes in the female rabbit urethra

The aim of the present investigation was to study the regional distribution of α-adrenoceptor subtypes in the female rabbit bladder base and urethra, using radioligand binding and mechanical activity studies. The binding studies performed on membranes prepared from the bladder base, and the proximal and distal part of the urethra, revealed that the number of α₁-adrenoceptors did not significantly differ between the three regions, whereas the number of α₂-adrenoceptors increased distally. The mechanical activity studies showed that noradrenaline and clonidine, but not phenylephrine, were more potent in the distal than the proximal part of the urethra. It is suggested that in the female rabbit urethra the lower EC₅₀-value found for noradrenaline and clonidine in the distal as compared to the proximal part of the urethra, at least in part, is attributable to a higher number of postjunctional α₂-adrenoceptors in the distal than in the proximal urethra.     

Enhancement of insulin secretion during selective blockade of α1, - and α2-adrenoceptors in the rat: Effects of somatostatin

The effects of somatostatin on plasma concentrations of insulin and glucose in the presence of the selective α₁-adrenoceptor blocking agent prazosin or the selective α₂-adrenoceptor blocking drug yohimbine were studied in vivo in anesthetized rats. Infusion of both prazosin (0.080 mg/min) and yohimbine (0.018 mg/min) increased plasma insulin levels within 10 min. Prazosin, but not yohimbine, caused a significant increment in plasma glucose concentration. Somatostatin (0.1 μg/min) promptly and extensively lowered plasma insulin concentrations during the infusion of both prazosin and yohimbine, suggesting that the inhibitory effect of somatostatin is not mediated via a direct action on α₁ or α₂-adrenoceptors. Plasma glucose concentration fell slightly during somatostatin administration. A marked increment in insulin release occurred in response to cessation of the somatostatin infusion, both during prazosin- and yohimbine-treatment. We conclude that somatostatin efficiently inhibits insulin secretion during selective α₁- and α₂-adrenoceptor blockade and, further, that the insulin off-response after somatostatin treatment is potentiated by α-adrenoceptor blockade. This study also indicates that blockade of α₁- as well as of α₂-adrenoceptors leads to an increased insulin secretion.     

Effects of α-adrenoceptor blockade by phentolamine on basal and stimulated insulin secretion in the mouse

The sympathetic nervous system is known to innervate the pancreatic islets and to have the capability to influence islet hormone release. The effects are, however, complex since the islet nerves contain catecholaminergic as well as peptidergic fibres, and the catecholamines stimulate α- as well as β-adrenoceptors. The present study was undertaken to establish the possible influence of the a-adrenoceptors on basal and stimulated insulin secretion under in vivo conditions. The α-adrenoceptor blocker phentolamine was injected at various dose levels i.p. to mice and a dose-dependent increase in plasma concentrations of insulin was seen. The maximal plasma insulin levels were observed 10 min after injection and were accompanied by decreased plasma glucose concentrations. Additionally, plasma glucose levels fell in response to phentolamine by an apparent insulin-independent manner, since at the low dose of 2.6 μmol kg^-1, plasma glucose levels did decrease without any apparent increase in plasma insulin levels. After injection of a low dose of phentolamine 10 min prior to a rapid i.v. injection of one of four different insulin secretagogues, the following effects on insulin release were observed. Glucose (+ 55%) and the cholinergic agonist carbachol (+ 140%) displayed a potentiated insulin secretory response after phentolamine pretreatment, whereas the β₂-adrenoceptor agonist terbutaline (-45%) had a blunted, though not abolished, insulin response. The absolute insulin secretory response to CCK-8 was unaffected by phentolamine despite the fact that plasma glucose levels were lowered by phentolamine. In conclusion, phentolamine enhanced insulin secretion and depressed plasma glucose levels in mice. Further, it influenced stimulated insulin secretion by a manner dependent on the nature of the secretagogue. The results thus suggest that α-adrenoceptors are involved in the precise regulation of basal and stimulated insulin secretion, and that a-adrenoceptor blockade does not always result in a potentiated insulin secretion.     

Middle cerebral artery blood velocity during exercise with β‐1 adrenergic and unilateral stellate ganglion blockade in humans

A reduced ability to increase cardiac output (CO) during exercise limits blood flow by vasoconstriction even in active skeletal muscle. Such a flow limitation may also take place in the brain as an increase in the transcranial Doppler determined middle cerebral artery blood velocity (MCA V_mean) is attenuated during cycling with β‐1 adrenergic blockade and in patients with heart insufficiency. We studied whether sympathetic blockade at the level of the neck (0.1% lidocain; 8 mL; n=8) affects the attenuated exercise – MCA V_mean following cardio‐selective β‐1 adrenergic blockade (0.15 mg kg^?1 metoprolol i.v.) during cycling. Cardiac output determined by indocyanine green dye dilution, heart rate (HR), mean arterial pressure (MAP) and MCA V_mean were obtained during moderate intensity cycling before and after pharmacological intervention. During control cycling the right and left MCA V_mean increased to the same extent (11.4 ± 1.9 vs. 11.1 ± 1.9 cm s^?1). With the pharmacological intervention the exercise CO (10 ± 1 vs. 12 ± 1 L min^?1; n=5), HR (115 ± 4 vs. 134 ± 4 beats min^?1) and ΔMCA V_mean (8.7 ± 2.2 vs. 11.4 ± 1.9 cm s^?1) were reduced, and MAP was increased (100 ± 5 vs. 86 ± 2 mmHg; P < 0.05). However, sympathetic blockade at the level of the neck eliminated the β‐1 blockade induced attenuation in ΔMCA V_mean (10.2 ± 2.5 cm s^?1). These results indicate that a reduced ability to increase CO during exercise limits blood flow to a vital organ like the brain and that this flow limitation is likely to be by way of the sympathetic nervous system.     

Quantification of α2A and α2C adrenoceptors in the rat striatum and in different regions of the spinal cord

The α_2C-adrenoceptor preferring radioligand [³H]-MK912 was used for labelling α_2A- and α_2C-adrenoceptors in the rat striatum, in the cervical, thoracic and lumbar parts of the spinal cord, and in the dorsal and ventral halves of the spinal cord. In addition, guanfacine was used as a tool to delineate the α_2A- and α_2C-adrenoceptors. In the striatum the sites were 72% α_2A- and 28% α_2C-adrenoceptors, while in all regions of the spinal cord the proportions of the sites were about 96% α_2A- and 4% α_2C-adrenoceptors. A multi-curve experimental design and computer analysis was used in order to enable the accurate quantification of the α_2A- and α_2C-adrenoceptors in the striatum and spinal cord.     

β1-and β2-adrenoceptor-mediated secretion of amylase from incubated rat parotid gland

The present in vitro investigation was undertaken in an attempt to obtain further information on β-adrenoceptor specificity and action in the rat parotid gland, with regard to amylase secretion. The β₁-selective agonist prenalterol was roughly 800 times more potent than the β₂-agonist terbutaline, and about 5 times more effective than noradrenaline in evoking amylase release. Propranolol was the most effective inhibitor of amylase release in all experiments. The β₁-selective antagonist metoprolol and H104/08 were also effective blockers of maximal noradrenaline-and prenalterol-induced release. The inhibition curves displayed biphasic shapes when amylase secretion was induced by noradrenaline, but not when prenalterol was the secretagogue. The β₂-antagonist H35/25 was without effect on maximal noradrenaline-and prenalterol-stimulated secretion. The amylase release evoked by submaximal concentration of terbutaline was inhibited by the two antagonists H35/25 and IPS 339. In another series of experiments propranolol and metoprolol clearly shifted the noradrenaline concentration-response curve to the right, whereas H35/25 was without effect. The results further demonstrate the major importance of the β₁-adrenoceptor (noradrenaline-activated) in eliciting amylase release from the rat parotid gland. However, it is also suggested that the β₂-adrenoceptors (terbutaline-activated) may to some extent serve the same function.     

Effects of selective α1 and α2 adrenoceptor active drugs on 86Rb+ efflux from pieces of rat parotid gland

Minute pieces of rat parotid gland were used in studies of adrenergic regulation of K+ efflux using ⁸⁶Rb+ as a probe for K+. Noradrenaline induced a concentration-dependent Rb+ efflux, whereas the β₁-selective agonist prenalterol was without effect. On the other hand, the β₂-selective drug, terbutaline, at high concentrations displayed a small enhancement of Rb+ -secretion. The selective α₁-adrenoceptor drug, phenylephrine, was as potent as noradrenaline, whereas the α₂-agonist clonidine had only a small effect. The noradrenaline-induced Rb+-efflux was effectively inhibited in the presence of prazosin, an α₁-blocker, whereas the α₂-antagonist, yohimbine, was roughly 50 times less potent. The results suggest that catecholamine-induced K+-secretion from the rat parotid gland is mediated via activation of post-synaptic α-adrenoceptors of the α₁-subtype.