Comparison of beta-adrenoceptors mediating vasodilatation in canine subcutaneous adipose tissue and skeletal muscle.

Blood flow changes in response to various drugs in simulataneously autoperfused canine subcutaneous adipose tissue and gracilis muscle were compared to study the vascular beta-adrenoceptors. Compared to isoprenaline the beta 2-selective agonist salbutamol was 4--6 times more potent as a vasodilator in the muscle than in adipose tissue. Furthermore two beta 1-selective agonists (Tazolol and H80/62) caused vasodilatation in adipose tissue but not in the gracilis muscle. When given by close i.a. injection after beta-adrenoceptor blockade, adrenaline was a more potent vasoconstrictor than noradrenaline in both tissues. Before beta-blockade, however, noradrenaline was the more potent vasoconstrictor in the gracilis muscle whereas adrenaline was more potent in adipose tissue. Intravenous infusion of adrenaline in doses causing vasodilatation in the muscle caused vasoconstriction in adipose tissue whereas intravenous infusion of noradrenaline caused vasoconstriction in both tissues. The present findings suggest that the beta-adrenoceptors mediating vasodilatation in skeletal muscle are mainly ose tissue. Since adrenaline is a much more potent beta2- than beta1-agonist, these differences point to different roles of intravascular adrenaline in the two sites. In skeletal muscle circulating adrenaline is mainly a vasodilator whereas in subcutaneous adipose tissue it mainly acts as a vasoconstrictor.     

Vasodilatation and modulation of vasoconstriction in canine subcutaneous adipose tissue caused by activation of β-adrenoceptors

The present experiments were undertaken to study the balance between vascular α- and β-adrenoceptors in canine subcutaneous adipose tissue during sympathetic nerve stimulation and noradrenaline injections. Propranolol potentiated and prolonged the vasoconstrictor response to close i.a. injections of noradrenaline. The vasoconstriction induced by brief nerve stimulation (0.5 to 8 Hz) was, however, unaltered by the β-adrenoceptor blockade. During prolonged nerve stimulation the vasoconstrictor response was well maintained at 1.5 Hz but at 4 Hz there was a gradual escape. The escape phenomenon at 4 Hz was diminished by propranolol. The β₁-selective antagonist practolol, like propranolol, potentiated and prolonged the vasoconstriction induced by noradrenaline injections and reduced the vasoconstrictor escape during prolonged nerve stimulation at 4 Hz. Furthermore, the vasodilatation induced by noradrenaline injection or nerve stimulation during α-adrenoceptor blockade was diminished by practolol. Practolol also blocked the lipolytic response to noradrenaiine and nerve stimulation. The β₂-selective antagonist H35/25 blocked the effects of the β₂-selective agonist salbutamol but failed to alter noradrenaline as well as nerve stimulation induced vascular and lipolytic β-adrenoceptor responses. The present results provide further support for the hypothesis that vascular β-adrenoceptors in adipose tissue are humoral (noninnervated), preferentially activated by circulating noradrenaline. Moreover, both vascular and lipolytic β-adrenoceptors activated by noradrenaline in adipose tissue are best classified as β₁-adrenoceptors.     

Vasodilatation and modulation of vasoconstriction in canine subcutaneous adipose tissue caused by activation of beta-adrenoceptors.

The present experiments were undertaken to study the balance between vascular alpha- and beta-adrenoceptors in canine subcutaneous adipose tissue during sympathetic nerve stimulation and noradrenaline injections. Propranolol potentiated and prolonged the vasoconstrictor response to close i.a. injections of noradrenaline. The vasoconstriction induced by brief nerve stimulation (0.5 to 8 Hz) was, however, unaltered by the beta-adrenoceptor blockade. During prolonged nerve stimulation the vasoconstrictor response was well maintained at 1.5 Hz but at 4 Hz there was a gradual escape. The escape phenomenon at 4 Hz was diminished by propranolol. The beta1-selective antagonist practolol, like propranolol, potentiated and prolonged the vasoconstriction induced by noradrenaline injections and reduced the vasoconstrictor escape during prolonged nerve stimulation at 4 Hz. Furthermore, the vasodilatation induced by noradrenaline injection or nerve stimulation during alpha-adrenoceptor blockade was diminished by practolol. Practolol also blocked the lipolytic response to noradrenaline and nerve stimulation. The beta2-selective antagonist H35/25 blocked the effects of the beta2-selective agonist salbutamol but failed to alter noradrenaline as well as nerve stimulation induced vascular and lipolytic beta-adrenoceptor responses. The present results provide further support for the hypothesis that vascular beta-adrenoceptors in adipose tissue are humoral (noninnervated), preferentially activated by circulating noradrenaline. Moreover, both vascular and lipolytic beta-adrenoceptors activated by noradrenaline in adipose tissue are best classified as beta1-adrenoceptors.     

Central hemodynamic effects of adrenaline with special reference to β2-adrenergic influence on heart rate and cardiac afterload in anesthetized cats

Central hemodynamic responses evoked by i. v.infusions of adrenaline and noradrenaline were studied in normovolemic anesthetized cats with intact adrenoceptors, after selective β₂-blockade (ICI 118,551), and after nonselective β-blockade (propranolol).The results demonstrated the presence of an important β₂-adrenergic component in the integrated response to ‘physiological’ doses of adrenaline contributing to increased cardiac output, decreased total peripheral resistance and virtually unchanged mean arterial blood pressure. Corresponding β₂-adrenergic effects of noradrenaline were small. The β₂-adrenergic effects of adrenaline on the heart seemed to be both direct and indirect. A moderate direct chronotropic response mediated by β₂-adrenoceptors apparently was present but there was no evidence of a direct β₂-adrenergic inotropic effect. An indirect, quite marked effect on the heart was accomplished by a β₂-adrenergic vasodilator interaction with the α-adrenergic vasoconstrictor influence on the systemic resistance vessels. This caused a net decrease in total peripheral resistance, thereby preventing an undue increase in cardiac afterload (arterial pressure) which seemed to be essential for evoking ‘optimal’ increases in cardiac output. It is suggested that such adrenaline evoked indirect, β₂-adrenergic improvement of cardiac performance is of functional importance in reflex sympatho-adrenal circulatory control.     

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.     

Influence of adenosine on the vascular responses to sympathetic nerve stimulation in the canine subcutaneous adipose tissue

Adenosine appears to regulate resting blood flow in canine subcutaneous adipose tissue. Sympathetic nerve stimulation has been shown to enhance the adenosine production in this tissue. This study therefore tested the possibility that adenosine may influence the vascular responses to sympathetic nerve stimulation. Intraarterial infusion of adenosine (5–20 μM in arterial blood) increased the resting vascular conductance (from 0.048 ± 0.007 to 0.095 ± 0.013 ml ± min^-1100 g^-1± mmHg^-1) and the percental reduction in vascular conductance due to sympathetic nerve stimulation (4 Hz) by 34 per cent (p<0.05) and to i. a.noradrenaline by 27 per cent (p<0.05). The vasodilator response due to nerve stimulation after α-blockade was reduced by adenosine. Dipyridamole (0.5–1.5 μM) + EHNA (3–10 μM), which increases plasma adenosine levels, had similar effects to adenosine, while theophylline (30–80 μM) decreased the vasoconstrictor response. The vasoconstrictor escape was enhanced by EHNA alone and in combination with dipyridamole, but was reduced by theophylline. On the other hand, the poststimulatory hyperemia was unaffected by adenosine, dipyridamole and EHNA, and theophylline. The results show that adenosine does not reduce the magnitude of the initial vasoconstrictor response in proportion to the increase in resting blood flow. The autoregulatory escape in adipose tissue during nerve stimulation appears to be mediated both by adenosine and by noradrenaline acting on β-adrenoceptors. Poststimulatory hyperemia does not seem to be greatly influenced by exogenous or endogenous adenosine     

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.     

Functional β1 - and β2-adrenoceptors in the human myocardium

Functional β-adrenoceptor populations in the human heart were studied in vitro in electrically-paced strips of the right auricular and ventricular myocardium. The relative potency of selected agonists in producing inotropic responses (T_max, T′_max) in the presence of blockers for neuronal and extraneuronal uptakes was found to be as follows: isoprenaline > noradrenaline = adrenaline = salbutamol > dobutamine. Prenalterol had a negative inotropic effect in these preparations. The selective β₁ -(practoloI) and β₂-(H 35/25) blockers reduced inotropic responses to adrenaline (T_max, T′_max) and noradrenaline (T′_max) in the auricular strips. These results indicate the participation of β₂-adrenoceptors in inotropic responses in the human auricular and ventricular myocardium. For comparison, inotropic responses of electrically-paced rat myocardium to β-adrenergic agonists in the presence of blockers for neuronal and extraneuronal uptakes were likewise studied. The relative potencies for T_max were: noradrenaline = adrenaline > prenalterol > dobutamine = salbutamol. Given the high relative potency of salbutamol in the human myocardial strips (analogous to that previous shown in the β₂-dominated atria of the frog and trout) and the low relative potency of salbutamol in the rat tissue, these findings indicate a greater population of functionally active β₂-adrenoceptors in the human than in the rat myocardium.     

Microsphere analysis of β2-adrenergic control of resistance in different vascular areas after hemorrhage

In cats exposed to bleeding (exsanguination of 15 ml×kg bwt^-1) the microsphere technique was used to determine regional vascular resistances in a large number of tissues before and after i.v. administration of the ‘selective’β₂-adrenoceptor antagonist ICI 118,551. β₂-blockade significantly raised vascular resistance in the stomach (+26%), small (+25%) and large (+38%) intestine, pancreas (+29%), kidney (+39%), omental (+33%) and subcutaneous (+26%) fat, ‘white’ skeletal muscle (+19%), and skin (+24%). These findings indicate that, with intact β-adrenoceptors, β₂-adrenergic dilator interaction counteracted the hemorrhage evoked vasoconstrictor influences. β₂-blockade also evoked quite a strong increase of total peripheral resistance (19%) and led to some redistribution of cardiac output. It is concluded that β₂-adrenergic inhibition of vascular tone significantly seems to improve tissue perfusion during bleeding in several vascular areas. Such effects may be of special significance during severe hemorrhage. In the intestine, pancreas, and adipose tissue, for example, protection against excessive vasoconstriction may serve to minimize the severe metabolic disturbances with secondary release of toxic factors into the circulation reported during hemorrhagic shock.     

Cardiovascular and Metabolic Actions of Neurotensin and (Gln4)-Neurotensin

Rosell , S., E. Burcher , D. Chang and K. Folkers . Cardiovascular and metabolic actions of neurotensin and (Gln⁴)-neurotensin. Acta physiol. scand. 1976. 98. 484–491. The actions of the tridecapeptides neurotensin and (Gln⁴)-neurotensin have been studied on the heart and on the blood flow in subcutaneous adipose tissue, skin and small intestine of anesthetized dogs. In addition, their possible actions have been investigated on blood glucose concentration and lipolysis in subcutaneous adipose tissue. The two peptides were found to he approximately equipotent. Intravenous infusion of 20–120 ng × kg % min produced slight hypotension, an initial vasodilatation in the small intestine and a delayed vasoconstriction in denervated subcutaneous adipose tissue and to a lesser extent in the skin and small intestine. At this infusion rate, neurotensin and (Gln⁴)-neurotensin did not elicit vasodilatation in the skin or adipose tissue and had no effect on heart rate. The delayed vasoconstriction in adipose tissue was not inhibited by local cr-receptor blockade. Both neurotensin and (Gln⁴)-neurotensin increased glucose concentration in the upper dose range. No effects on lipolysis were observed, either in vivo or in vitro. These experiments show that neurotensin and (Gln⁴)-neurotensin have both vasodilator and vasoconstrictor actions in the peripheral vasculature but seem to be without cardiac actions. They also increase blood glucose concentration. It remains to be shown whether these actions are direct or whether some are indirectly mediated.     

Relaxant effect of prostaglandin E1 on the isolated intestine of the toad (bufo melanostictus)

The pharmacological actions of prostaglandins E₁, F₁, E₂ and A₁ were studied on the longitudinal and circular muscles of the isolated small intestine of the toad. Prostaglandin E₁ caused relaxation, whereas prostaglandin A₁ was inactive and prostaglandins F₁ and E₂ caused contractions. Other substances which relaxed the toad intestine were adrenaline, noradrenaline and isoprenaline. On a molar basis, prostaglandin E₁ was seven times less potent than isoprenaline, but it was three times more potent than adrenaline and seventeen times more potent than noradrenaline. Phentolamine and propranolol blocked the relaxant effects of catecholamines in concentrations which did not alter the relaxant effect of prostaglandin E₁. The results suggested that prostaglandin E₁ acted directly on the intestinal smooth muscle of the toad rather than by the local release of catecholamines.     

Influence of circulating NE and Epi on adipose tissue vascular resistance and lipolysis in humans

The effects of circulating norepinephrine (NE) and epinephrine (Epi) on vascular resistance in subcutaneous adipose tissue and the calf as well as on plasma glycerol, an indicator of lipolysis, were studied in healthy volunteers. Adipose tissue blood flow was determined by the local clearance of 99mTcO-4 or 133Xe. The two isotopes gave similar results. Calf blood flow was determined by venous occlusion plethysmography. Intravenous infusion of NE caused increases in systolic and diastolic blood pressures, adipose tissue and calf vascular resistances, and plasma glycerol and a decrease in plasma insulin and heart rate, all of which were significant when arterial plasma NE was elevated from 1.17 +/- 0.14 to 8.38 +/- 0.30 nM (n = 16). Epi reduced diastolic and mean arterial pressures and adipose tissue and calf vascular resistances and increased plasma glycerol without affecting systolic blood pressure or plasma insulin. An increase of arterial plasma Epi from 0.20 +/- 0.03 to 1.15 +/- 0.05 nM (n = 6) was sufficient to induce vasodilatation in adipose tissue and lipolysis. Human adipose tissue differs from canine adipose tissue inasmuch as Epi causes vasodilatation in humans (present results) but vasoconstriction in the dog (previous results), presumably due to a predominance of vascular beta 2-adrenoceptors in human and beta 1-adrenoceptors in canine adipose tissue. Furthermore, Epi is a considerably more potent lipolytic hormone than NE in humans but not in the dog. Our results indicate that both NE and Epi may influence human adipose tissue blood flow and lipolysis as circulating hormones.     

Blood flow in skin, subcutaneous adipose tissue and skeletal muscle in the forearm of normal man during an oral glucose load

Blood flow to the forearm, and the subcutaneous tissue and skin in the forearm were measured by strain gauge plethysmography, 133Xe-elimination and Laser Doppler flowmetry during an oral glucose load (I g glucose kg-1 lean body mass) and during control conditions. The forearm blood flow remained constant during both experiments. Glucose induced a two-fold vasodilatation in subcutaneous tissue. In skin, glucose induced a relative vasodilatation and later a relative vasoconstriction compared with control experiments. When estimated from forearm blood flow and subcutaneous and skin blood flows, muscle blood flow decreased about 20-30% during both experiments. Proximal nervous blockade did not abolish the glucose-induced vasodilatation in subcutaneous tissue. In the glucose experiment, arterial glucose concentration increased to 7.8 +/- 1.17 mmol l-1 30 min after the load was given and then decreased to 4.5 +/- 0.34 mmol l-1 at the end of the experiment. In the control experiments glucose concentration was constant. Arterial noradrenaline concentration increased significantly from 1.0 +/- 0.13 to about 1.5 +/- 0.3 nmol l-1 120 min after glucose and remained at this level during the experiment. Similarly adrenaline increased from 0.16 +/- 0.11 to about 0.4 +/- 0.16 nmol l-1 180 min after glucose. It is hypothesized that the vasodilating effect of glucose in subcutaneous tissue is secondary to metabolic events connected to glucose uptake and energy deposition in adipose tissue.     

Relationship between the overflow of endogenous and radiolabelled noradrenaline from canine blood perfused gracilis muscle

The effects of sympathetic nerve stimulation (SNS) on the overflow of endogenous noradrenaline (NA) and on vasoconstrictor responses were studied in blood perfused canine gracilis muscle in situ. A conventional tracer technique with 3H-labelled NA (3H-NA) was used in parallel. At rest there was a net extraction of endogenous NA and adrenaline across the tissue. The SNS evoked overflow of endogenous NA was frequency-dependent and logarithmically correlated to the vasoconstrictor responses. The neuronal uptake inhibitor desipramine doubled the SNS induced overflow of endogenous NA without enhancing the vasoconstrictor responses. A further fourfold increase in NA overflow was caused by a dose of the alpha-blocker phenoxybenzamine which reduced the vasoconstrictor responses by 50-75%. Less than 10% of the spontaneous 3H efflux was recovered as unmetabolized 3H-NA, whereas virtually all 3H overflow evoked by SNS was 3H-NA. The fractional release of NA or 3H-NA per nerve impulse increased with increasing frequencies of SNS under all conditions studied. Although there was a preferential release of the newly stored radiolabelled transmitter, results concerning endogenous NA and 3H-NA overflow were qualitatively similar, also under conditions with marked changes in transmitter overflow. Endogenous NA gave a more reproducible index of transmitter overflow than did 3H-NA and, in particular, total 3H. The overflow of endogenous NA closely reflects SNS evoked neuronal release of NA in blood perfused skeletal muscle and seems more suitable than conventional radiotracer techniques for studies of NA release under in vivo conditions.     

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.     

Forearm vascular and neuroendocrine responses to graded water immersion in humans

The hypothesis that graded expansion of central blood volume by water immersion to the xiphoid process and neck would elicit a graded decrease in forearm vascular resistance was tested. Central venous pressure increased (P < 0.05) by 4.2 +/- 0.4 mmHg (mean +/- SEM) during xiphoid immersion and by 10.4 +/- 0.5 mmHg during neck immersion. Plasma noradrenaline was gradually suppressed (P < 0.05) by 62 +/- 8 and 104 +/- 11 pg mL-1 during xiphoid and neck immersion, respectively, indicating a graded suppression of sympathetic nervous activity. Plasma concentrations of arginine vasopressin were suppressed by 1.5 +/- 0.5 pg mL-1 (P < 0.05) during xiphoid immersion and by 2.0 +/- 0.5 pg mL-1 during neck immersion (P < 0.05 vs. xiphoid immersion). Forearm subcutaneous vascular resistance decreased to the same extent by 26 +/- 9 and 28 +/- 4% (P < 0.05), respectively, during both immersion procedures, whereas forearm skeletal muscle vascular resistance declined only during neck immersion by 27 +/- 6% (P < 0.05). In conclusion, graded central blood volume expansion initiated a graded decrease in sympathetic nervous activity and AVP-release. Changes in forearm subcutaneous vascular resistance, however, were not related to the gradual withdrawal of the sympathetic and neuroendocrine vasoconstrictor activity. Forearm skeletal muscle vasodilatation exhibited a more graded response with a detectable decrease only during immersion to the neck. Therefore, the forearm subcutaneous vasodilator response reaches saturation at a lower degree of central volume expansion than that of forearm skeletal muscle.     

Influence of angiotensin II, α- and β-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 α- adrenoceptor blockade. Angiotensin converting enzyme (ACE)-inhibition by benazeprilat increased nerve stimulation (2 Hz, 4 min)-evoked noradrenaline (NA) overflow (+21 ± 5 yo) with α- adrenoceptors intact, but reduced NA overflow (– 18 ± 6%) when α-adrenoceptors were blocked. Vasoconstrictor responses were slightly reduced by benazeprilat. Subsequent infusion of angiotensin II (Ang 11, 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 α-adrenoceptor blockade, despite high concentrations (± 10 nM) in arterial plasma. Following benazeprilat, propranolol reduced NA overflow (–24 ± 3 yo) only if the α-adrenoceptors were blocked. In conclusion, benazeprilat reduced evoked NA overflow in the presence of α- 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 α-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 β-adrenoceptors may facilitate evoked NA overflow in this model, circulating adrenaline is ineffective under physiological conditions even after α-adrenoceptor blockade. Also, β-adrenoceptor-mediated prejunctional effects do not seem to involve Ang II in canine skeletal muscle in vivo.     

β2-Adrenoceptors Facilitating Noradrenaline Secretion from Human Vasoconstrictor Nerves

Isolated superfused biopsy specimens of human peripheral arteries and veins, preincubated with ³H-(-)-noradrenaline (NA) to label the neural stores of NA, were used to study the β-adrenoceptors previously found to increase the secretion of ³H-NA evoked by electrical field stimulation of the adrenergic nerves of this tissue. The increase in nerve stimulation induced secretion of ³H-NA caused by 0.04μM isoprenaline was prevented by 1 μM propranolol. This &bT-blocking drug by itself slightly but significantly depressed the secretion of ³H-NA caused by nerve stimulation in the absence of isoprenaline. While the secretion of ³H-NA was not affected by two known β₁-agonists, it was dose-dependently and reversibly increased by two different β₂-agonists. The effect of isoprenaline on ³H-NA secretion was not altered by a selective β-antagonist, but strongly reduced or abolished by a β₂-blocking drug. The results indicate that the β-adrenoceptors involved in the control of NA secretion from the vasoconstrictor nerves of human omental blood vessels are only to a minimal extent stimulated by NA secreted from the nerves, and therefore do probably not mainly serve to mediate local positive feedback control of transmitter secretion; the receptors appear to be β₂ in nature.     

The influence of vascular β-adrenoceptors on the position and mobility of the rabbit incisor tooth

The influence of vascular β-adrenoceptors on the tooth-supporting functions of the periodontal ligament were studied in 30 anesthetized rabbits. Propranolol and the β₂-adrenoceptor antagonists ICI 118,551 and H 35/25 induced a marked extrusion of the incisor, probably due to reduced vasodilator tone in periodontal postcapillary blood vessels. Isoprenaline reversed the movement. β₁- and β₂-receptor antagonists decreased the intrusive responses to sympathetic nerve stimulation in teeth close to control position, but had no effect on responses in fully extruded teeth. Intrusive mobility, as tested by intermittent loading with 5–10 g, remained unaffected by β-adrenoceptor blockade. The results suggest that vascular β₂-adrenoceptors are important in the regulation of tooth position by their control of periodontal postcapillary resistance. Prejunctional β-receptors enhancing the vasoconstrictor - and intrusive - responses to sympathetic nerve stimulation are probably a mixture of β₁- and β₂-receptors. It would seem that the periodontal vasculature is important for the position of the rabbit tooth but, due to rapid adaptive mechanisms of the tooth-supporting tissues, the vasculature contributes little to the resistance against loadinduced intrusive movements of the tooth.