Cardioaccelerator Responses Research Articles

Peripheral δ-opioid receptors attenuate the exercise pressor reflex

In rats with ligated femoral arteries, the exercise pressor reflex is exaggerated, an effect that is attenuated by stimulation of peripheral μ-opioid receptors on group IV metabosensitive afferents. In contrast, δ-opioid receptors are expressed mostly on group III mechanosensitive afferents, a finding that prompted us to determine whether stimulation of these opioid receptors could also attenuate the exaggerated exercise pressor reflex in "ligated" rats. We found femoral arterial injection of [D-Pen2,D-Pen5]enkephalin (DPDPE; 1.0 μg), a δ-opioid agonist, significantly attenuated the pressor and cardioaccelerator components of the exercise pressor reflex evoked by hindlimb muscle contraction in both rats with ligated and patent femoral arteries. DPDPE significantly decreased the pressor responses to muscle mechanoreflex activation, evoked by tendon stretch, in ligated rats only. DPDPE (1.0 μg) had no effect in either group on the pressor and cardioaccelerator responses to capsaicin (0.2 μg), which primarily stimulates group IV afferents. DPDPE (1.0 μg) had no effect on the pressor and cardioaccelerator responses to lactic acid (24 mM), which stimulates group III and IV afferents, in rats with patent femoral arteries but significantly decreased the pressor response in ligated rats. Western blots revealed the amount of protein comprising the δ-opioid receptor was greater in dorsal root ganglia innervating hindlimbs with ligated femoral arteries than in dorsal root ganglia innervating hindlimbs with patent femoral arteries. Our findings support the hypothesis that stimulation of δ-opioid receptors on group III afferents attenuated the exercise pressor reflex.

Activation of melanocortin receptors in the intermediolateral cell column of the upper thoracic cord elicits tachycardia in the rat

Melanocortin receptors (MCRs) are present in the intermediolateral cell column of the spinal cord (IML). We tested the hypothesis that activation of MCRs in the IML elicits cardioacceleratory responses and the source of melanocortins in the IML may be the melanocortin-containing neurons in the hypothalamic arcuate nucleus (ARCN). Experiments were done in urethane-anesthetized, artificially ventilated adult male Wistar rats. Microinjections (50 nl) of α-melanocyte stimulating hormone (α-MSH) (0.4-2 mM) and adrenocorticotropic hormone (ACTH) (0.5-2 mM) into the right IML elicited increases in heart rate (HR). These tachycardic responses were blocked by microinjections of melanocortin receptor 4 (MC4R) antagonists [SHU9119 (0.25 mM) or agouti-related protein (AGRP, 0.1 mM)] into the right IML. Stimulation of right ARCN by microinjections (30 nl) of N-methyl-d-aspartic acid (NMDA, 10 mM) elicited increases in HR. Blockade of MC4Rs in the ipsilateral IML at T1-T3 using SHU9119 (0.25 mM) attenuated the tachycardic responses elicited by subsequent microinjections of NMDA into the ipsilateral ARCN. ARCN neurons retrogradely labeled by microinjections of Fluoro-Gold into the right IML showed immunoreactivity for proopiomelanocortin (POMC), α-MSH, and ACTH. Fibers immunoreactive for POMC, α-MSH, and ACTH were present in the IML at T1-T3. These results indicated that activation of MC4Rs in the right IML elicited tachycardia and one of the sources of melanocortins in the IML is the ARCN. Melanocortin levels are elevated in stress and ARCN neurons are activated during stress. Our results allude to the possibility that cardiac effects of stress may be mediated via melanocortin containing ARCN neurons that project to the IML.

Spinal cord GABA receptors modulate the exercise pressor reflex in decerebrate rats

Neurotransmitters and neuromodulators released by contraction-activated skeletal muscle afferents into the dorsal horn of the spinal cord initiate the central component of the exercise pressor reflex (EPR). Whether γ-aminobutyric acid (GABA), a major inhibitory neurotransmitter within the mammalian central nervous system, is involved in the modulation of the EPR at the level of dorsal horn remains to be determined. We performed local microinjection of either the GABA(A) antagonist bicuculline or the GABA(B) antagonist CGP 52432 into the ipisilateral L4/L5 dorsal horns to investigate the effect of GABA receptor blockade on the pressor response to either static contraction induced by stimulation of the peripheral end of L4/L5 ventral roots, passive stretch, or hindlimb arterial injection of capsaicin (0.1 μg/0.2 ml) in decerebrate rats. Microinjection of either bicuculline (1 mM, 100 nl) or CGP 52432 (10 mM, 100 nl) into the L4/5 dorsal horns significantly increased the pressor and cardioaccelerator responses to all stimuli. Microinjection of either bicuculline or CGP 52432 into the L5 dorsal horn significantly increased the pressor and cardioaccelerator responses to direct microinjection of l-glutatmate (10 mM, 100 nl) into this spinal segment. The disinhibitory effect of both GABA receptor antagonists on the EPR was abolished by microinjection of the broad-spectrum glutamate receptor antagonist kynurenate (10 mM/100 nl). These data suggest that 1) GABA exerts a tonic inhibition of the EPR at the level of dorsal horn; and 2) that an interaction between glutamatergic and GABAergic inputs exist at the level of dorsal horn, contributing to spinal control of the EPR.

Endoperoxide 4 receptors play a role in evoking the exercise pressor reflex in rats with simulated peripheral artery disease

Ligating the femoral artery for 72 h in decerebrated rats exaggerates the exercise pressor reflex. The sensory arm of this reflex is comprised of group III and IV afferents, which can be either sensitized or stimulated by PGE2. In vitro studies showed that endoperoxide (EP) 3 and 4 receptors were responsible for the PGE2-induced sensitization of rat dorsal root ganglion cells. This in vitro finding prompted us to test the hypothesis that blockade of EP3 and/or EP4 receptors attenuated the exaggerated exercise pressor reflex in rats with ligated femoral arteries. We measured the cardiovascular responses to static hindlimb contraction or tendon stretch before and after femoral arterial injection of L798106 (an EP3 antagonist) or L161982 (an EP4 antagonist). The pressor and cardioaccelerator responses to either contraction or tendon stretch were not attenuated by L798106 in either the ligated or freely perfused rats. Likewise in five rats whose hindlimb muscles were freely perfused, the pressor and cardioaccelerator responses to either contraction or tendon stretch were not attenuated by L161982. In the six ligated rats, however, the pressor response to contraction was attenuated by L161982, averaging 37 ± 3 mmHg before, 18 ± 2 mmHg afterward (P < 0.05). Western blotting analysis revealed that ligation of the femoral artery for 72 h increased the EP4 receptor protein in the L4 and L5 dorsal root ganglia over their freely perfused counterparts by 24% (P < 0.05). We conclude that EP4 receptors, but not EP3 receptors, play an important role in the exaggerated exercise pressor reflex found in rats with ligated femoral arteries.

Endoperoxide 4 receptors attenuate the exercise pressor reflex in rats with ligated femoral arteries

Ligating the femoral artery for 72 hours in in decerebrated rats exaggerates the exercise pressor response (EPR).The sensory arm of this reflex is comprised of group III and IV afferents, which can be either sensitized or stimulated by PGE2. Endoperoxide (EP) 3 and EP4 (PGE2 subtype) receptors were found to be responsible for the PGE2‐induced sensitization of rat dorsal root ganglion cells. We tested the hypothesis that L798106 (EP3 antagonist) or L161982 (EP4 antagonist) attenuated the exaggerated exercise pressor reflex in rats with ligated femoral arteries. We measured the cardiovascular responses to static hindlimb contraction or tendon stretch before and after iliac arterial injection of L798106 or L161982. The pressor and cardioaccelerator responses to either contraction or tendon stretch were not attenuated by L798106 in either the ligated or freely perfused rats. Likewise in five rats whose hindlimb muscles were freely perfused, the pressor and cardioaccelerator responses to either contraction or tendon stretch were not attenuated by L161982. In the five ligated rats, however, the pressor response to contraction was attenuated by L161982, averaging 37 ± 3 mmHg before, 18 ± 2mmHg afterward (p &lt; 0.05). In addition, western blots revealed that ligation of the femoral artery for 72 hours increased the EP4 receptor protein in the L4 and L5 dorsal root ganglion by 24% (p &lt; 0.05) over their freely perfused counterparts. We conclude that blockade of EP4 receptors, but not blockade of EP3 receptors, attenuated the EPR in rats with ligated femoral arteries.

Does ATPγS potentiate the muscle chemoreflex response to lactic acid?

Birdsong et al. (2010) found that acute exposure to ATP potentiated ASIC evoked currents from dorsal root ganglion cells innervating muscles of rats. This finding prompted us to determine whether the results seen in vitro would translate to an in vivo preparation. We measured the pressor and cardioaccelerator responses to injecting lactic acid (24mM; 0.4mL), an ASIC agonist, into the femoral artery of decerebrated rats with either freely perfused hindlimbs (n=6) or hindlimbs whose femoral artery was ligated (n=5). This was done both before and after injecting ATPγS (200μg/kg). In freely perfused rats, the pressor response to lactic acid after ATPγS was not different from that to lactic acid before ATPγS (15±2 vs. 14±2 mmHg; p&gt;0.05). The cardioaccelerator response to lactic acid after ATPγS was modestly greater than that evoked by lactic acid before ATPγS (3±1 vs. −2±1 bpm; p&lt;0.05). In ligated rats, the pressor response to lactic acid was greater after ATPγS than before, although the increase was not significant (28±6 vs. 21±4 mmHg; p=0.11). The cardioaccelerator response to lactic acid after ATPγS was not significantly different from that evoked by lactic acid before ATPγS (1±2 vs. 2±2 bpm; p&gt;0.05). We conclude that ATPγS does not potentiate the muscle chemoreflex response to lactic acid but may do so in rats with ligated femoral arteries. Supported by NIH RO1‐HL030710 and P01 HL096570.

Spinal Cord GABA Receptors Inhibit the Exercise Pressor Reflex in Decerebrate Rats

Neurotransmitters and neuromodulators released by contraction‐activated skeletal muscle afferents into the dorsal horn of the spinal cord initiate the central component of the exercise pressor reflex (EPR). Evidence suggests that transmission at this synapse is mainly mediated by excitatory amino acids (i.e., glutamate). However, whether GABA, a major inhibitory neurotransmitter within the mammalian central nervous system, is involved in the modulation of the EPR at the level of the dorsal horn remains to be determined. To test this hypothesis, we performed local microinjection of either the GABA(A) antagonist bicuculline or the GABA(B) antagonist CGP 52432 into the ipisilateral L4/L5 dorsal horns to determine the effect of these GABA receptor antagonists on the pressor response to either static contraction induced by stimulation of the peripheral end of L4/L5 ventral roots or passive stretch in decerebrate rats. We found that microinjection of either bicuculline (1 mM, 100 nl) or CGP 52432 (10 mM, 100 nl) into the L4/5 dorsal horns significantly increased the pressor and cardioaccelerator responses to either static contraction or passive stretch in decerebrate rats. Data are presented in the table. In addition, microinjection of these two antagonists also caused a temporary increase in the baseline blood pressure and heart rate which returned to normal level in 2–3 min. These data suggest that GABA evokes a tonic inhibition of the EPR at the level of dorsal horn in spinal cord.

Peripheral Delta Opioid Receptors Attenuate the Exercise Pressor Reflex in Decerebrate Rats

Delta opioid receptors have been identified on group III afferent fibers, which contribute to the mechanically‐sensitive arm of the exercise pressor reflex. We tested the hypothesis that activation of peripheral delta opioid receptors on these afferents attenuated the exercise pressor reflex in decerebrated rats. We measured the cardiovascular responses to static hindlimb contraction before and after femoral arterial injection of DPDPE (1 μg), a delta opioid receptor agonist (n=7). The pressor and cardioaccelerator responses to contraction before DPDPE averaged 18 ± 2 mmHg and 9 ± 2 bpm, respectively and 9 ± 2 mmHg and 2 ± 1 bpm afterwards (both p&lt;0.05). Likewise, femoral arterial injection of DPDPE (1 μg) attenuated the pressor response to tendon stretch, which stimulates group III mechanoreceptors (n=6; pre DPDPE: 9 ± 2 mmHg, post DPDPE: 3 ± 1 mmHg, p&lt;0.05). DPDPE (1 μg) had no effect on the pressor responses to femoral arterial injection of either capsaicin (0.2 μg), a TRPV1 receptor agonist found mostly on group IV afferents (n=8; pre DPDPE: 25 ± 5 mmHg, post DPDPE: 28 ± 5 mmHg) or lactic acid (0.864 mg), an ASIC agonist (n=8; pre DPDPE: 26 ± 6 mmHg, post DPDPE: 20 ± 6 mmHg; both p&gt;0.05). Our data suggests that delta opioid receptors on group III afferent fibers are capable of blocking the exercise pressor reflex.

Dorsal root tetrodotoxin-resistant sodium channels do not contribute to the augmented exercise pressor reflex in rats with chronic femoral artery occlusion

We investigated the contribution of tetrodotoxin (TTX)-resistant sodium channels to the augmented exercise pressor reflex observed in decerebrated rats with femoral artery ligation. The pressor responses to static contraction, to tendon stretch, and to electrical stimulation of the tibial nerve were compared before and after blocking TTX-sensitive sodium channels on the L3-L6 dorsal roots of rats whose hindlimbs were freely perfused and rats whose femoral arteries were ligated 72 h before the start of the experiment. In the freely perfused group (n=9), pressor (Δ22±4 mmHg) and cardioaccelerator (Δ32±6 beats/min) responses to contraction were attenuated by 1 μM TTX (Δ4±1 mmHg, P<0.05 and Δ17±4 beats/min, P<0.05, respectively). In the 72 h ligated group (n=9), the augmented pressor response to contraction (32±4 mmHg) was also attenuated by 1 μM TTX (Δ8±2 mmHg, P<0.05). The cardioaccelerator response to contraction was not significantly attenuated in these rats. In addition, TTX suppressed the pressor response to tendon stretch in both groups of rats. Electrical stimulation of the tibial nerve evoked similar pressor responses between the two groups (freely perfused: Δ74±9 mmHg and 72 h ligated: Δ78±5 mmHg). TTX attenuated the pressor response to the tibial nerve stimulation by about one-half in both groups. Application of the TTX-resistant sodium channel blocker A-803467 (1 μM) with TTX (1 μM) did not block the pressor response to tibial nerve stimulation to any greater extent than did application of TTX (1 μM) alone. Although the contribution of TTX-resistant sodium channels to the augmented exercise pressor reflex may be slightly increased in rats with chronic femoral artery ligation, TTX-resistant sodium channels on dorsal roots do not play a major role in the augmented exercise pressor reflex.

Blockade of acid sensing ion channels attenuates the exercise pressor reflex in cats

Although thin fibre muscle afferents possess acid sensing ion channels (ASICs), their contribution to the exercise pressor reflex is not known. This lack of information is partly attributable to the fact that there is no known selective in vivo antagonist for ASICs. Although amiloride has been shown to antagonize ASICs, it also has been shown to antagonize voltage-gated sodium channels, thereby impairing impulse conduction in sensory nerves. Our aim was to test the hypothesis that lactic acid accumulation in exercising muscle acted on ASICs located on thin fibre muscle afferents to evoke the metabolic component of the exercise pressor reflex. To test this hypothesis, we determined in decerebrate cats if amiloride attenuated the pressor and cardioaccelerator responses to static contraction, to tendon stretch and to arterial injections of lactic acid and capsaicin. We found a dose of amiloride (0.5 microg kg(-1); i.a.) that attenuated the pressor and cardioaccelerator responses to both contraction and lactic acid injection, but had no effect on the responses to stretch and capsaicin. A higher dose of amiloride (5 microg kg(-1), i.a.) not only blocked the pressor and cardioaccelerator responses to lactic acid and contraction, but also attenuated the responses to stretch and to capsaicin, manoeuvers in which ASICs probably play no significant role. In addition, we found that the low dose of amiloride (0.5 microg kg(-1)) had no effect on the responses of muscle spindles to tendon stretch and to succinylcholine, whereas the high dose (5 microg kg(-1)) attenuated the responses to both. Our data suggest the low dose of amiloride used in our experiments selectively blocked ASICs, whereas the high dose blocked ASICs and impulse conduction in muscle afferents. We conclude that ASICs play a role in the metabolic component of the exercise pressor reflex.

Evidence that A‐317567 is a selective ASIC antagonist for thin fiber muscle afferents in decerebrate cats

Lactic acid is widely hypothesized to accumulate in contracting muscle to activate the thin fiber muscle afferents causing the exercise pressor reflex. Testing this hypothesis has been difficult because of the lack of a selective ASIC antagonist. We, therefore, examined if A-317567 attenuated the pressor and cardioaccelerator responses to popliteal arterial injections of lactic acid (0.2 to 0.5 ml, 24mM) and capsaicin (2–5 μg) as well as to tendon stretch. In decerebrate cats we found that A-317567 (10 mM; 0.5 ml) blocked the pressor-cardioaccelerator responses to lactic acid injection but had no effect on the pressor-cardioaccelerator responses to either capsaicin injection or tendon stretch. For example, the pressor response to lactic acid injection averaged 28 ± 8 mmHg before A-317567 and 4 ± 5 mmHg 10 minutes afterwards (p = 0.027; n = 4). In contrast, the pressor response to capsaicin injection averaged 33 ± 8 mm Hg before the ASIC antagonist and 33 ± 7 mm Hg afterwards (p = 0.78; n = 4). A dose of 0.5 ml of 1 mM A-317567 had no effect of the pressor and cardioaccelerator responses to arterial injections of lactic acid and capsaicin. Our data suggest that A-317567 is a specific blocker of ASIC channels and may be a useful tool to examine the role played by these channels in the exercise pressor reflex.

The Role of ASIC Channels in the Exercise Pressor Reflex

In vivo, H+ activate thin fiber muscle afferents involved in the exercise pressor reflex; however, the receptor for this effect is unknown. We hypothesized that the hydrogen ions associated with lactic acid accumulation in the exercising muscles act on ASIC channels on thin fiber muscle afferents. To test this hypothesis we examined if amiloride, an ASIC antagonist, attenuated the reflex pressor and cardioaccelerator responses to static contraction, stretch of the calcaneal tendon, as well as popliteal arterial injections of lactic acid and capsaicin. We established a dose of amiloride that blocked the reflex pressor response to static contraction and lactic acid injection but had no effect on the reflex pressor responses to stretch and capsaicin injection. Specifically, in four decerebrate cats we examined the pressor and cardioaccelerator responses to static contraction, stretch of the calcaneal tendon, and popliteal artery injections of lactic acid (0.5 ml, 24 mM; i.a) and capsaicin (2-5 μg; i.a.) before and after popliteal arterial injection of amiloride. The pressor responses to static contraction averaged 28 ± 4 mmHg before amiloride and 5 ± 2 mmHg after (0.5 μg/kg; i.a.; P = 0.09; n=4). Likewise, the pressor response to lactic acid injections averaged 30 ± 4 mmHg before amiloride and 12 ± 3 mmHg after (P = 0.06; n = 4). The pressor responses to tendon stretch and capsaicin were unchanged by amiloride. The heart rate responses were similar to those of blood pressure. In three separate decerebrate cats a high dose of amiloride (5 μg/kg) abolished all cardiovascular responses to static contraction, stretch of the calcaneal tendon, and injections of lactic acid and capsaicin. These data suggest ASIC channels may play a role in the exercise pressor reflex.

Disuse atrophy increases the muscle mechanoreflex in rats

We investigated the effect of disuse atrophy on the magnitude of the muscle mechanoreflex. The left leg of eight rats (6-7 wk, male) was put in a plaster cast for 1 wk. The rats were decerebrated at the midcollicular level. We recorded the pressor and cardioaccelerator responses to 30-s stretch of the calcaneal tendon, which selectively stimulated the muscle mechanosensitive receptors in the left atrophied and right control triceps surae muscles. Atrophied muscles showed significantly lower mass control muscles (1.0 +/- 0.1 vs. 1.4 +/- 0.1 g; P < 0.05). At the same stretch tension (229 +/- 20 g), the pressor response to stretch was significantly greater in the atrophied muscles than in the control muscles (13 +/- 3 vs. 4 +/- 2 mmHg, P < 0.05). The cardioaccelerator response was not significantly different (8 +/- 4 vs. 4 +/- 2 beats/min). Comparing responses at the same relative tension (57 +/- 6 vs. 51 +/- 8% of maximal tension), the pressor response was still significantly greater in the atrophied triceps surae than in the control (14 +/- 4 vs. 4 +/- 2 mmHg; P < 0.05). These results suggest that disuse atrophy increases the magnitude of muscle mechanoreflex.

Has the phoenix risen?

Has the phoenix risen?

Effects of melanocortins on cardiovascular regulation in rats.

1. Of the melanocortin peptides, gamma(2)-melanocyte-stimulating hormone (MSH) has been attributed a cardiovascular effect, inducing an increase in blood pressure and heart rate. Although still controversial, this effect, based on pharmacological blockade experiments, is supposed to be mediated through sympathetic activation. 2. The aims of the present study were to identify the N-terminal pro-opiomelanocortin (N-POMC) fragments and melanocortins that influence blood pressure and heart rate and to investigate the real-time changes in baroreflex sensitivity and in sympathetic and vagal modulation underlying cardiovascular effects in conscious rats without the use of pharmacological blockade. 3. Intracerebroventricular administration of different melanocortins and N-POMC induced a long-lasting dose- dependent pressor response from 1 nmol onwards, with only a small initial bradycardic response with the highest dose. 4. Coinciding with this pressor response, an elicitation of the low-frequency (LF) component was observed in spectral analysis of both blood pressure variability (BPV) and heart rate variability (HRV), followed by the high-frequency (HF) component in at least BPV. Baroreflex sensitivity remained unchanged. 5. After intravenous administration, gamma(2)-MSH produced a short-lasting dose-dependent pressor and cardioaccelerator response with very rapid onset with concentrations from 1 nmol onwards. 6. Continuous infusion of gamma(2)-MSH depressed baroreflex sensitivity and simultaneously increased both components of BPV, with a radical reduction of the LF component and a preserved vagal HF component in HRV. 7. Of all the intravenously administered melanocortins, only gamma(2)-MSH was active. The central effect is likely to depend on an increase of (alpha-)sympathetic outflow. 8. For the peripheral effect, gamma(2)-MSH appeared to act as a baroreceptor reflex-blocking agent, being compatible with a role in the acute stress response.

Mediation by nucleus tractus solitarii glutamatergic neurotransmission of the cardiovascular reflex evoked by distal esophageal distension

Distention of the rat distal esophagus evokes an arterial pressor and a cardioaccelerator response that depends upon activation of a vagal afferent projection to the nucleus tractus solitarii (NTS). The present study aimed to determine in urethane-anesthetized rats if the afferent limb of this reflex (a) relays in the NTS subdivision known ro receive esophageal afferents, and (b) utilizes glutamatergic synapses. To this end, tetrodotoxin or the glutamate antagonists γ- d-glutamyl-glycine, 6-7-dinitroquinoxaline-2,3-dione (DNQX) and 2-amino-5-phosphonovaleric acid (AP-5) were applied to the NTS extraventricular surface rostral to the obex. All four agents inhibited both components of the reflex. DNQX or AP-5 produced a similar reversible inhibition upon pressure ejection in the vagal esophageal afferent projection area. Application of tetrodotoxin to the dorsomedial medulla oblongata caudal to the area postrema (AP) was ineffective. Basal heart rate (HR) (except in the case of AP-5) and blood pressure increased upon NTS surface application of the antagonists but not after intra-NTS ejection. At corresponding dorsal NTS sites, focal excitation of solitarial neurons with glutamate evoked hypotension and cardiac slowing. At adjacent ventral sites in the NTS subnucleus centralis (NTSc) and/or its immediate vicinity, glutamate elicited an arterial pressor response that coincided with an esophageal contraction in most but not all cases. In conclusion, afferent fibers of the esophago-cardiovascular reflex (ECVR) probably (1) terminate in the vicinity of esophageal premotor neurons comprising the NTSc and (2) activate second-order neurons via glutamate receptors of both the NMDA and non-NMDA subtype.

Organization of the sympathetic innervation of the forelimb resistance vessels in the cat.

Detailed information on the outflow pathway of sympathetic vasoconstrictor fibers to the upper extremity is lacking. We studied the organization of the sympathetic innervation of the forelimb resistance vessels and of the sinoatrial (SA) node in the decerebrated, artificially respirated cat. The distal portion of sectioned individual rami T1-8 and the sympathetic chain immediately caudal to T8 on the right side were electrically stimulated while the right forelimb perfusion pressure (forelimb perfused at constant flow) and heart rate were recorded. Increases in perfusion pressure were evoked by stimulation of T2-8 (maximal response T7: 55 +/- 2.3 mm Hg). Responses were still evoked by stimulation of the sympathetic chain immediately caudal to T8 (44 +/- 15 mm Hg). Increases in heart rate were evoked by the stimulation of more rostral rami (T1-5; maximal response T3: 55.2 +/- 8 bpm). These vasoconstrictor and cardioacceleratory responses were blocked by the cholinergic antagonists hexamethonium and scopolamine. Sectioning of the vertebral nerve and the T1 ramus abolished the vasoconstrictor response. Stimulation of the vertebral nerve and of the proximal portion of the sectioned T1 ramus increased perfusion pressure (69 +/- 9 and 34 +/- 14 mm Hg, respectively), which was unaffected by ganglionic cholinergic block. These data suggest that forelimb resistance vessel control is subserved by sympathetic preganglionic neurons located mainly in the middle to caudal thoracic spinal segments. Some of the postganglionic axons subserving vasomotor function course through the T1 ramus, in addition to the vertebral nerve. Forelimb vasculature is controlled by sympathetic preganglionic neurons located in middle to caudal thoracic spinal segments and by postganglionic axons carried in the T1 ramus and vertebral nerve. This helps to provide the anatomical substrate of interruption of sympathetic outflow to the upper extremity produced by major conduction anesthesia of the stellate ganglion or spinal cord.

Receptor subtypes mediating spinal cardiovascular effects of angiotensin II in rat using losartan and PD 123319

It has previously been shown in this laboratory that intrathecal administration of 10 μg of angiotensin II produces an increase in arterial pressure and heart rate. As two receptor subtypes of angiotensin II, termed AT 1 and AT 2, have been identified in central nervous tissue this study examines the effects of selective antagonists on the pressor and cardioacceleratory responses to intrathecal administration of 10 μg of angiotensin II to the ninth thoracic spinal cord. The two non-peptide antagonists were losartan (2- n-butyl-4-chloro-5-hydroxymethyl-1-[(2′-(1 H)-tetrazol-5-yl)biphenyl-4-yl)methyl]imidazole), which is selective for the angiotensin AT 1 receptor, and PD 123319 (1-[[4-(dimethylamino)-3-methylphenyl]methyl]-5-(diphenylacetyl)-4,5,6,7-tetrahydro-1 H-imidazo[4,5- c]pyridine-6-carboxylic acid, ditrifluoroacetate, dihydrate), which is selective for the angiotensin AT 2 receptor. Intravenous administration of losartan blocked both pressor and cardioacceleratory effects of angiotensin II. Intrathecal administration of losartan blocked only the pressor effects, raising the possibility that block of the heart rate response was in the periphery. Intrathecal administration of PD 123319 blocked the pressor effect of angiotensin II but had no effect on the cardioacceleratory response. However, by itself the antagonist produced a transient increase in arterial pressure and a slower increase in heart rate. The data support the involvement of the angiotensin AT 1 receptor in mediating the effects of exogenously administered angiotensin II but also indicate a possible role of angiotensin AT 2 receptors at the spinal level.

Reflexes mediated by cardiac sympathetic afferents during myocardial ischaemia: role of adenosine.

1. Myocardial ischaemia and infarction activate vagal and sympathetic sensory endings in the ischaemic myocardium, resulting in powerful reflex effects. The vagal afferents are either mechano- or chemosensitive, whereas sympathetic afferents may be mechano-, chemosensitive or both. 2. Activation of vagal afferents results in sympathoinhibitory, cardioinhibitory, vasodepressor responses. Cardiac sympathetic afferents activated during myocardial ischaemia mediate sympathoexcitatory, vasoconstrictor cardioaccelerator responses. 3. The focus of the present review is on the activation of sympathetic afferents by myocardial ischaemia and on the resulting reflex responses that they mediate. 4. These endings are more likely to be activated as the degree of ischaemia progresses from subendocardial towards transmural. They are evenly distributed between the anterior and inferoposterior wall. Although it has been suggested that these endings are activated by bradykinin, recent evidence indicates that they are activated by adenosine released from the ischaemic myocardium. Results from our laboratory indicate that this effect is due to the activation of adenosine A1, but not adenosine A2 receptors. 5. Activation of ventricular vagal and sympathetic afferent fibres during myocardial ischaemia in humans is responsible for the autonomic changes observed and, in the case of the sympathetic afferents, for the sensation of angina pectoris.

Acute hypotension alters hemodynamic response to methionine-enkephalin in conscious dogs

In the conscious dog, intravenous administration of methionine-enkephalin produces simultaneous increases in both heart rate (HR) and mean arterial blood pressure (MAP). This report describes both depressor and cardioaccelerator responses to methionine-enkephalin (10 μg/kg IV) in conscious dogs following acute hypotension induced by either bolus injection of isoproterenol (0.1–5.0 μg/kg IV) or infusion of sodium nitroprusside (SNP, 3–8 μg/kg/min). Cardiovascular responses to methionine-enkephalin were blocked by naloxone. Pretreatment of the dogs with the β-adrenergic receptor antagonist propranolol failed to prevent the hypotensive response to methionine-enkephalin following SNP infusion. The results indicate that the hemodynamic responses to methionine-enkephalin can be altered by acute manipulation of blood pressure. These results may have implications relative to the role of endogenous opiates in regulation of blood pressure, especially in acute hypotensive states.