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Biomedical subjects

N A Flores

Publications and source records attributed to N A Flores.

At least 19 recordsLinked to original sources
PubMed2001

Capillary filtration is reduced in lungs adapted to chronic heart failure: morphological and haemodynamic correlates.

OBJECTIVE: To determine pulmonary capillary filtration in experimental chronic heart failure and to investigate some morphological and haemodynamic mechanisms that could account for reduced filtration in lungs adapted to chronic heart failure. METHODS: We studied pulmonary capillary filtration, vascular resistances and morphology in lungs from guinea-pigs adapted to chronic heart failure. Heart failure was induced by banding of the ascending aorta (n=66) or sham control operation (n=78) in guinea-pigs which were studied at 150+/-8 days post-operation. RESULTS: Reduced cardiac output, increased systemic vascular resistance and LV end diastolic pressure and increased LV and RV weight:body weight ratio (all P<0.05) indicated chronic heart failure at 5 months following aortic banding in guinea-pigs. Lung weight was increased (61%, P<0.05) in heart failure compared with controls, but lung water content was reduced (5.5%, P<0.05), a reversal of the pattern seen acutely. Studies in isolated perfused lungs demonstrated a reduced capillary filtration coefficient (0. 018+/-0.003 vs. 0.003+/-0.002 ml min(-1)mmHg(-1)g(-1), P<0.001), increased arterial (61%) and venous resistance (50%) in heart failure lungs, P<0.05. Wall thickness:lumen ratio was increased in small (<250 microm) pulmonary arterioles (0.15+/-0.02 vs. 0.08+/-0. 01) and venules (0.06+/-0.005 vs. 0.04+/-0.002) in heart failure, P<0.01. Alveolar septal volume fractions (35.2+/-5.1 vs. 23.1+/-2.7) and septal:air-space volume ratios (60.5+/-13.6 vs. 31.9+/-5.3) were also increased in heart failure, P<0.05. CONCLUSIONS: Pulmonary adaptation to chronic heart failure is associated with vascular and alveolar remodelling that contributes to increased vascular resistance and reduced capillary filtration. These changes are likely to be important in mediating resistance to pulmonary oedema in chronic heart failure.

Adaptation, Physiological↗
PubMed2001

Investigation of mechanisms that mediate reactive hyperaemia in guinea-pig hearts: role of K(ATP) channels, adenosine, nitric oxide and prostaglandins.

1. Reactive hyperaemia is a transient vasodilatation following a brief ischaemic period. ATP-dependent K(+) (K(ATP)) channels may be important in mediating this response, however it is unclear whether mitochondrial K(ATP) channels contribute to this in the heart. 2. We examined the involvement of K(ATP) channels and the relative role of mitochondrial channels as mediators of coronary reactive hyperaemia and compared them to mechanisms involving NO, prostaglandins and adenosine in the guinea-pig isolated heart. 3. Reactive hyperaemic vasodilatation (peak vasodilator response and flow debt repayment) were assessed after global zero-flow ischaemia (5 -- 120 s) in the presence of nitro-L-arginine methyl ester (L-NAME, 10(-5) M, n=9), 8-phenyltheophylline (8-PT, 10(-6) M, n=12) and indomethacin (10(-5) M, n=12). 4. Glibenclamide (10(-6) M, n=12) a non-selective K(ATP) channel inhibitor and 5-hydroxy-decanoic acid (5-HD, 10(-4) M, n=10) a selective mitochondrial K(ATP) channel inhibitor were also used. The specificity of the effects of glibenclamide and 5-HD (n=6 each) were confirmed using pinacidil (38 nmol -- 10 micromol) and diazoxide (42 nmol -- 2 micromol). Glibenclamide was most effective in blocking the hyperaemic response (by 87%, P<0.001) although 5-HD and 8-PT also had a marked effect (40% inhibition, P<0.001 and 32%, P<0.001, respectively). L-NAME and indomethacin had little effect. 5. Perfusion with L-NAME and glibenclamide significantly reduced baseline coronary flow (22%, P<0.01 and 33%, P<0.01) while 8-PT, indomethacin and 5-HD had no effect. 6. K(ATP) channels are the major mediators of the coronary reactive hyperaemic response in the guinea-pig. Although mitochondrial K(ATP) channels contribute, they appear less important than sarcolemmal channels.

Adenosine↗
PubMed2001

Changes in extracellular pH and myocardial ischaemia alter the cardiac effects of diadenosine tetraphosphate and pentaphosphate.

1. The structural conformation of diadenosine tetraphosphate (Ap(4)A) and pentaphosphate (Ap(5)A) has been reported to alter as pH is reduced. As such, it is possible that the cardiac effects of Ap(4)A and Ap(5)A vary during acidosis and myocardial ischaemia due to changes in ligand structure, receptor proteins or intracellular signalling. 2. We investigated whether the cardiac electrophysiological and coronary vasomotor effects of Ap(4)A and Ap(5)A are preserved under conditions of extracellular acidosis (pH 6.5) and alkalosis (pH 8.5) and whether Ap(4)A has any electrophysiological or antiarrhythmic effects during ischaemia. 3. Transmembrane right ventricular action potentials, refractory periods and coronary perfusion pressure were recorded from isolated, Langendorff-perfused guinea-pig hearts under constant flow conditions. The effects of 1 nM and 1 microM Ap(4)A and Ap(5)A were studied at pH 7.4, 6.5 and 8.5. The effects of 1 microM Ap(4)A were studied during global low-flow ischaemia and reperfusion. 4. At pH 7.4, Ap(4)A and Ap(5)A increased action potential duration (APD(95)) and refractory period (RP) and reduced coronary perfusion pressure. The electrophysiological effects were absent at pH 6.5 while the reductions in perfusion pressure were attenuated. At pH 8.5, Ap(4)A increased RP but the effects of Ap(4)A and Ap(5)A on perfusion pressure were attenuated. During ischaemia, Ap(4)A had no antiarrhythmic or electrophysiological effects. 5. These data demonstrate the importance of extracellular pH in influencing the effects of Ap(4)A and Ap(5)A on the heart and indicate that any potentially cardioprotective effects of these compounds during normal perfusion at physiological pH are absent during ischaemia.

Action Potentials↗
PubMed2001

Coronary vasomotor and cardiac electrophysiologic effects of diadenosine polyphosphates and nonhydrolyzable analogs in the guinea pig.

Platelet activation in heart disease is important owing to the effects of platelet-derived compounds on myocardial perfusion and cardiac electrophysiology. Diadenosine polyphosphates are secreted from platelets and present in the myocardium, but their electrophysiologic and vasomotor effects are incompletely understood. We used isolated guinea-pig hearts to study the effects of diadenosine triphosphate (Ap3A), tetraphosphate (Ap4A), pentaphosphate (Ap5A), and hexaphosphate (Ap6A) (10 pM-0.1 mM), comparing their actions to those of adenosine, adenosine triphosphate, and non-hydrolyzable Ap4A and Ap5A analogs. Diadenosine polyphosphates (0.1 nM-0.1 microM) transiently reduced coronary perfusion pressure, which recovered during the continued presence of the compounds. At concentrations greater than 0.1 microM effects were maximal and sustained (perfusion pressure decreased from 36.5+/-3.4 to 18.6+/-2.5 mm Hg, p < 0.001, with 1 microM Ap4A). The changes in action potential duration and refractory period developed slowly but were maintained (0.1 nM-1 microM). With 1 nM Ap4A, action potential duration increased from 170.6+/-2.6 to 187.3+/-3.8 ms, p < 0.05, and refractory period increased from 138.5+/-1.6 to 147.9+/-2.0 ms, p < 0.05. Ap4A and its analog reduced QRS duration (from 24.7+/-1.1 to 13.9+/-1.6 ms with 1 microM Ap4A, p < 0.05). P2-purinergic (adenosine triphosphate) receptor antagonism (suramin) reduced perfusion pressure but was without electrophysiologic effect. Other changes in coronary perfusion pressure and electrophysiologic variables associated with Ap4A were not seen in the presence of suramin. P1-(adenosine) antagonism (8-[p-sulfophenyl]theophylline) attenuated the electrophysiologic effects only. Diadenosine polyphosphates have potent cardiac electrophysiologic and coronary vasomotor effects via purinergic receptors, suggesting an important role during platelet activation in acute coronary syndromes.

Action Potentials↗
PubMed2001

Contribution of nitric oxide and prostanoids to the cardiac electrophysiological and coronary vasomotor effects of diadenosine polyphosphates.

We investigated the hypothesis that the coronary vasomotor and cardiac electrophysiological effects of diadenosine polyphosphates (Ap(n)A) are mediated via release of nitric oxide and prostanoids. Transmembrane right ventricular action potentials, refractory periods, and coronary perfusion pressure were recorded from isolated, Langendorff-perfused guinea pig hearts studied under constant flow conditions. The effects of threshold (1 nM) and maximal (1 microM) concentrations of diadenosine triphosphate (Ap3A), tetraphosphate (Ap4A), pentaphosphate (Ap5A), and hexaphosphate (Ap6A) were studied in the presence of nitric oxide (NO) synthase inhibitors [L-NG-nitroarginine methyl ester, 300 microM; or L-N5-(1-iminoethyl)ornithine, 30 microM] or cyclooxygenase inhibitors (indomethacin, 100 microM or meclofenamate, 10 microM). Inhibition of cyclooxygenase and NO synthase both prevented the increases in action potential duration and refractory periods seen in response to Ap(n)A. Cyclooxygenase inhibition altered the vasomotor effects of the Ap(n)A in a manner that was related to the structure of the Ap(n)A compound (the effects of Ap3A were attenuated and those of Ap4A and Ap5A were prevented, while those of Ap6A were not abolished.) Inhibition of NO synthase did not abolish the vasomotor responses. These results demonstrate the importance of nitric oxide and prostanoids in the cardiac responses to Ap(n)A and support the hypotheses that the coronary vasomotor responses to Ap(n)A are mediated via release of prostanoids, that this is related to the structure of the compound, and that the cardiac electrophysiological responses to Ap(n)A involve both nitric oxide and prostanoid release.

Action Potentials↗
PubMed2001

Tedisamil (Solvay).

Tedisamil, a potassium channel blocker (class III anti-arrhythmic agent)from Solvay, is in phase II trials for the potential treatment of atrial fibrillation [342434]. The drug had completed phase III trials for angina pectoris [342434], [177648], and although an NDA dossier for angina pectoris in refractory patients was ready for filing with the US FDA, Solvay has decided to pursue the broader indication of atrial fibrillation instead [342434]. Tedisamil is bradycardic without producing a negative inotropic effect. In a canine model of exercise-induced angina, myocardial function was maintained. In rat, rabbit, canine and simian hearts, there was a marked prolongation of action potential, due to tedisamil's modulating effects on potassium channels. Diastolic arterial pressure was not influenced [276934]. Tedisamil also rapidly terminated sustained atrial fibrillation and prevented its reinitiation in a canine model of the condition [315378]. The class III antiarrhythmic effect of tedisamil is related predominantly to the strong blocking effect of the drug on the rapid component of the delayed rectifier potassium current [334806].

Angina Pectoris↗
PubMed2000

Endogenous and exogenous coronary vasodilatation are attenuated in cardiac hypertrophy: a morphological defect?

Reactive hyperaemia (RH) following brief ischaemia is reduced in hypertrophied hearts, and this may contribute to reduced coronary flow reserve. We studied vasodilatation during RH and in response to exogenous stimuli in control and hypertrophied hearts and explored the mechanisms underlying RH. Vascular reactivity was assessed in isolated hypertrophied hearts (55+/-3 days after aortic banding or sham operation) by constructing dose-response curves to acetylcholine (ACh), sodium nitroprusside (SNP) and adenosine. Reactive hyperaemic vasodilatation was assessed after global ischaemia (5-120 s) in the presence/absence of L -NAME, 8-phenyltheophylline (8-PT) and glibenclamide. Purine release and NO overflow in the coronary perfusate were analysed. Aortic constriction increased heart/body weight ratio (47%), myocyte size (19%) and arteriolar wall thickness (51%), all P<0.01. Coronary reserve was reduced in hypertrophy (105+/-8%v 182+/-12%, P<0.01). Dose response curves for ACh, SNP and adenosine were reduced in hypertrophy (69%, 86% and 68%, all P<0.01) v shams; however ED(50)values were unchanged. The peak flow and duration of RH were also attenuated (50%, P<0.001) in hypertrophy. While purine washout during RH was related to the duration of preceding ischaemia, nitrate washout was not. RH experiments in the presence of L -NAME, 8-PT and glibenclamide indicated that RH is mediated by combined actions of K(ATP)channels>adenosine>NO in both groups. RH is mediated by similar mechanisms in control and hypertrophied hearts. All vasodilatation was similarly attenuated in hypertrophy, independent of endothelial activation. We hypothesize that increased arteriolar wall thickness may limit vasodilator responses to all stimuli in hypertrophy.

Animals↗
PubMed2000

Storage pool defect in pooled buffy coat platelet concentrates within the shelf-life period.

Platelet concentrate (PC) transfusions are useful for maintaining haemostasis in a variety of clinical situations. The function of transfused platelets is of critical importance, and changes on storage of buffy coat-prepared PC may influence their haemostatic potential. Total platelet adenine nucleotide content and platelet aggregation responses were studied, serially, in pooled buffy coat-derived PCs (n = 7), stored under UK recommended blood bank conditions, over the stipulated shelf-life of 5 days. Mean platelet volume (MPV), platelet counts and platelet distribution width (PDW) were also quantified. Total platelet ADP content decreased from 4.45+/-0.78 to 3.71+/-0.69 nmol/108 platelets (P<0.01, day 1 versus day 5, mean +/- SEM) over the shelf-life period. This was associated with reduced aggregatory responses: responses (expressed as percentage of maximum height) to 5 and 10 microM ADP decreased from 10.8+/-2.8% to 1.0+/-1.0% (P<0.005, 5 microM, day 1 versus day 5) and from 18.0+/-5.4% to 4.7+/-2.2% (P<0.02, 10 microM, day 1 versus day 5) while the decreased responsiveness was more pronounced for 4 microg/ml of collagen: 49.0+/-13.3% to 7.2+/-7.1% (P<0.01, day 1 versus day 4) and 49.9 +/-13.3% to 2.1+/-1.9% (P<0.001, day 1 versus day 5). These data indicate an acquired storage pool defect that is maximal by day 4 or 5 and accompanied by decreased platelet function, characterized by significant decreases in platelet aggregation responses. Addition of freeze-thawed plasma (autologous day 1) to PCs on days 2, 3, 4 and 5 did not alter the responses to ADP and collagen.

Adenosine Diphosphate↗
PubMed1999

The effects of diadenosine polyphosphates on the cardiovascular system.

Diadenosine polyphosphates are members of a group of dinucleoside polyphosphates that are ubiquitous, naturally occurring molecules. They form a recently identified class of compounds derived from ATP and consist of two adenosine molecules bridged by up to six phosphate groups. These compounds are stored in high concentrations in platelet dense granules and are released when platelets become activated. Some of the compounds promote platelet aggregation, while others are inhibitory. Possible roles as neurotransmitters, extracellular signalling molecules or 'alarmones' secreted by cells in response to physiologically stressful stimuli have been postulated. Recent studies suggest a role for these compounds in atrial and synaptic neurotransmission. Studies using isolated mesenteric arteries indicate an important role of phosphate chain length in determining whether diadenosine polyphosphates produce vasodilation or vasoconstriction, but in the coronary circulation, diadenosine polyphosphates generally produce vasodilation via mechanisms thought to involve release of NO or prostacyclin (PGI2). They produce cardiac electrophysiological effects by altering ventricular refractoriness at submicromolar concentrations and reduce heart rate. Mechanisms involving KATP channels have been proposed in addition to the involvement of P1- and P2-purinergic receptors and the specific diadenosine polyphosphate receptor identified on isolated cardiac myocytes. Clinical evidence suggests a role for diadenosine polyphosphates in hypertensive patients and those with the Chédiak-Higashi syndrome. This review outlines the effects of these compounds on the cardiovascular system and considers their potential involvement in mediating the pathophysiological effects associated with platelet activation during myocardial ischaemia.

Action Potentials↗
PubMed1996

Platelet activation during myocardial ischaemia: a contributory arrhythmogenic mechanism.

Experimental and clinical observations of the involvement of platelets in the pathophysiology of myocardial ischaemia indicate the importance of interactions between these formed elements and the heart. The aim of this review is to outline evidence linking platelet activation, myocardial ischaemia and infarction, and to present evidence for a link between platelet activation, arrhythmogenesis and sudden death. A brief review of platelet physiology and pharmacology is provided, with a review of the cardiac electrophysiological effects of ischaemia and the electrophysiological effects of platelet-derived substances. The concept that platelet activation during myocardial ischaemia is a contributory arrhythmogenic mechanism is discussed.

Animals↗
PubMed1995

Neutrophil interactions with endothelium and platelets: possible role in the development of cardiovascular injury.

Polymorphonuclear neutrophils (PMN) cause myocardial injury during ischaemia and reperfusion by their direct effects on the myocardium; PMN release highly cytotoxic free oxygen radicals and proteolytic enzymes and PMN aggregates are involved in capillary plugging and the no-reflow phenomenon. In addition, PMN-derived factors including free oxygen radicals, lipoxygenase products, cytokines and proteolytic enzymes have been shown to modify the function of endothelium and platelets. However, both endothelium and platelets are capable of modulating PMN activation. Endothelial cells modulate PMN function by the expression of adhesion molecules and by release of soluble factors including nitric oxide, prostacyclin, endothelins, platelet activating factor and interleukin-8. Platelets affect PMN activation by release of thromboxane A2, platelet derived growth factor, serotonin, lipoxygenase products, proteases and adenosine. Thus, in addition to their direct injurious effect on ischaemic myocardium, neutrophils are involved in the functional balance between endothelium and platelets and exert an indirect effect on the myocardium.

Blood Platelets↗
PubMed1995

Nitric oxide and prostacyclin modulate the alterations in cardiac action potential duration mediated by platelets during ischaemia.

OBJECTIVE: To investigate the effects of alterations of nitric oxide (NO) and prostacyclin (PGI2) availability on platelet-mediated electrophysiological effects during myocardial ischaemia. METHODS: Transmembrane action potentials and electrograms were recorded from isolated, Langendorff-perfused guinea-pig hearts during normal perfusion, global myocardial ischaemia and reperfusion during infusion of washed human platelets. Experiments were performed in the presence of 100 microM NG-nitro-L-arginine methyl ester (L-NAME), 30 microM L-arginine, 10 microM haemoglobin, 100 microM sodium nitroprusside and 2.3 nM iloprost, or using hearts obtained from DL-lysine monoacetylsalicylate (Aspisol, 50 mg.kg-1 i.p.)-treated animals. RESULTS: Perfusion with L-NAME and haemoglobin increased perfusion pressure by 33% (P = 0.0017) and 23% (P = 0.0026) while sodium nitroprusside and iloprost reduced it (17%, P = 0.0004, and 24%, P = 0.0006). In the absence of platelets, these compounds had no effect on arrhythmogenesis, but in the presence of platelets L-NAME reduced the onset time of ventricular tachycardia during ischaemia from 19.4 (s.e.m. 2.0) min to 12.9 (2.1) min, P = 0.04 and accentuated the ischaemia-induced reduction of action potential duration at 95% repolarization (APD95): 95(6) vs. 115(5) ms, P < 0.05 at 25 min. Sodium nitroprusside in the presence of platelets attenuated the ischaemia-induced reduction in APD95, while iloprost in the presence of platelets was antiarrhythmic (ventricular fibrillation 25 vs. 75%, P = 0.04) and attenuated the reduction in APD95 during ischaemia 115(4) vs. 94(4) ms, P < 0.05 at 20 min. Infusion of platelets into hearts obtained from DL-lysine-monoacetylsalicylate-treated guinea-pigs accentuated the ischaemia-induced reduction in APD95 (94(4) vs. 119(7) ms, P < 0.05 at 20 min) and this was reversed by sodium nitroprusside (117(7) ms, P < 0.05 at 20 min). L-NAME and haemoglobin had no effect on the aggregatory responses of the platelets to 5 microM ADP and 4 micrograms.ml-1 collagen, while sodium nitroprusside and iloprost ablated the responses to ADP and reduced the responses to collagen (maximum height of the aggregatory response reduced by 75 and 84%, respectively, both P = 0.03.) CONCLUSIONS: Inhibition of NO and PGI2 synthesis exacerbates the reduction in cardiac action potential duration associated with platelet activation during ischaemia, while provision of exogenous NO and PGI2 attenuates the reduction in cardiac action potential duration. Provision of exogenous NO and PGI2 (as iloprost) was associated with inhibition of platelet reactivity.

Action Potentials↗
PubMed1994

Hypertrophy causes delayed conduction in human and guinea pig myocardium: accentuation during ischaemic perfusion.

OBJECTIVE: The aim was to investigate why cardiac hypertrophy causes increased vulnerability to arrhythmias during myocardial ischaemia. METHODS: The electrophysiological basis for this increased vulnerability was studied in isolated perfused guinea pig hearts obtained 50 and 150 d after aortic constriction, and in sham operated controls. Cellular electrophysiology, conduction, and refractory periods were examined during control perfusion and during low flow (coronary flow reduced to 10% of control) and zero flow ischaemia. ECGs in patients with left ventricular hypertrophy and in controls matched for age and heart rate were also studied. RESULTS: Aortic constriction increased heart weight:body weight ratio by 33% at 50 d and by 69% at 150 d. Action potentials were unchanged in hypertrophied hearts. Significant conduction delay occurred in 150 d hypertrophied hearts [conduction time index 23(SEM 4) ms v 18(3) ms, p < 0.001; QRS width 40(1) ms v 35(1) ms, p < 0.01], but not in 50 d hypertrophied hearts. Conduction delay was also present in humans with left ventricular hypertrophy [QRS width 96(13) ms v 87(8) ms, p < 0.01]. Although the QTc interval was increased in humans, at 422(23) ms v 411(17) ms in controls, p < 0.05, this could be explained by the increased QRS duration. During ischaemia, ventricular arrhythmias tended to occur earlier in hypertrophied hearts. Hypertrophy was also associated with a greater increase in conduction delay. Ischaemia reduced action potential duration and refractory periods; the reduction in action potential duration was attenuated by hypertrophy (p < 0.01), although the reverse was apparent during low flow ischaemia at 50 d. CONCLUSIONS: Delayed conduction is an important feature of severe cardiac hypertrophy in guinea pigs and man. Hypertrophy is associated with accentuated conduction delay and altered repolarisation during ischaemia.

Animals↗
PubMed1994

Myocardial ischaemia induces platelet activation with adverse electrophysiological and arrhythmogenic effects.

OBJECTIVE: The aim was to investigate how platelet activation during myocardial ischaemia can induce electrophysiological and arrhythmogenic effects, and examine the involvement of different platelet membrane receptors in producing these effects. METHODS: Transmembrane action potentials and electrograms were recorded from isolated, Langendorff perfused guinea pig hearts during normal perfusion, global myocardial ischaemia, and reperfusion during infusion of human platelets. Platelet reactivity was altered by treating platelets with forskolin, aspirin, the platelet activating factor (PAF) receptor antagonist BN 52021, the thromboxane A2 (TP) receptor antagonist GR 32191B, and the alpha 2 adrenoceptor antagonist yohimbine. Myocardial catecholamine depletion was induced by treatment with 6-hydroxydopamine. RESULTS: Platelet infusion had no electrophysiological effects during normal perfusion, but during ischaemia it enhanced the reduction in action potential duration at 95% repolarisation [APD95, 110(SEM 3) ms v 121(5) ms, p < 0.05, at 15 min] and increased the incidence of ventricular arrhythmias (from 56% to 94%, p = 0.04) compared to hearts receiving buffer but no platelets. The reductions in APD95 and the arrhythmogenic effects were attenuated when forskolin treated, aspirin treated or GR 32191B treated platelets were infused (VF: 50% v 94%, p = 0.03; 50% v 94%, p = 0.02; 22% v 94%, p < 0.001, respectively). Similar results were obtained when normal platelets were infused into catecholamine depleted hearts (VF: 60% v 94%, p = 0.0549). These differences were associated with inhibited aggregatory responses to thrombin (for forskolin treated platelets) and the thromboxane mimetic U44069 (for GR 32191B treated platelets). Yohimbine was antiarrhythmic in the presence and absence of platelets, suggesting direct myocardial effects, but BN 52021 had no antiarrhythmic effects. CONCLUSIONS: Myocardial ischaemia causes platelet activation resulting in electrophysiological and arrhythmogenic effects. PAF receptor antagonism does not prevent these effects, but inhibition of platelet reactivity, platelet thromboxane receptor antagonism, and myocardial catecholamine depletion are effective. These findings suggest that the arrhythmogenic effects of platelet activation during myocardial ischaemia are principally mediated by a thromboxane dependent mechanism, while catecholamine release has a contributory role.

Animals↗