Ahmmed Ally

Ventrolateral medullary control of cardiovascular activity during muscle contraction

An overview of the role of ventrolateral medulla (VLM) in regulation of cardiovascular activity is presented. A summary of VLM anatomy and its functional relation to other areas in the central nervous system is described. Over the past few years, various studies have investigated the VLM and its involvement in cardiovascular regulation during static muscle contraction, a type of static exercise as seen, for example, during knee extension or hand-grip exercise. Understanding the neural mechanisms that are responsible for regulation of cardiovascular activity during static muscle contraction is of particular interest since it helps understand circulatory adjustments in response to an increase in physical activity. This review surveys the role of several receptors and neurotransmitters in the VLM that are associated with changes in mean arterial pressure and heart rate during static muscle contraction in anesthetized animals. Possible mechanisms in the VLM that modulate cardiovascular changes during static muscle contraction are summarized and discussed. Localized administration of an excitatory amino-acid antagonist into the rostral portion of the VLM (RVLM) attenuates increases in blood pressure and heart rate during static muscle contraction, whereas its administration into the caudal part of the VLM (CVLM) augments these responses. Opioid or 5-HT1A receptor stimulation in the RVLM, but not in the CVLM, attenuates cardiovascular responses to muscle contraction. Furthermore, intravenous, intracerebroventricular or intracisternal injection of an alpha 2-adrenoceptor agonist or a cholinesterase inhibitor attenuates increases in blood pressure and heart rate during static muscle contraction. Finally, the possible involvement of endogenous neurotransmitters in the RVLM and the CVLM associated with cardiovascular responses during static muscle contraction is discussed. An overview of the role of the VLM in the overall cardiovascular control network in the brain is presented and critically reviewed.

Glutamate neurotransmission and nitric oxide interaction within the ventrolateral medulla during cardiovascular responses to muscle contraction.

We previously reported that nitric oxide, within the RVLM and CVLM, plays an opposing role in modulating cardiovascular responses during static muscle contraction [B.J. Freda, R.S. Gaitonde, R. Lillaney, A. Ally, Cardiovascular responses to muscle contraction following microdialysis of nitric oxide precursor into ventrolateral medulla, Brain Res. 828 (1999) 60-67]. In this study, we determined whether the effects of administering L-arginine, a precursor for the synthesis of nitric oxide, and N(G)-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase inhibitor, into the rostral (RVLM) and caudal (CVLM) ventrolateral medulla on cardiovascular responses elicited during static muscle contraction were mediated via an alteration of localized glutamate concentrations using microdialysis techniques. In experiments within the RVLM (n=8), muscle contraction increased MAP and HR by 21+/-2 mmHg and 22+/-3 bpm, respectively. Glutamate increased from 1.1+/-0.4 to 4.4+/- 0.6 ng/5 microl measured from bilateral RVLM areas. Microdialysis of L-arginine (1.0 microM) for 30 min attenuated the contraction-evoked increases in MAP, HR, and glutamate levels. After subsequent microdialysis of L-NMMA (1.0 microM) into the RVLM, contraction augmented the pressor and tachycardic responses and glutamate release. In experiments within CVLM (n=8), muscle contraction increased MAP and HR by 22+/-3 mmHg and 20+/-2 bpm, respectively. Glutamate increased from 0.8+/-0. 4 to 3.6+/-0.6 ng/5 microl measured from the CVLM. L-Arginine augmented the cardiovascular responses and glutamate release and L-NMMA attenuated all the effects. Results suggest that nitric oxide within the RVLM and CVLM plays opposing roles in modulating cardiovascular responses during static exercise via decreasing and increasing, respectively, extracellular glutamate levels.

Rostral ventrolateral medulla opioid receptor activation modulates glutamate release and attenuates the exercise pressor reflex

We previously reported that the administration of [D-Ala(2)]methionine enkephalinamide (DAME), an opioid receptor agonist, into the rostral (RVLM) but not into the caudal ventrolateral medulla (CVLM), attenuated increases in mean arterial pressure (MAP) and heart rate (HR) during static muscle contraction that had been blocked by prior microdialysis of the opioid receptor antagonist, naloxone [Am. J. Physiol. 274 (1998) H139-H146]. In this study, we determine whether this RVLM-mediated opioidergic-modulation of cardiovascular responses is associated with localized changes in extracellular concentrations of glutamate, an excitatory amino acid, using microdialysis techniques in anesthetized rats. Muscle contraction increased MAP and HR by 37+/-5 mmHg and 23+/-3 bpm, respectively. Extracellular glutamate concentrations, determined using HPLC-ECD, increased from 0.8+/-0.2 to 6.6+/-1.2 ng/5 microliter in the bilateral RVLM areas. Microdialysis of DAME (100 microM) for 30 min attenuated the contraction-evoked increases in MAP, HR, and glutamate levels (20+/-4 mmHg, 10+/-2 bpm, and 1.8+/-0.2 ng/5 microliter, respectively). After microdialysis of naloxone (100 microM) for 30 min into the RVLM, muscle contraction blocked the attenuations (35+/-5 mmHg, 26+/-4 bpm, and 5.8+/-1.0 ng/5 microliter, respectively). Developed muscle tensions were similar throughout the protocol (676+/-38, 678+/-37 and 687+/-37 g, respectively). These results suggest that an opioidergic receptor-mediated mechanism within the RVLM attenuates cardiovascular responses during static exercise via modulating extracellular concentrations of glutamate in the RVLM.

Cardiovascular responses to muscle contraction following microdialysis of nitric oxide precursor into ventrolateral medulla

We determined the effects of administering L-arginine, a precursor for the synthesis of nitric oxide, and L-NMMA (NG-monomethyl-L-arginine), a nitric oxide synthase blocker, into the rostral (RVLM) and caudal (CVLM) ventrolateral medulla on cardiovascular responses elicited during static contraction of the triceps surae muscle. Two microdialysis probes were inserted bilaterally into the RVLM or CVLM of anesthetized Sprague-Dawley rats using stereotaxic guides. For RVLM experiments, static muscle contraction evoked by stimulation of the tibial nerve increased mean arterial pressure (MAP) and heart rate (HR) by 29+/-3 mmHg and 44+/-7 bpm, respectively (n=8). Microdialysis of L-arginine (1.0 microM) for 30 min attenuated the contraction-evoked increases in MAP and HR. After discontinuing L-arginine, L-NMMA (1.0 microM) was microdialyzed into the RVLM for an additional 30 min followed by a muscle contraction. This contraction augmented the pressor response (37+/-4 mmHg) and HR (61+/-11 bpm) with respect to control values. For CVLM experiments, muscle contraction increased MAP and HR by 23+/-3 mmHg and 25+/-5 bpm, respectively (n=9). Microdialysis of L-arginine (1.0 microM) for 30 min potentiated the contraction-evoked increases in MAP and HR. Subsequent administration of L-NMMA (1.0 microM) into the CVLM for an additional 30 min blocked the augmented MAP and HR responses. Developed tensions did not alter during contractions throughout both RVLM and CVLM protocols. These results suggest that nitric oxide, within the RVLM and CVLM, plays an opposing role in modulating cardiovascular responses during static muscle contraction.

Changes in extracellular glutamate and pressor response during muscle contraction following AMPA-receptor blockade in the RVLM and CVLM

We examined whether modulation of cardiovascular responses by administering 6-cyano-7-nitroquinoxaline-2,3-dione (CNQX, an AMPA-receptor antagonist) into the rostral (RVLM) or caudal (CVLM) ventrolateral medulla are mediated via changes in extracellular levels of glutamate. Microdialysis probes were inserted bilaterally into the RVLM or the CVLM. For the RVLM experiments (n=8), muscle contraction for 2 min increased mean arterial pressure (MAP) and heart rate (HR) by 18+/-3 mmHg and 24+/-5 bpm, respectively. Extracellular glutamate concentrations increased from 1.5+/-0.3 to 4.3+/-0.9 ng/5 microl during the contraction. Microdialysis of CNQX (1.0 microM) for 30 min into the RVLM attenuated the increases in MAP, HR, and glutamate concentration in response to a muscle contraction (8+/-2 mmHg, 11+/-3 bpm, and 2.2+/-0.7 ng/5 microl, respectively). Developed tensions did not change during contractions before and after CNQX. Microdialysis of CNQX into the CVLM (n=8) potentiated the contraction-evoked responses in MAP (19+/-3 vs. 34+/-3 mmHg) and HR (25+/-4 vs. 49+/-5 bpm) without a change in developed tension. Following CNQX perfusion into the CVLM, the levels of extracellular glutamate in the CVLM were also augmented during the contraction. Results suggests that AMPA-receptors within the RVLM and CVLM differentially modulate cardiovascular responses during static muscle contraction via increasing and decreasing, respectively, extracellular glutamate concentrations.

Modulation of extracellular glutamate and pressor response to muscle contraction during NMDA-receptor blockade in the rostral ventrolateral medulla.

Recently our laboratory demonstrated increases in extracellular glutamate concentrations within the rostral ventrolateral medulla (RVLM) during static muscle contraction (Caringi, D.C., Maher, T., Chaiyakul, P., Asmundsson, G., Ishide, T., Ally, A. Pflügers Arch. Eur. J. Physiol., 435:465-471, 1998). In this study, we determined effects of microdialyzing D(-)2-amino-7-phosphonohepatanoic acid (AP-7), an NMDA-receptor antagonist, into the RVLM on changes in mean arterial pressure (MAP), heart rate (HR), and extracellular glutamate levels during muscle contraction in anesthetized rats. Bilateral placements of microdialysis probes into the RVLM were verified by perfusing L-glutamate and obtaining a pressor response. Muscle contraction for 2 min, increased MAP and HR by 22+/-4 mmHg and 28+/-5 bpm, respectively. Extracellular glutamate as determined by microdialysis increased from 0.8+/-0.2 to 6.3+/-1.2 ng/5 microl. Microdialysis of AP-7 (1.0 microM) for 30 min inhibited contraction-evoked MAP and HR responses (10+/-3 mmHg and 13+/-3 bpm) and attenuated increases in glutamate during muscle contraction. Developed tensions did not differ during contractions before and after AP-7. Results demonstrate that NMDA-receptor blockade in the RVLM inhibits cardiovascular responses during static muscle contraction via a reduction in extracellular glutamate levels.

Effects of nitric oxide and GABA interaction within ventrolateral medulla on cardiovascular responses during static muscle contraction.

We hypothesized that nitric oxide (NO) has opposing roles in regulating cardiovascular responses within the rostral (RVLM) and caudal (CVLM) ventrolateral medulla by modulating release of gamma-aminobutyric acid (GABA). We have measured GABA concentrations within the RVLM and CVLM during increases in mean arterial pressure (MAP) and heart rate (HR) following a 2-min tibial nerve stimulation-evoked static muscle contraction before and after microdialysis of the NO precursor, L-arginine (1.0 microM), for 30 min, and after the NO inhibitor, L-NMMA (1.0 microM), for 30 min. In eight anesthetized rats, muscle contraction significantly increased MAP, HR and GABA levels within the RVLM area (from 0.53+/-0.09 to 1.22+/-0.10 ng/10 microl). Following microdialysis of L-arginine, muscle contraction augmented GABA levels (from 0.45+/-0.07 to 2.18+/-0.09 ng/10 microl) and attenuated changes in MAP and HR. Subsequent application of L-NMMA significantly decreased GABA levels (from 0.47+/-0.08 to 0.22+/-0.07 ng/10 microl) but potentiated MAP and HR responses to a muscle contraction. In contrast, muscle contraction significantly increased MAP and HR but decreased GABA concentrations within the CVLM (from 1.20+/-0.20 to 0.78+/-0.17 ng/10 microl). Following microdialysis of L-arginine, muscle contraction significantly attenuated GABA levels (from 1.34+/-0.19 to 0.33+/-0.10 ng/10 microl) and augmented changes in MAP and HR in response to muscle contraction. A subsequent microdialysis of L-NMMA into the CVLM reversed the effects of L-arginine. These results demonstrate that NO within the RVLM and CVLM differentially modulates cardiovascular responses during static muscle contraction and that NO influences exercise-induced cardiovascular responses by modulating GABA release within the ventrolateral medulla.

Cardiovascular responses and neurotransmitter changes following blockade of nNOS within the ventrolateral medulla during static muscle contraction.

Nitric oxide (NO) is synthesized from L-arginine through the activity of the synthetic enzyme, NO synthase (NOS). Previous studies have demonstrated the roles of the three isoforms of NOS, namely endothelial NOS (eNOS), neuronal NOS (nNOS), and inducible NOS (iNOS) in cardiovascular regulation. However, no investigation has been done to study their individual role in modulating cardiovascular responses during static skeletal muscle contraction. In this study, we determined the effects of microdialyzing a specific nNOS antagonist into the rostral (RVLM) and caudal ventrolateral medulla (CVLM) on cardiovascular responses and glutamatergic/GABAergic neurotransmission during the exercise pressor reflex using rats. We hypothesized that the NO modulation of the exercise pressor reflex was largely influenced by specific nNOS activity within the ventrolateral medulla. Bilateral microdialysis of a selective nNOS antagonist, 1-(2-trifluoromethylphenyl)-imidazole (1.0 microM), for 30 or 60 min into the RVLM potentiated cardiovascular responses and glutamate release during a static muscle contraction. Levels of GABA within the RVLM were decreased. The cardiovascular responses and neurochemical changes to muscle contraction recovered following discontinuation of the drug. In contrast, bilateral application of the nNOS antagonist into CVLM attenuated cardiovascular responses and glutamate release during a static muscle contraction, but augmented GABA release. These results demonstrate that nNOS in the ventrolateral medulla plays an important role in modulating glutamatergic/GABAergic neurotransmission that regulates the exercise pressor reflex, and contributes to the sympathoexcitatory and sympathoinhibitory actions of NO within the RVLM and CVLM, respectively.

Rostral ventrolateral medullary opioid receptor activation modulates pressor response to muscle contraction

The effects of an opioid agonist, [D-Ala2]methionine enkephalinamide (DAME), administered into the rostral ventrolateral medulla (rVLM) or caudal ventrolateral medulla (cVLM) on cardiovascular responses to isometric muscle contraction were determined in anesthetized rats. A 30-s contraction evoked by tibial nerve stimulation increased mean arterial pressure (MAP) and heart rate (HR) by 34 +/- 6 mmHg and 40 +/- 7 beats/min, respectively, with a developed tension of 322 +/- 30 g, after bilateral insertion of microdialysis probes into the rVLM. Thirty-minute dialysis of DAME (10 and 100 microM) attenuated the contraction-evoked cardiovascular changes dose dependently (10 microM: MAP = 25 +/- 4 mmHg, HR = 27 +/- 3 beats/min, tension = 333 +/- 25 g; 100 microM: MAP = 14 +/- 4 mmHg, HR = 16 +/- 5 beats/min, tension = 330 +/- 34 g). Preadministration of an opioid antagonist, naloxone (100 microM), augmented contraction-evoked MAP and HR responses and blocked effects of 100 microM DAME. Microdialysis of DAME into the cVLM produced no changes in the pressor response to contraction. At end of each experiment, tibial nerve stimulation after neuromuscular blockade evoked no MAP or HR change. Results demonstrate that opioid receptor activation within the rVLM modulates cardiovascular responses to isometric muscle contraction.The effects of an opioid agonist, [d-Ala2]methionine enkephalinamide (DAME), administered into the rostral ventrolateral medulla (rVLM) or caudal ventrolateral medulla (cVLM) on cardiovascular responses to isometric muscle contraction were determined in anesthetized rats. A 30-s contraction evoked by tibial nerve stimulation increased mean arterial pressure (MAP) and heart rate (HR) by 34 ± 6 mmHg and 40 ± 7 beats/min, respectively, with a developed tension of 322 ± 30 g, after bilateral insertion of microdialysis probes into the rVLM. Thirty-minute dialysis of DAME (10 and 100 μM) attenuated the contraction-evoked cardiovascular changes dose dependently (10 μM: MAP = 25 ± 4 mmHg, HR = 27 ± 3 beats/min, tension = 333 ± 25 g; 100 μM: MAP = 14 ± 4 mmHg, HR = 16 ± 5 beats/min, tension = 330 ± 34 g). Preadministration of an opioid antagonist, naloxone (100 μM), augmented contraction-evoked MAP and HR responses and blocked effects of 100 μM DAME. Microdialysis of DAME into the cVLM produced no changes in the pressor response to contraction. At end of each experiment, tibial nerve stimulation after neuromuscular blockade evoked no MAP or HR change. Results demonstrate that opioid receptor activation within the rVLM modulates cardiovascular responses to isometric muscle contraction.

Simultaneous glutamate and γ-aminobutyric acid release within ventrolateral medulla during skeletal muscle contraction in intact and barodenervated rats

The purpose of this study was to determine if baroreflex modulates cardiovascular responses and neurotransmitter release within rostral (RVLM) and caudal (CVLM) ventrolateral medulla during static contraction of skeletal muscle using anesthetized rats. We evoked cardiovascular responses by a static muscle contraction and measured simultaneous release of glutamate and gamma-aminobutyric acid (GABA) in both the RVLM and CVLM using microdialysis probes, two inserted bilaterally into the RVLM and two into the CVLM. In intact anesthetized rats, a muscle contraction increased release of glutamate concomitantly in both the RVLM and CVLM along with significant increases in heart rate and arterial blood pressure. In contrast, concentrations of GABA increased within the RVLM, but decreased significantly within the CVLM during the pressor response. These changes were due to contraction-evoked activation of muscle afferents since tibial nerve stimulation following muscle paralysis failed to evoke glutamate, GABA, or any cardiovascular changes. On the other hand, static muscle contractions in baroreceptor denervated rats augmented the increases in heart rate and blood pressure. Furthermore, muscle contraction significantly enhanced the release of glutamate in the RVLM but attenuated its release in the CVLM. In addition, concentrations of GABA within the RVLM were attenuated following a muscle contraction in denervated rats without any changes in GABA within the CVLM. These results demonstrate that the baroreceptors influence cardiovascular responses to static muscle contraction associated with dynamic changes in glutamate and GABA release within the RVLM and CVLM.