Adrenergic Neurone Blocking Research Articles

Release of calcitonin gene-related peptide (CGRP) from capsaicin-sensitive vasodilator nerves in the rat mesenteric artery

The effect of perivascular nerve stimulation (PNS) and capsaicin treatment on the release of calcitonin gene-related peptide (CGRP) was examined by radioimmunoassay (RIA) in isolated, perfused rat mesenteric arteries. In the preparation precontracted by methoxamine and treated with guanethidine, an adrenergic neuron blocker, PNS and capsaicin induced vasodilator responses and increase of CGRP-like immunoreactivity (CGRP-LI) in the perfusate in a frequency-dependent manner. The CGRP-LI released by capsaicin was identified as CGRP and its oxidized form by high-performance liquid chromatography coupled with RIA. After the tissue was treated with capsaicin, PNS didn't cause both the vasodilator response and the increase of CGRP-LI in the perfusate. These findings suggest that CGRP plays a neurotransmitter role in capsaicin-sensitive vasodilator nerves in rat mesenteric arteries.

Nerve-induced nonadrenergic vasoconstriction and vasodilatation in skeletal muscle

Intravital microscopy was used to study the effect of motor nerve stimulation on microvessel diameters in the rabbit tenuissimus muscle. Stimulation of the motor nerve (0.5-5 ms, 2-20 Hz, 5-15 V) evoked pulse duration- and frequency-dependent constriction of transverse and terminal arterioles. The vasoconstriction induced by low-frequency stimulation (2 Hz) was abolished by the alpha-adrenoceptor antagonist phentolamine, whereas high-frequency stimulation (10-20 Hz) resulted in a response that was only partially inhibited by phentolamine. However, desensitization of the tissue to the vasoconstrictor effects of neuropeptide Y (NPY) changed the response remaining after phentolamine into vasodilatation. Independent of stimulation parameters, pretreatment of the tissue with the adrenergic neuron blocker guanethidine reversed the constriction into dilatation that was resistant to propranolol, atropine, and indomethacin. The results document the functional presence of both vasoconstrictor and vasodilator fibers in the rabbit tenuissimus muscle motor nerve, and they suggest that part of the nerve-induced vasoconstriction at higher stimulation frequencies is caused by neuronally released NPY.

Slow hyperpolarizing action of tryptamine on myenteric neurons of the isolated guinea-pig ileum.

In the present study, tryptamine produced a slow hyperpolarization in a few neurons other than a slow depolarization in myenteric neurons of the isolated guinea-pig ileum. Neither the adrenergic neuron blocker, guanethidine nor the 5-hydroxytryptamine uptake inhibitor, zimelidine, which can inhibit the release of 5-hydroxytryptamine from enteric neurites induced by tryptamine (M. Takaki et al. (1985) Neuroscience 16, 223-240), affected this slow hyperpolarization. Therefore, it was concluded that the slow hyperpolarization induced by tryptamine in myenteric neurons was not mediated via the release of 5-hydroxytryptamine or noradrenaline. It might be possible that the hyperpolarization was induced by a direct action of tryptamine on myenteric neurons per se.

Changes in Clinical Characteristics and Drug Treatment of Hypertension Over 40 Years at the Dunedin Hypertension Clinic

The clinical characteristics of the 4,170 hypertensive patients referred to the Dunedin Clinic from 1950 to 1989 have been compared for eight successive 5-year periods. A gradual decrease in the severity of referred hypertension and an increase in the proportion of patients already on treatment at the time of referral (currently 50%) were noted. For male patients, mean ± SD initial lying blood pressure was 179 ± 27/116 ± 19 mm Hg in 1950–1954 and 158 ± 25/91 ± 14 mm Hg in 1985–1989. Corresponding prevalence data for target organ damage among male patients were retinal grade 3 or 4, 49% and 3%; cardiomegaly on chest radiograph, 60% and 26%; electrocardiogram left ventricle strain pattern, 28% and 3%; and serum urea levels > 10 mmol/L, 16% and 5%, respectively. For women there was a similar trend. The number of patients on drugs in each of nine categories and the percent use of each drug category for each year during 1950–1989 was recovered from computerized data files. The percentage peak usage of ganglion blockers was in 1950–1958, adrenergic neuron blockers in 1963–1970, centrally acting drugs in 1965–1968, diuretics in 1960–1982, β-blockers in 1974–1987, α-blockers in 1980–1987, and angiotensin converting enzyme inhibitors and calcium antagonists in 1989. The diuretics have been the most enduring drugs, followed by the β-blockers.

Changes in Clinical Characteristics and Drug Treatment of Hypertension Over 40 Years at the Dunedin Hypertension Clinic

The clinical characteristics of the 4,170 hypertensive patients referred to the Dunedin Clinic from 1950 to 1989 have been compared for eight successive 5-year periods. A gradual decrease in the severity of referred hypertension and an increase in the proportion of patients already on treatment at the time of referral (currently 50%) were noted. For male patients, mean +/- SD initial lying blood pressure was 179 +/- 27/116 +/- 19 mm Hg in 1950-1954 and 158 +/- 25/91 +/- 14 mm Hg in 1985-1989. Corresponding prevalence data for target organ damage among male patients were retinal grade 3 or 4, 49% and 3%; cardiomegaly on chest radiograph, 60% and 26%; electrocardiogram left ventricle strain pattern, 28% and 3%; and serum urea levels greater than 10 mmol/L, 16% and 5%, respectively. For women there was a similar trend. The number of patients on drugs in each of nine categories and the percent use of each drug category for each year during 1950-1989 was recovered from computerized data files. The percentage peak usage of ganglion blockers was in 1950-1958, adrenergic neuron blockers in 1963-1970, centrally acting drugs in 1965-1968, diuretics in 1960-1982, beta-blockers in 1974-1987, alpha-blockers in 1980-1987, and angiotensin converting enzyme inhibitors and calcium antagonists in 1989. The diuretics have been the most enduring drugs, followed by the beta-blockers.

Adrenergic modulation of calcitonin gene-related peptide (CGRP)-containing nerve-mediated vasodilation in the rat mesenteric resistance vessel

Pharmacological studies showed that periarterial nerve stimulation (PNS) of the perfused rat mesenteric vascular bed contracted with endothelin, a vasoconstrictor peptide, in the presence of prazosin (α 1-adrenoceptor antagonist) produced a frequency-dependent neurogenic vasodilation when the adrenergic neurotransmission was blocked by the adrenergic neuron blocker, guanethidine. The PNS-evoked vasodilation was attenuated by tetrodotoxin and capsaicin treatment, and was also inhibited when the adrenergic neurotransmitter (norepinephrine; NE) release was left intact in the absence of guanethidine. However, in the combined presence of anα 2-adrenoceptor anagonist (yohimbine) and prazosin, PNS caused a marked neurogenic vasodilation even when the neuronal release of NE was left intact. These results suggest that NE released from adrenergic nerves regulates the release of a vasodilator substance, CGRP, through activation ofα 2-adrenoceptors on CGRP-containing vasodilator nerves.

First-Choice Antihypertensive Drug Use in the Glasgow Blood Pressure Clinic

The evolution of antihypertensive drug use in the Glasgow Blood Pressure Clinic between 1969 and 1986 was determined, from computerized data, by extracting percentages of new patients prescribed different drugs at their first clinic visit. Prescribing of adrenergic neuron blockers and centrally acting drugs (methyldopa and clonidine) was common in the early years but declined rapidly until, after 1975 and 1980, respectively, it remained at 10% or less. Diuretics, mainly thiazides, were prescribed for 20% of patients in 1969 to a peak of 55% in 1980. β-Blockers were first used during the early 1970s and their use peaked in 1980, when they were prescribed for over 60% of new patients. They remained a first-choice treatment in more than 40% of patients. Calcium channel blockers were first used in 1980 and by 1986 were prescribed for 15% of new patients. Angiotensin-converting enzyme inhibitors were used from 1982 and in 1986 were prescribed for 7% of new patients. These two classes of drugs are more expensive than older drugs. However, because of their low usage, this did not greatly influence treatment costs up to 1986, as β-blockers and thiazides remained widely used.

First-Choice Antihypertensive Drug Use in the Glasgow Blood Pressure Clinic

The evolution of antihypertensive drug use in the Glasgow Blood Pressure Clinic between 1969 and 1986 was determined, from computerized data, by extracting percentages of new patients prescribed different drugs at their first clinic visit. Prescribing of adrenergic neuron blockers and centrally acting drugs (methyldopa and clonidine) was common in the early years but declined rapidly until, after 1975 and 1980, respectively, it remained at 10% or less. Diuretics, mainly thiazides, were prescribed for 20% of patients in 1969 to a peak of 55% in 1980. beta-Blockers were first used during the early 1970s and their use peaked in 1980, when they were prescribed for over 60% of new patients. They remained a first-choice treatment in more than 40% of patients. Calcium channel blockers were first used in 1980 and by 1986 were prescribed for 15% of new patients. Angiotensin-converting enzyme inhibitors were used from 1982 and in 1986 were prescribed for 7% of new patients. These two classes of drugs are more expensive than older drugs. However, because of their low usage, this did not greatly influence treatment costs up to 1986, as beta-blockers and thiazides remained widely used.

Neurogenic vasodilation and release of calcitonin gene-related peptide (CGRP) from perivascular nerves in the rat mesenteric artery

The effect of perivascular nerve stimulation (PNS) on the release of calcitonin gene-related peptide (CGRP) was examined by radioimmunoassay (RIA) in isolated, perfused rat mesenteric arteries. The released CGRP-like immunoreactivity (CGRP-LI) was identified to be CGRP itself and its oxidized form by combined analysis with RIA and high performance liquid chromatography. CGRP-LI was localized in the perivascular nerves of the large mesenteric artery and its branches. In the preparation precontracted by methoxamine, and perfused with a solution containing guanethidine, an adrenergic neuron blocker, PNS induced vasodilator responses and an increase of CGRP-LI in the perfusate in a frequency-dependent manner. Both the responses were attenuated by tetrodotoxin (10 −6 M), suggesting that they were neurogenic in origin. Removal of Ca 2+ from the perfusing solution also abolished the PNS-induced release of CGRP-LI. These findings suggest that CGRP plays a transmitter role in the neurogenic vasodilation in the rat mesenteric vascular bed.

CHARACTERIZATION AND LOCALIZATION OF (—‐)[125I]‐CYANOPINDOLOL BINDING TO NON‐β‐ADRENOCEPTOR SITES IN DOG KIDNEY

1. (-)[125I]-Cyanopindolol (CYP) binding to non-beta-adrenoceptor sites in dog kidney was characterized in homogenate preparations and their distribution in sections determined using autoradiography. 2. In homogenate studies, (-)[125I]-CYP bound to a single population of non-interacting sites (Bmax = 5.45, s.e.m. = 1.00 fmol/mg wet weight; nH = 0.99, s.e.m. = 0.01) with high affinity (KD = 3.84, s.e.m. = 0.76 nmol/l, n = 40. 3. In competition studies, compounds selective for alpha- and beta-adrenoceptors, muscarinic cholinoceptors and receptors for 5-HT, histamine and benzodiazepines, calcium channel antagonists, catecholamine uptake inhibitors, MAO inhibitors and adrenergic neurone blockers were ineffective at concentrations of 10 mumol/l. 4. Compounds selective for dopamine D1-receptors (fluphenazine, SCH 23390 and SK & F 82526) and D2-receptors (pimozide, domperidone, spiperone, haloperidol, sulpiride, cis- and trans-flupenthixol) competed with similar affinities (5-25 mumol/l) for (-)[125I]-CYP binding. 5. In autoradiographic studies, (-)[125I]-CYP binding to non-beta-adrenoceptor sites was localized over glomeruli, juxtaglomerular apparatus, distal tubules, blood vessels and medullary rays and tubules. 6. It is concluded that in dog kidney, (-)[125I]-CYP binds to a site closely associated with dopamine receptors.

Evidence for the coexistence and co-release of [met]enkephalin and noradrenaline from sympathetic nerves of the bovine vas deferens

The localization and neurosecretion of methionine-enkephalin was studied in sympathetic nerves of the bovine vas deferens. Immunostaining showed methionine-enkephalin-like immunoreactivity in a network of varicose nerve fibres in the smooth muscle layers of the vas deferens. When vas deferens homogenates were subjected to differential and sucrose density gradient centrifugation, methionineenkephalin was found to parallel the distribution of noradrenaline in the more dense region of the gradient, where “heavy” or large dense-cored vesicles are present. Electron microscopic immunochemistry confirmed this finding and showed methionine-enkephalin-like immunoreactivity in large dense-cored vesicles. The release of methionine-enkephalin upon electrical stimulation was studied in superfusion experiments. The methionine-enkephalin secretion was shown to be Ca 2+-dependent and was inhibited by adding the adrenergic neuron blocking drug guanethidine to the superfusion medium. We conclude that in the bovine vas deferens methionine-enkephalin is only present in large dense-cored vesicles of adrenergic neurons and that the peptide is released from these vesicles together with noradrenaline by a Ca 2+-dependent mechanism.

Blood pressure control during exercise in the Atlantic cod, Gadus morhua.

Atlantic cod were subjected to 12-15 min swimming exercise at 2/3 body lengths s-1 in a Blazka-type swim tunnel. Pre- and postbranchial blood pressures, cardiac output (ventral aortic blood flow) and heart rate were continuously recorded, and blood samples for measurement of arterial and mixed venous oxygen tension were taken before and at the end of the exercise period. In a second group of fish, subjected to similar exercise regimes, blood samples were taken for analysis of the plasma concentrations of catecholamines. Pre- and postbranchial blood pressures and cardiac output increase during exercise, while the mixed venous oxygen tension decreases. The effect on cardiac output is due to an increase of both heart rate and stroke volume. There are no significant changes in either systemic or branchial vascular resistances, or in the plasma concentrations of catecholamines. Injection of the adrenergic neurone-blocking drug bretylium produces a decrease in postbranchial blood pressure in resting cod, due to a decrease in the systemic vascular resistance. Exercising cod treated with bretylium have a significantly lower pre- and postbranchial blood pressure than exercising control cod. This is due mainly to a dramatic reduction in the systemic vascular resistance. The alpha-adrenoceptor antagonist phentolamine does not further affect the blood pressure in cod treated with bretylium. It is concluded that the exercise hypertension observed in cod depends on the effect of adrenergic vasomotor fibres maintaining the systemic vascular resistance, and also on the increase in cardiac output. An adrenergic innervation of the heart may play some role in the control of cardiac performance both at rest and during exercise, but the main cardioregulatory mechanism is likely to be non-adrenergic, most probably including cardiac control via variation of the cholinergic vagal cardioinhibitory tonus.

Pre- and Postsynaptic Effects of Indoramin on Sympathetic Neuroeffector Transmission in Rabbit Aorta and Pulmonary Artery

The effects of indoramin on sympathetic neuroeffector transmission in rabbit isolated blood vessels were examined. Indoramin reduced the contractions of pulmonary artery evoked by electrical-field stimulation. The IC50 was 7.4 X 10(-8) M. In the presence of cocaine + corticosterone + propranolol, the IC50 was 5 X 10(-7) M. Amphetamine did not antagonize the steady-state inhibition caused by indoramin. Indoramin caused a slight enhancement of the field-stimulation-evoked 3H-overflow from pulmonary artery preloaded with 3H-noradrenaline. In the presence of cocaine + corticosterone + propranolol, indoramin also enhanced the stimulation-evoked 3H-overflow slightly. The effect of indoramin on stimulation-evoked 3H-overflow depended only slightly on stimulation frequencies (1-30 Hz): small enhancement at 1 Hz and nonsignificant changes at 3-30 Hz. Pretreatment with indoramin did not attenuate the inhibitory effect of clonidine on the stimulation-evoked 3H-overflow seen with bretylium. Indoramin and desmethylimipramine reduced the 3H-accumulation by aorta preloaded with 3H-noradrenaline. The IC50 was 3 X 10(-5)M (indoramin) and 10(-8)M (desmethylimipramine). Indoramin inhibited the contractions of aorta evoked by noradrenaline, phenylephrine, histamine and serotonin in a competitive manner. The corresponding pA2 values were 7.54, 7.98, 7.45, and 6.61. Indoramin decreased the maximal contractions of rabbit aorta evoked by potassium. These results suggest that indoramin is a potent competitive antagonist of postsynaptic alpha 1-adrenoceptors, while it may only have a slight inhibitory effect on presynaptic alpha 2-adrenoceptors. Indoramin is devoid of bretylium-like adrenergic neurone blocking activity, while it may act as reserpine. It is a weak inhibitor of the uptake-1 mechanism.(ABSTRACT TRUNCATED AT 250 WORDS)

The distribution of (-)-propranolol in the isolated rabbit iris.

It has been postulated that propranolol lowers the intraocular pressure by adrenergic neurone block. However, in the isolated iris of albino rabbits, there was only a small degree of cocaine-sensitive (i.e., neuronal) accumulation of 3H-(-)-propranolol, and none at all after pretreatment of the animals with reserpine. Moreover, after preloading of the iris with 3H-(-)-propranolol, veratridine failed to release any labelled material. Hence, any adrenergic neurone blocking action of propranolol is highly unlikely. Albino and pigmented irides were first exposed to 3H-(-)-propranolol and then washed out. The results and their compartmental analysis indicated an extensive binding of 3H-(-)-propranolol in or at pigment cells; the binding is characterized by a low dissociation constant. It is very likely that the initial binding and the subsequent slow dissociation from pigment cells explains the long duration of action of beta-adrenoceptor antagonists in human therapy.

α-Adrenergic regulation of the activity of thymidylate synthetase and thymidine kinase during liver regeneration after partial hepatectomy

The increases in activity of hepatic thymidylate synthetase and of thymidine kinase, which catalyze the formation of thymidylate via the de novo and salvage pathways, respectively, were significantly suppressed during liver regeneration in rats which had been given α-adrenoceptor antagonists (phenoxybenzamine and phentolamine) or adrenergic neuron blockers (guanethidine and reserpine). These suppressions were not observed with a β-adrencoceptor antagonist (propranolol), or an anticholinergic agent (atropine methyl nitrate). The rise in the activity of the thymidylate-synthesizing enzymes was closely correlated with the increase in the DNA content of the liver. It is concluded that catecholamine regulates the increase in the activity of thymidylate synthetase and thymidine kinase, which are key enzymes in DNA synthesis in regenerating liver. It is also suggested that sympathetic nerves play an important role in liver regeneration.

Guanethidine blocks the 2-deoxy- d-glucose-induced hypothalamic noradrenergic drive to hyperglycemia

To determine whether 2-deoxy- d-glucose (2-DG)-induced hyperglycemia is neurally mediated we administered guanethidine, an adrenergic neuron blocker, to 2-DG-treated rats. While 2-DG increased both medial basal hypothalamic noradrenergic neuronal acitivity (MBH NNA) and serum glucose, the rise in serum glucose was blocked by guanethidine while MBH NNA was even further increased. We conclude that 2-DG-induced hypothalamic noradrenergic drive to hyperglycemia is mediated by direct sympathetic nervous system activation of liver glucose output.

Hypertension in pregnancy. Pathophysiology and management.

Hypertension in pregnancy has implications for both maternal and fetal welfare. Extrapolation from concepts of mechanisms operating in hypertension in general to pregnancy-related hypertension is not justified. In the latter, the major features are a hyper-adrenergic state, plasma volume reduction and an increased systemic resistance. A reduction in uteroplacental perfusion may result from or may activate the mechanisms that elevate blood pressure. Humoral factors (e.g. hormonal attenuation of vascular reactivity) and prostacyclin deficiency may be central to the disordered physiology. Treatment of hypertension in pregnancy should aim at avoiding the vascular damage due to blood pressure elevation but not cause a reduction in uteroplacental perfusion. Unlike earlier antihypertensive regimens using centrally acting sympatholytics, adrenergic neuron blockers or diuretics, regimens using beta-blockers or combinations of beta-blockers with alpha-blockers or vasodilating agents such as hydralazine permit effective blood pressure control, even in severe hypertension, and pregnancy can often proceed until term or until fetal maturity is secured. Adverse effects on the fetus (growth retardation, cardiorespiratory depression, hypoglycaemia, hyperbilirubinaemia) formerly attributed to beta-blockers are more likely related to poorly controlled hypertension. Specific benefits of maternal beta-adrenoceptor blockade are suggested by evidence for prevention of proteinuric deterioration and a decrease in the incidence and severity of respiratory distress in premature infants. Hypertension in pregnancy still presents a formidable therapeutic challenge and requires comprehensive management with close monitoring of fetal welfare. The presence or development of proteinuria in a hypertensive pregnant woman implies a major increase in risk to the fetus and warrants immediate admission to hospital for specialist management.

The antiarrhythmic activity of meobentine sulfate in man.

Meobentine (sulfate) has antifibrillatory and antiarrhythmic activity in canine models. The antiarrhythmic, pharmacokinetic, and adrenergic neuronal blocking effects of meobentine were assessed in 15 patients with chronic, high-frequency ventricular ectopic depolarizations (VEDs). Eleven of the 15 patients had recurrent nonsustained ventricular tachycardia. The patients were given a series of gradually increasing single doses of meobentine; six received oral meobentine and nine had infusions. The antiarrhythmic efficacy of meobentine was assessed by a comparison of arrhythmia frequency during placebo given on days just prior to meobentine. Oral therapy with meobentine at dosages above 20 mg/kg caused diarrhea, and well-tolerated dosages achieved peak concentrations of 0.69 micrograms/ml (range 0.5-1.0 micrograms/ml). Antiarrhythmic activity was seen in only one patient with oral meobentine. In contrast, intravenous infusions (6.75-34.2 mg/kg) achieved concentrations ranging from 1.3-9.8 micrograms/ml. There was a linear relationship between pseudo-steady-state plasma concentrations and dosage, r = 0.82, p less than 0.01. Antiarrhythmic activity was seen in four of nine patients who received intravenous meobentine over a range of concentrations from 2.5-4.5 micrograms/ml. Four patients developed evidence of adrenergic neuronal blockage (loss of the venous reflex response); two at dosages of 16.2 mg/kg, one at 24.3 mg/kg, and one at 34.2 mg/kg. In one individual (24.3 mg/kg), the adrenergic neuronal blockade was associated with an acute episode of shortness of breath, orthopnea, and cough. With intravenous meobentine, there was a linear relationship between dosage and AUC, and the elimination half-life ranged from 11-27 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Bretylium tosylate in patients with acute myocardial infarction

Experience with bretylium tosylate accumulated during a period of over 10 years, during which time > 1,500 patients with acute myocardial infarction were treated, is summarized. On the diagnosis of acute infarction, the agent was given by continuous intravenous drip at a rate of 10 mg/kg/24 hours for 5 to 7 days for prophylaxis of ventricular fibrillation. Bretylium administration prevented primary ventricular fibrillation in about 99% of these patients. No undesirable side effects were observed with this protocol, which lessens the initial sympathomimetic effect of the drug while allowing sufficient time for the adrenergic neuronal blocking effect to develop. The beneficial effects of the drug are believed to be due, in part, to a direct electrophysiologic effect on both normal and ischemic myocardium. This effect equalizes the duration of both the effective refractory periods and the ventricular action potentials, and it creates conditions capable of blocking reentrant pathways. Bretylium stabilizes the duration of electrical systole in patients with acute myocardial infarction. Hemodynamic studies during bretylium treatment further confirm the effectiveness of this drug and have prompted additional studies to evaluate its potential as an agent capable of decreasing impedance in acute myocardial infarction.

Effects of Intravenous Acetaldehyde, Acrolein, Formaldehyde and Propionaldehyde on Arterial Blood Pressure Following Acute Guanethidine Treatment

Guanethidine (G) is currently used in the treatment of essential hypertension. Acetaldehyde (A), acrolein (AR), formaldehyde (F) and propionaldehyde (P) are constituents of cigarette smoke and (A) is also an intermediate oxidative metabolite of ethanol. These aldehydes are known to produce sympathomimetic effects by the release of NE from adrenergic neurons and to exert cardioinhibitory effects. The type of predominant effect is dose-dependent. This study was undertaken to determine if these aldehydes result in sympathomimetic effects in the presence of G (15 mg/kg iv) in anesthetized rats. G enhanced the pressor responses to A and P in dose ranges of 5-20 and 5-10 mg/kg respectively. However, AR and F at dose ranges of 0.05-5 and 0.1-10 mg/kg, respectively, elicited only depressor responses after G. Thus, A and P exerted greater sympathomimetic effects through the release of intraneuronal NE in the presence of G. The adrenergic neuronal blocking action of G changes the blood pressure effects of AR and F. When these two compounds are administered in the absence of G, they cause predominant pressor effects, whereas in the presence of G a depressor response is noted. This depressor response is possibly by vagal stimulation and/or direct vasodilation.