ABSTRACT
The present study was designed to evaluate yoga's impact on blood pressure (BP) and quality of life (QOL) and on stress, depression and anxiety in patients with hypertension in a primary care setting. We conducted a multi-centre randomized controlled trial with follow-up after 12-week intervention completion. Adult primary care patients diagnosed with hypertension were randomly allocated to yoga or usual care. The intervention group performed a short home-based Kundalini yoga programme 15 min twice-daily during the 12-week intervention period. At baseline and follow-up, the participants underwent standardized BP measurements and completed questionnaires on QOL, stress, anxiety and depression. Data obtained from 191 patients (mean age 64.7 years, s.d. 8.4) allocated to yoga intervention (n=96) and control group (n=95), with a total proportion of 52% women, showed a significant reduction in systolic and diastolic BP for both groups (-3.8/-1.7 mm Hg for yoga and -4.5/-3.0 mm Hg for control groups, respectively). However, the BP reduction for the yoga group was not significantly different from control. There were small but significant improvements for the yoga group in some of the QOL and depression measures (P<0.05, Hospital Anxiety and Depression scale, HADS-D) compared with control. The findings of our study, which is the largest study from an OECD country (Organization for Economic Co-operation and Development) to date, do not support the suggestion from previous smaller studies that yoga lowers the BP. Further clinical trials are needed to confirm these findings. However, the yoga patients had other health benefits.
Subject(s)
Blood Pressure , Hypertension/therapy , Primary Health Care , Yoga , Adult , Aged , Female , Humans , Male , Middle Aged , Outcome Assessment, Health CareABSTRACT
AIMS/HYPOTHESIS: Improved glucose control in type 2 diabetes is known to reduce the risk of microvascular events. There is, however, continuing uncertainty about its impact on macrovascular disease. The aim of these analyses was to generate more precise estimates of the effects of more-intensive, compared with less-intensive, glucose control on the risk of major cardiovascular events amongst patients with type 2 diabetes. METHODS: A prospectively planned group-level meta-analysis in which characteristics of trials to be included, outcomes of interest, analyses and subgroup definitions were all pre-specified. RESULTS: A total of 27,049 participants and 2,370 major vascular events contributed to the meta-analyses. Allocation to more-intensive, compared with less-intensive, glucose control reduced the risk of major cardiovascular events by 9% (HR 0.91, 95% CI 0.84-0.99), primarily because of a 15% reduced risk of myocardial infarction (HR 0.85, 95% CI 0.76-0.94). Mortality was not decreased, with non-significant HRs of 1.04 for all-cause mortality (95% CI 0.90-1.20) and 1.10 for cardiovascular death (95% CI 0.84-1.42). Intensively treated participants had significantly more major hypoglycaemic events (HR 2.48, 95% CI 1.91-3.21). Exploratory subgroup analyses suggested the possibility of a differential effect for major cardiovascular events in participants with and without macrovascular disease (HR 1.00, 95% CI 0.89-1.13, vs HR 0.84, 95% CI 0.74-0.94, respectively; interaction p = 0.04). CONCLUSIONS/INTERPRETATION: Targeting more-intensive glucose lowering modestly reduced major macrovascular events and increased major hypoglycaemia over 4.4 years in persons with type 2 diabetes. The analyses suggest that glucose-lowering regimens should be tailored to the individual.
Subject(s)
Blood Glucose/analysis , Diabetes Mellitus, Type 2/physiopathology , Diabetic Angiopathies/prevention & control , Blood Glucose/metabolism , Blood Pressure , Cholesterol/blood , Clinical Trials as Topic , Diabetes Mellitus, Type 2/blood , Fasting , Follow-Up Studies , Glycated Hemoglobin/analysis , Homeostasis , Humans , Patient Compliance , Patient Selection , Risk Reduction Behavior , Treatment OutcomeABSTRACT
Abundant evidence has accumulated showing that angiotensin converting enzyme (ACE) inhibitors reduce long-term cardiovascular morbidity and mortality rates in patients with heart failure and myocardial infarction. Fewer completed trials have assessed their potential benefits in this regard in hypertensive subjects, but evidence of benefit is beginning to accrue from studies examining patients with hypertension, particularly in the presence of diabetes and after infarction. Ongoing trials of blood pressure (BP) lowering using ACE inhibition fall into three main categories: 1) those comparing ACE inhibitors with older drugs such as diuretics and beta blockers; 2) those examining more aggressive versus less aggressive lowering of BP; and 3) those investigating BP lowering in patients at high risk for a cardiac event. Among those in the last group is the Perindopril Protection Against Recurrent Stroke Study (PROGRESS), which examines the effects of perindopril-based ACE inhibitor therapy in both normotensive and hypertensive patients who have survived a stroke. This trial is particularly important because it serves as a model for studies of BP lowering across a wide range of BP and BP-related conditions.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Clinical Trials as Topic , Hypertension/drug therapy , Blood Pressure/drug effects , Humans , Perindopril/therapeutic useABSTRACT
Opioid receptors are activated during severe hemorrhage, resulting in sympathoinhibition and a profound fall in blood pressure. This study examined the location and subtypes of opioid receptors that might contribute to hypotension after hemorrhage. Intrathecal naloxone methiodide (100 nmol) abolished the fall in blood pressure after hemorrhage (1.5% of body wt; mean arterial pressure 122 +/- 8 mmHg after naloxone methiodide vs. 46 +/- 5 mmHg in controls, P < 0. 001). Intracisternal naloxone methiodide was less effective than intrathecal naloxone methiodide, whereas intravenous naloxone methiodide, which does not cross the blood-brain barrier, did not alter the fall in blood pressure after hemorrhage. These results demonstrate that spinal opioid receptors contribute to hypotension after hemorrhage but do not exclude supraspinal effects. In separate experiments, the subtype-specific opioid antagonists ICI-174864 (delta-antagonist), norbinaltorphimine (nor-BNI; kappa-antagonist), and H-D-Phe-Cys-Tyr-D-Trp-Orn-Thr-Pen-Thr-NH2 (CTOP; mu-antagonist) were each administered intrathecally to determine the minimum dose that would attenuate hypotension during severe hemorrhage. These antagonists were effective at similar doses (3 nmol for CTOP, 6 nmol for ICI-174864, and 10 nmol for nor-BNI), although the binding affinities of these three different agents for their target receptors varied >1600-fold. Comparisons of the minimum effective doses of these antagonists in relation to their binding affinities provides strong evidence for the participation of delta-receptors in mediating hypotension after hemorrhage. In contrast, the dose at which nor-BNI was effective suggests an effect at delta-receptors but not kappa-receptors. The efficacy of CTOP, albeit at a high dose, also suggests an effect at mu-receptors.
Subject(s)
Hemorrhage/physiopathology , Hypotension/physiopathology , Receptors, Opioid, kappa/physiology , Receptors, Opioid, mu/physiology , Spinal Cord/chemistry , Animals , Blood Pressure/physiology , Consciousness , Dynorphins/physiology , Endorphins/physiology , Enkephalin, Leucine/analogs & derivatives , Enkephalin, Leucine/pharmacology , Heart Rate/physiology , Hemorrhage/complications , Hypotension/etiology , Male , Naloxone/pharmacology , Narcotic Antagonists/pharmacology , Neural Inhibition/drug effects , Rats , Rats, Inbred WKY , Somatostatin/analogs & derivatives , Somatostatin/pharmacology , Spinal Cord/drug effects , Sympathetic Nervous System/drug effects , Sympathetic Nervous System/physiologyABSTRACT
In this study we examined blood pressure and heart rate responses to intrathecal administration of a synthetic NK1-receptor agonist, H2N-(CH2)4-CO-Phe-Phe-Pro-NmeLeu-Met-NH2 (GR 73,632), in spontaneously hypertensive rats (SHR) and their progenitor strain, the Wistar-Kyoto rat (WKY). Sodium pentobarbitone anaesthetised rats with implanted intrathecal catheters were paralysed (pancuronium dibromide) and artificially ventilated. Injection of GR 73,632 at the T9 spinal level evoked dose-dependent increases in mean arterial pressure (MAP) in WKY and SHR. SHR had a lower MAP response threshold than WKY but increase in response with increasing dose was less in SHR than WKY. Biphasic blood pressure responses at high doses were observed in both strains. Prior administration of the NK1-receptor antagonist (3 aR,7aR)-7,7-diphenyl-2-[1-imino-2(methoxyphenyl)ethyl] perhydroisoindol-4-one (RP 67,580) significantly reduced the pressor response in WKY but not SHR. The depressor response was not attenuated in either strain.
Subject(s)
Blood Pressure/drug effects , Receptors, Neurokinin-1/physiology , Spinal Cord/physiology , Analgesics/pharmacology , Animals , Heart Rate/drug effects , Hypertension/physiopathology , Indoles/pharmacology , Injections, Spinal , Isoindoles , Neurons/chemistry , Neurons/drug effects , Neurons/physiology , Peptide Fragments/pharmacology , Rats , Rats, Inbred SHR , Rats, Inbred WKY , Receptors, Neurokinin-1/agonists , Substance P/analogs & derivatives , Substance P/pharmacology , Sympathetic Nervous System/chemistry , Sympathetic Nervous System/cytology , Sympathetic Nervous System/physiologyABSTRACT
To characterise respiratory neurons in the pre-Bötzinger complex of adult rats, extracellular recordings were made from 302 respiratory neurons in the ventral respiratory group of sodium pentobarbitone anaesthetised adult rats. Neurons were located 0 to 1.6 mm caudal to the facial nucleus, and ventral to the nucleus ambiguus. The pre-Bötzinger complex comprised expiratory neurons (22%, 22/100), inspiratory neurons (37%, 37/100) and phase-spanning neurons (41%, 41/100). In contrast, 80% (125/157) of Bötzinger neurons were expiratory, and 80% (36/45) of rostral ventral respiratory group neurons were inspiratory. Rostrocaudally, the pre-Bötzinger complex extended about 400 microns, starting at the caudal pole of the nucleus ambiguus compact formation. The pre-Bötzinger complex was also characterised by a predominance of propriobulbar neurons (81%, 13/16). Furthermore, 68% (33/48) of expiratory-inspiratory neurons found were located within the pre-Bötzinger complex. The variety of neuronal subtypes in the pre-Bötzinger complex, including many firing during the expiratory-inspiratory transition is consistent with the hypothesis that this nucleus plays a key role in respiratory rhythm generation in the adult rat.
Subject(s)
Medulla Oblongata/cytology , Medulla Oblongata/physiology , Motor Neurons/physiology , Respiration , Action Potentials/drug effects , Action Potentials/physiology , Age Factors , Animals , Axons/physiology , Electric Stimulation , Electrophysiology , Homocysteine/analogs & derivatives , Homocysteine/pharmacology , Motor Neurons/drug effects , Motor Neurons/ultrastructure , Periodicity , Phrenic Nerve/cytology , Phrenic Nerve/physiology , Rats , Rats, Sprague-Dawley , Spinal Cord/cytology , Spinal Cord/physiology , VagotomyABSTRACT
Our previous work suggests that virtually all of the synapses on sympathetic preganglionic neurons projecting to the rat adrenal medulla are immunoreactive for either the inhibitory amino acid, gamma-aminobutyric acid (GABA) or the excitatory amino acid, L-glutamate. To investigate whether or not this is true for other groups of sympathetic preganglionic neurons, and to determine whether or not the proportion of inputs containing each type of amino acid neurotransmitter is the same for different groups of sympathetic preganglionic neurons, we retrogradely labelled rat and rabbit sympathetic preganglionic neurons projecting to the superior cervical ganglion and used post-embedding immunogold on ultrathin sections to localise GABA- and glutamate-immunoreactivity. The cell bodies and dendrites of both rat and rabbit sympathetic preganglionic neurons projecting to the superior cervical ganglion received synapses and direct contacts from nerve fibres immunoreactive for GABA and from nerve fibres immunoreactive for glutamate. In the rat, GABA was present in 48.9% of the inputs to sympathetic preganglionic neurons projecting to the superior cervical ganglion, and glutamate was present in 51.7% of inputs. Double immunogold labelling for glutamate and GABA on the same section, as well as labelling of consecutive serial sections for the two antigens, indicated that GABA and glutamate occur in separate populations of nerve fibres that provide input to rat sympathetic preganglionic neurons projecting to the superior cervical ganglion. We now have shown that GABA or glutamate is present in virtually all of the inputs to sympathetic preganglionic neurons projecting to the superior cervical ganglion and in essentially all of the inputs to sympathetic preganglionic neurons supplying the adrenal medulla. These findings are consistent with the hypothesis that all fast synaptic transmission in central autonomic pathways may be mediated by either excitatory or inhibitory amino acids. Furthermore, we showed a statistically significant difference in the proportion of glutamate-immunoreactive inputs between sympathetic preganglionic neurons projecting to the superior cervical ganglion and sympathoadrenal neurons (data from Llewellyn-Smith et al. [Llewellyn-Smith, I.J., Phend, K.D., Minson, J.B., Pilowsky, P.M., Chalmers, J.P., 1992. Glutamate immunoreactive synapses on retrogradely labelled sympathetic neurons in rat thoracic spinal cord. Brain Res. 581, 67-80]), with preganglionics supplying the adrenal medulla receiving more excitatory inputs than those supplying the superior cervical ganglion. This increased excitatory input to sympathoadrenal neurons may explain the predominant activation of these neurons following baroreceptor unloading.
Subject(s)
Glutamic Acid/analysis , Neurons/chemistry , Superior Cervical Ganglion/chemistry , Synapses/chemistry , gamma-Aminobutyric Acid/analysis , Animals , Cholera Toxin , Glutamic Acid/immunology , Male , Microscopy, Immunoelectron , Neural Pathways , Neurons/ultrastructure , Rats , Rats, Inbred WKY , Spinal Cord/cytology , Superior Cervical Ganglion/cytology , Synapses/ultrastructure , gamma-Aminobutyric Acid/immunologyABSTRACT
AIM: To compare the efficacy of indapamide (1.25 mg daily) and low-salt diet (<100 mmol/day) separately and in combination in essential hypertensive patients with inadequate BP response to perindopril. DESIGN AND METHODS: Randomized double-blind, double-dummy, crossover design. The randomized treatments were indapamide 1.25 mg daily, sodium chloride 80 mmol daily, the combination of indapamide and sodium chloride and placebo. All patients received perindopril 4 mg daily and maintained a low-sodium diet. RESULTS: 19 patients entered and 17 completed the study. Prior to randomization, average clinic sitting blood pressure was 162/101 mm Hg and average 24-h urine sodium excretion was 157 mmol/day. Compared to the phase in which patients received perindopril with sodium repletion, clinic and ambulatory BPs were significantly reduced (p<0.01) in all the other phases. Indapamide had a greater effect on BP than dietary sodium restriction, and in combination their effects were additive. The effect of indapamide on ambulatory BP persisted throughout 24 h, but the effect of the low-salt diet was predominantly observed during waking hours. CONCLUSIONS: In hypertensives with BP resistant to the angiotensin converting enzyme (ACE) inhibitor perindopril, the diuretic indapamide had greater additional efficacy and longer duration of action than dietary sodium restriction. In combination they had additive effects on BP.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/therapeutic use , Diet, Sodium-Restricted , Diuretics/therapeutic use , Hypertension/therapy , Adolescent , Adult , Aged , Aged, 80 and over , Blood Pressure/drug effects , Body Weight/drug effects , Combined Modality Therapy , Drug Resistance , Heart Rate/drug effects , Humans , Hypertension/diet therapy , Hypertension/drug therapy , Indapamide/therapeutic use , Indoles/therapeutic use , Middle Aged , PerindoprilABSTRACT
Hypertension in the conscious rat, elicited by i.v. infusion of phenylephrine, evoked expression of the immediate early gene c-fos in discrete groups of brain stem neurons. Fos-immunoreactive neurons were located in the caudal ventrolateral medulla (CVLM); others were located in the nucleus of the tractus solitarius (NTS). Because of their sensitivity to alterations in arterial pressure, these neurons are likely to subserve the arterial baroreceptor reflex. The aim of this study was to identify the brain stem projections and the neurotransmitter content of the barosensitive CVLM neurons using neuronal tracing and immunohistochemistry. Some of the barosensitive CVLM neurons projected directly to the rostral ventrolateral medulla (RVLM), and many contained the GABA synthesizing enzyme, glutamic acid decarboxylase (GAD). Other CVLM neurons, containing markers of glutamate or catecholamine synthesis, were insensitive to baroreceptor stimulation. This study delineates neuronal pathways acting in the arterial baroreceptor reflex and identifies precisely GABA-synthesizing CVLM neurons as the source of inhibitory input to the RVLM.
Subject(s)
Baroreflex/physiology , Medulla Oblongata/metabolism , Neurons/metabolism , Proto-Oncogene Proteins c-fos/analysis , gamma-Aminobutyric Acid/biosynthesis , Animals , Blood Pressure/physiology , Brain Stem/physiology , Immunohistochemistry , Medulla Oblongata/cytology , Neural Pathways/physiology , Rats , Rats, Inbred WKYABSTRACT
The immediate early gene c-fos is a transcription regulating factor that is widely employed as a marker of neuronal activation. In this study we have used c-fos expression to identify vasomotor neurons in the brainstem and spinal cord that are activated after interventions that alter blood pressure. These neurons are likely to be those that subserve the arterial baroreceptor reflex and maintain blood pressure within a defined range. With the combination of Fos expression and neuronal tracing, we describe the location and central connections of these neurons. The differential expression of Fos in neurons in separate regions of the brainstem and spinal cord, after either hypotensive or hypertensive stimuli in conscious rats, supports current opinion about baroreflex circuitry. The central processes of baroafferent neurons synapse with second order baroreflex neurons in the nucleus tractus solitarius. From this region baroreceptor information is transmitted to neurons in the caudal ventrolateral medulla and then to neurons in the rostral ventrolateral medulla. The sympathetic preganglionic neurons in the intermediolateral column of the thoracolumbar spinal cord are the final crucial site involved in the arterial baroreflex.
Subject(s)
Baroreflex/genetics , Baroreflex/physiology , Genes, fos , Neurons/physiology , Vasomotor System/cytology , Vasomotor System/physiology , Adrenergic alpha-Agonists/administration & dosage , Animals , Brain Stem/cytology , Brain Stem/physiology , Gene Expression , Hypertension/chemically induced , Hypertension/genetics , Hypertension/physiopathology , Immunohistochemistry , Male , Medulla Oblongata/cytology , Medulla Oblongata/physiology , Nitroprusside/administration & dosage , Phenylephrine/administration & dosage , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , Rats , Rats, Inbred WKY , Solitary Nucleus/cytology , Solitary Nucleus/physiology , Spinal Cord/cytology , Spinal Cord/physiologyABSTRACT
Substance P is involved in cardiovascular control at the spinal cord level, where it acts through neurokinin-1 receptors. In this study we used immunocytochemistry and retrograde tracing to investigate the presence of the neurokinin-1 receptor and its ultrastructural localization in rat sympathetic preganglionic neurons that project to the superior cervical ganglion or the adrenal medulla. Immunofluorescence for the neurokinin-1 receptor outlined the somatic and dendritic surfaces of neurons in autonomic subnuclei of spinal cord segments T1-T12, whereas immunofluorescence for the tracer, cholera toxin B subunit, filled retrogradely labelled cells. There was a significant difference in the proportion of neurokinin-1 receptor-immunoreactive sympathetic preganglionic neurons supplying the superior cervical ganglion and the adrenal medulla. Thirty-eight percent of the neurons that projected to the superior cervical ganglion were immunoreactive for the neurokinin-1 receptor compared to 70% of neurons innervating the adrenal medulla. Of neurons projecting to the superior cervical ganglion, significantly different proportions showed neurokinin-1 receptor immunoreactivity in spinal cord segment T1 (15%) versus segments T2 T6 (45%). At the ultrastructural level, neurokinin-1 receptor staining occurred predominantly on the inner leaflets of the plasma membranes of retrogradely labelled sympathetic preganglionic neurons. Deposits of intracellular label were often observed in dendrites and in the rough endoplasmic reticulum and Golgi apparatus of cell bodies. Neurokinin-1 receptor immunoreactivity was present at many, but not all, synapses as well as at non-synaptic sites, and occurred at synapses with substance P-positive as well as substance P-negative nerve fibres. Only 37% of the substance P synapses occurred on neurokinin-1-immunoreactive neurons in the intermediolateral cell column. These results show that presence of the neurokinin-1 receptor in sympathetic preganglionic neurons is related to their target. The ultrastructural localization of the receptor suggests that sympathetic preganglionic neurons may be affected (i) by substance P released at neurokinin-1 receptor-immunoreactive synapses, (ii) by other tachykinins (e.g., neurokinin A), which co-localize in substance P fibres in the intermediolateral cell column, acting through other neurokinin receptors, and (iii) by substance P that diffuses to neurokinin-1 receptors from distant sites.
Subject(s)
Adrenergic Fibers/chemistry , Neurons/chemistry , Receptors, Neurokinin-1/immunology , Adrenal Medulla/innervation , Adrenergic Fibers/ultrastructure , Animals , Female , Fluorescent Antibody Technique , Male , Microscopy, Electron , Neurons/ultrastructure , Rats , Rats, Inbred WKY , Receptors, Neurokinin-1/analysis , Receptors, Neurokinin-1/ultrastructure , Spinal Cord/chemistry , Spinal Cord/cytology , Substance P/analysis , Substance P/immunology , Superior Cervical Ganglion/cytology , Synapses/chemistry , Synapses/ultrastructureABSTRACT
OBJECTIVE: To compare with placebo the efficacies of once-daily administrations of lacidipine and hydrochlorothiazide separately and in combination to elderly patients with systolic hypertension. DESIGN AND METHODS: Nineteen elderly subjects (five men and 14 women, median age 71 years, range 62-79 years) participated in the study, which had a randomized double-blind crossover design. For each subject there were four treatment phases, each of duration 4 weeks. The initial treatments in each phase were 2 mg lacidipine once a day and 25 mg hydrochlorothiazide once a day, separately and in combination, and placebo. Doses of each agent could be doubled after 2 weeks in each phase if the patient's goal systolic blood pressure had not been achieved. The numbers of subjects administered the higher dose of each treatment were 13 for placebo, 14 for lacidipine, 11 for hydrochlorothiazide and eight for lacidipine plus hydrochlorothiazide. RESULTS: End-of-phase mean clinic blood pressures were 164/85 mmHg with placebo, 159/82 mmHg with lacidipine, 157/84 mmHg with hydrochlorothiazide and 152/82 mmHg with lacidipine plus hydrochlorothiazide. Systolic blood pressure was significantly reduced during all active treatment phases compared with placebo and that for the lacidipine plus hydrochlorothiazide phase was also significantly less than those for both of the other active treatment phases. There was no difference between sitting and standing blood pressure for any phase. Factorial analysis of the main effects of treatment indicated that the effects of lacidipine and hydrochlorothiazide on clinic blood pressure were additive and also that heart rate was higher when hydrochlorothiazide had been administered. Ambulatory blood pressure monitoring confirmed the pattern of the responses of blood pressure and showed that administration of hydrochlorothiazide had a significantly greater effect on systolic blood pressure and a longer duration of action than did administration of lacidipine. There was no difference in the frequency of adverse effects among any of the phases. CONCLUSIONS: In treating elderly systolic hypertensives the diuretic hydrochlorothiazide is a more effective antihypertensive agent with a longer duration of action than is the calcium channel antagonist lacidipine. In combination the effects of these two drugs on blood pressure are additive.
Subject(s)
Antihypertensive Agents/therapeutic use , Dihydropyridines/therapeutic use , Hydrochlorothiazide/therapeutic use , Hypertension/drug therapy , Aged , Aged, 80 and over , Aorta/physiopathology , Blood Pressure/drug effects , Cross-Over Studies , Dihydropyridines/adverse effects , Double-Blind Method , Drug Combinations , Female , Heart Rate/drug effects , Humans , Hydrochlorothiazide/adverse effects , Hypertension/physiopathology , Male , Middle Aged , Monitoring, Ambulatory , SystoleABSTRACT
1. We have used microinjections of glutamate, an ionotropic excitatory amino acid receptor antagonist (kynurenate) and selective ionotropic (NMDA and kainate) and metabotropic (1S-3R-ACPD, trans-ACPD and L-AP4) receptor agonists in the thoracic IML of the rat to define the receptors mediating the tachycardia produced by excitatory amino acid antagonists. 2. Injection of glutamate (delta heart rate = 76 +/- 8 beats/min n = 16), NMDA (delta heart rate = 116.5 +/- 5 beats/min n = 6) or kainate (delta heart rate = 92 +/- 22 beats/min n =6 evokes a tachycardia when injected into the thoracic intermediolateral column. Kynurenate blocked the response to NMDA (-2% of initial response) and markedly attenuated the response to kainate (14% of initial response) but did not alter the response to glutamate (106% of initial response). 3. IS-3R-ACPD did not elicit a tachycardia when injected into the thoracic intermediolateral column and neither trans-ACPD nor L-AP4 induced a tachycardia after kynurenate injection into the thoracic intermediolateral column. 4. Thus stimulation of either NMDA or AMPA/kainate receptors elicits tachycardia in rat thoracic spinal cord but glutamate also activates another receptor type to elicit a tachycardia. The lack of a tachycardia when trans-ACPD, 1S-3R-ACPD or L-AP4 were injected into the thoracic spinal cord suggests that the kynurenate resistant tachycardia elicited by glutamate is not mediated by metabotropic receptors. The kynurenate resistant tachycardia elicited by glutamate is not mediated by any of the known excitatory amino acid receptor types.
Subject(s)
Excitatory Amino Acid Agonists/pharmacology , Excitatory Amino Acid Antagonists/pharmacology , Glutamic Acid/pharmacology , Kynurenic Acid/pharmacology , Spinal Cord/drug effects , Tachycardia/chemically induced , Aminobutyrates/pharmacology , Analysis of Variance , Animals , Blood Pressure/drug effects , Cycloleucine/analogs & derivatives , Cycloleucine/pharmacology , Heart Rate/drug effects , Injections, Spinal , Kainic Acid/pharmacology , N-Methylaspartate/antagonists & inhibitors , N-Methylaspartate/pharmacology , Rats , Rats, Inbred WKY , Receptors, Metabotropic Glutamate/agonists , Tachycardia/prevention & controlABSTRACT
We have investigated the effects of microinjection of L-glutamate, D-serine and glycine into the caudal ventrolateral medulla (CVLM) of spontaneously hypertensive (SHR) and Wistar Kyoto (WKY) rats. In SHR the depressor responses to L-glutamate were significantly enhanced compared to WKY rats, while those to the NMDA-glycine site agonists, D-serine and glycine (in the presence of strychnine) were significantly diminished. Depressor responses to NMDA and D-serine could be blocked with 5-fluro-indole-2-carboxylic acid (FICA, an NMDA-glycine site antagonist). In support of our previous findings, the larger responses of NMDA-glutamate site agonists and smaller responses of NMDA-glycine site agonists in SHR, may suggest that SHR have reduced levels of the endogenous glutamate antagonist, kynurenic acid.
Subject(s)
Glutamic Acid/pharmacology , Hypertension/drug therapy , Medulla Oblongata/drug effects , Neurons/drug effects , Receptors, Glycine/agonists , Serine/pharmacology , Animals , Blood Pressure/physiology , Hypertension/physiopathology , Kynurenic Acid/metabolism , Medulla Oblongata/cytology , Microinjections , Rats , Rats, Inbred SHR , Rats, Inbred WKY , StereoisomerismABSTRACT
The immediate early genes c-fos and c-jun are transcription regulating factors. c-fos expression is widely used as a marker of neuronal activation and has been used in this study to identify those neurons, presumably vasomotor neurons, that are activated after interventions that alter blood pressure. c-fos and c-jun are expressed in the rostral ventral medulla (RVM) when the tonically active inhibitory inputs to the RVM are removed, either acutely or chronically, as in the SHR model of gentic hypertension. The injection of antisense oligonucleotide complementary to c-fos mRNA in the RVM attenuates the expression of c-fos, lowers resting blood pressure and attenuates blood pressure responses that are evoked via RVM mechanisms. These studies suggest a link between immediate early gene expression in neurons in the RVM and the regulation of blood pressure. c-fos could have an important role in regulating the activity of these central cardiovascular neurons. The role of the immediate early gene c-jun in cardiovascular control remains to be elucidated.
Subject(s)
Blood Pressure/genetics , Genes, Immediate-Early , Animals , Base Sequence , Blood Pressure/physiology , Gene Expression/drug effects , Genes, Immediate-Early/drug effects , Genes, fos/drug effects , Genes, jun/drug effects , Male , Medulla Oblongata/drug effects , Medulla Oblongata/physiology , Molecular Sequence Data , Nitroprusside/pharmacology , Oligonucleotides, Antisense/genetics , Oligonucleotides, Antisense/pharmacology , Proto-Oncogene Proteins c-fos/genetics , Proto-Oncogene Proteins c-fos/metabolism , Proto-Oncogene Proteins c-jun/genetics , Proto-Oncogene Proteins c-jun/metabolism , Rats , Rats, Inbred SHR , Rats, Inbred WKYABSTRACT
Blood flow in the renal artery, superior mesenteric artery and infra-renal abdominal aorta of conscious rabbits was measured by Doppler ultrasound. Arterial pressure, heart rate and blood flow responses were assessed following 0.2 and 0.8 nmol/kg intravenous endothelin-1. The effects of the following antagonists on these responses were examined: phentolamine, propranolol, scopolamine, captopril, nifedipine, indomethacin, the V1-vasopressin receptor antagonist d(CH2)5Tyr(Me)AVP and the competitive nitric oxide (NO) synthase inhibitor NG-nitro L-arginine (NOLA). Hindlimb resistance and arterial pressure responded in two phases, initial vasodilatation followed by vasoconstriction. Renal and mesenteric vasoconstriction occurred without initial vasodilatation. Following 0.2 nmol/kg endothelin-1, arterial pressure decreased by 18.5 +/- 0.8 mmHg, then increased by 25.2 +/- 1.7 mmHg (n = 27). Heart rate changed reciprocally. Renal resistance increased by 533 +/- 73% (n = 12). Mesenteric resistance increased by 420 +/- 34%. Hindlimb resistance decreased 54 +/- 2% (n = 12, all P < 0.01) then increased slightly (P < 0.05). All changes were greater at 0.8 nmol/kg, particularly the hindlimb vasoconstriction. The only antagonist to alter significantly these responses was NOLA, which in the hindlimb attenuated the vasodilatation and accentuated the vasoconstriction. We conclude that most of the haemodynamic effects of endothelin-1 are direct, but that NO generated by NO synthase causes part of the hindlimb vasodilatation, and that endothelin-1-induced vasoconstriction is attenuated by release of NO.
Subject(s)
Endothelin-1/pharmacology , Hindlimb/blood supply , Renal Circulation/drug effects , Splanchnic Circulation/drug effects , Animals , Blood Pressure/drug effects , Endothelin-1/antagonists & inhibitors , Heart Rate/drug effects , Hemodynamics/drug effects , Male , RabbitsABSTRACT
OBJECTIVES: To explore the rat caudal raphe nuclei for neurons that respond to activation of baroreceptor nerves and that have a spinal axon, and to compare the behavioural properties of barosensitive bulbospinal neurons in the rat caudal raphe with the properties of barosensitive bulbospinal neurons in the rostral ventrolateral medulla. DESIGN: Extracellular unit recordings were obtained from an area extending up to 1.0 mm caudally from the caudal edge of the facial nucleus. Two sites were explored: the rostral ventrolateral medulla and the midline. MATERIALS AND METHODS: Single-unit recordings were made in anaesthetized (75 mg/kg chloral hydrate and 30 mg/kg sodium pentobarbitone then 3-6 mg intravenously as required), immobilized (2 mg pancuronium as required) Sprague-Dawley rats. Central respiratory drive was recorded from phrenic nerve discharge. The barosensitivity of single units was assessed by R-wave triggered histograms and by histograms of their responses to aortic nerve stimulation or to intravenous injection of phenylephrine. Nociceptors were activated by a brief pinch of the tail. RESULTS: Eleven spontaneously active units in the midline that were inhibited by baroreceptor stimulation and had a spinal axon were studied. Respiratory modulation was present and was predominantly inspiratory. Barosensitive neurons in the rostral ventrolateral medulla were activated by nociceptive inputs; midline barosensitive neurons were not. CONCLUSIONS: The behavioural characteristics of midline neurons differ from those of the bulbospinal barosensitive neurons in the rostral ventrolateral medulla, indicating that raphe spinal neurons have different sets of afferent inputs and may subserve to a distinct physiological role. The present paper is the first report of bulbospinal neurons in the rat caudal raphe that are inhibited by activation of arterial baroreceptors.
Subject(s)
Adrenergic Fibers/physiology , Heart/innervation , Pressoreceptors/metabolism , Raphe Nuclei/physiology , Serotonin/metabolism , Spinal Cord/physiology , Animals , Electric Stimulation , Electrocardiography , Heart/physiology , Male , Raphe Nuclei/anatomy & histology , Rats , Rats, Sprague-DawleyABSTRACT
This study tested the hypothesis that treatment with a nonsteroidal anti-inflammatory drug will not alter the hypotensive effect of a dihydropyridine calcium channel antagonist. Fifteen essential hypertensives (ages 58-80 years) had a supine diastolic blood pressure (DBP) < 100 mmHg after 4 weeks monotherapy with nitrendipine 5-20 mg twice daily. They entered a double-blind randomised crossover study in which the addition of indomethacin 25 mg three times daily was compared with placebo in treatment phases each of 4 weeks duration. Subjects were seen weekly and measurements in the last 2 weeks of each phase were compared. Supine blood pressure (mean +/- SE) was higher in the indomethacin phase (158 +/- 4/80 +/- 2) than in the placebo phase (154 +/- 4/76 +/- 3) (p < 0.01 for DBP). In 6/15 (40%) of subjects the increase in supine diastolic blood pressure with indomethacin was > 5 mmHg. Plasma urea was also increased in the indomethacin phase: 7.6 +/- 0.6 mmol/l compared with placebo: 6.3 +/- 0.5 mmol/l (p < 0.001). The study has demonstrated that concurrent treatment with the NSAID indomethacin impairs the blood pressure lowering effect of the dihydropyridine calcium channel antagonist nitrendipine. This increase in blood pressure with indomethacin in subjects treated with nitrendipine may represent either an independent pressor effect of indomethacin or a reduced vasodilator prostanoid contribution to the hypotensive effect of nitrendipine. This blood pressure increase may be sufficient to interfere significantly with clinical blood pressure control in some subjects.
Subject(s)
Blood Pressure/drug effects , Hypertension/drug therapy , Indomethacin/therapeutic use , Nitrendipine/therapeutic use , Aged , Aged, 80 and over , Analysis of Variance , Body Weight/drug effects , Double-Blind Method , Female , Heart Rate/drug effects , Humans , Indomethacin/adverse effects , Male , Middle AgedABSTRACT
The synaptic input from glutamate- or gamma-aminobutyric acid (GABA)-immunoreactive nerve fibers to sympathetic preganglionic neurons projecting to the superior cervical ganglion was assessed using retrograde tracing with cholera toxin B subunit and post-embedding immunogold labelling. Half the boutons that synapsed on or directly contacted this group of neurons were immunoreactive for glutamate and half were immunoreactive for GABA. In previous studies, about 2/3 of the synapses on sympathoadrenal neurons were found to be glutamate-immunoreactive and about 1/3, GABA immunoreactive and these two amino acids were not co-localized. Thus, 100% of the boutons that synapse on sympathetic preganglionic neurons supplying the superior cervical ganglion or the adrenal medulla are likely to contain either glutamate or GABA. Anterograde tracing combined with amino acid immunocytochemistry indicated that at least some glutamate-containing and some GABA-containing nerve fibers in the intermediolateral cell column could come from the rostral ventral medulla.