Alpha-receptor Stimulation Research Articles

The effect of generalized alpha-receptor stimulation on regional myocardial blood flow distal to a severe coronary artery stenosis.

HomeCirculationVol. 65, No. 7The effect of generalized alpha-receptor stimulation on regional myocardial blood flow distal to a severe coronary artery stenosis. Free AccessAbstractPDF/EPUBAboutView PDFSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessAbstractPDF/EPUBThe effect of generalized alpha-receptor stimulation on regional myocardial blood flow distal to a severe coronary artery stenosis. H Gewirtz, A S Most and D O Williams H GewirtzH Gewirtz Search for more papers by this author , A S MostA S Most Search for more papers by this author and D O WilliamsD O Williams Search for more papers by this author Originally published1 Jun 1982https://doi.org/10.1161/01.CIR.65.7.1329Circulation. 1982;65:1329–1336 Previous Back to top Next FiguresReferencesRelatedDetailsCited By Ovchinnikov V, Suzuki G, Canty J and Fallavollita J (2005) Blunted functional responses to pre- and postjunctional sympathetic stimulation in hibernating myocardium, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00273.2005, 289:4, (H1719-H1728), Online publication date: 1-Oct-2005. Ertl G, Hu K, Bauer W and Bauer B (1996) The renin-angiotensin system and coronary vasomotion, Heart, 10.1136/hrt.76.3_Suppl_3.45, 76:3 Suppl 3, (45-52), Online publication date: 1-Nov-1996. Baumgart D and Heusch G (1995) Neuronal control of coronary blood flow, Basic Research in Cardiology, 10.1007/BF00789444, 90:2, (142-159), . Krajcar M and Heusch G (1993) Lokale und neurohumorale Kontrolle der Koronardurchblutung Angiotensin und Herz, 10.1007/978-3-662-11145-1_3, (29-47), . Krajcar M and Heusch G (1993) Local and neurohumoral control of coronary blood flow Angiotensin and the Heart, 10.1007/978-3-642-72497-8_3, (25-42), . Heusch G (1990) Alpha-adrenergic mechanisms in myocardial ischemia., Circulation, 81:1, (1-13), Online publication date: 1-Jan-1990. Klein L, Segal B and Helfant R (1987) Dynamic coronary stenosis behavior in classic angina pectoris: active process or passive response?, Journal of the American College of Cardiology, 10.1016/S0735-1097(87)80012-8, 10:2, (311-313), Online publication date: 1-Aug-1987. Feigl E (1987) The paradox of adrenergic coronary vasoconstriction., Circulation, 76:4, (737-745), Online publication date: 1-Oct-1987. Maturi M, Greene R, Donqhue B, Dorsey L, Green M, Bacharach S, Vitale D and Patterson R (1986) Functional consequences and intracoronary localization of alpha-adrenergic stimulation of the canine coronary circulation, Journal of the American College of Cardiology, 10.1016/S0735-1097(86)80431-4, 8:4, (885-893), Online publication date: 1-Oct-1986. Neri Serneri G, Gensini G, Abbate R, Prisco D, Rogasi P, Castellani S, Casolo G, Fazi A, Fantini F, Donato M and Dabizzi R (1986) Impaired cardiac PGI2 and PGE2 biosynthesis in patients with angina pectoris, American Heart Journal, 10.1016/0002-8703(86)90509-0, 112:3, (472-478), Online publication date: 1-Sep-1986. Grover G, Talafih K and Weiss H (1985) The effect of graded doses of norepinephrine on the O2 supply/ consumption balance in ischemic and nonischemic rabbit myocardium, European Journal of Pharmacology, 10.1016/0014-2999(85)90277-8, 108:1, (9-18), Online publication date: 1-Jan-1985. Kern M, Horowitz J, Ganz P, Gaspar J, Colucci W, Lorell B, Barry W and Mudge G (1985) Attenuation of coronary vascular resistance by selective alpha1,-adrenergic blockade in patients with coronary artery disease, Journal of the American College of Cardiology, 10.1016/S0735-1097(85)80421-6, 5:4, (840-846), Online publication date: 1-Apr-1985. Gewirtz H, Gross S, Williams D and Most A (1984) Contrasting effects of nifedipine and adenosine on regional myocardial flow distribution and metabolism distal to a severe coronary arterial stenosis: observations in sedated, closed-chest, domestic swine., Circulation, 69:5, (1048-1057), Online publication date: 1-May-1984. Gewirtz H, Williams D and Most A (1983) Quantitative assessment of the effects of a fixed 50% coronary artery stenosis on regional myocardial flow reserve and transmural distribution of blood flow, Journal of the American College of Cardiology, 10.1016/S0735-1097(83)80140-5, 1:5, (1273-1280), Online publication date: 1-May-1983. Gewirtz H, Williams D, Ohley W and Most A (1983) Influence of coronary vasodilation on the transmural distribution of myocardial blood flow distal to a severe fixed coronary artery stenosis, American Heart Journal, 10.1016/0002-8703(83)90086-8, 106:4, (674-680), Online publication date: 1-Oct-1983. Heusch G and Deussen A (1983) The effects of cardiac sympathetic nerve stimulation on perfusion of stenotic coronary arteries in the dog., Circulation Research, 53:1, (8-15), Online publication date: 1-Jul-1983.Buffington C and Feigl E (1983) Effect of coronary artery pressure on transmural distribution of adrenergic coronary vasoconstriction in the dog., Circulation Research, 53:5, (613-621), Online publication date: 1-Nov-1983.Gewirtz H, Brautigan D, Olsson R, Brown P and Most A (1983) Role of adenosine in the maintenance of coronary vasodilation distal to a severe coronary artery stenosis. Observations in conscious domestic swine., Circulation Research, 53:1, (42-51), Online publication date: 1-Jul-1983. Bassenge E and Heusch G (1990) Endothelial and neuro-humoral control of coronary blood flow in health and disease Reviews of Physiology, Biochemistry and Pharmacology, Volume 94, 10.1007/3540528806_4, (77-165), . June 1, 1982Vol 65, Issue 7 Advertisement Article InformationMetrics Copyright © 1982 by American Heart Associationhttps://doi.org/10.1161/01.CIR.65.7.1329 Originally publishedJune 1, 1982 PDF download Advertisement

Pharmacology of B-HT 920 in some isolated smooth muscles of the guinea-pig.

The effects of B-HT 920 were investigated on four isolated preparations from the guinea-pig, namely the aorta, trachea, ileum and vas deferens. The latter three preparations were studed during electrical field stimulation, which induced contractions by activating cholinergic neurones (trachea and ileum) or adrenergic neurones (vas deferens), respectively. Comparative studies were also made with clonidine and noradrenaline. In ileum and trachea B-HT 920 was almost equipotent with noradrenaline to inhibit the electrically induced contractions. In these tissues, B-HT 920 also displayed almost the same maximal effect as noradrenaline. Clonidine also inhibited the contractions in ileum and trachea; the drug was slightly more potent than noradrenaline. However, in contrast to the intrinsic activity of B-HT 920 that of clonidine was only submaximal. In vas deferens both B-HT 920 and clonidine induced inhibition of contractions on electrical field stimulation at low concentrations. In this organ, both drugs were capable of inducing complete inhibition of the contractile response. In aorta B-HT 920 as well as clonidine were only weak agonists in comparison to noradrenaline. The alpha2-blocker, yohimbine, completely blocked the effect of B-HT 920 in ileum at low concentrations (1 x 10(-7) M). Remarkably, however, the inhibitory action of B-HT 920 in trachea was only marginally affected even by high concentrations of yohimbine (1 x 10(-6) M). It is suggested from the present results that B-HT 920 can induce inhibition of both cholinergic and adrenergic neurotransmission presumably by inducing selective stimulation of prejunctional alpha2-receptors. In fact, the selectivity of B-HT 920 seems to be comparable to that of clonidine for the alpha2-receptor. However, the mode of action of B-HT 920 in trachea may be somewhat uncertain since its effect was not inhibited by yohimbine.

Neurogenic Pulmonary Oedema

Five cases of neurogenic pulmonary oedema (NPE) are described. The causes were mechanical trauma to the skull, subarachnoid haemorrhage and epileptic seizure. In every case a frank pulmonary oedema was diagnosed that resolved within a few days. Treatment of the underlying disease resulted in a favourable outcome. The literature has been reviewed. The basic mechanism seems to be an increased intracranial pressure (ICP) precipitating an increased central sympathetic nerve activity mediated via peripheral alpha- or beta-adrenergic discharge. NPE results from a predominant alpha-receptor stimulation with massive increase in pre- and afterload. The major therapeutic efforts should be directed towards the underlying cause and, in addition, mechanical ventilation with passive hyperventilation is vital. High positive end-expiratory pressure should not be used without strict monitoring of ICP.

Calcium Antagonists and ??2-Adrenoceptors

A survey concerning the influence of calcium antagonists on the vasoconstriction induced by the selective stimulation of either postsynaptic alpha 1- or alpha 2-adrenoceptors in the resistance vessels of pithed rats and cats, as well as in ganglion-blocked rabbits, is presented. In every species studied, all calcium antagonists (organic: verapamil, D 600, diltiazem, nifedipine, nisoldipine, and a variety of new compounds; inorganic: Co2+, Ni2+, and Mn2+) significantly reduced the pressor response towards the stimulation of postsynaptic vascular alpha 2-adrenoceptors with B-HT 920 (and other agonists). However, the various calcium antagonists showed little influence on the vasoconstriction provoked by the excitation of vascular postsynaptic alpha 1-adrenoceptors. A correlation study revealed that there exists a close correlation between the depressant influence of the calcium-antagonistic drugs on the vasoconstriction due to alpha 2-adrenoceptor stimulation and the calcium-antagonistic potency in vitro. Accordingly, it is speculated that the vasoconstriction due to alpha 2-receptor stimulation requires the influx of calcium ions from the extracellular space across the membrane. This process is obviously sensitive to the influence of calcium-antagonistic drugs.

Specificity of muscarinic acetylcholine receptor regulation by receptor activity.

Regulation of muscarinic acetylcholine receptor concentration by receptor activity in neuron-like NG108-15 hybrid cells is a highly specific process. Receptor levels, monitored by binding of [3H]quinuclidinyl benzilate ([3H]QNB), decreased 50--75% following 24-h incubation of cells with muscarinic agonists, but none of the following cellular processes was altered by this chronic receptor stimulation: (1) glycolytic energy metabolism, measured by [3H]deoxy-D-glucose ([3H]DG) uptake and retention; (2) rate of cell division; (3) transport, measured by [3H]valine and [3H]uridine uptake; (4) RNA biosynthesis, measured by [3H]uridine incorporation; (5) protein biosynthesis, measured by [3H]valine and [35S]methionine incorporation into total protein and into protein fractions obtained by polyacrylamide gel electrophoresis. In contrast, chronic stimulation did cause a threefold decrease in the capacity of carbachol to stimulate phosphatidylinositol (PI) turnover, a receptor-mediated response. In addition to cholinomimetics, the neuroeffector adenosine (1 mM for 24 h) also caused a decrease in [3H]QNB binding levels, but chronic stimulation of alpha-adrenergic, opiate, prostaglandin E1, and prostaglandin F2 alpha receptors found on NG108-15 cells caused no changes. The data indicate that loss of muscarinic receptors caused by receptor stimulation is not a consequence of fundamental changes evoked in overall cellular physiology but reflects a specific regulation of cholinoceptive cell responsiveness.

Dual influence of hydralazine on constrictor response to noradrenaline in isolated arterial smooth muscle.

The effects of hydralazine (Hyd) on vascular smooth muscle contractile response to alpha-receptor stimulation by exogeneous and endogenous noradrenaline (NA) in the absence and presence of Mg2+ (1.2 mM) were examined using a proximal segment of rabbit's ear artery. Intraluminal perfusion with Hyd (2 x 10(-4) M) in normal Krebs bicarbonate mediuim inhibited the NA-induced contraction only in the presence of Mg2+ (1.2 mM) in the medium. The extraluminal superfusion of the artery with Hyd (2 x 10(-4) M) enhanced the vasoconstriction to extraluminally superfused NA in either the presence or absence of Mg2+ in the medium. However, when the artery was preincubated with an adrenergic neuron blocker, guanethidine (3.2 x 10(-6) M), Hyd (2 x 10(-4) M) inhibited NA-induced vasoconstriction. Contrary to the effects of Hyd on intraluminal NA, Hyd potentiated the response of this superfused artery to electrical stimulation in the presence of Mg2+ (1.2 mM) whereas in the Mg2+-free medium, it inhibited the constriction. These findings suggest that Hyd may have dual effects on isolated vascular smooth muscle by directly inhibiting the contractile activation and indirectly by an interference at adrenergic nerves, which potentiates the effects of exogenous NA and(or) alters the release of endogenous NA.

Cardiocirculatory dynamics in the normal and failing heart.

Congestive heart failure is associated with ventricular hypertrophy and dilatation, increased circulating catecholamines, and peripheral vasoconstriction. The extent to which these changes occur, whether they are a favorable "compensatory mechanism" or contribute to cardiocirculatory dysfunction, depends on the cause and severity of the heart failure. The addition of new sarcomeres through ventricular hypertrophy distributes the excess workload of the failing ventricle over more contractile units. In ventricular pressure overload, hypertrophy primarily increases wall thickness and ventricular volume is not usually increased; the converse is true with ventricular volume overload. Hypertrophy can result in enhanced or depressed contractile performance, depending on the stimulus for hypertrophy and method by which contractility is evaluated. The "ventricular function curve," which relates stroke volume to ventricular filling pressure or volume, overestimates the role played by the "Starling principle" as a compensatory mechanism and underestimates how well contractile performance is preserved. The evaluation of end systolic pressure-volume relationships under conditions of variable afterload closely reflects the isometric length-tension relationship and is therefore a more accurate way to quantitate cardiac muscle performance. Pressure overload hypertrophy usually leads to a depression in contractility whereas volume overload may not. An exaggerated sympathoadrenal response is another hallmark of severe heart failure that enhances contractility, helps initiate hypertrophy, and maintains arterial perfusion pressure. A generalized increase in peripheral vascular resistance occurs and is most prominent in those circulations most susceptible to neurohumoral control (renal, splanchnic, cutaneous). This favors perfusion of the cerebral and coronary circulations. Vasoconstriction is further enhanced by the activation of the renin-angiotensin-aldosterone system and secretion of ADH. This results in sodium retention and plasma volume expansion. In early mild heart failure, vasomotor tone may be normal at rest; however, the sympathoadrenal response to exercise may be intense. Moderate alpha receptor stimulation reduces skeletal muscle blood supply and favors the intramuscular redistribution of blood flow from inactive to active muscle fibers, thereby maintaining a normal oxygen consumption. During the later stages of heart failure, increased vascular stiffness due to increased sodium content and excessive norepinephrine appears to restrict nutritional blood flow to exercising muscle at the conductance-vessel level. Vasodilator drugs may reduce aortic impedance and improve cardiac output, may lower ventricular filling pressure, and relieve congestive symptoms, and may result in complex but favorable changes in the distribution of blood flow to the regional circulations.

Tyramine-induced contractions in the rabbit ear and basilar arteries.

This study examined in vitro tyramine (TY)-induced contractions of the isolated ring segments of the rabbit basilar and ear arteries in relation to their sympathetic innervations. The TY dose--response relationship in the basilar artery was not affected by cocaine, chronic sympathectomy, or reserpine pretreatment. However, these treatments shifted the TY dose--response relationship in the ear arteries significantly to the right. These results indicate that the TY-induced contraction in the basilar artery is due solely to its direct stimulation of the postsynaptic alpha-receptors, but in the ear artery it is due both to its indirect [release of norepinephrine (NE)] and direct actions. The failure of TY to induce contraction in the basilar artery by the indirect mechanism is probably in part due to a wide synaptic cleft distance and the reported insensitivity of alpha-receptors of this artery. These results suggest that the endogenous NE releasable from the sympathetic nerve in the basilar artery is insufficient to bring about vasoconstriction. This is turn favors our previous hypothesis that transmural-nerve-stimulation (TNS)-induced constriction of this artery is to a transmitter other than NE. It further suggests that the functional significance of the sympathetic innervations to different regions of the vessels is highly variable even when they are of the same ganglionic origin.

Separation of drinking and pressor responses to central angiotensin by monoamines.

This study investigated the neurotransmitters involved in the increase in blood pressure and drinking produced when angiotension II is injected intraventricularly (ivt). Using pharmacologic manipulations of the monoamines norepinephrine, dopamine, and serotonin it has been possible to separate the pressor response from dipsogenic responses to angiotension II. Alpha-adrenergic blockade with phentolamine restricted to the brain blocked the pressor response to angiotensin II in a dose-related manner, while drinking remained unaffected. Norepinephrine alone, injected into the ventricles elevated blood pressure, but did not produce drinking. The norepinephrine effect was also blocked by phentolamine by the same ventricular route. Other monoamines were not involved. Dopamine alone did not produce thirst. Cardiovascular effects with dopamine were observed only with large doses. The dopaminergic agonist apomorphine produced no change in blood pressure or drinking. Reduction of central serotonin stores by p-chlorophenylalanine intraperitoneally or 5,7-dihydroxytryptamine intraventricularly had no effect on the pressor or dipsogenic effects of angiotensin II. The serotonin agonist N,N-dimethyl-5-methoxytryptamine ivt did not produce a rise in blood pressure or drinking. It is concluded that the pressor effect of angiotensin II, but not the drinking effect is mediated by noradrenergic stimulation of alpha-receptors. The drinking response does not appear to be mediated by the monoamines.

Regulation by secretin, vasoactive intestinal peptide, and somatostatin of cyclic AMP accumulation in cultured brain cells.

Secretin stimulates the accumulation of cyclic AMP (half maximally stimulating concentration: 10-20 nM) in cultured mouse brain cells mainly consisting of glioblasts. Vasoactive intestinal peptide (VIP) is much less potent in raising the level of cyclic AMP in these cultures. The effect of secretin but not that of VIP is inhibited by secretin-(5-27), a synthetic antagonist of secretin. Stimulation of the adrenergic alpha-receptors and the adenosine A1-receptors present on the cells attenuates the increase in cyclic AMP evoked by secretin and VIP. Somatostatin at low concentrations inhibits the accumulation of cyclic AMP (half-maximally inhibitory concentration: 3 nM), in the absence or presence of secretin, VIP, or isoproterenol. The results suggest that secretin might regulate the concentration of cyclic AMP in brain and provoke the question of a possible involvement of glial cells in the action of peptide hormones in the brain.

Stress hyperglycemia and the adrenergic regulation of pancreatic hormones in hypoxia

Stress hyperglycemia occurs in normal and chronically hypoxemic dogs when PaO 2's are acutely lowered below 30 torr. Several factors are thought to contribute to the rise in blood glucose. The initial fall in PaO 2 activates the sympathetic nervous system, stimulating alpha and beta adrenergic receptors. Because of reduced beta receptor function, alpha receptor effects predominate, promoting glucagon and inhibiting insulin release. The changes in pancreatic hormones in conjunction with the direct effects of hypoxemia and alpha receptor stimulation increase hepatic glycogenolysis. Meanwhile, glucose clearance is decreased because of elevated circulating levels of catecholamines and low insulin concentrations. This combination of events plays a major role in the development of hyperglycemia. Since high blood glucose levels seems to protect the brain and other vital organs at low oxygen tensions, the development of hyperglycemia may represent an important protective mechanism in severely hypoxemic animals, including humans.

Adrenergic modulation of human pancreatic polypeptide (hPP) release

Serum human pancreatic polypeptide (hPP) responses to adrenergic modulation were measured in 24 normal subjects. Epinephrine (6 μg/min) was infused to stimulate adrenergic alpha- and beta-receptors. Beta-receptor stimulation was achieved by infusing epinephrine and selectively blocking alphareceptors with phentolamine, and alpha-receptor stimulation was achieved by infusing epinephrine and blocking beta-receptors with propranolol. Combined alpha- and beta-receptor stimulation caused a small but insignificant rise in hPP concentration. Phentolamine alone caused a twofold rise in hPP concentration, which was abolished by simultaneous atropine infusion. Propranolol alone had no effect. Adrenergic beta-receptor stimulation with epinephrine plus phentolamine caused a sevenfold rise from 45 ± 10 to 351 ± 60 pM (P < 0.05), whereas adrenergic alpha-receptor stimulation caused a significant fall from 100 ± 25 pM (the rise in hPP concentration induced by epinephrine) to 44 ± 7.8 pM. The changes in hPP concentration did not correlate with changes in serum insulin, glucose, or free fatty acid (FFA) concentrations. The pattern of the response was quite different from insulin, which reached a peak within 1 min of phentolamine administration, whereas hPP levels rose slowly to a peak at 45 min. The rise induced by adrenergic beta-receptor stimulation with epinephrine plus phentolamine was equivalent to the rise from 40 ± 11 to 280 ± 48 pM caused by an insulin-induced fall in serum glucose of about 50% and that induced by isoproterenol infusion, which caused a fourfold rise from 69 ± 3 to 271 ± 84 pM. These data suggest that the adrenergic system may be important in the regulation of hPP release.

Alpha-adrenergic vasoconstriction in arterial and arteriolar sections of the canine coronary circulation.

Using a method which allowed the in-situ measurement of segmental coronary vascular resistances, the reaction of arterial and arteriolar sections of the coronary vascular system to alpha-receptor stimulation was studied i anaesthetized dogs. The left coronary artery was cannulated, and the perfusion pressure was kept constant. Allowance was made for extravascular and metabolic influences of alpha-stimulation on coronary vascular resistances. On an average, submaximal alpha-stimulation with xylometazoline increased the arterial resistance by about 60% and the arteriolar resistance by about 90%. The cannulation of the left coronary artery increased the sympathetic reactivity of the arterioles. Moreover, xylometazoline increased the extravascular component of the coronary vascular resistance by about 4%. Thus it can be assumed that under normal in-vivo conditions alpha-receptor vasoconstriction might be less different in coronary arteries and arterioles. Since the arterial resistance ranges from 20% to 50% of total coronary resistance, a sympathetic vasoconstriction of this vascular section might lead even to a critical limitation of coronary blood flow. On the other hand, a predominant constriction in arterioles leads to an increase in peripheral coronary pressure, i.e. to a "reverse coronary steal phenomenon".

Structure-activity relationships of clonidine- and tolazoline-like compounds at histamine and alpha-adrenoceptor sites.

1 Thirty clonidine- and tolazoline-like compounds with differing phenyl ring substituents were tested for agonistic actions at histamine H1-receptors (guinea-pig ileum), histamine H2-receptors (guinea-pig driven right ventricular strips), post-junctional alpha-adrenoceptors (rat desheathed was deferens) and pre-junctional alpha-adrenoceptors (inhibition of sympathetic stimulation in guinea-pig driven left atria). 2 All compounds were inactive at histamine H1-receptors, while 21 of the 30 compounds displayed varying stimulant activity at H2-receptors. 3 At post-junctional alpha-receptors all 30 compounds produced stimulant actions, whereas at prejunctional alpha-receptors the compounds displayed either agonistic or antagonistic actions. 4 Thus structure-activity-relationships (SAR) could only be validated for histamine H2- and post-junctional alpha-receptor effects. These studies show that the most potent compounds are those with 2,6-phenyl substituents in which rotation is restricted so that the two rings are aplanar. Electronic effects of the substituents have a greater influence on activity at H2- than at alpha-receptors. 5 The major difference in SAR involves the influence of substituents in the 3, 4 or 5 positions on the phenyl ring. The presence of these substituents abolish significant activity at H2-receptors, while alpha-receptor stimulant activity is retained.

Alpha-Adrenergic receptors modulate beta-receptor affinity in rat kidney membranes.

Adrenergic receptors were first classified into two calsses--alpha and beta--on the basis of the relative pharmacological potencies of agonist compounds, and this classification has been supported by subsequent studies. In some tissues, such as the heart and liver, they exert similar physiological responses, and in other tissues, such as the uterus and vasculature, they have opposing roles. The occurrence of both classes of receptor in the same tissue lewwds to the problem of what determines whether the overall response observed is alpha-type or beta-type, as adrenaline and noradrenaline bind to both receptor classes. Furthermore, direct binding studies have demonstrated that the two receptor classes are distinct and separate entities. We show here that stimulation of alpha-receptors in renal membranes causes a specific decrease in the affinity of the agonist compound isoprenaline for beta-receptors in the same membranes. This demonstrates that interactions occur between renal alpha- and beta-adrenergic receptors. Such interactions may modulate the response of the kidney to sympathetic stimulation.

Multiple Extremity Amputations in Hypotensive Patients Treated With Dopamine

Dopamine hydrochloride has been established as effective in the treatment of hypotension and shock in patients with adquate blood volume. The physiological response is dose related. Administration of more than 10 microgram/kg/min results in alpha-receptor stimulation and vasoconstriction, and peripheral extremity ischemia has been reported. Four patients treated with dopamine subsequently had the development of peripheral ischemia and gangrene, resulting in the need for multiple extremity amputations. These reactions represent a major complication of treatment.

The Role of Alpha Receptors in the Facilitation of the Chemoreflex and Inhibition of the Carotid Occlusion Reflex by Clonidine

The influence of alpha receptor blockers on the facilitation of the chemoreflex by clonidine was examined in anesthetized dogs. Intravertebral arterial administration of clonidine reduced blood pressure, facilitated chemoreflex-induced vasoconstriction and inhibited carotid occlusion-induced vasoconstriction. Intravertebral arterial administration of phentolamine (0.01-0.03 mg/kg), yohimbine (0.01-0.02 mg/kg), or piperoxan (0.05 mg/kg) prevented the inhibition of carotid occlusion-induced responses by clonidine, and the latter two alpha blockers reduced the hypotensive effect. Facilitation of the chemoreflex by clonidine was decreased by yohimbine and piperoxan, but not affected by phentolamine. Intravertebral infusion of propranolol (0.1 mg/kg) had no influence on clonidine's effect on reflex responses, but appeared to accentuate its hypotensive effect. The results support a role for alpha receptor stimulation in clonidine-induced hypotension and inhibition of the carotid occlusion reflex and suggest participation of alpha receptors in the potentiation by clonidine of chemoreflex-induced vasoconstriction.

Relative importance of α and β adrenergic receptors during resuscitation

Successful resuscitation from cardiac arrest in the asphyxiated dog model has been ascribed to the use of artificial ventilation, closed chest cardiac massage, and administration of a vasopressor. Controversy remains over whether the most commonly employed vasopressor, epinephrine, exerts its effects primarily by elevating diastolic pressure and reestablishing coronary flow, or by exciting cardiac pacemaker cells and enhancing myocardial contractility. To observe pure alpha and beta adrenergic receptor influences during resuscitation, three groups (alpha-blocked, beta-blocked, unblocked) of dogs were studied. beta-blocked dogs resuscitated with phenylephrine and unblocked dogs resuscitated with epinephrine experienced 100% successful resumption of spontaneous circulation after 5 min of asphyxia-induced arrest. Only 27% of alpha-blocked animals resuscitated with isoproterenol were successfully revived. The appearance of the ECG during cardiac arrest and resuscitation could in no way be used to predict the outcome of resuscitation attempts. Results suggest that, initially, alpha receptor stimulation with concomitant diastolic pressure elevation is more important to the success of resuscitation than beta receptor stimulation.

HYPERPOLARIZING ‘α2’‐ADRENOCEPTORS IN RAT SYMPATHETIC GANGLIA

1 Receptors mediating catecholamine-induced hyperpolarization of isolated superior cervical sympathetic ganglia of the rat have been characterized by means of an extracellular recording method.2 (-)-Noradrenaline (EC(50), 1.7 +/- 0.6 muM) produced an immediate low-amplitude (< 400 muV) hyperpolarization. The hyperpolarization was increased on removal of external Ca(2+) or on reduction of external K(+) from 6 to 2 mM. Hyperpolarization was unaffected by changing the temperature from 25 degrees to 37 degrees C.3 Hyperpolarization was also produced by the following agonists (potencies relative to (-)-noradrenaline): (-)-noradrenaline 1; (+/-)-isoprenaline 0.41; (-)-phenylephrine 0.40; (+)-noradrenaline 0.13; 2-amino-6,7-dihydroxy tetrahydronaphthalene (ADTN) 0.25; dopamine 0.1; methoxamine 0.012; amidephrine 0.0015.4 Responses were antagonized by phentolamine (1 muM) but not by (+/-)-propranolol (1 muM), haloperidol (10 muM) or alpha-flupenthixol (1 muM). This suggested that hyperpolarization was mediated solely through alpha-receptor stimulation not through stimulation of beta-receptors or dopamine-receptors.5 Dose-ratio shifts produced by phentolamine varied with different agonists. The shift increased in inverse proportion to the ability of the agonists to inhibit [(3)H]-(-)-noradrenaline uptake, suggesting that uptake of agonists limited the dose-ratio shift. Cocaine and nortriptyline reduced catecholamine-induced hyperpolarization in concentrations (10 muM and 1 muM respectively) necessary to inhibit [(3)H]-(-)-noradrenaline uptake.6 Clonidine (0.01 to 1 muM), oxymetazoline (0.01 to 1 muM) and ergometrine (0.1 to 10 muM) produced a persistent, low-amplitude hyperpolarization, as though they were partial agonists. Responses to the agonists were blocked by yohimbine (1 muM) but not be prazosin (1 muM).7 It is concluded that the adrenergic cell bodies in the ganglion were hyperpolarized through activation of the same type of alpha-receptor (;alpha(2)-receptors') as those present at adrenergic nerve terminals.

ADRENERGIC INPUTS TO THE AMYGDALA AND THE CONTROL OF GONADOTROPHIN RELEASE

Drugs able to mimic or to antagonize the action of catecholamines have been implanted bilaterally into the basomedial region of the amygdala of adult castrated female rats. The animals were killed at different intervals after the implantation of the different drugs, and serum levels of LH and FSH were measured by radioimmunoassay. The results have shown that the intra-amygdalar implantation of the alpha-adrenergic blocker phenoxybenzamine induces a significant increase of the release both of LH and FSH. The implantation of the beta-adrenergic blocker propranolol brings about a rise of LH only. The dopamine receptor blocker pimozide stimulates the release of LH and exerts a biphasic effect (stimulation followed by inhibition) of FSH secretion. The alpha-receptor stimulant clonidine and the dopaminergic drug 2-Br-alpha-ergocryptine were without significant effects. From these observations it is suggested that the adrenergic signals reaching the basomedial area of the amygdala (possibly from the brain stem) may be involved in the modulation of gonadotrophin secretion.