Biomedical subjects

J C Longhurst

Publications and source records attributed to J C Longhurst.

At least 37 records · Page 2Linked to original sources

PubMed1998

Endogenous bradykinin activates ischaemically sensitive cardiac visceral afferents through kinin B2 receptors in cats.

1. Activity of ischaemically sensitive cardiac visceral afferents during myocardial ischaemia induces both angina and cardiovascular reflexes. Increased production of bradykinin (BK) and cyclo-oxygenase products (i.e. prostaglandins (PGs)) occurs during myocardial ischaemia. However, the role of these agents in activation of ischaemically sensitive cardiac afferents has not been established. The present study tested the hypothesis that BK produced during ischaemia activates cardiac afferents through kinin B2 receptors. 2. Single-unit activity of cardiac afferents innervating the left ventricle was recorded from the left thoracic sympathetic chain (T1-T4) of anaesthetized cats. Ischaemically sensitive cardiac afferents were identified according to their response to 5 min of myocardial ischaemia. The mechanism of BK in activation of ischaemically sensitive cardiac afferents was determined by injection of BK (1 microgram kg-1 i.a.), des-Arg9-BK (1 microgram kg-1 i.a., a specific kinin B1 receptor agonist), kinin B2 receptor antagonists: HOE140 (30 micrograms kg-1 i.v.) and NPC-17731 (40 micrograms kg-1 i.v., cyclo-oxygenase inhibition with indomethacin (5 mg kg-1 i.v.) and NPC-17731 (40 micrograms kg-1 i.v.) after pretreatment with indomethacin (5 mg kg-1 i.v.). 3. We observed that BK increased the discharge rate of all eleven ischaemically sensitive cardiac afferents from 0.39 +/- 0.12 to 1.47 +/- 0.37 impulses s-1 (P < 0.05). Conversely, des-Arg9-BK did not significantly increase the activity of eleven ischaemically sensitive fibres (0.58 +/- 0.02 vs. 0.50 +/- 0.18 impulses s-1. HOE140 significantly attenuated the response of twelve afferents to ischaemia (0.61 +/- 0.22 to 1.85 +/- 0.5 vs. 0.53 +/- 0.16 to 1.09 +/- 0.4 impulses s-1). NPC-17731, another kinin B2 receptor antagonist, had similar inhibitory effects on six other ischaemically sensitive cardiac afferents (0.35 +/- 0.14 to 1.19 +/- 0.29 vs. 0.22 +/- 0.08 to 0.23 +/- 0.07 impulses s-1). Indomethacin significantly reduced the responses of seven afferents to ischaemia (0.35 +/- 0.13 to 1.89 +/- 0.48 vs. 0.40 +/- 0.10 to 0.76 +/- 0.24 impulses s-1). Indomethacin also significantly reduced the responses of six ischaemically sensitive cardiac afferents to BK (2.65 +/ 1.23 to 1.2 +/- 0.51 impulses s-1. In six cats pretreated with indomethacin, NPC-17731 attenuated the impulse activity of six ischaemically sensitive cardiac afferents (0.39 +/- 0.12 to 1.0 +/- 0.3 vs. 0.26 +/- 0.14 to 0.48 +/- 0.20 impulses s-1. 4. This study demonstrates that BK produced during ischaemia contributes to stimulation of ischaemically sensitive cardiac visceral afferents through activation of kinin B2 receptors. Furthermore, BK stimulates ischaemically sensitive cardiac visceral afferents through a mechanism that is, at least in part, independent of cyclo-oxygenase activation.

Animals↗

PubMed1998

Role of 5-HT3 receptors in activation of abdominal sympathetic C fibre afferents during ischaemia in cats.

1. Activation of abdominal sympathetic afferents during ischaemia reflexly excites the cardiovascular system. We have shown previously that exogenous 5-hydroxytryptamine (5-HT, i.e. serotonin) stimulates abdominal sympathetic afferent nerve endings, and recently have documented increased concentrations of 5-HT in intestinal lymph and portal venous plasma during brief abdominal ischaemia. The present investigation evaluated the role of endogenously produced 5-HT in activation of ischaemically sensitive abdominal sympathetic afferents. 2. Nerve activity of single-unit C fibre afferents innervating duodenum, mesentery, pancreas, portal hepatis, bile duct, gall bladder and jejunum was recorded from the right thoracic sympathetic chain of anaesthetized cats. Ischaemically sensitive C fibre afferents were identified according to their response to 5-10 min of abdominal ischaemia. 3. Intra-arterial injection of 5-HT (20 microg kg-1) increased discharge activity of twelve afferents from 0. 23 +/- 0.05 to 0.96 +/- 0.09 impulses s-1 after an onset latency of 5.7 +/- 1.4 s. Also, 2-methylserotonin (100 microg kg-1, i.a.), a 5-HT3 receptor agonist, stimulated eleven of twelve afferents to significantly increase their discharge activity from 0.25 +/- 0.05 to 0.90 +/- 0.10 impulses s-1 after a latency of 3.3 +/- 0.4 s. Furthermore, intravenous injection of tropisetron (200 microg kg-1), a 5-HT3 receptor antagonist, significantly attenuated the increase in activity of twelve other C fibre afferents during 10 min of abdominal ischaemia from 1.62 +/- 0.18 to 0.94 +/- 0.22 impulses s-1, and eliminated the response of eleven other afferents to 5-HT. 4. Both the 5-HT2 receptor agonist, alpha-methylserotonin (100 microg kg-1, i.a.), and the 5-HT1 receptor agonist, 5-carboxamidotryptamine (100 microg kg-1, i.a.), did not alter the impulse activity of these twelve afferents (0.29 +/- 0.05 to 0.31 +/- 0.06, and 0.26 +/- 0.06 to 0.29 +/- 0.06 impulses s-1, respectively). 5. Treatment with indomethacin (5 mg kg-1, i.v.) in eight different cats did not alter the response of nine C fibre afferents to exogenous 5-HT (0.91 +/- 0. 17 vs. 1.19 +/- 0.25 impulses s-1, P > 0.05). 6. The results suggest that, during mesenteric ischaemia, endogenous 5-HT contributes to the activation of abdominal sympathetic afferents, mainly through direct stimulation of 5-HT3 receptors and that the action of 5-HT on these afferents appears to be independent of the cyclo-oxygenase pathway.

Adrenergic Fibers↗

PubMed1998

Reversal of reflex-induced myocardial ischemia by median nerve stimulation: a feline model of electroacupuncture.

BACKGROUND: Acupuncture is reported to reduce myocardial ischemia, arrhythmias, and hypertension. To investigate the physiological mechanisms underlying these observations, a model of reflex-induced, reversible myocardial ischemia was developed to test the effects of median nerve stimulation as a surrogate for electroacupuncture. METHODS AND RESULTS: Chloralose-anesthetized cats were instrumented to measure arterial blood pressure, left ventricular pressure, left ventricular dP/dt, heart rate, left anterior descending (LAD) coronary blood velocity, and regional wall motion. The LAD artery either was partially occluded or a small diagonal branch was ligated. Subsequently, transient reflex activation of the cardiovascular system was evoked by application of bradykinin (typically 1 microg/mL) to the gallbladder, which significantly increased myocardial oxygen demand (double product), left ventricular dP/dt, and coronary blood velocity and caused ischemia-induced regional dysfunction, evidenced by significant (P<.05) reduction in normalized wall thickening (10.7+/-4.2% versus -23.6+/-2.9%; control versus ischemia; n=7). However, when median nerves were stimulated with low frequency (5 Hz) to mimic electroacupuncture, bradykinin-induced change in normalized wall thickening was significantly improved (-23.6+/-2.9% versus 9.8+/-4.9%; ischemia versus median nerve stimulation, P<.05) and remained augmented > or = 1 hour. Results were similar in partial and complete occlusion groups. Significant improvement in wall thickening was associated with unchanged increment of coronary blood velocity and significantly diminished increments of double product and diastolic blood pressure. CONCLUSIONS: These results suggest that stimulation of the median nerve to mimic electroacupuncture diminishes regional myocardial ischemia triggered by a sympathetically mediated increase in cardiac oxygen demand. The mechanism of this effect is related to reduction in cardiac oxygen demand, secondary to a diminished pressor response. These data provide the first documentation of the physiological mechanisms underlying the possible beneficial effect of electroacupuncture in the context of restricted coronary blood flow and augmented myocardial oxygen demand.

Animals↗

PubMed1998

Bradykinin BK2 receptors contribute to reflex cardiovascular responses during brief abdominal ischemia.

Ischemically sensitive visceral sympathetic nerve fibers, which are thought to represent the afferent limb of a strong cardiovascular pressor reflex, can be stimulated by exogenously applied bradykinin (BK). During ischemia, BK also is known to be produced locally and to serve as an endogenous stimulus for activation of ischemically sensitive nerve endings. It is unclear, however, whether ischemically induced BK production is sufficient to elicit a reflex cardiovascular response. Accordingly, femoral arterial and venous catheters were positioned in anesthetized cats, and the superior mesenteric and celiac arteries were isolated for placement of snare occluders. After dual occlusion of these arteries (20 min), one of two chemically dissimilar specific kinin B2 (BK2) receptor antagonists, HOE-140 (30-40 micrograms/kg iv, n = 8) or NPC-17731 (30-40 micrograms/kg iv, n = 11), was administered and dual occlusion was repeated. The reflex rise of mean arterial blood pressure (BP) of 16 +/- 3.7% was significantly (P < 0.05) reduced by HOE-140 to 8.4 +/- 2.0%. NPC-17731 similarly attenuated the reflex BP increment from 13 +/- 1.2 to 6.2 +/- 1.6% (P < 0.05). In a separate set of control animals the first and second periods of ischemia induced reflex BP increments that did not differ significantly (16 +/- 2.7 and 16 +/- 5.7%, respectively). Qualitatively similar decrements of the BP response were produced by the BK2 receptor antagonists in two additional groups in which blood flow to the superior mesenteric and celiac arteries was diverted to a venous reservoir to eliminate the initial transient (mechanically induced) rise in BP associated with artery ligation that is known not to be associated with the reflex response. These results indicate that the stimulation of BK2 receptors on visceral afferent nerves by BK is responsible, at least in part, for the reflex cardiovascular response during visceral ischemia.

Abdomen↗

PubMed1998

Signal transduction in activation of ischemically sensitive abdominal visceral afferents: role of PKC.

Abdominal ischemia reflexly activates the cardiovascular system by stimulating abdominal visceral afferent nerve endings. Whereas many ischemic metabolites responsible for activating these nerves have been identified (e.g., bradykinin), their precise mechanism of action is unclear. Protein kinase C (PKC) is an important part of the signal transduction process underlying the action of metabolites such as bradykinin and is a regulator of neuronal activity. Therefore, we hypothesized that PKC contributes to stimulation of ischemically sensitive abdominal visceral afferents. Single-unit activity was recorded from the right thoracic sympathetic chain of anesthetized cats. Exogenous activation of PKC using phorbol 12, 13-dibutyrate (PDBu, 5 microg/kg ia) increased the impulse activity of ischemically sensitive C-fiber afferents from 0.04 +/- 0.01 to 0. 67 +/- 0.23 impulses/s (n = 11; P < 0.05). The influence of endogenous activation of PKC also was evaluated during 10 min of mesenteric ischemia. Inhibition of PKC using PKC-(19-36) (20 microg/kg iv) reduced ischemia-induced increases in afferent activity from 0.46 +/- 0.11 to 0.19 +/- 0.08 impulses/s (n = 7, P < 0.05). Moreover, PKC-(19-36) (20 microg/kg iv) reduced the response of ischemically sensitive C fibers to bradykinin (0.5-1.0 microg/kg ia) from 1.18 +/- 0.20 to 0.66 +/- 0.14 impulses/s (n = 13, P < 0. 05). These results indicate that PKC contributes to activation of abdominal visceral afferents during ischemia and specifically to part of the bradykinin-induced activation of these afferents.

Abdomen↗

PubMed1998

Reflex pressor response to arterial phenylbiguanide: role of abdominal sympathetic visceral afferents.

Phenylbiguanide (PBG), a 5-HT3 (serotonin) receptor agonist, has been used in many studies as a "selective" agonist to elicit reflex bradycardia and hypotension through activation of cardiac and pulmonary vagal afferents. Because we have shown that endogenous 5-HT stimulates ischemically sensitive abdominal sympathetic afferents through 5-HT3 receptors, we investigated the possibility that left ventricular (LV) and intra-arterial administration of PBG may evoke a competing reflex response by increasing the activity of sympathetic visceral afferents in anesthetized cats. Mean arterial pressure (MAP) and heart rate (HR) were monitored. When both vagal and sympathetic afferents were intact, PBG (40 microgram/kg, injected into the LV) significantly decreased MAP and HR in 8 of 10 cats but increased MAP in the remaining 2 cats. After bilateral cervical vagotomy, LV PBG significantly increased MAP. PBG (40 microgram/kg ia) significantly increased MAP and HR, whereas intravenous PBG significantly decreased MAP and HR (n = 10 cats). Furthermore, the pressor response to PBG (40 microgram /kg ia) was reduced by 68% (P < 0.05; n = 4 cats) by celiac and mesenteric ganglionectomies. In studies of single-unit abdominal sympathetic afferents, intra-arterial but not intravenous PBG (40 microgram/kg) significantly increased activity of 10 ischemically sensitive afferents but not ischemically insensitive afferents. Blockade of 5-HT3 receptors with tropisetron (200 microgram/kg iv) eliminated the response of the afferents and the pressor response to PBG. These data indicate that PBG administered into the LV usually, but not always, evokes a depressor response that is converted to a pressor response following cervical vagotomy. Also, intra-arterial PBG induces a pressor response by stimulating 5-HT3 receptors largely associated with ischemically sensitive abdominal sympathetic afferents.

Abdomen↗

PubMed1997

The power athlete.

A number of normal daily and athletic activities require isometric or static exercise. Sports such as weight lifting and other high-resistance activities are used by power athletes to gain strength and skeletal muscle bulk. Static exercise, the predominant activity used in power training, significantly increases blood pressure, heart rate, myocardial contractility, and cardiac output. These changes occur in response to central neural irradiation, called central command, as well as a reflex originating from statically contracting muscle. Studies have demonstrated that blood pressure appears to be the regulated variable, presumably because the increased pressure provides blood flow into muscles whose arterial inflow is reduced as a result of increases in intramuscular pressure created by contraction. Thus, static exercise is characterized by a pressure load on the heart and can be differentiated from the hemodynamic response to dynamic (isotonic) exercise, which involves a volume load to the heart. Physical training with static exercise (i.e., power training) leads to concentric cardiac (particularly left ventricular) hypertrophy, whereas training with dynamic exercise leads to eccentric hypertrophy. The magnitude of cardiac hypertrophy is much less in athletes training with static than dynamic exercise. Neither systolic nor diastolic function is altered by the hypertrophic process associated with static exercise training. Many of the energy requirements for static exercise, particularly during more severe levels of exercise, are met by anaerobic glycolysis because the contracting muscle becomes comes deprived of blood flow. Power athletes, training with repetitive static exercise, derive little benefit from an increase in oxygen transport capacity, so that maximal oxygen consumption is increased only minimally or not at all. Peripheral cardiovascular adaptations also can occur in response to training with static exercise. Although the studies are controversial, these adaptations include modest decreases in resting blood pressure, reduced increases in blood pressure and sympathetic nerve activity during a given workload, enhanced baroreflex function, increases in muscle capillary-to-fiber ratio, possible improvements in lipid and lipoprotein profiles, and increases in glucose and insulin responsiveness. Some of these adaptations can occur in cardiac or hypertensive patients with no concomitant cardiovascular complications. In both healthy individuals and those with cardiovascular disease, the manner in which resistance training is performed may dictate the extent to which these adjustments take place. Specifically, training that involves frequent repetitions of moderate weight (and hence contains dynamic components) seems to produce the most beneficial results.

Adaptation, Physiological↗

PubMed1997

Mechanical stimulation is not responsible for activation of gastrointestinal afferents during ischemia.

Abdominal ischemia reflexly excites the cardiovascular system through activation of visceral sympathetic afferents. Although a number of ischemic metabolites are known to stimulate sympathetic afferents, the contribution of mechanical stimulation to activation of afferents during abdominal ischemia remains uncertain. Thus the present study examined the role of changes in motility in activation of gastrointestinal afferents during ischemia. Single-unit activity of C fiber afferents located on the stomach, duodenum, jejunum, or colon was recorded from the right sympathetic chain of anesthetized cats during 15 min of ischemia. Intraluminal pressure, as a reflection of local mechanical activity, was measured by an open catheter placed in the lumen of the gastrointestinal tract. The results show that gastrointestinal motility was mainly inhibited during abdominal ischemia. Changes in intraluminal pressure did not correlate with afferent discharge activity during ischemia (r = -0.32, n = 10). Furthermore, discharge frequency of gastrointestinal afferents during ischemia was not altered significantly by topical application of 100 micrograms/ml of atropine (3.98 +/- 0.62 to 3.83 +/- 0.59 imp/s, n = 12), which profoundly inhibited local gastrointestinal motility. Collectively, these data indicate that gastrointestinal motility changes during abdominal ischemia do not contribute to activation of gastrointestinal sympathetic C fiber afferents.

Animals↗

PubMed1997

Cardiovascular reflex responses to ischemia during occlusion of celiac and/or superior mesenteric arteries.

Global abdominal visceral ischemia leads to profound cardiovascular reflex adjustments. However, the separate contributions of the celiac artery and superior mesenteric artery (SMA) vascular beds to this reflex are unknown. Accordingly, we compared the effects of single and combined occlusions of these vessels on blood pressure (BP) in anesthetized cats. Tissue mass and pH of selected organs, regional blood gases, pH, and lactate also were measured as potential contributing factors. Occlusion of the SMA or celiac artery produced significantly (P < 0.05) different increments in BP (30 +/- 4 vs. 18 +/- 4 mmHg, respectively). Combined occlusion of the two vessels augmented BP by 53 +/- 12 mmHg, a significantly greater increase than during celiac ligation. Venous lactate levels increased significantly during SMA, but not celiac, occlusion, and the decline in venous pH was significantly greater in the SMA than in the celiac vascular bed (-0.20 +/- 0.03 vs. -0.08 +/- 0.02 pH units, P < 0.05, respectively). The decline in tissue pH of SMA-perfused organs during SMA occlusion was significantly greater than in celiac-perfused organs during celiac occlusion. Conversely, tissue mass subserved by the celiac artery was significantly greater than that subserved by the SMA (182 +/- 27 vs. 131 +/- 17 g, respectively). These data suggest that the larger cardiovascular reflex produced by SMA occlusion compared with celiac occlusion may be related to a greater increase of lactic acid concentration in tissue supplied by the SMA. In addition, the large reflex increase in BP produced by combined occlusion of these vessels is an additive effect, presumably related to larger organ mass and recruitment of more sensory nerve fibers.

Animals↗

PubMed1997

Spatiotemporal aspects of sympathetic C-fiber afferent activity in pressor reflex during abdominal ischemia.

Activation of abdominal sympathetic visceral afferents during ischemia elicits excitatory cardiovascular reflexes. The present study examined the time course and discharge patterns of activation of ischemically sensitive sympathetic C-fiber afferents, and then the relationship between summated afferent activity and the pressor reflex induced by prolonged abdominal ischemia was determined. Single-unit activity of abdominal C-fiber afferents was recorded from the right thoracic sympathetic chain of anesthetized cats during 30 min of ischemia. The reflex pressor response to abdominal ischemia was induced by occlusion of celiac and superior mesenteric arteries. Of 68 C-fiber afferents studied, 36 (approximately 53%) were activated during 30 min of ischemia, whereas the activity of the remaining 32 were not altered. Onset latencies of 36 C-fiber afferents activated by ischemia ranged from 1.0 to 17.4 min with an average of 6.1 +/- 0.8 min. The majority of activated afferents manifested a bursting pattern of discharge activity as ischemia was prolonged beyond 10 min. Summated response of activated afferents, but not individual afferent activity, was related closely to the reflex pressor response during 30 min of ischemia. These results suggest that both recruitment of sufficient numbers of C-fiber afferents and adequate discharge frequency of afferents constitute an encoding mechanism for the pressor reflex during abdominal ischemia.

Abdomen↗

PubMed1997

Increased histamine and 5-HT in portal vein plasma and mesenteric lymph during brief ischemia and reperfusion.

Brief mesenteric ischemia (10 min) can stimulate both visceral A delta- and C-fiber afferents and evoke reflex excitation of the cardiovascular system. We have shown that exogenous histamine causes reflex cardiovascular responses and that intra-arterial injection of 5-hydroxytryptamine (5- HT) into a mesenteric artery stimulates visceral A delta- and C-fiber afferents. We therefore hypothesized that brief abdominal ischemia is associated with release of histamine and 5-HT into the interstitium, where these mediators could stimulate or sensitize ischemically sensitive visceral afferent nerve endings. Accordingly, we measured concentrations of histamine and 5-HT in portal venous blood plasma and intestinal lymph fluid in cats. Cannulas were placed in a portal vein and in an intestinal lymphatic duct distal to the lymph node. Lymph and plasma histamine and 5-HT concentrations were measured by high-performance liquid chromatography before, during, and immediately after 10-min occlusion of the descending thoracic aorta. Histamine concentration increased significantly (P < 0.01) in portal venous blood plasma from a preocclusion level of 2.2 +/- 0.6 to 4.6 +/- 1.0 and 6.4 +/- 1.3 nmol/ml and in lymph fluid from a preocclusion level of 3.4 +/- 1.0 to 6.3 +/- 1.3 and 6.4 +/- 1.3 nmol/ml (n = 18) during brief ischemia and reperfusion, respectively. Also, the 5-HT concentration was significantly (P < 0.01) elevated in portal venous blood plasma from a preocclusion concentration of 1.1 +/- 0.5 to 2.7 +/- 0.8 and 2.5 +/- 0.8 nmol/ml and in lymph from a preocclusion level of 1.8 +/- 0.7 to 4.0 +/- 1.4 and 4.6 +/- 1.3 nmol/ml (n = 13) during brief ischemia and reperfusion, respectively. Because visceral afferent nerve endings are located in the interstitium, elevation of the interstitial concentration of histamine and 5-HT may contribute to the stimulation or sensitization of these nerve terminals during the brief ischemia and reperfusion period.

Animals↗

PubMed1997

Endogenous histamine stimulates ischemically sensitive abdominal visceral afferents through H1 receptors.

Abdominal ischemia stimulates sympathetic visceral afferents to reflexly activate the cardiovascular system. We have shown previously that topical application of histamine (HA) to the gastric wall causes reflex cardiovascular responses and have documented increased histamine concentrations in intestinal lymph and portal venous plasma during brief abdominal ischemia. In the present study, we hypothesized that histamine produced during ischemia activates ischemically sensitive C-fiber afferents by stimulation of H1 receptors. Nerve activity of single-unit abdominal visceral C-fiber afferents was recorded from the right thoracic sympathetic chain of anesthetized cats. Injection of histamine (25 micrograms/kg ia) significantly increased activity of nine ischemically sensitive C fibers from 0.09 +/- 0.06 to 1.11 +/- 0.20 imp/s. An H1-receptor agonist, 2-(3-chlorophenyl)histamine (250 micrograms/kg ia), also increased activity of these afferents from 0.11 +/- 0.04 to 0.64 +/- 0.18 imp/s (P < 0.05). Furthermore, an H1-receptor antagonist (pyrilamine, 0.2 mg/kg i.v.) significantly attenuated the increased activity in 11 other C fibers from 0.91 +/- 0.16 to 0.35 +/- 0.06 imp/s ischemia vs. pyrilamine + ischemia) and eliminated the response of 9 separate ischemically sensitive afferents to histamine. Conversely, both the H2-receptor agonist dimaprit (500 micrograms/kg ia) and the H3-receptor.agonist (R)-alpha-methylhistamine (250 micrograms/kg ia) did not significantly alter the activity of these nine afferents. In nine separate cats treated with indomethacin (5 mg/kg i.v.), pyrilamine (0.2 mg/kg i.v.) further significantly attenuated the increased activity in seven of nine C fibers during ischemia, and indomethacin (5 mg/kg i.v.) attenuated the response of eight other afferents to histamine. These data suggest that during mesenteric ischemia endogenous histamine contributes to the activation of afferents through direct stimulation of histamine H1 receptors and that histamine's stimulating effect on these afferents is dependent partially on production of prostaglandins.

Abdomen↗

PubMed1997

Endothelin-1 limits increases in blood flow to native and collateral-dependent myocardium.

We hypothesized that blood flow to collateralized and noncollateralized myocardium is improved by antagonism of endothelin (ET) A receptors. Coronary collateral development was stimulated by placing an ameroid constrictor around the left circumflex coronary artery (LCx; collateralized region) in 11 swine. After 35 +/- 2 days, the left anterior descending coronary artery (LAD; noncollateralized region) was autoperfused at constant pressure using blood from a femoral artery. In group 1 (n = 6) transmural blood flow was measured using radioactive microspheres in the LAD, LCx, and border regions (i.e., area between LAD and LCx) during pacing stress while vehicle (phosphate-buffered saline) was infused into the LAD coronary artery (pace 1). Approximately 55 min later, a second period of pacing (pace 2) was performed in the presence of ETA receptor antagonism (BQ-123; 5 mg.ml-1.min-1 ic). In the time control group (group 2, n = 5) vehicle was infused during both pacing periods. Indexes of myocardial oxygen demand were similar between paces 1 and 2 in each group. Compared with the first pacing period, transmural blood flow (ml.100 g-1.min-1) was higher (P < 0.05) during ETA receptor antagonism (i.e., pace 2) in the LAD (105 +/- 8 vs. 139 +/- 9), border (51 +/- 5 vs. 83 +/- 7), and LCx regions (22 +/- 3 vs. 41 +/- 4, respectively) in group 1. In group 2, while perfusion in the border (98 +/- 17 vs. 103 +/- 16) and LCx regions (19 +/- 4 vs. 27 +/- 6) was similar in paces 1 and 2, LAD transmural flow was greater (134 +/- 9 vs. 160 +/- 13; P < 0.05) during the second pacing period. However, the percent increase in LAD flow comparing pace 1 with 2 was greater (P < 0.05) in group 1 (39 +/- 6%) compared with group 2 (20 +/- 7%). These data suggest that during the stress of pacing blood flow to collateralized and noncollateralized myocardium is improved in the presence of ETA receptor blockade.

Animals↗

PubMed1996

Ischaemia-sensitive sympathetic afferents innervating the gastrointestinal tract function as nociceptors in cats.

1. Activation of sympathetic visceral afferents during mesenteric ischaemia induces visceral pain and reflexly excites the cardiovascular system. The present study investigated the differential responses of ischaemically sensitive and insensitive sympathetic C fibre afferents to graded distension of the gastrointestinal tract. 2. Single-unit activity of C fibre afferents innervating the stomach, duodenum and jejunum was recorded from the right thoracic sympathetic chain of anaesthetized cats. Ischaemically sensitive and insensitive C fibre afferents were identified according to their response to 5-20 min of ischaemia. The functional characteristics of the stimulus-response relationships of afferents were determined by distension of a balloon placed in the corresponding segment of gastrointestinal tract. 3. The results show that ischaemically insensitive C fibre afferents had a lower threshold in response to distension (13 +/- 5 mmHg, n = 10). The discharge frequency of these afferents was saturated within a low pressure range of distension. However, ischaemically sensitive C fibre afferents had a high threshold (86 +/- 12 mmHg, n = 10) and a larger peak response to mechanical distension in the noxious range (60-180 mmHg). There were no differences between ischaemically sensitive and insensitive C fibre afferents with regard to their testing activity or responses to bradykinin (10 micrograms I.A.). 4. This study demonstrates that the gastrointestinal system is innervated by low and high threshold sympathetic C fibre afferents, the latter having the distinct ability to encode nociceptive information such as excessive distension and ischaemia.

Animals↗

PubMed1996

Role of summation of afferent input in cardiovascular reflexes from splanchnic nerve stimulation.

Stimulation of abdominal sympathetic visceral afferents reflexly excites the cardiovascular system. The present study examined the role of summation of afferent input in this reflex. Single-unit activity of A delta- and C-fiber afferents was recorded from the right thoracic sympathetic chain in anesthetized cats to determine the relationship between intensities of electrical stimulation and the types of nerve fibers within the right greater splanchnic nerve. The differential effect of cooling on A delta- and C-fiber axons in the sympathetic chain also was examined by recording single-unit afferent activity. Reflex cardiovascular responses were induced by electrical stimulation of the central cut end of the right greater splanchnic nerve. We observed that the numbers of A delta and C fibers activated by electrical stimulation were proportional to the intensity of stimulation. However, neither local cooling nor intensity of stimulation provided a means to separate A delta and C fibers contained in the sympathetic chain. The results demonstrate that the magnitude of excitatory cardiovascular reflexes is frequency dependent and is related directly to intensity of electrical stimulation, suggesting that both adequate discharge frequency of the afferent and sufficient numbers of afferents recruited are crucial factors for full expression of reflex cardiovascular responses.

Animals↗

PubMed1996

Hypoxia does not directly stimulate ischemically sensitive abdominal visceral afferents during ischemia.

Abdominal ischemia activates ischemically sensitive sympathetic visceral afferents and evokes reflex excitation of the cardiovascular system. These afferents respond to ischemic metabolites, including lactic acid, bradykinin, prostaglandins, and reactive oxygen species. Severe hypoxemia also has been shown to activate these afferents. It is not known, however, if the regional tissue hypoxia induced by abdominal ischemia directly or indirectly activates ischemically sensitive visceral afferents. To determine the role of tissue hypoxia in activation of ischemically sensitive abdominal afferents, continuous single-unit activity of ischemically sensitive abdominal sympathetic C-fiber afferents (conduction velocity = 0.51-1.48 m/s) and regional tissue PO2, measured by a polarographic oxygen electrode in the porta hepatis, duodenum, or pancreas, were recorded simultaneously in anesthetized cats before and during 10-15 min of ischemia. Abdominal ischemia rapidly decreased regional tissue PO2 from 161 +/- 10 to 8 +/- 2 mmHg (P < 0.01) within an interval of 136 +/- 12 s. By contrast, after longer latency (399 +/- 24 s, P < 0.01 vs. PO2 interval), the activity of these afferents increased from 0.06 +/- 0.01 to 0.33 +/- 0.07 imp/s (P < 0.01). Furthermore, the activity of ischemically sensitive afferents gradually increased throughout ischemia with peak activity (0.68 +/- 0.14 imp/s) occurring at 600 +/- 39 s, although tissue PO2 remained constant. There was no correlation between the changes of tissue PO2 and discharge activity of these afferents (r = -0.428, P = 0.144). These data suggest that tissue hypoxia induced by abdominal ischemia is not directly responsible for activation of ischemically sensitive sympathetic visceral afferents but likely acts in an indirect fashion by promoting formation of other metabolic products capable of activating these nerve endings.

Abdomen↗

PubMed1996

Hydroxyl radical production during myocardial ischemia and reperfusion in cats.

We previously showed that generation of reactive oxygen species during myocardial ischemia and reperfusion stimulates cardiac sympathetic afferent nerve endings. We hypothesized that, in this feline model of brief ischemia and reperfusion, HO. is produced during ischemia and the rate and concentration of production of HO.during reperfusion is dependent on the duration of myocardial ischemia. Therefore, we evaluated the time dependency of production of HO. during reperfusion after 2, 5, and 10 min of reversible occlusion of the left anterior descending (LAD) coronary artery to induce ischemia in cats (n = 10). Blood samples collected from the coronary vein at 0.25, 1, 2, and 4 min after 2 min of ischemia revealed net cumulative rate of production of p-, m-, and o-tyrosine of 99 +/- 31, 10 +/- 5.1, and 0.8 +/- 0.2 nmol.min-1.g-1, respectively. After 5 min of ischemia, net cumulative rates of production of p-, m-, and o-tyrosine during reperfusion were 177 +/- 63, 74 +/- 26, and 1.6 +/- 0.8 nmol.min-1.g-1, respectively, whereas after 10 min of ischemia production rates were 153 +/- 42, 78 +/- 29, and 2.1 +/- 0.5 nmol.min-1.g-1, respectively. The highest rate of production of tyrosines was observed immediately after ischemia, perhaps indicating a washout of HO.-derived products that had accumulated in the myocardium during ischemia. To evaluate production of HO. during ischemia, deoxygenated saline (PO2 10 +/- 0.9 mmHg) containing phenylalanine was perfused into the ischemic coronary vascular bed through a cannula placed in the LAD (n = 16). Perfusate was collected from the coronary vein during the 10 min of ischemia. Net production of HO. during ischemia, measured by the production of p-, m-, and o-tyrosine, was 82 +/- 11, 6.6 +/- 0.4, and 1.7 +/- 0.3 nmol.min-1.g-1, respectively. Pretreatment with deferoxamine (10 mg/kg, n = 7) or dimethylthiourea (10 mg/kg, n = 6) decreased net production of HO. during ischemia and reperfusion. These results demonstrate that HO. is produced during brief ischemia and reperfusion, with the greatest amount being produced immediately after ischemia. Additionally, we show that the duration of brief ischemia determines the rate of production of HO. during reperfusion.

Animals↗

PubMed1996

Production of hydroxyl radicals in contracting skeletal muscle of cats.

Reactive oxygen species increase during exhaustive contraction of skeletal muscle, but characterization of the specific species involved and their rates of production during nonexhaustive muscle contraction have not been investigated. We hypothesized that the production rate of hydroxyl radical (.OH) increases in contracting muscle and that this rate is attenuated by pretreatment with deferoxamine (Def) or dimethylthiourea (DMTU). We measured the rate of production of .OH before, during, and after 5 min of intermittent static contraction of the triceps surae muscles in cats (n = 6) using the formation of p-, m-, and o-tyrosines by hydroxylation of phenylalanine. L-Phenylalanine (30 mg/kg i.v.) was administered to each animal 3 min before contraction. Blood samples were collected from the popliteal vein 1 min before contraction; 1, 3, and 4.5 min during contraction; and 1 min after contraction. During and after contraction, the cumulative production rates of p-, m-, and o-tyrosines were elevated by 42.84 +/- 5.41, 0.25 +/- 0.04, and 0.21 +/- 0.03 nmol.min-1.g-1, respectively, compared with noncontracting triceps surae muscles. Pretreatment with Def (10 mg/kg i.v.; n = 5) or DMTU (10 mg/kg i.v.; n = 4) decreased the cumulative rates of production of p-, m-, and o-tyrosines during and after contraction. Additionally, the rate of tyrosine production increased in proportion to the percentage of maximal tension developed by the triceps surae muscles. These results directly demonstrate that .OH is produced in vivo in the skeletal muscle of cats during intermittent static contraction and that production can occur before the onset of fatigue.

Animals↗