Effects Of Ganglionic Blockade Research Articles

Mechanisms Responsible for Genetic Hypertension in Schlager BPH/2 Mice.

It has been 45 years since Gunther Schlager used a cross breeding program in mice to develop inbred strains with high, normal, and low blood pressure (BPH/2, BPN/3, and BPL/1 respectively). Thus, it is timely to gather together the studies that have characterized and explored the mechanisms associated with the hypertension to take stock of exactly what is known and what remains to be determined. Growing evidence supports the notion that the mechanism of hypertension in BPH/2 mice is predominantly neurogenic with some of the early studies showing aberrant brain noradrenaline levels in BPH/2 compared with BPN/3. Analysis of the adrenal gland using microarray suggested an association with the activity of the sympathetic nervous system. Indeed, in support of this, there is a larger depressor response to ganglion blockade, which reduced blood pressure in BPH/2 mice to the same level as BPN/3 mice. Greater renal tyrosine hydroxylase staining and greater renal noradrenaline levels in BPH/2 mice suggest sympathetic hyperinnervation of the kidney. Renal denervation markedly reduced the blood pressure in BPH/2 but not BPN/3 mice, confirming the importance of renal sympathetic nervous activity contributing to the hypertension. Further, there is an important contribution to the hypertension from miR-181a and renal renin in this strain. BPH/2 mice also display greater neuronal activity of amygdalo-hypothalamic cardiovascular regulatory regions. Lesions of the medial nucleus of the amygdala reduced the hypertension in BPH/2 mice and abolished the strain difference in the effect of ganglion blockade, suggesting a sympathetic mechanism. Further studies suggest that aberrant GABAergic inhibition may play a role since BPH/2 mice have low GABAA receptor δ, α4 and β2 subunit mRNA expression in the hypothalamus, which are predominantly involved in promoting tonic neuronal inhibition. Allopregnanolone, an allosteric modulator of GABAA receptors, which increase the expression of these subunits in the amygdala and hypothalamus, is shown to reduce the hypertension and sympathetic nervous system contribution in BPH/2 mice. Thus far, evidence suggests that BPH/2 mice have aberrant GABAergic inhibition, which drives neuronal overactivity within amygdalo-hypothalamic brain regions. This overactivity is responsible for the greater sympathetic contribution to the hypertension in BPH/2 mice, thus making this an ideal model of neurogenic hypertension.

Abstract 035: Differential Effects of Bardet-biedl Syndrome 1 Gene Deletion From Agouti-related Peptide Neurons

Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive human disorder associated with several clinical features including obesity and hypertension. We previously demonstrated that Bbs1 gene deletion from the central nervous system caused obesity and hypertension in mice highlighting the importance of neuronal BBS proteins for energy homeostasis and cardiovascular regulation. Here, we investigated the role of Bbs1 gene in the orexigenic agouti-related peptide (AgRP) neurons. We crossed Bbs1 fl/fl mice with AgRP Cre mice and confirmed Cre recombinase activity in AgRP neurons using td-Tomato reporter mice. Interestingly, female AgRP Cre /Bbs1 fl/fl mice developed profound obesity as indicated by the increased body weight (46.8±2.0 g vs control littermates, 35.5±1.9 g at 25 weeks of age). In contrast, body weight of male AgRP Cre /Bbs1 fl/fl mice (48.5±1.2 g) was similar to the controls (46.7±1.2 g). There was no change in the expression of hypothalamic genes regulating food intake (AgRP, proopiomelanocortin and neuropeptide Y) in AgRP Cre /Bbs1 fl/fl mice relative to controls. Next, we assessed the consequence on arterial pressure (AP) and sympathetic nerve activity (SNA) of ablating the Bbs1 gene from AgRP neurons. Interestingly, deletion of the Bbs1 gene in AgRP neurons did not recapitulate the hypertension phenotype of BBS as indicated by the lack of difference in mean AP (107±5.0 vs 106±5.2 mmHg in controls) and heart rate (597±23.5 vs 589±16.4 in control). However, conscious renal SNA was significantly higher in AgRP Cre /Bbs1 fl/fl mice relative to controls (114±10 vs 78±6 spikes/sec, p<0.05). In addition, the depressor effect of ganglionic blockade (hexamethonium) was higher in AgRP Cre /Bbs1 fl/fl mice (-64.4±10 vs -55.8±8.3 mmHg in control). Finally, we used wire myography to measure mesenteric artery vascular function and found impairment in acetylcholine induced relaxation in AgRP Cre /Bbs1 fl/fl mice (Max. relaxation: 78 ± 6% vs 26 ± 9% in controls; p<0.05), but no changes in the relaxation evoked by sodium nitroprusside, suggesting endothelial, but not smooth muscle, dysfunction. These findings demonstrate that Bbs1 gene in AgRP neurons is critical for energy homeostasis, renal sympathetic outflow and vascular endothelial function.

Abstract 083: Metabolic and Cardiovascular Effects of BBS1 Ablation From the POMC-containing Neurons

Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive disorder associated with several features including obesity and hypertension. Deletion of Bbs genes globally, in the nervous system or in the leptin receptor-expressing cells recapitulated many of the BBS phenotypes including obesity and hypertension. Here, we assessed the effect of ablating the Bbs1 gene from the neurons expressing proopiomelanocortin (POMC) neurons. Breeding Bbs1 flox mice with POMC Cre mice created mice deficient in Bbs1 gene only in the POMC-positive neurons (visualized by tdTomato expression). Importantly, POMC Cre /Bbs1 fl/fl mice display an obesity phenotype as indicated by the increased (P<0.05) body weight (48.6±1.7 vs 34.9±0.8 g in controls) and fat pads (3.3±0.3 vs. 0.7±1.1 g for inguinal fat, 2.1±0.2 vs. 0.4±0.05 g for perirenal fat, 3.3±0.3 vs. 0.8±0.3 g for reproduction fat and 0.4±0.02 vs. 0.2±0.02 g for brow fat) associated with increased (P<0.05) food intake (3.79.±0.14 vs. 2.97±0.15 g in controls) in 25 weeks old mice. POMC Cre /Bbs1 fl/fl mice displayed decreased (P<0.05) O 2 consumption (2.6±0.03 vs. 3±0.04 mL O 2 /100g/min in controls) and heat production (8.0±0.09 vs. 9.2±0.13 kcal/kg/hr in controls). These results indicate that hyperphagia and decreased energy expenditure contribute to the development of obesity in POMC Cre /Bbs1 fl/fl mice. Next, we assessed the consequence on arterial pressure (AP) and sympathetic nerve activity (SNA) of ablating the Bbs1 gene from POMC neurons. Interestingly, deletion of the Bbs1 gene in POMC neurons did not recapitulate the hypertension phenotype of BBS as indicated by the slight, but not significant increase in mean AP (116±4.7 vs 109±6.1 mmHg in controls). However, conscious renal SNA was significantly higher in POMC Cre /Bbs1 fl/fl mice relative to controls (132.4±11 vs 74.3±4.2 spikes/sec, P<0.05). Finally, the depressor effect of ganglionic blockade (hexamethonium) was exaggerated in POMC Cre /Bbs1 fl/fl mice (-68.6±4.4 vs -45.2±9.4 mmHg in control, P=0.017). These findings demonstrate that Bbs1 gene in the POMC neurons is critical for energy homeostasis, but not for arterial pressure regulation.

Abstract 016: Bbs1 Gene Deletion From The Leptin Receptor Neurons Causes Obesity And Hypertension In Mice

Bardet-Biedl syndrome (BBS) is a pleiotropic autosomal recessive disorder associated with several features including obesity and hypertension. Deletion of BBS genes globally or in the nervous system recapitulated many of the BBS phenotypes including obesity and hypertension. Here, we assessed the effect of ablating the Bbs1 gene from the neurons expressing the long signaling form of the leptin receptor (LepRb). Breeding Bbs1 flox with LepRb Cre mice created mice deficient in the Bbs1 gene only in LepRb-positive neurons (visualized by tdTomato expression) as indicated by loss of leptin activation of Stat3. Importantly, Bbs1 flox /LepR Cre mice display an obesity phenotype as indicated by the increased (P<0.05) body weight (39±2 vs. 30±1 g in controls) and fat mass measured by MRI (14±3 vs. 4±1 g in controls) associated with increased (P<0.05) food intake (3.4±0.1 vs. 2.9±0.1 g in controls) in 25 weeks old mice. However, body weight and fat pads of pair-fed LRb Cre /Bbs1 fl/fl mice remained significantly elevated compared to controls suggesting that LRb Cre /Bbs1 fl/fl mice have reduced energy expenditure. Consistent with this possibility, LRb Cre /Bbs1 fl/fl mice displayed decreased (P<0.05) O 2 consumption (2.6±0.1 vs. 3.1±0.1 mL/100g/min in controls) and heat production (8.1±0.3 vs. 9.6±0.3 kcal/kg/h in controls). These results indicate that hyperphagia and decreased energy expenditure contribute to the development of obesity in Bbs1 flox /LepR Cre mice. Next, we assessed the effect on arterial pressure (AP) and sympathetic nerve activity (SNA) of ablating the Bbs1 gene from the LepR-containing neurons. Interestingly, deletion of the Bbs1 gene in LepR neurons recapitulates the hypertension phenotype of BBS as indicated by elevated mean AP (125±4 vs 109±3 mmHg in controls, P=0.03). Conscious renal SNA was also elevated in LRb Cre /Bbs1 fl/fl mice relative to controls (97±8 vs 62±10 spikes/sec, P<0.05). Finally, the depressor effect of ganglionic blockade (hexamethonium) was exaggerated in Bbs1 flox /LepR Cre mice (-57±5 vs -38±5 mmHg in control, P=0.01). These findings demonstrate that the Bbs1 gene in LepR neurons is critical for energy homeostasis and arterial pressure regulation.

Reversal of acute effects of high dose morphine on lymphocyte activity by chlorisondamine

To explore the mechanisms mediating the effects of acute morphine on the immune system, effects of ganglionic blockade with chlorisondamine on acute high dose morphine-induced alterations in blood lymphocyte proliferation, white blood cell counts, spleen lymphocyte proliferation and splenic natural killer (NK) cell cytolytic activity were examined in male Sprague–Dawley rats. Two hours after morphine (30 mg/kg, s.c.) administration, blood lymphocyte proliferation (ConA) was decreased 85%; this effect was antagonized by chlorisondamine (5 mg/kg, i.p.). Notably, however, such morphine exposure did not significantly decrease splenic lymphocyte proliferation, although depression of NK cell activity was also evident and appeared to be chlorisondamine-sensitive. Immune effects of morphine 1 h after treatment were somewhat different. In this case, blood lymphocyte proliferation decreased and plasma levels of corticosterone increased, with ED 50 values of 2.2 and 7.8 mg/kg, respectively. Splenic lymphocyte proliferation and NK activity were also significantly depressed in the 1-h exposure paradigm, but only after administration of 30 mg/kg morphine. These results indicate that chlorisondamine blocks the effects of relatively high doses of morphine on blood lymphocyte activity and indicate that blood lymphocyte proliferation is more sensitive to effects of acute morphine exposure than splenic lymphocyte proliferation, NK cell cytolytic activity and activation of the HPA axis.

Sympathetically Mediated Hypertension in Autonomic Failure

Approximately 50% of patients with primary autonomic failure have supine hypertension. We investigated whether this supine hypertension could be driven by residual sympathetic activity. In patients with multiple system atrophy (MSA) or pure autonomic failure (PAF), we studied the effect of oral yohimbine on seated systolic blood pressure (SBP), the effect of ganglionic blockade (with trimethaphan) on supine SBP and plasma catecholamine levels, and the effect of alpha(1)-adrenoreceptor blockade (phentolamine) on supine SBP. The SBP response to yohimbine was greater in patients with MSA than in those with PAF (area under the curve, 2248+/-543 versus 467+/-209 mm Hg. min; P=0.022). MSA patients with a higher supine SBP had a greater response than those with a lower supine SBP (3874+/-809 versus 785+/-189 mm Hg. min; P=0. 0017); this relationship was not seen in PAF patients. MSA patients had a marked depressor response to low infusion rates of trimethaphan; the response in PAF patients was more variable. Plasma norepinephrine decreased in both groups, but heart rate did not change in either group. At 1 mg/min, trimethaphan decreased supine SBP by 67+/-8 and 12+/-6 mm Hg in MSA and PAF patients, respectively (P<0.0001). Cardiac index and total peripheral resistance decreased in MSA patients by 33.4+/-5.8% and 40.7+/-9.5%, respectively (P=0. 0015). Patients having a depressor response to trimethaphan also had a depressor response to phentolamine. In MSA patients, the pressor response to yohimbine and the decrease in SBP with 1 mg/min trimethaphan were correlated (r=0.98; P=0.001). Residual sympathetic activity drives supine hypertension in MSA. It contributes to, but does not completely explain, supine hypertension in PAF.

Hemodynamic Profile of Neuropeptide Y in Dogs: Effect of Ganglionic Blockade

Hashim, M. A., W. W. Harrington, A. J. Daniels and A. S. Tadepalli. Hemodynamic profile of neuropeptide Y in dogs: Effect of ganglionic blockade. Peptides 18(2) 235–239, 1997.—The hemodynamic effects of neuropeptide Y (NPY) were examined over a dose range of 0.03–30 nmol/kg, IV, in anesthetized, open-chest, ventilated dogs with and without ganglionic blockade. In normal (non-ganglion-blocked) animals, NPY produced significant, dose-dependent, and sustained (lasting 15–45 min) increases in mean arterial blood pressure and systemic vascular resistance (SVR) with a threshold dose of 0.3 nmol/kg and a maximum effective dose of 10 nmol/kg. Cardiac index (CI) decreased at doses > 1 nmol/kg, but stroke volume was not altered; heart rate (HR) decreased significantly at and above the 3 nmol/kg dose. No significant changes were observed in the left ventricular dP/dt (LVdP/dt) or the contractility index (LVdP/dt ÷ systolic pressure). In ganglion-blocked animals, pressor and SVR responses to NPY were similar to those seen in normal animals but HR was not affected and a small but significant decrease in CI was seen only at the 30 nmol/kg. Furthermore, whereas LVdP/dt of ganglion-blocked dogs increased significantly at and above the 1 nmol/kg dose, the contractility index increased slightly only with the 10 and 30 nmol/kg doses. These data indicate that NPY produces sustained hypertension in dogs secondary to peripheral vasoconstriction, has a weak, direct positive inotropic action on the heart, and lacks chronotropic effects.

Ganglion-blocking agents enhance neurally mediated bronchoconstriction in the guinea-pig: possible role of sensory neuropeptides

The effect of ganglion blockade by hexamethonium bromide (0.1–100 μmol · kg −1) and pentolinium tartrate (0.01–3 μmol · kg −1) on the bronchoconstriction induced by vagal nerve stimulation (15 HZ, 0.2 ms, 3 s, 7–20 V) was evaluated in the anaesthetized guinea-pig. Both ganglion-blocking agents potentiated this response dose dependently. When the neural bronchoconstriction was suppressed by atropine, hexamethonium restored this response dose dependently. Hexamethonium produced inhibitory effects on vagally induced bronchoconstriction in capsaicin-desensitized and in propranolol- or reserpine-pretreated guinea-pigs. Propranolol (0.03–3 μmol · kg −1) produced a marked dose-dependent increase of neural bronchoconstriction (which was markedly reduced, about 10 times) in capsaicin-desensitized animals. Our results show that ganglion-blocking agents potentiate neural bronchoconstriction in the guinea-pig and that sensory neuropeptides may have a role in this effect. Moreover, β-adrenergic modulation of the release of neuropeptides from vagal sensory fibers is suggested.

Effect of Ganglion Blockade with Pentolinium on Circulating Neuropeptide Y Levels in Conscious Rats

The vasoconstrictor peptide, neuropeptide Y (NPY), is present in perivascular noradrenergic neurons of all mammals studied and may be important in the regulation of blood pressure. High plasma levels of NPY have been measured in the rat. To investigate partially the source and factors controlling the release of the circulating peptide, the effect of pentolinium tartrate administration has been studied in conscious rats. Pentolinium given as a bolus (5 mg/kg) followed by an infusion of a further 5 mg/kg/30 min produced a highly significant reduction in blood pressure of more than 40 mm Hg, when compared to either basal values or control animals treated with saline. Pentolinium treatment resulted in significantly lower plasma neuropeptide Y levels (31.0 +/- 6.7 fmol/ml) compared with those of control animals (78.6 +/- 8.2 fmol/ml). Circulating catecholamines were also significantly reduced in those animals receiving pentolinium. These results are compatible with circulating NPY arising from the sympathetic nervous system, with release being controlled by the mechanisms already established for catecholamines.

Sensitivity of Intestinal Resistance Vessels to Vasopressin After Ganglionic Blockade in the Conscious Cat

Superior mesenteric arterial flow, arterial pressure, and heart rate were recorded, and plasma arginine-vasopressin (AVP) concentration was measured, during intravenous infusions of AVP (0.1-8.1 mU X kg-1 X min-1) in conscious unrestrained cats under two experimental situations--when autonomic function remained intact and, on other days, when it had been impaired by pretreatment of the animals with the ganglionic blocking agent pentolinium tartrate (2.5 mg X kg-1 and 0.125 mg X kg-1 X min-1). The dose-related increases in the plasma concentrations of AVP attained during the infusions of the peptide were similar under the two experimental situations. The curve expressing the relationship between the dose of AVP and the decrease in superior mesenteric arterial conductance (ml X min-1 X kg-1 X mm Hg-1) for when ganglia were blocked was similar to the curve for when autonomic function remained intact. Elevations in the circulating levels of the peptide within the physiological range (less than 30 fmol X ml-1) were associated with significant decreases in conductance, both when ganglia were blocked and when they were intact. In contrast to conductance, the curve expressing the relationship between the dose of AVP and the increase in arterial pressure for when ganglia were blocked was displaced markedly to the left when compared with the curve for when reflexes remained intact, even though the effect of ganglion blockade on pressor responses did not reach statistical significance with the two lowest doses of AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

Analysis of mechanisms responsible for the bradycardic action of naloxone after haemorrhage in the conscious rabbit

We have analyzed the efferent mechanisms responsible for the bradycardia that occurs when naloxone (6 mg/kg) is given i.v. to conscious rabbits after acute blood loss of 17–20 ml/kg. Atenolol and hyoscine methyl bromide were given intrapericardially (i.p.c.), singly and in combination, to allow factorial analysis of the contributions of sympathoadrenal β-adrenergic and vagal cholinergic mechanisms. In addition, the effects of ganglion blockade with mecamylamine on the heart rate response to naloxone, and of i.p.c. naloxone on the cardiac pacemaker, were tested. The treatments had little effect on the pressor response to naloxone. Central nervous mechanisms were responsible for most of the bradycardia of - 160 beats/min evoked by naloxone in sham-treated, bled, rabbits. Increased vagal drive accounted for one-half the response, withdrawal of sympathoadrenal drive for 20%, and there was no significant interaction. These effects appeared to be due to evocation of a baroreceptor-heart rate reflex by the concomitant rise in blood pressure. Non-cholinergic, non-adrenergic mechanisms were responsible for a fall in heart rate of - 35 beats/min. part of which was due to a direct action of naloxone on the cardiac pacemaker.

Hemodynamic changes during onset of high-sodium one-kidney figure-8 renal hypertension.

The hemodynamic changes associated with the onset of one-kidney, figure-8, renal-wrap hypertension were monitored in rats fed a high-sodium diet. In addition, the hemodynamic contributions of the sympathetic nervous system (SNS) and arginine vasopressin (AVP) were assessed during the 1st week of hypertension. Renal wrapping caused mean arterial pressure (MAP) to increase significantly from 108 +/- 4 to 140 +/- 4 mmHg on day 5 after renal surgery. The hypertension was associated with a significant bradycardia and no significant change in cardiac output (CO), as measured with an electromagnetic flow probe. Total peripheral resistance (TPR) was significantly elevated to 140% above control value on day 5 after renal surgery. Ganglionic blockade caused similar decreases in MAP and TPR in normotensive and hypertensive animals. Sympathetic blockade after pretreatment with a specific vascular antagonist of AVP, [1-beta-mercapto-beta, beta-cyclopentamethylene propionic acid), 2-(O-methyl)tyrosine]Arg8-vasopressin ([d(CH2)5Tyr(Me)]AVP), caused a greater depressor response in the renal-wrapped animals as compared with the effect of ganglionic blockade alone in these animals. The effect of [d(CH2)5Tyr(Me)]AVP alone on the hemodynamics was not different between the two groups of rats. After ganglionic blockade pretreatment, [d(CH2)5Tyr(Me)]AVP caused a significant decrease in MAP and TPR in the renal-wrapped animals. In addition, the difference in MAP and TPR between the two groups of rats was eliminated after combined blockade of AVP and the SNS. The results of this study indicated that the onset of hypertension was a result of an activation of neurohumoral mechanisms to increase TPR.(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of ganglionic blockade on endogenous circulating pancreatic polypeptide, vasoactive intestinal polypeptide, substance P, neurotensin and noradrenaline in healthy controls and long-term insulin-dependent diabetic patients

Plasma pancreatic polypeptide (PP), vasoactive intestinal polypeptide (VIP), substance P (SP), neurotensin (NT) and noradrenaline (NA) were measured in eight healthy subjects and 12 long-term insulin-dependent diabetic patients with and without autonomic neuropathy, before and after intravenous infusion of the ganglionic blocking agent trimethaphan camsylate, in order to determine the influence of the autonomic nervous system on the baseline values of the substances. The basal levels of the measured substances were not significantly different in healthy subjects and patients with or without diabetic autonomic neuropathy. In healthy subjects, the ganglionic blockade induced a significant decrease in PP (80%) (P less than 0.02), NA (58%) (P less than 0.05), NT (27%) (P less than 0.05) and a significant increase in SP (30%) (P less than 0.05), while the VIP concentration remained unchanged. The diabetic patients had nearly the same significant decrease in PP (68%) (P less than 0.01), NA (50%) (P less than 0.01), NT (22%) (P less than 0.02), VIP (21%) (P less than 0.05) and increase in SP (73%) (P less than 0.01). No relationship was found between the autonomic neuropathy and changes of the substances during ganglionic blockade. The results indicate that the postganglionic part of the autonomic nervous system participates in the maintenance of a normal baseline level of PP, NT and NA, but not of VIP. The regulation of VIP may be disturbed in long-term diabetic subjects.

Effect of Ganglionic Blockade with Trimethaphan on Corticosteroid Responses to Metoclopramide in Rhesus Monkeys

In order to investigate whether metoclopramide stimulates 18-hydroxycorticosterone and aldosterone production directly by way of the autonomic nervous system, we have examined the effects of ganglionic blockade with trimethaphan on the responses to metoclopramide (200 micrograms/kg) in rhesus monkeys. Trimethaphan, infused at a rate (200 micrograms/kg/min) which significantly decreased mean arterial pressure from 122 +/- 7 to 62 +/- 4 mmHg, did not alter the peak plasma 18-OHB and aldosterone responses to metoclopramide. These results suggest that 18-hydroxycorticosterone and aldosterone responses to metoclopramide occur independently of adrenergic neuronal input.

Effect of Ganglionic Blockade with Trimethaphan on Corticosteroid Responses to Metoclopramide in Rhesus Monkeys

Effect of Ganglionic Blockade with Trimethaphan on Corticosteroid Responses to Metoclopramide in Rhesus Monkeys

Effect of ganglionic blockade on catecholamine secretion in exercised dogfish.

A brief bout of vigorous exercise results in significant increases in plasma epinephrine (E) and norepinephrine (NE) in the dogfish, Squalus acanthias. Since the presence of a functioning sympathetic nervous system in dogfish is in doubt, experiments were undertaken to show whether or not exercise-induced catecholamine (CA) secretion is under autonomic neurogenic control. Changes in plasma E and NE in a control group of exercised fish were compared with changes in fish exercised while under the influence of ganglionic blockade. Ganglionic blockade was induced in dogfish by hexamethonium infusion before exercise. CA secretion in response to a subsequent bout of exercise was significantly reduced without impairment of the ability of the fish to exercise. The pattern of systemic arterial pressure response to exercise and recovery (initial decrease during exercise followed by a prompt recovery to control level) was not significantly altered by ganglionic blockade. It is concluded that in dogfish some fraction of CA secretion capacity is possibly or potentially under neurogenically related control. Apparently the fraction of CA secretion under such control is not essential for performing exercise. The pattern of CA secretion accompanying the events of exercise and recovery in dogfish suggests that CA may play a more important role in recovery from exercise than in its performance.

Effects of ganglionic blockade on noradrenaline release and cell injury in the acutely ischemic rat myocardium.

We investigated the mechanisms responsible for ischemia-induced myocardial noradrenaline release in pentobarbitone-anaesthetized rats with left coronary artery occlusion. By means of tissue analysis of catecholamines and the Hillarp-Falck fluorescence histochemical technique for visualizing catecholamines in tissues, we studied the effect of a ganglionic blocker (chlorisondamine 0.1 mg/kg i.v.) on the ischemia-induced changes of the myocardial adrenergic nerve endings. In addition, the myocardial creatine kinase activity and potassium content were determined to estimate the extent of ischemic cell injury. In rats treated with either saline or chlorisondamine, the tissue noradrenaline content of the ischemic left ventricle was markedly reduced after 2.5 h of coronary ligation. In saline-treated rats 0.5 h of ischemia caused a slight decrease in left ventricular noradrenaline content, and this tended to be even less marked in chlorisondamine-treated animals. The changes in catecholamine fluorescence of the acutely ischemic myocardium seen after ganglionic blockade were essentially the same in both groups, but the size of the regions with reduced catecholamine fluorescence was more variable in the chlorisondamine-treated rats. Chlorisondamine caused a reduction in arterial blood pressure and heart rate and tended to reduce the degree of ischemic cell damage. We conclude that in our model the decrease in myocardial noradrenaline content after 2.5 h of ischemia is largely due to a local, nerve impulse--independent release of noradrenaline caused by ischemic changes in the tissue. The acute release of noradrenaline seen during 0.5 h of ischemia may be the combined result of local, ischemia-induced release of noradrenaline and an increased sympathetic nerve activation of the heart.

Effect of ganglionic blockade on pressor responses to angiotensin II during converting enzyme inhibition.

AbstractDose-response curves to angiotensin II were consecutively performed in rats after anesthesia (pentobarbital 60 mg/kg ip), converting enzyme inhibition (SQ14225 1 mg/kg iv), and ganglionic blockade (pentolinium 10 mg/kg sc) to explore the participation of the sympathetic nervous system in the immediate pressor action of the peptide. Experiments were conducted after the animals were maintained on a sodium-deficient diet for 2 weeks. Converting enzyme inhibition was maintained during ganglionic blockade to avoid changes in the circulating level of endogenous angiotensin II which might be caused by the latter maneuver. SQ14225 caused a 35 ± 4 mm Hg (P < 0.001) fall in systolic pressure and a significant shift to the left of the dose-response curve to angiotensin II compared to that obtained after anesthesia alone. In contrast, pentolinium did not further modify responses to angiotensin II despite significantly lowering systolic blood pressure 49 ± 5 mm Hg (P < 0.001). Our data confirm that a major det...

Effect of ganglionic blockade on bronchial reactivity in atopic subjects.

To determine the site in the parasympathetic pathway responsible for the increased bronchial reactivity in 5 atopic subjects, we studied the effect of premedication with aerosols of hexamethonium, a ganglionic blocking agent, and atropine, a postganglionic blocking agent, on the bronchomotor responses to histamine and methacholine aerosols. After 7 mg of aerosolized atropine, baseline specific airway resistance (SRaw) decreased, and the increases in SRaw produced by histamine and by methacholine were prevented in each subject (p < 0.001). After 1 g of hexamethonium, baseline SRaw was decreased to a similar level, and the increase in SRaw produced by histamine was again Prevented in each subject (P < 0.001); However, the increase in SRaw produced by methacholine was not affected significantly in 3 subjects (p > 0.5) and was increased or decreased only slightly in 2 subjects (p < 0.05). These results suggest that bronchial hyperreactivity in atopic subjects may be due to a change in the characteristics of the efferent parasympathetic pathway at a site distal to the ganglion, possibly at the smooth muscle, and that bronchodilation caused by atropine and hexamethonium cannot, by itself, account for their effects on bronchomotor responses.

The effects of ganglionic blockade on tracheobronchial muscle in fetal and newborn lambs

Changes in diameters of the trachea and bronchi of fetal and newborn lambs were studied by cineroentgenograms and histological sections after administration of a ganglionic blocking agent. Mean increases in diameters of the trachea and left and right bronchi were 90 %, 69 % and 62 %, respectively, in the fetal lambs. In the newborn lambs, the mean increases in tracheal and left and right bronchial diameters (51 %, 38 % and 60 %, respectively) were considerably less than those observed in the fetal lambs. This suggests that after birth the enhanced activity of the sympathetic component of the autonomic nervous system under normal circumstances overcomes the parasympathetic dominance over the respiratory tract which is characteristic of fetal life.