Biomedical subjects

J C Longhurst

Publications and source records attributed to J C Longhurst.

At least 55 records · Page 3Linked to original sources

PubMed1996

Reactive oxygen species modify reflex cardiovascular responses to static contraction.

Reactive oxygen species can reflexly activate the cardiovascular system through stimulation of abdominal visceral afferents. The mechanism appears to involve hydroxyl radicals. We tested the hypothesis that reactive oxygen species contribute to the reflex cardiovascular response to static muscle contraction (i.e., the exercise pressor reflex). Thus blood pressure and heart rate responses to 5 min of intermittent electrically stimulated static contraction of the triceps surae muscles (15 s on, 15 s off) in anesthetized cats were compared before and after intravenous administration of the free radical scavengers dimethylthiourea (DMTU; 10 mg/kg; n = 8) or deferoxamine (Def; 10 mg/kg; n = 15). The contraction-induced pressor response was augmented from 51 +/- 6 to 61 +/- 7 mmHg after treatment with DMTU (P < 0.05) and from 44 +/- 8 to 58 +/- 8 mmHg after administration of Def (P < 0.05). Corresponding heart rate responses were not affected by either drug. Because this DMTU- or Def-induced augmentation of the exercise pressor reflex may have been due to a reduction in free radical-evoked vasodilation in the contracting skeletal muscle, popliteal artery blood velocity was measured with a Doppler flow transducer before and during contraction in the absence and presence of Def (n = 8). Blood velocity during contraction was not altered by Def (16 +/- 5 vs. 24 +/- 6 cm/s). These data suggest that reactive oxygen species exert an inhibitory effect on the exercise pressor reflex that is not associated with their local vasodilator properties. This response is opposite to that observed during stimulation of visceral afferents by reactive oxygen species.

Animals↗

PubMed1996

Cardiac reflex effects of intracoronary bradykinin in humans.

BACKGROUND: Endogenous production of bradykinin (BK) has been postulated to cause hemodynamic changes and cardiac pain during myocardial ischemia, presumably because of the stimulation of cardiac afferent fibers. METHODS: To test the hypothesis that BK results in cardiac reflex responses and can cause the sensation of angina, 10 patients with and without coronary atherosclerosis had BK injected into their right (RCA) and left (LCA) coronary arteries in graded concentrations up to 10(-5) m. Patients were monitored for hemodynamic changes and the presence and quality of pain. RESULTS: Intracoronary BK 10(-5) m caused a significant reduction in blood pressure in most patients with either injection into the RCA or LCA (RCA: 151 +/- 10/90 +/- 5 mm Hg to 119 +/- 11/70 +/- 6 mm Hg, LCA: 161 +/- 11/88 +/- 6 mm Hg to 118 +/- 10/65 +/- 6 mm Hg) that began 12 to 14 seconds after injection. Injection into the LCA also resulted in a significant increase in heart rate (69 +/- 4 to 81 +/- 7 beats/minute), while injection into the RCA did not. Pain occurred after changes in blood pressure in all but one patient, which was present in 5 of 9 patients with RCA injection and 8 of 9 patients with LCA injection, and was often associated with flushing and nausea. Pain caused by BK was not similar to previous clinical ischemic pain in the patients with coronary atherosclerosis. CONCLUSIONS: The absence of a chronotropic response associated with arterial hypotension following injection of BK into the RCA is consistent with activation of cardiac vagal afferents in the left ventricle. The latency and quality of pain in these patients following injection of BK suggests that, while BK is nociceptive, it likely is not the cause of angina in patients with myocardial ischemia.

Adult↗

PubMed1995

Limitation of reperfusion injury by a monoclonal antibody to C5a during myocardial infarction in pigs.

The complement system has been implicated in reperfusion injury during acute myocardial infarction. We therefore attempted to reduce reperfusion injury with a monoclonal antibody (MAb) to the complement component, C5a. In 13 control pigs and 9 pigs pretreated with this MAb, ischemia was induced by a 50-min occlusion of the left anterior descending coronary artery, followed by 3 h of reperfusion. Infarct area (as percent of risk area) was reduced from 58 +/- 5% in controls to 38 +/- 7% (P < 0.05) in MAb-treated animals. Heart rate-systolic blood pressure product, left ventricular (LV) first derivative of pressure, LV end-diastolic pressure, and coronary blood flow were similar (P > 0.05) in the two groups. At 15 min of reperfusion, immunoreactive factor Bb began to increase significantly (P < 0.05) in regional coronary venous plasma, consistent with activation of the alternative complement pathway. The anti-C5a MAb did not attenuate formation of the membrane attack complex (C5b-9) as assessed by a hemolytic complement assay. Myocardial myeloperoxidase activity, a marker of tissue neutrophil concentration, was similar in the risk regions of the two groups, suggesting that neutrophil infiltration was unaltered by the MAb. However, in vitro the MAb (15 and 30 micrograms/ml) reduced C5a-stimulated neutrophil aggregation (67.4 and 70.9%), chemotaxis (52.5 and 81.4%), degranulation (66.7 and 75.8%), and superoxide generation (26.7 and 100%). In conclusion, myocardial infarction-reperfusion is associated with activation of the alternative complement pathway. Furthermore, a MAb to C5a that inhibits neutrophil cytotoxic activity, but neither the membrane attack complex nor myocardial neutrophil accumulation, decreases infarct size in pigs. These data suggest an important role of the alternative complement pathway and C5a in the propagation of ischemia cardiac damage during reperfusion.

Animals↗

PubMed1995

Role of spinal NK1 receptors in cardiovascular responses to chemical stimulation of the gallbladder.

The present study examined the role of substance P (SP) as a sensory neurotransmitter in cardiovascular responses to bradykinin applied on the gallbladder. Experiments were performed in anesthetized cats in which sympathetic chains were transected at the T5-T6 level, and the tip of the intrathecal catheter was positioned at T6-T7 to limit the injectate between T6 and L2. Bradykinin (10 micrograms/ml) was applied onto the gallbladder before and after intrathecal injection of [D-Pro2,D-Phe7,D-Trp9]SP (100-200 micrograms, NK1/NK2-receptor antagonist), CP-99,994 (50-100 micrograms, selective NK1 antagonist), MEN-10,376 (100-500 micrograms, selective NK2 antagonist), or vehicle. Intrathecal injection of NK1 but not NK2 antagonist significantly reduced increases in mean arterial pressure, heart rate, and maximal rate of left ventricular pressure change by 28 +/- 2 mmHg (33 +/- 4%), 4 +/- 1 beats/min (42 +/- 5%), and 497 +/- 46 mmHg/s (36 +/- 4%), respectively. Intrathecal injection of NK1 or NK1/NK2 antagonist had no effect on cardiovascular responses evoked by electrical stimulation in the rostral ventral lateral medulla. These data suggest that endogenous SP, acting as a sensory neurotransmitter, is involved in the excitatory cardiovascular reflex caused by chemical stimulation of the gallbladder through its action on NK1 receptors in the spinal cord.

Animals↗

PubMed1995

An ultrasonic system for measurement of absolute myocardial thickness using a single transducer.

We have developed an ultrasonic instrument that can measure absolute regional myocardial wall motion throughout the cardiac cycle using a single epicardial piezoelectric transducer. The methods in place currently that utilize ultrasound to measure myocardial wall thickness are the transit-time sonomicrometer (TTS) and, more recently, the Doppler echo displacement method. Both methods have inherent disadvantages. To address the need for an instrument that can measure absolute dimensions of myocardial wall at any depth, an ultrasonic single-crystal sonomicrometer (SCS) system was developed. This system can identify and track the boundary of the endocardial muscle-blood interface. With this instrument, it is possible to obtain, from a single epicardial transducer, measurement of myocardial wall motion that is calibrated in absolute dimensional units. The operating principles of the proposed myocardial dimension measurement system are as follows. A short duration ultrasonic burst having a frequency of 10 MHz is transmitted from the piezoelectric transducer. Reflected echoes are sampled at two distinct time intervals to generate reference and interface sample volumes. During steady state, the two sample volumes are adjusted so that the reference volume remains entirely within the myocardium, whereas half of the interface sampled volume is located within the myocardium. After amplification and filtering, the true root mean square values of both signals are compared and an error signal is generated. A closed-loop circuit uses the integrated error signal to continuously adjust the position of the two sample volumes. We have compared our system in vitro against a known signal and in vivo against the two-crystal TTS system during control, suppression (ischemia), and enhancement (isoproterenol) of myocardial function. Results were obtained in vitro for accuracy (> 99%), signal linearity (r = 0.99), and frequency response to heart rates > 450 beats/min, and in vivo data were acquired for end-systolic dimension (r = 0.99), end-diastolic dimension (r = 0.99), and percent wall thickness (r = 0.99). Both in vitro and in vivo tests indicate that the SCS functions identically to the two-crystal TTS. Use of the SCS allows measurement of absolute wall thickness and hence myocardial function, for both acute and chronically instrumented animal studies, with minimal or no trauma to myocardium.

Animals↗

PubMed1995

Cardiac-cardiovascular reflexes induced by hydrogen peroxide in cats.

We have shown previously that reactive oxygen species stimulate abdominal sympathetic afferents to cause reflex cardiovascular activation. Because myocardial ischemia and reperfusion also generate reactive oxygen species, we investigated the possibility that cardiovascular reflexes could be induced by topical application of H2O2 to the anterior or posterior ventricular surface in cats anesthetized with alpha-chloralose. Mean arterial pressure (MAP), heart rate (HR), left ventricular (LV) pressure, aortic flow (AF), and first derivative of LV pressure at 40 mmHg developed pressure (LV dP/dt40) were monitored. H2O2 (44 and 130 mumol) significantly increased MAP but not HR or LV dP/dt40 in intact cats (n = 8). Application of H2O2 (44 mumol) significantly increased MAP (129 +/- 9 to 152 +/- 10 mmHg), HR (240 +/- 11 to 245 +/- 10 beats/min), AF (191 +/- 13 to 212 +/- 17 ml/min), total peripheral resistance (0.68 +/- 0.13 to 0.73 +/- 0.04 peripheral resistance units), and LV dP/dt40 (2,666 +/- 145 to 3,012 +/- 205 mmHg/s) after bilateral cervical vagotomy (n = 6). These H2O2-induced excitatory responses were abolished after bilateral T1-T4 ganglionectomy. In six additional cats, H2O2 (44 mumol) significantly decreased MAP (114 +/- 5 to 102 +/- 5 mmHg), HR (207 +/- 7 to 190 +/- 7 beats/min), and LV dP/dt40 (2,776 +/- 168 to 2,600 +/- 153 mmHg/s) after sympathectomy. These depressor responses were eliminated after vagotomy. The magnitude of the cardiovascular reflexes was increased or decreased in a dose-dependent fashion in vagotomized or sympathectomized cats, respectively, over a range of 440 nmol to 44 mumol H2O2. Application of H2O2 to the anterior or posterior ventricular surface resulted in similar pressor or depressor reflexes. Dimethylthiourea and deferoxamine abolished pressor or depressor responses evoked by H2O2 in both vagotomized (n = 8) and sympathectomized (n = 8) cats. We conclude that reactive oxygen species, particularly the hydroxyl radical, can participate in activating cardiac afferents responsible for reflex cardiovascular responses during myocardial ischemia and reperfusion. An inhibitory reflex is transmitted through vagal afferents, whereas an excitatory reflex is conducted by sympathetic cardiac afferents.

Animals↗

PubMed1995

Lack of a role of adenosine in activation of ischemically sensitive cardiac sympathetic afferents.

Adenosine has been implicated in the pathogenesis of cardiac pain through activation of cardiac sympathetic afferents. The present study was performed to assess directly the contribution of adenosine in activating ischemically sensitive cardiac sympathetic afferents. Single-unit activity of ischemically sensitive afferents located in both ventricles was recorded from the left thoracic sympathetic chain or rami communicantes of anesthetized cats during 5 min of myocardial ischemia. Intracardiac injection (5 mg) or epicardial application (1-5 mg/ml) of adenosine onto the receptive fields failed to activate 31 ischemically sensitive A delta- and C fiber afferents, which were responsive to topical application of bradykinin (10 micrograms/ml). Intracardiac injection (5 mg) or topical application (1-5 mg/ml) of an adenosine A1 receptor agonist, N6-cyclopentyladenosine, also did not increase the discharge activity of 13 other ischemically sensitive C fiber afferents. Treatment with dipyridamole (1 mg/kg iv) to inhibit the cellular uptake of adenosine did not significantly potentiate the response of 10 separate C fiber afferents to 5 min of myocardial ischemia. Furthermore, blockade of adenosine receptors with aminophylline (5 mg/kg iv) did not significantly attenuate the response of 10 other C fiber afferents to 5 min of myocardial ischemia. The results of the present study demonstrate that exogenous and endogenous adenosine do not contribute to activation of ischemically sensitive cardiac sympathetic afferents. The findings of the present study fail to support a substantial role for adenosine and its A1 receptors in activation of cardiac sympathetic afferents during myocardial ischemia.

Adenosine↗

PubMed1995

Differential effect of 5- and 15-lipoxygenase products on ischemically sensitive abdominal visceral afferents.

The effects of 5- and 15-lipoxygenase products, leukotriene B4 (LTB4) and (8R,15S)-dihydroxyeicosa(5E-9,11,13Z)tetraenoic acid (8R,15S-diHETE), on ischemically sensitive abdominal visceral C fiber afferents were evaluated, because this system is important in sensitizing cutaneous afferents. Single-unit activity of abdominal visceral C fiber afferents was recorded from the right thoracic sympathetic chain of anesthetized cats during 5 min of ischemia. Inhibition of 5-lipoxygenase with WY-50295 tromethamine (5 mg/kg iv) augmented the impulse activity from 0.48 +/- 0.15 to 0.79 +/- 0.24 impulses/s (P < 0.05) in seven ischemically sensitive afferents. Conversely, topical application of LTB4 (125 ng) directly onto the receptive field attenuated impulse activity of 10 ischemically sensitive C fiber afferents from 0.82 +/- 0.23 to 0.42 +/- 0.10 impulses/s (P < 0.05). In additional cats, application of 8R,15S-diHETE (125 ng) onto the receptive field augmented the impulse activity of nine ischemically sensitive C fiber afferents (from 0.48 +/- 0.15 to 0.70 +/- 0.15 impulses/s, P < 0.05) and significantly decreased the mechanical threshold of these nine afferents, whereas application of 8S,15S-diHETE (125 ng), a stereoisomer of 8R,15S-diHETE, attenuated the impulse activity from 0.77 +/- 0.48 to 0.45 +/- 0.13 impulses/s (P < 0.05) in six additional ischemically sensitive C fiber afferents. In animals pretreated with aspirin (50 mg/kg iv, n = 6) or 8S,15S-diHETE (125 ng, n = 6), WY-50295 tromethamine (5 mg/kg iv) still potentiated the impulse activity of ischemically sensitive C fiber afferents. These data indicate that 8R,15S-diHETE interacts with stereospecific receptors to sensitize, whereas LTB4 reduces, the response of abdominal visceral afferents to ischemia. Furthermore the data suggest that the augmented response of afferents to abdominal ischemia after inhibition of 5-lipoxygenase is, at least in part, independent of shunting to the cyclooxygenase or 15-lipoxygenase system.

Abdomen↗

PubMed1995

Ischemia- and reperfusion-sensitive cardiac sympathetic afferents: influence of H2O2 and hydroxyl radicals.

Activation of cardiac sympathetic afferents leads to excitatory cardiovascular reflexes and pain during myocardial ischemia. We hypothesized that cardiac sympathetic afferents are activated by reactive oxygen species produced during ischemia and reperfusion. Single-unit nerve activity of 55 afferents was recorded from the left paravertebral sympathetic chain (T1-T4) in cats anesthetized with alpha-chloralose. Receptive fields of all afferents were located on the right or left ventricle. Mechanical and chemical sensitivities of each afferent ending were evaluated by von Frey hairs, cardiac distension, and local application of bradykinin (BK, 142 pmol) or H2O2 (7.5-15 mumol) to the receptive field. Thirty-one afferents (56%) were responsive to bradykinin (BK), H2O2, and ischemia (2 or 10 min). Deferoxamine (Def, 10-100 mg/kg), dimethylthiourea (DMTU, 10-100 mg/kg), or iron-loaded Def (10 mg/kg) were employed to evaluate the role of H2O2 and hydroxyl radicals (.OH) in activating these afferents (10A delta and 21C fibers) during ischemia and reperfusion. Treatment with the nonspecific scavenger DMTU (n = 10) significantly diminished the increase in discharge activity evoked by ischemia and reperfusion. Treatment with Def also significantly attenuated the responses during ischemia and reperfusion. Thus reactive oxygen species, particularly .OH, activate a group of cardiac sympathetic A delta- and C-fiber afferents during myocardial ischemia and reperfusion and may play an important role in mediating cardiovascular sympathetic reflex responses and/or pain transmission.

Animals↗

PubMed1994

Endogenous BK stimulates ischemically sensitive abdominal visceral C fiber afferents through kinin B2 receptors.

Abdominal ischemia and reperfusion reflexly activate the cardiovascular system. In the present study, we evaluated the role of endogenously produced bradykinin (BK) in the stimulation of ischemically sensitive visceral afferents. Single-unit activity of abdominal visceral C fiber afferents was recorded from the right thoracic sympathetic chain of anesthetized cats during 5 min of abdominal ischemia. Abdominal ischemia increased the portal venous plasma BK level from 49 +/- 10 to 188 +/- 66 pg/ml (P < 0.05). Injection of BK (1 microgram/kg ia) into the descending aorta significantly increased impulse activity (0.88 +/- 0.16 impulses/s) of 10 C fibers, whereas a kinin B1-receptor agonist, des-Arg9-BK (1 microgram/kg), did not alter the discharge rate. Inhibition of kininase II activity with captopril (4 mg/kg i.v.) potentiated impulse activity of 14 ischemically sensitive C fibers (0.44 +/- 0.09 vs. precaptopril, 0.33 +/- 0.08 impulses/s; P < 0.05). In addition, a kinin B2-receptor antagonist (NPC-17731; 40 micrograms/kg i.v.) attenuated activity of afferents during ischemia (0.39 +/- 0.08 vs. pre-NPC-17731, 0.72 +/- 0.13 impulses/s; P < 0.05) and eliminated the response of 10 C fibers to BK. Another kinin B2-receptor antagonist, Hoe-140 (30 micrograms/kg iv), had similar inhibitory effects on six other ischemically sensitive C fibers. In 15 separate cats treated with aspirin (50 mg/kg i.v.), Hoe-140 (30 micrograms/kg i.v.) attenuated impulse activity of only 3 of 16 ischemically sensitive C fibers. These data suggest that BK produced during abdominal ischemia contributes to the stimulation of ischemically sensitive visceral C fiber afferents through kinin B2 receptors.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent Pathways↗

PubMed1994

Brief mesenteric ischemia increases PGE2, but not PGI2, in intestinal lymph of cats.

Mesenteric ischemia of short duration (5-10 min) can stimulate A delta- and C-fiber afferent nerve endings in the viscera to reflexly activate the cardiovascular system. The mechanism of activation of abdominal visceral afferents is probably multifactorial and may involve prostaglandins (PGs), which have been shown to directly stimulate and/or sensitive visceral afferents when administered exogenously. We hypothesized that brief visceral ischemia is accompanied by release of PGI2 and PGE2 into the interstitium, where these cyclooxygenase products could stimulate or sensitize visceral afferent nerve endings. Accordingly, we measured immunoreactive PGE2 (iPGE2) and 6-keto-PGF1 alpha (i6-keto-PGF1 alpha), the stable metabolite of PGI2, in lymph draining the ischemic viscera as well as in portal venous blood. An intestinal lymph duct distal to the lymph node was cannulated in pentobarbital sodium-anesthetized cats. Lymph and plasma iPGE2 and i6-keto-PGF1 alpha concentrations were measured by radioimmunoassay before, during, and immediately after a 5- to 10-min occlusion of the descending aorta. The i6-keto-PGF1 alpha concentration increased significantly (P < 0.001) in portal venous plasma (61 +/- 12 to 107 +/- 18 pg/0.1 ml; n = 14) but not in lymph (148 +/- 30 to 159 +/- 24 pg/0.1 ml; n = 16). In contrast, iPGE2 concentration was significantly (P < 0.01) elevated in both venous plasma (156 +/- 16 to 207 +/- 26 pg/0.1 ml; n = 19) and lymph (520 +/- 48 to 590 +/- 52 pg/0.1 ml; n = 20).(ABSTRACT TRUNCATED AT 250 WORDS)

6-Ketoprostaglandin F1 alpha↗

PubMed1994

Cardiovascular reflexes during abdominal ischemia in cats.

The cardiovascular effects of regional abdominal ischemia and reperfusion were studied in cats anesthetized with alpha-chloralose. In group 1 (n = 9), central venous pressure was kept constant by a servo-controller while the celiac and superior mesenteric arteries were occluded by loop snares for 10 min. In group 2 (n = 9), a constant-perfusion circuit to the celiac and superior mesenteric arteries that could divert flow to the femoral vein was used to induce abdominal ischemia. In group 3 (n = 7), venous return from the inferior vena cava was controlled, and a constant-perfusion circuit was used to induce abdominal ischemia. Abdominal ischemia significantly (P < 0.05) increased portal venous blood lactate from 4.3 +/- 0.6 to 6.0 +/- 0.6 mM in group 3. The early increases in blood pressure caused by passive volume shifts in groups 1 and 2 were abolished in group 3. The late, i.e., 10 min, response to abdominal ischemia consisted of significant (P < 0.05) increases in mean arterial pressure (29 +/- 7, 24 +/- 7, and 33 +/- 8 mmHg in groups 1, 2, and 3, respectively). Abdominal ischemia also significantly (P < 0.05) increased the first derivative of left ventricular pressure at 40 mmHg developed pressure from 4,355 +/- 377 to 4,839 +/- 407 mmHg/s in group 3. Celiac and superior mesenteric ganglionectomy abolished the late but not the early hemodynamic changes. Ganglionectomy also significantly (P < 0.05) enhanced the decrease in mean arterial pressure during reperfusion in all groups. We conclude that the pressor and contractile responses during 10 min of abdominal ischemia and the relative maintenance of blood pressure during reperfusion after ischemia are reflex in nature.

Abdomen↗

PubMed1993

Limitation of myocardial infarct size in pigs with a dual lipoxygenase-cyclooxygenase blocking agent by inhibition of neutrophil activity without reduction of neutrophil migration.

OBJECTIVES: The purpose of this study was to assess the effect of the dual cyclooxygenase-lipoxygenase blocking agent BW755C on the extent of myocardial infarction in the pig and to identify the mechanisms of any cardioprotective action of this drug. BACKGROUND: Activated neutrophils contribute to reperfusion injury after myocardial infarction and inhibition of neutrophil function can limit infarct size. METHODS: In 9 control and 10 study pigs pretreated with intravenous BW755C (10 mg/kg body weight) 30 min before coronary occlusion, ischemia was induced by a 50-min occlusion of the mid-left anterior descending coronary artery, followed by 3 h of reperfusion. Heart rate, arterial pressure, left ventricular end-diastolic pressure, the first derivative of left ventricular pressure (dP/dt) and regional myocardial blood flow were measured during control, occlusion and reperfusion periods. Infarct size was determined by histochemical staining; and myeloperoxidase activity, a marker for tissue neutrophil content, was assessed in normal and infarcted myocardium. The effect of BW755C on the function of isolated neutrophils stimulated with zymosan-activated serum was evaluated by measuring neutrophil degranulation, leukotriene B4 production, superoxide generation and chemotaxis. RESULTS: Hemodynamic function and regional myocardial blood flow were similar in control and BW755C-treated animals. BW755C significantly reduced myocardial infarct size compared with that in control animals, as measured by infarct/risk areas by histochemical staining (39 +/- 5% vs. 63 +/- 7%, p < 0.05). Myocardial myeloperoxidase activity was similar in normal, salvaged and infarcted areas in the control and treated groups, indicating that neutrophil accumulation in injured myocardium was unaltered by BW755C. However, this agent attenuated function of isolated, stimulated (zymosan-activated serum) neutrophils. At a concentration of 0.03 mg/ml, BW755C inhibited degranulation (-46%), leukotriene B4 production (-48%) and superoxide generation (-74%), but there was minimal inhibition of chemotaxis in vitro. CONCLUSIONS: These findings demonstrate that myocardial infarct size can be reduced by selective inhibition of neutrophil cytotoxic activity without affecting neutrophil migration into injured myocardium.

4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyraz↗

PubMed1993

Response of collateral-dependent myocardium to vasopressin release during prolonged intense exercise.

We hypothesized that vasopressin concentrations during exercise attenuate the increase in collateral-dependent blood flow leading to left ventricular dysfunction in Ameroid-occluded miniswine. An Ameroid occluder was placed around the proximal left circumflex coronary artery (LCX) of 19 miniswine. Ten weeks later V1 receptor blockade with the use of [d(CH2)5Tyr-(Me)]arginine vasopressin (10-12 micrograms/kg iv) increased resting transmural flow (radioactive microspheres) in the LCX region, indicating the presence of V1 receptors. Neither injection of lysine vasopressin (125 pmol/kg) after V1 receptor blockade nor injection of two specific V2 receptor agonists caused changes in mean arterial pressure, heart rate, or left anterior descending coronary arterial flow velocity, indicating that V2 receptors mediate no appreciable vasodilation in the swine coronary circulation. Next the ratio of collateral to noncollateral flow and regional systolic wall thickening (sonomicrometer dimension gauges) were measured at rest and after 20 min of prolonged, intense treadmill exercise (85-90% of heart rate reserve) in the presence and absence of V1 receptor antagonism. This degree of exertion increased plasma lysine vasopressin from 6.2 +/- 1.0 at rest to 21.0 +/- 7.0 pg/ml (P < 0.05) during the unblocked run. However, the decrease in transmural blood flow ratio (collateral to noncollateral flow) from rest was similar during exercise before and after V1 receptor blockade (0.78 +/- 0.07 and 0.80 +/- 0.05, respectively; P < 0.05 vs. rest). Likewise, percent systolic wall thickening in the collateral-dependent region decreased from rest to exercise in the absence and presence of V1 receptor antagonism (35.9 +/- 4.5 and 39.5 +/- 3.8%, respectively; P < 0.05 vs. rest).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

C5a-induced myocardial ischemia: role for CD18-dependent PMN localization and PMN-platelet interactions.

Intracoronary C5a in swine decreases coronary blood flow and regional myocardial segment shortening, responses mediated by thromboxane (Tx) A2-induced coronary vasoconstriction and intramyocardial trapping of granulocytes (PMNs). We sought to determine the origin of TxA2 and to investigate the role of CD18-dependent PMN function by utilizing an anti-CD18 monoclonal antibody, IB4. Isolated C5a-stimulated PMNs or platelets did not produce TxB2. However, together, C5a-stimulated PMNs and platelets produced TxB2. IB4 bound porcine PMN surface CD18 and blocked C5a-induced PMN functions. In vivo, IB4 loading (2 mg/kg) transiently decreased arterial blood pressure and circulating platelet counts in six of nine animals (390 +/- 31 vs. 176 +/- 41 X 10(6)/ml, control vs. IB4; P < 0.002) and significantly ameliorated C5a-induced decreases in coronary venous PMN count (-4.1 +/- 0.6 vs. -1.4 +/- 0.8 X 10(6) cells/ml), coronary artery blood flow (-10 +/- 1 vs. -4 +/- 1 ml/min), and segment shortening (-15 +/- 2 vs. -8 +/- 2%, C5a vs. C5a + IB4). We conclude that 1) production of TxB2 in response to C5a is mediated by a PMN-platelet interaction, 2) IB4 functionally blocks CD18 on porcine PMNs, and 3) C5a-induced myocardial PMN extraction is mediated, in part, by a CD18-dependent mechanism. These results suggest that PMN-platelet interactions and CD18-dependent PMN extraction are important in C5a-induced myocardial ischemia.

Animals↗

PubMed1993

Bradykinin contributes to the exercise pressor reflex: mechanism of action.

This study determined the receptors responsible for mediating bradykinin's effect on skeletal muscle afferents that cause the pressor reflex in anesthetized cats. In eight cats, 1 microgram of bradykinin was injected intra-arterially into the gracilis muscle before and after intravenous injection of a kinin B2-receptor antagonist (NPC 17731, 20 micrograms/kg). Initial injection of bradykinin reflexly increased mean arterial pressure by 23 +/- 7 mmHg, maximal change in pressure over time by 439 +/- 272 mmHg/s, and heart rate by 11 +/- 4 beats/min. The hemodynamic response to bradykinin was abolished by kinin B2-receptor blockade. Similar injection of the kinin B1-receptor agonist des-Arg9-bradykinin caused no cardiovascular responses (n = 6). In eight different animals, mean arterial pressure, maximal change in left ventricular pressure over time, and heart rate responses to 30 s of electrically stimulated hindlimb contraction were attenuated by 50 +/- 6, 55 +/- 7, and 41 +/- 8%, respectively, after kinin B2-receptor blockade. In eight other animals, mean arterial pressure, maximal change in left ventricular pressure over time, and heart rate responses were reduced by 58 +/- 8, 66 +/- 6, and 40 +/- 12%, respectively, after inhibition of prostaglandin synthesis with indomethacin (2.5-3 mg/kg iv) and were then abolished by subsequent B2-receptor blockade. These data suggest that bradykinin contributes to the exercise pressor reflex through its action on kinin B2 receptors located on the nerve endings of the muscle afferents.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗

PubMed1993

Activation of ischemia- and reperfusion-sensitive abdominal visceral C fiber afferents. Role of hydrogen peroxide and hydroxyl radicals.

Abdominal ischemia and reperfusion evoke reflex excitation of the cardiovascular system and generate reactive oxygen species. We have shown previously that the reactive oxygen species hydrogen peroxide (H2O2) elicits reflex excitation of the cardiovascular system after serosal application to abdominal organs. However, it is not known if ischemia-sensitive afferents respond to reactive oxygen species or if scavengers such as dimethylthiourea (DMTU) inhibit the response of these afferents to ischemia or reperfusion. Therefore, to provide more information on the neurophysiological mechanisms underlying the activation of these afferents, we studied their responses to H2O2 applied to the receptive field during recordings of single-unit activity of ischemia-insensitive or -sensitive abdominal visceral C fiber afferents in anesthetized cats. Additionally, we recorded single-unit activity of ischemia and reperfusion-sensitive afferents before and after treatment with DMTU (10 mg/kg), which scavenges H2O2 and hydroxyl radicals or the iron chelator deferoxamine (DEF, 10 mg/kg), which inhibits hydroxyl radical formation. Application of 44 mumol H2O2 to afferent endings increased the discharge frequency in nine of 11 ischemia-sensitive units, from 0.01 +/- 0.01 to 0.67 +/- 0.16 impulses per second. In contrast, only one of 10 ischemia-insensitive C fibers responded to H2O2 application. In an additional 13 ischemia-sensitive C fibers, DMTU significantly (p < 0.05) attenuated ischemia-induced increases in discharge frequency from 0.42 +/- 0.18 to 0.24 +/- 0.1 impulses per second (ischemia versus DMTU + ischemia, respectively). In eight additional C fibers, we found that reperfusion after 5 minutes of ischemia was associated with an increase in discharge activity from a baseline activity of 0.02 +/- 0.01 to 0.44 +/- 0.07 impulses per second. DMTU significantly attenuated the reperfusion-induced increases in discharge frequency from 0.08 +/- 0.04 to 0.18 +/- 0.06 impulses per second. DEF significantly (p < 0.05) attenuated the increased discharge activity from 0.39 +/- 0.07 to 0.10 +/- 0.04 impulses per second (ischemia versus DEF + ischemia, respectively) in an additional 11 ischemia-sensitive C fibers. In contrast, iron-saturated DEF did not attenuate ischemia- and reperfusion-induced increases in impulse activity. Thus, ischemia-sensitive but not ischemia-insensitive abdominal visceral afferents respond to H2O2. Furthermore, ischemia- and reperfusion-sensitive afferents decreased their impulse activity to a repeated period of ischemia or reperfusion after DMTU or DEF treatment. These data suggest that reactive oxygen species, particularly H2O2 and hydroxyl radicals, activate abdominal visceral C fibers in the cat during brief periods of ischemia and reperfusion.

Abdomen↗

PubMed1993

Repeated dipyridamole administration enhances collateral-dependent flow and regional function during exercise. A role for adenosine.

Two main hypotheses concerning the mechanisms responsible for coronary collateral growth suggest the involvement of chemical or mechanical factors. Since we recently demonstrated that the development of the coronary collateral circulation is not closely related to the extent or duration of myocardial ischemia, we hypothesized that chronic repeated vasodilation and increased myocardial blood flow using dipyridamole would enhance collateral development in miniswine with an ameroid-occluded left circumflex coronary artery (LCx). Two days after surgical instrumentation, the animals received dipyridamole (n = 9), diltiazem as an adenosine-independent vasodilator (n = 8), or control vehicle (n = 7) 90 minutes per day, 5 days per week for 8 weeks. At 5 and 8 weeks, transmural blood flow and systolic wall thickening were measured during infusion of dipyridamole, diltiazem, or vehicle. Transmural blood flow increased similarly in the LCx and nonoccluded regions at 30 and 60 minutes during infusion of either vasodilator. Thus, we believe that similar mechanical stimulation resulted from dipyridamole and diltiazem infusion. There was no change in blood flow during administration of the vehicle. Systolic wall thickening in the collateral-dependent region was not altered by infusion of dipyridamole, diltiazem, or vehicle. Therefore, both vasodilators increased blood flow without eliciting ischemia. After 8 weeks of repeated treatment with each pharmacological agent, at least 24 hours after the last drug infusion, near maximal physiological capacity of the coronary collateral vessels was assessed during treadmill running (approximately 240 beats per minute). Transmural myocardial blood flow ratios, expressed as flow in the LCx divided by flow in the nonoccluded region of the left ventricle, were similar at rest for animals treated with dipyridamole (0.90 +/- 0.03), diltiazem (0.97 +/- 0.05), and control vehicle (0.89 +/- 0.02). However, collateral-dependent myocardial blood flow during exercise was greater (P < .05) in the dipyridamole-treated animals (0.78 +/- 0.04) than in either diltiazem-treated (0.63 +/- 0.09) or vehicle-treated (0.62 +/- 0.02) animals. LCx systolic wall thickening at rest was similar in animals treated with dipyridamole (44.4 +/- 6.3%), diltiazem (42.2 +/- 3.0%), and control vehicle (38.1 +/- 2.8%). During exercise, however, myocardial function in the collateral-dependent region was greater (P < .05) in the dipyridamole-treated (39.2 +/- 5.2%) compared with diltiazem-treated (23.9 +/- 4.0%) and vehicle-treated (26.9 +/- 2.9%) animals.(ABSTRACT TRUNCATED AT 400 WORDS)

Adenosine↗