A preliminary, clinical pharmacological assessment of L-659,066, a novel alpha 2-adrenoceptor antagonist.

1. The alpha 2-adrenoceptor antagonist activity of L-659,066 has been investigated in studies of healthy normotensive males to whom doses of up to 8 mg were administered by short intravenous infusion. 2. L-659,066 had no effect on basal levels of glucose or insulin and no significant effect on the plasma glucose and plasma insulin time profiles following an intravenous glucose load. 3. There was a non-significant trend for plasma noradrenaline concentrations to be higher after L-659,066. 4. L-659,066 had no significant effects on mood changes or on physical symptom scores. 5. There were no significant effects on supine blood pressure but there were consistent increases in heart rate both supine (non-significant) and erect (P < 0.01). 6. Ex vivo platelet aggregation studies confirmed alpha 2-adrenoceptor antagonist activity with L-659,066 but with an approximately 9-fold lesser potency than yohimbine. 7. While L-659,066 has alpha 2-adrenoceptor antagonist activity these results suggest that it is unlikely to present a new therapeutic approach for improving insulin release.     

Blockade of peripheral α2-adrenoceptors by L-659,066 enhances glucose tolerance and insulin release in mice

The purpose of this study was to compare the effects of a peripherally selective (L-659,066) vs. a centrally and peripherally active (L-657,743; MK-912) α₂-adrenergic antagonist on murine plasma glucose and insulin levels following fasting or administration of hyperglycemic agents (α₂-adrenergic agonists, glucose). The intravenous administration of L-657,743 or L-659,066 alone did not cause major alterations in plasma glucose or insulin levels. Pretreatment of mice with either of these agents, however, at selective α₂-adrenoceptor blocking doses (0.3–3 mg/kg) prevented the elevations of plasma glucose levels induced by the α₂-adrenoceptor agonists clonidine or 3,4-dihydroxyphenylimino-2-imidazoline (DPl). Prazosin, an α₁-adrenergic antagonist, did not alter clonidine-induced elevations of plasma glucose levels. Pretreatment of fasted mice with L-657,743 or L-659,066 (1 mg/kg) 5 min before receiving intravenous glucose resulted in higher plasma insulin levels and improved glucose tolerance compared to saline-pretreated animals. Moreover, both α₂-adrenergic antagonists enhanced the acute insulin response to glucose. These findings indicate that, under conditions of hyperglycemia, insulin release is enhanced by the blockade of peripheral α₂-adrenoceptors α₂-Adrenoceptor antagonists, such as L-657,743 or the peripherally selective agent L-659,066, may prove effective in treating noninsulin-dependent diabetes mellitus.     

Effects of pharmacological doses of 2-deoxyglucose on plasma catecholamines and glucose levels in patients with schizophrenia

Rationale Several lines of evidence suggest that the pathophysiology of schizophrenia may be associated with altered noradrenergic and glucoregulatory function.Objective The aim of this study was to investigate these alterations during a perturbed homeostatic state.Methods Fifteen patients with schizophrenia and 13 healthy individuals were given a glucose deprivation challenge through administration of pharmacological doses of 2-deoxyglucose (2DG; 40 mg/kg), and their plasma was assayed over the next 60 min for concentrations of norepinephrine (NE), the intraneuronal NE metabolite dihydroxyphenylglycol (DHPG), epinephrine and glucose.Results 2DG induced significant increases in plasma NE, epinephrine and glucose levels in both groups with significantly greater NE and glucose increments in patients than in controls. For DHPG, 2DG produced increases in patients and decreases in the control subjects. NE responses correlated positively and significantly with the DHPG and glucose responses in schizophrenics, but not in controls.Conclusions These findings suggest that patients with schizophrenia have exaggerated NE and glucose responses to an acute metabolic perturbation.Data presented in part at the 2002 Annual Scientific Meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico.     

Type I and II metabotropic glutamate receptor agonists and antagonists evoke cardiovascular effects after intrathecal administration in conscious rats.

1. In the present study, the role of metabotropic glutamate receptors (mGluRs) in central cardiovascular regulation in conscious rats was examined. To this end, agonists and antagonists for type I and II mGluRs were administered intrathecally, and the temporal changes in blood pressure and heart rate were recorded. 2. L-glutamate (1 micromol) and the prototypical mGluR agonist (1S,3R)-ACPD (0.1 and 0. 3 micromol) both increased mean arterial pressure (MAP) and heart rate (HR), implicating functional mGluRs in the spinal cord. The type I mGluR agonist DHPG (0.01 - 0.1 micromol) evoked increases in MAP (max=25+/-5 mmHg) and HR (max=88+/-23 beats min-1). The duration of action, but not the maximum effects, were dose-related and ranged from approximately 10 min to <90 min and 1 min to >90 min for MAP and HR, respectively. 3. The type I/II mGluR agonist CCG-1 (0.1 and 0. 3 micromol) caused smaller, variable increases in MAP and HR of intermediate duration (5 - 20 min), whereas the type II MGluR agonist APDC (0.1 and 1.0 micromol) caused marked, but transient (3 - 5 min), pressor and tachycardic responses. The highest doses of DHPG and CCG-1, but not APDC, also evoked behavioural responses similar to a spontaneous nociceptive behavioural effect reported previously. 4. The type I and II mGluR antagonists (AIDA and LY307452, respectively) were also given approximately 5 min before the administration of the respective type I and II mGluR agonists (DHPG and APDC). Both compounds caused pressor and tachycardic responses, with the effect of AIDA, but not LY307452, returning to control levels before mGluR agonist administration. AIDA significantly attenuated the overall cardiovascular effects of DHPG, while LY307452 significantly attenuated the overall cardiovascular effects of APDC. 5. These results indicate that functional type I and II mGluRs exist in the spinal cord, and that their activation evokes prolonged cardiovascular effects.     

Alpha 2-adrenergic stimulation and vasopressin in congestive heart failure

Patients with chronic heart failure (CHF) have increased plasma levels of the antidiuretic hormone arginine vasopressin (AVP). The stimulus for increased AVP secretion is unknown, but appears to involve a nonosmotic drive which alters normal osmoregulatory mechanisms. Centrally acting alpha 2-adrenergic agonists suppress AVP secretion in experimental animals. To examine the hypothesis that such effects might be apparent on the chronically elevated AVP levels in patients with CHF, we measured AVP, heart rate (HR), mean arterial pressure (MAP), and plasma norepinephrine (NE) after 4 mg oral guanabenz in nine patients with this disease. Plasma NE decreased from 513 +/- 131 to a minimum of 371 +/- 117 pg/ml (p less than 0.02) 5 h postdrug. HR decreased from 80 +/- 9.3 to 74 +/- 10 beats/min (p less than 0.05) and MAP decreased from 88 +/- 8.5 to 83 +/- 10 mm Hg (p less than 0.05). Plasma AVP, however, did not change from baseline levels of 5.6 +/- 1.6 pg/ml. Serum osmolality was also constant. These data do not support a possible role for acute increases of alpha 2-adrenergic activity in suppressing the increased plasma AVP levels of CHF, at least under basal conditions at constant osmolality.     

Pindolol increases plasma norepinephrine concentration by stimulation of beta 2-adrenoceptors in conscious spontaneously hypertensive rats.

The beta-adrenoceptor antagonist pindolol [10-1,000 micrograms/kg subcutaneously (s.c.)] caused dose-related decreases in mean arterial pressure (MAP) and increased heart rate (HR) in conscious spontaneously hypertensive rats (SHR). The lowest dose of pindolol (10 micrograms/kg) decreased MAP by 25 mm Hg (-16%) without affecting plasma norepinephrine (NE) or plasma renin concentration (PRC). However, higher doses of pindolol elicited dose-related increases in plasma NE concentration and PRC. Plasma epinephrine concentration was not altered by pindolol. The selective beta 2-adrenoceptor antagonist ICI 118,551 (3 mg/kg, s.c.) prevented the tachycardia but not the increase in PRC caused by 100 micrograms/kg pindolol. Treatment with ICI 118,551 completely eliminated the 45% increase in plasma NE elicited by 100 micrograms/kg of pindolol even though the decrease in MAP caused by this dose of pindolol was the same in the presence (-33 mm Hg) and absence (-34 mm Hg) of beta 2-adrenoceptor blockade. These results indicate that the vasodepressor action of pindolol in SHR does not result from an agonistic effect at postjunctional beta 2-adrenoceptors in the vasculature. In addition, the increases in plasma NE concentration produced by pindolol result from stimulation of beta 2-adrenoceptors. These beta 2-adrenoceptors may be located prejunctionally on sympathetic neurons.     

Effects of risperidone on the peripheral noradrenegic system in patients with schizophrenia: a comparison with clozapine and placebo.

Risperidone is an atypical antipsychotic drug that increases plasma norepinephrine (NE) levels, but the mechanism behind this effect is unclear. We measured arterial plasma levels of NE and other catechols during intravenous infusion of tritium-labeled NE (3H-NE) in risperidone-treated patients and compared their data with those from patients treated with clozapine or placebo. NE levels in risperidone patients were significantly higher than in placebo patients, but lower than in clozapine patients. Neither drug, however, had significant effect on plasma levels of the main neuronal metabolite of NE, dihydroxyphenylglycol (DHPG), suggesting that adrenoceptors blockade alone would not explain the NE findings. The rate of release of endogenous NE into the bloodstream (spillover) was elevated in both risperidone and clozapine patients in a manner that paralleled their NE levels; the NE clearance in both groups did not differ from placebo. Following 3H-NE infusion in risperidone-treated individuals, production of 3H-DHPG was normal, as it was in the clozapine group, suggesting that risperidone does not impede neuronal uptake or intraneuronal metabolism of NE by monoamine oxidase. Our data suggest that both risperidone and clozapine elevate plasma NE levels via enhanced neurotransmitter spillover, with risperidone producing a smaller effect.     

The effects of idazoxan and other alpha 2-adrenoceptor antagonists on urine output in the rat.

1. In normally-hydrated Wistar rats the alpha 2-adrenoceptor antagonist, idazoxan (1, 3, 10 mg kg-1 i.p.), increased urine output during the 6 h following injection. 2. The more selective and specific alpha 2-adrenoceptor antagonist, RX811059 (0.3, 1, 3 mg kg-1 i.p.), and the peripherally-acting alpha 2-adrenoceptor antagonist, L-659,066 (1, 3, 10 mg kg-1 i.p.), had no effect on urine output in normally-hydrated animals. 3. In rats given a 25 ml kg-1 water-load orally, idazoxan (10 mg kg-1, i.p.) produced an initial antidiuretic response which was followed by an increase in urine output which was apparent 4 and 6 h after drug administration. 4. RX811059 (1, 3 mg kg-1 i.p.) and L-659,066 (3, 10 mg kg-1 i.p.) significantly decreased urine output in water-loaded rats in the 2 h after injection. 5. The antidiuretic effects of L-659,066 were attenuated in Brattleboro rats which are deficient in vasopressin; only the highest dose (10 mg kg-1 i.p.) decreased urine output, and this was only a small response in comparison with its virtual abolition of urine output in water-loaded Wistar rats. 6. The results with the selective alpha 2-adrenoceptor antagonists in Wistar and Brattleboro rats suggest that alpha 2-adrenoceptors in the periphery may play a physiological role in the control of water balance through a mechanism which involves vasopressin. 7. The paradoxical diuretic effects of idazoxan contrast with the effects of the other alpha 2-adrenoceptor antagonists and therefore may be attributed to a property of this compound unrelated to alpha 2-adrenoceptor blockade.     

Differential effects of central and peripheral desipramine on sympathoadrenal function and heart rate in conscious rabbits.

The effects of the tricyclic antidepressant, desipramine, on the baroreflex regulation of renal sympathetic nerve activity (SNA) and heart rate (HR), the nasopharyngeal reflex, plasma epinephrine and blood pressure (BP) were studied in conscious rabbits. Renal SNA and HR were recorded during slow ramp changes in mean arterial pressure (MAP) and during inhalation of cigarette smoke. Intracisternal (i.c.) and intravenous (i.v.) drug administration were compared, using doses which produced similar total central nervous system (CNS) concentrations. After a brief sympathoexcitation, i.c. desipramine inhibited renal SNA and MAP and increased plasma adrenaline and HR. The renal sympathetic baroreflex was substantially attenuated, with reflex range and gain reduced by 46 and 31%, respectively, but the cardiac baroreflex and nasopharyngeal reflex were affected minimally. Sixty-four percent of the desipramine remaining in the brain was concentrated in the medulla oblongata and spinalis; levels in cortex, thalamus, midbrain, lower spinal cord, and peripheral tissues were minimal. Treatment with i.v. desipramine decreased renal SNA and increased HR without altering MAP or epinephrine release. There was a slight attenuation of the nasopharyngeal reflex, a slight baroreceptor-independent reduction in renal SNA at most MAP levels, and an augmentation of the cardiac baroreflex. The drug was uniformly distributed throughout the CNS; only 20% of the centrally accumulated dose was in the medulla. Thus, i.c. desipramine produces a differentiated pattern of sympathoadrenal effects, probably by increasing norepinephrine (NE) concentrations at several sites within the medulla. The effects of i.v. desipramine were different, owing to poorer access to the medulla and the consequences of peripheral neuronal uptake blockade, which may include a modest inhibition at the sympathetic ganglia and an excitation at cardiac and vasoconstrictor neuroeffector junctions.     

Effect of ketanserin on blood pressure in rats

Ketanserin, a selective serotonergic (5-HT2) antagonist, also has affinity for alpha 1-adrenoceptors. It is not clear whether the hypotensive mechanism of ketanserin is due to its antagonistic action to 5-HT2 receptor or to its affinity for alpha 1 adrenoceptors. The hypotensive mechanism of ketanserin was studied in both stroke-prone spontaneously hypertensive rats (SHRSP) and Wistar Kyoto rats (WKY). Anesthetized rats were used (alpha-chloralose + urethane, i.p.). Up to 3 ml of blood was drawn from each rat for analysis. Plasma norepinephrine (NE) was determined by radioenzymatic assay. Plasma serotonin (5-HT) was determined by HPLC-ECD. Adrenal nerve discharges were counted by a digital pulse counter. Ketanserin (0.5 mg/kg, 5.0 mg/kg, i.v.) produced a dose-dependent reduction of mean arterial pressure (MAP) in both SHRSP and WKY. MAP of SHRSP decreased significantly as compared with WKY. Both plasma NE and 5-HT showed a tendency to increase during ketanserin administration (5.0 mg/kg, i.v.). Ketanserin significantly antagonized the BP response induced by exogenously injected 5-HT (30 micrograms/kg) and NE (10 micrograms/kg). Adrenal nerve activity was reduced in parallel with the decrease in BP and HR. These findings suggest that ketanserin produced a decrease in BP via both peripheral and central action in rats.     

Plasma concentration-effect relationship of felodipine intravenously in patients with congestive heart failure

The pharmacodynamics of felodipine were analyzed in patients with congestive heart failure in a randomized, double-blind, placebo-controlled study. Felodipine at a dose of 1 mg (n = 11) or placebo (n = 12) was given intravenously during a 60-min period. Hemodynamic measurements and plasma samples were obtained every 15 min during a 2-hour period. An increase in heart rate (HR, +8%, p less than 0.01) and cardiac output (CO, +36%, p less than 0.001), and a decrease in mean arterial pressure (MAP, -24%, p less than 0.001) and systemic vascular resistance (SVR, -46%, p less than 0.001), were found. Pulmonary artery, right atrial, wedge pressure, and stroke-work index did not change. Linear regression analysis showed a significant correlation between felodipine plasma levels and changes in HR (r = 0.71, p less than 0.05), MAP (r = 0.94, p less than 0.01), CO (r = 0.73, p less than 0.05), and SVR (r = 0.88, p less than 0.01). A strong hyperbolic correlation was demonstrated between individual plasma levels and changes in MAP (r = 0.97, p less than 0.001). Hysteresis analysis showed that plasma levels are directly related to the concentration at the receptor site. A clockwise hysteresis was found in HR, CO, and SVR, but not in MAP. It is concluded that changes in flow and resistance are based on a physiological adjustment, a baroreflex-mediated response to vasodilation induced by felodipine, resulting in MAPs that remain closely related to felodipine plasma levels over a wide range.     

Modulation of pressor response to muscle contraction via monoamines following AMPA-receptor blockade in the ventrolateral medulla

We hypothesized that cardiovascular responses to static muscle contraction are mediated via changes in extracellular concentrations of monoamines (norepinephrine, dopamine and serotonin) following the administration of 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, an AMPA-receptor antagonist) into the rostral (RVLM) or caudal (CVLM) ventrolateral medulla. For the RVLM experiments (n= 8), a 2-min static muscle contraction increased the mean arterial pressure (MAP) and heart rate (HR) by 23 +/- 2 mmHg and 28 +/- 8 bpm, respectively. During this contraction, the concentrations of norepinephrine, dopamine, and serotonin within the RVLM increased by 278 +/- 52%, 213 +/- 23%, and 232 +/- 24%, respectively. Microdialysis of CNQX (1.0 microM) for 30 min into the RVLM attenuated the increases in MAP and HR ( 11 +/- 2 mmHg and 14 +/- 5 bpm) without a change in developed muscle tension. The levels of norepinephrine, dopamine, and serotonin within the RVLM were also attenuated. In contrast, microdialysis of CNQX into the CVLM (n= 8) potentiated the contraction-evoked responses in MAP ( 21 +/- 2 vs 33 +/- 5 mmHg) and HR ( 25 +/- 5 vs 46 +/- 8 bpm) without any effect on the monoamine levels within the CVLM region. These results suggest that AMPA-receptor blockade within the RVLM and CVLM has opposing effects on cardiovascular responses during static muscle contraction. In addition, such receptor blockade modulates extracellular concentrations of monoamines within the RVLM but not in the CVLM. These results provide evidence that AMPA receptors within the ventrolateral medulla play a role in exercise pressor reflex.     

ω-CONOTOXIN GVIA AND PRAZOSIN, BUT NOT FELODIPINE, CAUSE POSTURAL HYPOTENSION IN RABBITS

1. The aim was to compare the effect of N-type calcium channel blockade by ω-conotoxin GVIA (ω-CTX) with α₁-adrenoceptor or L-type calcium channel blockade on postural adaptation in conscious rabbits. 2. Orthostatic responses were assessed by rapidly tilting the rabbits through 90° for 1 min. Tilts were performed before, 30 and 60 min after i.v. bolus administration of vehicle (propylene glycol 0.17mL/kg; n = 8), prazosin (0.5mg/kg; n= 8), felodipine (30μg/kg; n= 8) or ω-CTX (3 & 7 μg/kg; n = 9). 3. Prazosin, felodipine or ω-CTX caused significant falls in mean arterial pressure (MAP) with corresponding increases in heart rate (HR). Vehicle administration had no effect on MAP but caused a small fall in HR. 4. Before drug or vehicle administration, a small rise in MAP and HR occurred in response to tilt in all rabbits. In the vehicle treatment group, similar responses were observed to tilt at 30 and 60 min. Postural hypotension was observed in the prazosin treatment group, but not following administration of felodipine. Tilts 30 and 60 min after ω-CTX (3μg/kg) caused an increase in HR but no change in MAP, different to the small pressor response observed following vehicle administration. However, following administration of ω-CTX 7 μg/kg (total dose, 10μg/kg), significant falls in MAP with tachycardia were observed in response to tilt. 5. In conclusion, orthostatic hypotension was observed following acute α_l-adrenoceptor or N-type calcium channel blockade in the conscious rabbit. These findings are compatible with the expectation that agents which are directly sympatholytic interfere with postural adaptation. In contrast, L-type calcium channel antagonism with felodipine did not elicit postural hypotension.     

Adrenergic and noradrenergic plasma levels in Lesch-Nyhan disease.

Noradrenergic dysfunction and abnormality in monoamine oxidase (MAO) enzyme activity have been reported previously in Lesch-Nyhan (LN) disease. This study examines peripheral indices of adrenergic, noradrenergic, and MAO function in children and young adults with LN disease (n = 11), and healthy subjects (n = 9). Blood samples, collected in identical conditions prior to a positron emission tomography (PET) study, were assayed for concentrations of epinephrine (EPI), norepinephrine (NE), and 3-methoxy-4-hydroxyphenylglycol (DHPG) (which results from the degradation of NE by monoamine oxidase type A [MAO-A]). The LN subjects had significantly higher EPI levels by 245% (p < .00) and lower DHPG levels by 42% (p < .00) compared to the control group. No group differences were noted in NE plasma levels. Cognitive function (IQ tested by Stanford Binet Intelligence Scale) was associated with EPI in the LN group (r = 0.77, p = .009), but not in the control group. The abnormally high EPI plasma concentrations may indicate another biochemical dysfunction secondary to the absence of the HPRT enzyme in LN patients. Such a biochemical deficit is likely to originate from the adrenal medulla, which is the primary site of EPI synthesis. The adrenal medulla may be directly affected by the absence of hypoxanthine guanine phosphoribosyl transferase (HPRT) enzyme, or may receive inappropriately high descending activation input from the brain. The abnormally low DHPG levels, in the context of normal NE levels, indicates low MAO activity, either as a primary deficit, or as secondary adaptive changes to spare NE levels that would otherwise be too low for adequate noradrenergic function.     

Role of norepinephrine in the dorsomedial hypothalamic panic response: an in vivo microdialysis study

Blockade of gamma-aminobutyric acid-A (GABA(A)) receptors in the dorsomedial hypothalamus (DMH) elicits a panic-like response that includes increases in heart rate (HR), blood pressure (BP), respiration rate (RR), and anxiety. Norepinephrine (NE) has been postulated to be critical in regulating panic and anxiety responses. Therefore, the first study sought to determine changes in extracellular NE levels within the DMH following acute blockade of GABA(A) receptors in the DMH using in vivo microdialysis. Rats were implanted with femoral arterial catheters and microdialysis probes into the DMH. Following recovery, the DMH of conscious rats were perfused with 100, 150, or 200 microM solutions of the GABA(A) receptor antagonist bicuculline methiodide (BMI) via the microdialysis probe. HR and BP responses were recorded and the changes in extracellular levels of NE in the dialysate samples from the DMH were determined by HPLC. Rats receiving BMI injections showed dose-dependent increases in both the extracellular NE levels in the DMH as well as HR and BP. The second study was conducted to test the functional importance of NE in the DMH to the BMI-induced physiological responses. The effects of BMI microinjection into the DMH were measured at baseline and 10 days after local injection of either vehicle or two doses of 6-hydroxydopamine (6-OHDA), a neurotoxin known to lesion NE terminals. There was a significant loss of tissue NE levels as well as BMI-induced HR, BP and RR responses in the 6-OHDA-treated but not vehicle-treated rats. Thus, blockade of GABA(A) receptors in the DMH results in NE release and the presence of NE appears to be necessary for eliciting the physiological components of the panic-like responses in this region.     

The pressor response to central administration of beta-endorphin results from a centrally mediated increase in noradrenaline release and adrenaline secretion.

1. The effects of intracerebroventricular (i.c.v.) and intracisternal (i.c.) administration of beta-endorphin (0.01, 0.1 and 1.0 nmol kg-1) were examined in conscious rabbits. 2. After i.c.v. beta-endorphin, mean arterial pressure (MAP) increased, heart rate (HR) fell, plasma noradrenaline, adrenaline and glucose increased and there was a rise in PaCO2 and fall in PaO2; these effects were reversed by intravenous (i.v.) naloxone (300 nmol kg-1). 3. A combination of prazosin (2 mg kg-1) and yohimbine (1 mg kg-1), given i.v., prevented the rise in MAP induced by i.c.v. beta-endorphin. 4. After i.c. beta-endorphin, MAP, HR and plasma catecholamines were not significantly altered but there was a similar degree of respiratory depression. 5. Clonidine (1.0 micrograms kg-1, i.c.) reduced MAP and HR; these effects were not blocked by i.v. naloxone (6 mumol kg-1). 6. These results demonstrate that beta-endorphin acts centrally, probably mainly on periventricular mu-opioid receptors, to increase adrenaline secretion and sympathetic nerve activity leading to alpha-adrenoceptor-mediated vasoconstriction. The respiratory depression is probably mediated by brainstem mu-receptors. 7. A role for beta-endorphin in the central hypotensive action of alpha 2-adrenoceptor agonists was opposed by finding that opioid receptor antagonism with naloxone did not block the effects of clonidine.     

Study on adrenergic function after development of tolerance to ethylene glycol dinitrate (EGDN) in rats

The effects of sustained exposure to ethylene glycol dinitrate (EGDN; 50 mg.kg-1.2, 10 days) on heart rate (HR) and mean arterial blood pressure (MAP), isolated strips from aorta and vena cava, catecholamine (CA) and DOPAC levels in brain, heart, adrenals and plasma, and synaptosomal uptake of noradrenaline (NA) have been investigated in rats. Aortic strips showed a decreased responsiveness to EGDN and were more sensitive to NA than were control strips 2, 24 and 96 hrs after cessation of EGDN. Acute cumulative doses of EGDN induced a decrease in MAP at all time intervals but 2 hrs after cessation of chronic EGDN-treatment, while NA induced a dose-dependent increase in MAP. MAP was lower 2 hrs after cessation of EGDN, than in the control rats, while HR was higher. After 24 hrs, MAP was slightly higher than in the controls and HR was still elevated. EGDN induced a decrease in the accumulation of L-DOPA and DOPAC in all brain structures measured, which was especially prominent 2 hrs after cessation of EGDN. The levels of CA's and DOPAC in peripheral tissues did generally not change significantly, although there was a tendency to a decrease. L-DOPA, NA and adrenaline (A) in plasma decreased significantly, while DOPAC and dopamine (DA) increased. No consistent effects on uptake of NA into synaptosomes could be distinguished. However, the amount of protein was generally lower at all times after cessation of EGDN. It is suggested that prolonged exposure to EGDN not only induces tolerance at the cellular level, but also interferes with arterial smooth muscle sensitivity to NA and with resetting of MAP and HR. The decrease in the synthesis and turnover of CA's and DOPAC in the brain indicated a decrease in nervous activity, which is reflected by a corresponding decrease of NA and A levels in plasma.     

Potentiation by dopexamine of the cardiac responses to circulating and neuronally released norepinephrine: a possible mechanism for the therapeutic effects of the drug

Dopexamine is a new dopamine receptor agonist which also inhibits the uptake of norepinephrine (NE) into sympathetic nerves. Dopexamine was infused intravenously (i.v.) in anesthetized dogs at a rate used for treatment of congestive heart failure (4 micrograms/kg/min) before and during i.v. infusions of NE (0.26 +/- 0.06 and 0.57 +/- 0.12 micrograms/kg/min) and before and during cardioaccelerator nerve stimulation (0.25 and 0.50 Hz). Increments in cardiac contractile force produced by both infusion rates of NE were greater during dopexamine infusion; increases in heart rate (HR) and mean arterial pressure (MAP) produced by the higher infusion of NE also were increased by dopexamine. During cardioaccelerator nerve stimulation, 0.25 and 0.50 Hz, the increments in HR were significantly greater during dopexamine infusion; MAP also increased significantly during cardioaccelerator nerve stimulation (0.50 Hz) in the presence of dopexamine. Plasma NE concentration was significantly elevated during infusion of dopexamine. However, dopexamine did not enhance the elevated plasma NE concentration produced by NE infusions. This study demonstrates that infusion of dopexamine potentiates the cardiovascular effects resulting from neuronally released and exogenously infused NE.     

Endothelin-1-induced elevation in blood pressure is independent of increases in sympathetic nerve activity in normotensive rats

This study was performed to determine if endothelin-1 (ET-1)-induced pressor responses in urethane-anesthetized, normotensive rats are due to increased sympathetic nerve activity. Renal sympathetic nerve activity (RSNA) was used as an index of sympathetic nerve activity. ET-1 (30- 1000 pmol/kg) or sarafotoxin (S6c, ET B receptor agonist, 10-3,000 nmol/kg) given by bolus injection produced transient decreases in mean arterial pressure (MAP) and increases in RSNA and heart rate (HR). ET-1 caused a delayed but sustained increase in MAP that was not inhibited by acute sinoaortic denervation or alpha 1 -adrenergic receptor blockade. ET-1 never caused a sustained change in HR or RSNA. A-192621 (ET B receptor antagonist, 12 mg/kg) increased MAP (10-20 mm Hg) and decreased HR and RSNA. A-192621 blocked the transient decrease in MAP and increase in RSNA and HR caused by ET-1 and S6c. In A-192621-treated rats, ET-1, but not S6c, caused a sustained increase in MAP and decrease in HR and RSNA. After A-192621 treatment, ET-1 infusion caused a sustained elevation in MAP; HR and RSNA decreased only after the highest ET-1 dose. These results indicate that the initial increase in RSNA after ET-1 or S6c is secondary to ET B receptor-mediated vasodilation. Increased RSNA does not contribute to ET-1-induced pressor responses; these responses are likely due to vasoconstriction in normotensive, anesthetized rats. Finally, baroreceptor reflexes function after ET-1 or S6c treatment.