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Biomedical subjects

D J Paterson

Publications and source records attributed to D J Paterson.

At least 55 records · Page 3Linked to original sources
PubMed1998

Inhibition of nitric oxide synthase slows heart rate recovery from cholinergic activation.

The role of nitric oxide (NO) in the cholinergic regulation of heart rate (HR) recovery from an aspect of simulated exercise was investigated in atria isolated from guinea pig to test the hypothesis that NO may be involved in the cholinergic antagonism of the positive chronotropic response to adrenergic stimulation. Inhibition of NO synthesis with NG-monomethyl-L-arginine (L-NMMA, 100 micro M) significantly slowed the time course of the reduction in HR without affecting the magnitude of the response elicited by bath-applied ACh (100 nM) or vagal nerve stimulation (2 Hz). The half-times (t1/2) of responses were 3.99 +/- 0.41 s in control vs. 7. 49 +/- 0.68 s in L-NMMA (P < 0.05). This was dependent on prior adrenergic stimulation (norepinephrine, 1 micro M). The effect of L-NMMA was reversed by L-arginine (1 mM; t1/2 4.62 +/- 0.39 s). The calcium-channel antagonist nifedipine (0.2 micro M) also slowed the kinetics of the reduction in HR caused by vagal nerve stimulation. However, the t1/2 for the reduction in HR with antagonists (2 mM Cs+ and 1 micro M ZD-7288) of the hyperpolarization-activated current were significantly faster compared with control. There was no additional effect of L-NMMA or L-NMMA+L-arginine on vagal stimulation in groups treated with nifedipine, Cs+, or ZD-7288. We conclude that NO contributes to the cholinergic antagonism of the positive cardiac chronotropic effects of adrenergic stimulation by accelerating the HR response to vagal stimulation. This may involve an interplay between two pacemaking currents (L-type calcium channel current and hyperpolarization-activated current). Whether NO modulates the vagal control of HR recovery from actual exercise remains to be determined.

Acetylcholine↗
PubMed1997

Interactive effects of K+, acid, norepinephrine, and ischemia on the heart: implications for exercise.

We tested the hypothesis that cardiac ischemia uncouples the beneficial interaction among hyperkalemia, acidosis, and raised plasma catecholamines when these chemicals are changed to mimic their exercise levels. Potassium chloride, lactic acid, and norepinephrine (NE) were infused intravenously for 2 min into anesthetized, artificially ventilated, thoracotomized rabbits during either occlusion of the left circumflex artery (3 min; n = 10) or after a period of prolonged ischemia (20 min; n = 7) that led to a small infarction. NE (1 microg x kg(-1) x min(-1) iv) offset the negative cardiac effects of hyperkalemia (up to 8.7 +/- 0.7 mM) and acidosis (arterial pH 7.09 +/- 0.03) in normal hearts. Cardiac performance was not significantly depressed by either acute or chronic ischemia before any infusions. However, the protective effect of NE during acute ischemia or after prolonged ischemia with hyperkalemia and acidosis was substantially reduced. These results show that cardiac ischemia attenuates the protective action of NE and increases the depressive effects of hyperkalemia and acidosis. Whether myocardial ischemia amplifies the cardiotoxic effects of hyperkalemia and acidosis during vigorous exercise by attenuating the beneficial effect of catecholamines remains to be determined.

Acidosis↗
PubMed1997

Nitric oxide can increase heart rate by stimulating the hyperpolarization-activated inward current, I(f).

We investigated the chronotropic effect of increasing concentrations of sodium nitroprusside (SNP, n = 8) or 3-morpholinosydnonimine (SIN-1, n = 6) in isolated guinea pig spontaneously beating sinoatrial node/atrial preparations. Low concentrations of NO donors (nanomolar to micromolar) gradually increased the beating rate, whereas high (millimolar) concentrations decreased it. The increase in rate was (1) enhanced by superoxide dismutase (50 to 100 U/mL, n = 6), (2) prevented by the guanylyl cyclase inhibitors 6-anilino-5,8-quinolinedione (5 mumol/L, n = 6) or 1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one (10 mumol/L, n = 6), and (3) mimicked by 8-bromo-cGMP (n = 6) with no additional positive chronotropic effect of SIN-1 (n = 5). The response to 10 mumol/L SNP (n = 28) or 50 mumol/L SIN-1 (n = 16) was unaffected by IcaL antagonism with nifedipine (0.2 mumol/L) but was abolished after blockade of the hyperpolarization-activated inward current (I(f)) by Cs+ (2 mmol/L) or 4-(N-ethyl-N-phenylamino)-1,2-dimethyl-6-(methylamino)pyrimidinium chloride (1 mumol/L). The effect on I(f) was further evaluated in rabbit isolated patch-clamped sinoatrial node cells (n = 21), where we found that 5 mumol/L SNP or SIN-1 caused a reversible Cs(+)-sensitive increase in this current (+130% at -70 mV and +250% at -100 mV). In conclusion, NO donors can affect pacemaker activity in a concentration-dependent biphasic fashion. Our results indicate that the increase in beating rate is due to stimulation of I(f) via the NO-cGMP pathway. This may contribute to the sinus tachycardia in pathological conditions associated with an increase in myocardial production of NO.

Animals↗
PubMed1997

Potassium and breathing in exercise.

The increase in ventilation caused by exercise is controlled by a combination of neural and chemical events, although the precise contribution and relative importance of these signals is still debated. It is generally agreed that the genesis of exercise hyperpnoea lies within the central nervous system and that peripheral reflexes, both chemical and neural, modulate central drive. Recently, attention has once again focused on the idea that circulating factors, in particular potassium, may play an important role in this modulation by stimulating known areas of peripheral chemoreception. Arterial chemoreceptors, muscle chemoreflex and slowly adapting pulmonary stretch receptors are all excited by hyperkalaemia. When potassium is raised to mimic exercise concentrations it increases ventilation in anaesthetised animals. This response is abolished by surgical denervation of the arterial chemoreceptors and is markedly reduced by chemical denervation with hyperoxia. Hypoxia enhances the ventilatory response to hyperkalaemia, and the stimulatory effects of potassium are further increased when combined with lactic acid or raised concentrations of noradrenaline. Hyperkalaemia can also increase the hypoxic sensitivity of the arterial chemoreflex in exercise. There is a close temporal relationship between potassium and ventilation during exercise, but changes in potassium are not proportionally related to changes in ventilation. When all data are taken together, there is good evidence that potassium has a supporting role in the control of exercise hyperpnoea, predominantly through modulation of the arterial chemoreflex.

Arteries↗
PubMed1996

Role of potassium in the regulation of systemic physiological function during exercise.

In exercise, potassium (K+) is released from contracting muscle predominately through K+ channels associated with the repolarization phase of the action potential. Increases in extracellular K+ are directly related to increases in metabolic rate and may reach concentrations as high as 8-9 mM in the arterial blood during exhaustive work. Exercise-induced hyperkalaemia has been implicated in several physiological processes, in particular skeletal muscle fatigue, hyperaemia, pressor reflex, arterial chemosensitivity and myocardial stability. There is no direct evidence to show that hyperkalaemia causes muscle fatigue, although raised extracellular [K+] may contribute to fatigue during prolonged tetani by depressing the propagation of the action potential down the t-tubule system, thus impairing the release of Ca2+ from the sarcoplasmic reticulum. The vasodilating properties of K+ may transiently contribute to the early phase of exercise hyperaemia and interact synergistically with other vasoactive substances to cause relaxation by hyperpolarizing K+ channels in vascular smooth muscle. Hyperkalaemia has been implicated in the regulation of arterial blood pressure through activation of the muscle afferent reflex where potassium-depolarized C fibres may contribute to a reflex increase in arterial blood pressure. K+ can also increase ventilation and the sensitivity of the ventilatory response to hypoxia through direct excitation of the arterial chemoreceptors. Finally, to maintain myocardial electrical stability in exercise, there is a beneficial interaction between raised K+ and catecholamines on the heart, so that when they combine, each offsets the other's deleterious effects.

Animals↗
PubMed1996

Restoration of cardiac contraction by angiotensin II during raised [K+]O in the rabbit.

Catecholamines restore cardiac contraction depressed by hyperkalaemia (raised [K+]O) and acidosis, yet in exercise hyperkalaemia and acidosis are tolerated during beta adrenergic blockade. To test whether the negative effects of raised [K+]O are offset by a non-adrenergic hormone, angiotensin II (AII) was given to rabbit papillary muscle (All 75 nM, n = 9) and rabbit isolated working hearts (All 5 nM, n = 8) perfused with 8 and 10 mM K+ Tyrode at 37 degrees C. A similar protocol was also performed in a further nine isolated hearts treated with propranolol (1 microM) and prazosin (1 microM). All caused a significant (P < 0.01) increases in contraction and aortic flow in normal Tyrode and maintained aortic flow during high [K+]O. In the papillary muscle and isolated heart treated with adrenergic blockers, high [K+]O reduced the stimulatory effects of All, but contraction and aortic flow was still significantly greater (P < 0.01) than in high [K+]O alone. These results show that All can ameliorate the depressive effects of high [K+]O on the heart. The local release of All in the heart during activation of the sympathetic nervous system and the rise in circulating All during exercise could therefore play a role in protecting the heart from hyperkalaemia.

Angiotensin II↗
PubMed1996

Role of K+ in regulating hypoxic cerebral blood flow in the rat: effect of glibenclamide and ouabain.

We assessed the role of extracellular potassium ([K+]e) on the increase in cerebral blood flow (CBF) during hypoxia, and we tested whether it was affected by glibenclamide or ouabain. Cortical CBF was measured using the hydrogen clearance technique in enflurane-anesthetized rats, and local [K+]e was measured with K+ microelectrodes adjacent to the hydrogen electrode. Eucapnic hypoxia (arterial Po2 approximately 35-40 Torr) increased CBF twofold and caused a modest rise in [K+]e (from 2.9 +/- 0.2 to 3.7 +/- 0.2 mM; mean arterial blood pressure, ABP, 86 +/- 5 mmHg). If ABP fell < 70 mmHg during hypoxia, no increase in CBF was seen, whereas [K+]e increased to > 20 mM. Glibenclamide (10-100 microM intracortically) attenuated [K+]e and CBF during hypoxia (ABP approximately 75 mmHg, P < 0.01). Ouabain (20-1,000 microM) increased [K+]e; however, it did not remove the hypoxic-induced rise in [K+]e. We conclude that glibenclamide-sensitive potassium channels contribute to the accumulation of [K+]e during hypoxia, although an increase in CBF during hypoxia can occur without a marked rise in [K+]e. Furthermore, if ABP falls below the lower limit of autoregulation during hypoxia, there is no increase in CBF, yet there is a large increase in [K+]e.

Animals↗
PubMed1996

Antiarrhythmic mechanisms during exercise.

Exercise disturbs cardiac sympathovagal and ionic balance. In arterial blood, vigorous exercise can double plasma K(+), decrease pH by 0.4 unit, and raise catecholamines 15-fold. If any of these changes are experienced at rest, there is an increased risk of arrhythmia and cardiac arrest, yet in exercise they are usually tolerated. How the heart is protected from the chemical stress caused by exercise is not fully understood but may be related to a collective antiarrhythmic effect of these chemical changes, so when they combine there is a mutual antagonism. Catecholamines can offset the harmful cardiac effects of hyperkalemia and acidosis in isolated hearts and whole hearts in vivo and improve action-potential characteristics in K(+)-depolarized ventricular myocytes. This results from an increase in the inward Ca2(+) current that is modulated by both adrenergic and nonadrenergic hormones. Conversely, hyperkalemia can reduce or abolish the incidence of norepinephrine-induced arrhythmias. The efficacy of the mutual antagonism is reduced when the combination of acidosis, hyperkalemia, and high levels of norepinephrine are superimposed on a heart with regional ischemia or a small infarct. However, the heart may be at greatest risk in the postexercise period when plasma K(+) is low and the adrenergic tone is high. Little is known about this period, but abnormal regulation of electrolyte and cardiac sympathovagal balance may increase the incidence of arrhythmia, especially if there is underlying ischemia. Although regular physical activity can reduce the incidence of sudden cardiac death, recent epidemiological studies show that vigorous exercise can trigger myocardial infarction and sudden cardiac death, especially in habitually sedentary subjects with coronary artery disease. This may be partly related to disruption of the normal protective mechanism that allows the heart to cope with the chemical stress caused by exercise.

Animals↗
PubMed1995

Effects of high potassium and the bradycardic agents ZD7288 and cesium on heart rate of rabbits and guinea pigs.

The effects of 2 mM cesium (Cs+) and a novel selective bradycardic agent ZD7288 (0.64 microM) on sinoatrial Node (SAN) pacing rate were investigated in an isolated guinea pig SAN/atrial preparation, rabbit SAN preparation, and isolated working rabbit heart preparation. The effect of Cs+ and ZD7288 on the response of the preparations to increased extracellular potassium concentration ([K+]o) was also studied. Cs+ reduced beating frequency by 24% in isolated rabbit SAN (n = 16, p < 0.01) and by 21% in isolated working rabbit heart (n = 9, p < 0.01). ZD7288 decreased beating rate by 53% in guinea pig SAN (n = 7, p < 0.01) and by 38% in isolated working rabbit heart (n = 6, p < 0.01). In all three preparations, increased [K+]o significantly decreased the rate (p < 0.01) in normal Tyrode's solution but had no effect in the presence of Cs+ and caused tachycardia (p < 0.01) in the presence of ZD7288. We conclude that Cs+ and ZD7288 decrease pacing rate in rabbits and guinea pigs, possibly through modulation of the hyperpolarization-activated current (I(f)). ZD7288 is a more effective bradycardic agent than Cs+.

Animals↗
PubMed1995

Role of the sympathetic nervous system in cardiac performance during hyperkalaemia in the anaesthetized pig.

Cardiovascular performance was studied in 18 alpha-chloralose anaesthetized pigs when arterial potassium ([K+]a) was raised to levels observed in heavy exercise. The effects of hyperkalaemia were then studied during cardiac sympathetic nerve stimulation or during an infusion of noradrenaline. Elevation of [K+]a up to ca. 10 mM caused a progressive decline in cardiovascular performance. However, right cardiac sympathetic nerve stimulation elevated all cardiovascular parameters in the presence of raised [K+]a and offset the negative cardiac effects of hyperkalaemia. Electrical pacing of the right atrium to heart rates (HRs) equivalent to those observed during right cardiac sympathetic nerve stimulation did not offset the depressive effects of hyperkalaemia and, indeed, hastened the decline in cardiovascular performance. Infusion of noradrenaline (1 microgram kg min-1 i.v.) during hyperkalaemia caused an increase in all cardiovascular parameters similar to that seen during sympathetic nerve stimulation. After propranolol (0.5 mg kg-1 i.v.), sympathetic nerve stimulation slightly increased HR, systolic blood pressure (SBP) and dP/dtmax. Elevation of [K+]a occurred more rapidly after propranolol, but the heart was still protected from hyperkalaemia during cardiac sympathetic stimulation. Infusion of noradrenaline elicited arrhythmias in six pigs. Infusion of KCl reduced the incidence of arrhythmias and in some cases abolished them. These findings may be related to how the heart is protected from exercise-induced changes in potassium and catecholamines.

Adrenergic Fibers↗
PubMed1995

Effect of verapamil on restoration of cardiac performance in raised [K+]o by adrenergic stimulation in the rabbit.

Modulation of the L-type calcium channel by catecholamines improves action potential parameters in single ventricular myocytes depolarized by high [K+]o Tyrode. Whether this modulation is important in offsetting the negative effects of hyperkalaemia in the whole heart is not known. We tested the effects of the calcium channel antagonist, verapamil, on restoration of cardiac performance by adrenergic stimulation in high [K+]o in anaesthetized rabbits and isolated perfused working rabbit hearts. Raised [K+]o decreased SBP, LVP and LVdP/dtmax in vivo ([K+]a 8.6 +/- 0.2 mM; n = 10) and aortic flow (AF) in the isolated heart (8 mM [K+]o Tyrode; n = 25). However, the negative effects of raised [K+]a were offset by isoprenaline (Iso, 1 microgram kg-1 min-1 i.v.) in vivo and by noradrenaline (NA, 80 nM) in the isolated heart. Verapamil (0.15 mg kg-1 i.v.; 15 nM isolated heart) markedly potentiated the negative inotropic effects of raised [K+]o in both preparations. Verapamil attenuated the effect of isoprenaline in vivo but in the isolated heart, the protective effect of NA in 8 mM [K+] Tyrode (AF 97 +/- 10 mL min-1 in 8 mM [K+]o compared with AF 141 +/- 8.5 mL min-1 in 8 mM [K+]o + NA) was offset by the drug (90 +/- 8 mL min-1 in 8 mM [K+]o + NA + V). Furthermore, verapamil abolished aortic flow in 8 mM [K+]o alone. These findings suggest that the heart may be critically dependent on modulation of intracellular calcium in order to tolerate concentrations of K+ similar to those seen during a short burst of intensive exercise ([K+]a 8.6 mM).

Action Potentials↗
PubMed1995

Effect of L-NMMA, cromakalim, and glibenclamide on cerebral blood flow in hypercapnia and hypoxia.

Sulfonylureas reduce cerebral blood flow (CBF) during hypoxia but not during hypercapnia, whereas blockers of nitric oxide (NO) synthesis reduce hypercapnic CBF. However, the effect of NO blockers on hypoxic CBF is uncertain. CBF was measured in the cortex of 51 enflurane-anesthetized rats by the hydrogen clearance technique during eucapnia, hypercapnia (arterial PCO2 65 Torr), and hypoxia (arterial PO2 40 Torr). CBF increased twofold in both hypercapnia and hypoxia from eucapnia. Intracortical (ic) NG-monomethyl-L-arginine (L-NMMA, 100 microM-5 mM) attenuated both the hypercapnic and hypoxic dilations by 60-70%, and L-arginine (300 mg/kg iv) partially reversed these effects. Glibenclamide (10 microM ic) and L-NMMA gave no further attenuation of the hypoxic dilation than L-NMMA alone. Cromakalim (10 microM, ic) increased CBF in eucapnia, but this was not seen in the presence of glibenclamide. The adenosine antagonist 8-phenyl-theophylline did not attenuate the hypoxic dilation. This suggests that NO synthesis plays a major role in the regulation of CBF in hypercapnia and hypoxia. But the combined effects of glibenclamide and L-NMMA do not further attenuate CBF in hypoxia.

Animals↗
PubMed1994

Effect of raised potassium on ventilation in euoxia, hypoxia and hyperoxia at rest and during light exercise in man.

The purpose of this study was to determine whether changes in arterial plasma potassium concentration [K+]a affect expired ventilation (VE) in euoxia, hypoxia and hyperoxia during rest and light exercise in humans. Three periods of ventilatory measurements were undertaken in eight healthy subjects at rest and in seven other subjects during cycle ergometry (70 W). The first period of measurement was before the ingestion of 64 mmol of potassium chloride (KCl), the second 20 min after ingestion of KCl when [K+]a levels were elevated, and the third 3 h after the ingestion of KCl when [K+]a had returned substantially to normal. During each period, end-tidal PO2 was cycled between euoxia, hypoxia and hyperoxia, whilst the end-tidal PCO2 was maintained constant. The acute ventilatory response to hypoxia (AHVR) was calculated as the difference in VE during hypoxia and hyperoxia within each period of measurement. Oral KCl produced a 1.3 +/- 0.2 mM (mean +/- S.E.M.) increase in [K+]a at rest and a 0.8 +/- 0.2 mM increase during exercise. There was no significant difference in ventilation during euoxia between the three periods of measurement at rest or during exercise. There was a significant increase in AHVR with the rise in [K+]a of 21 min-1 mM-1 at rest (arterial PO2 during hypoxia ca 57 Torr) and 10 l min-1 mM-1 during exercise (arterial PO2 during hypoxia ca 52 Torr). There was a significant difference in the absolute increase in AHVR with [K+]a between rest and exercise, but this difference was not significant if the increase in AHVR with [K+]a was expressed as a percentage of the initial AHVR. We conclude that changes in [K+]a of the order of 1 mM have little effect on euoxic ventilation at rest or during light exercise in humans. We also conclude that [K+]a changes of this order increase AHVR at rest and during light exercise and that increases in [K+]a contribute to the increase in AHVR with exercise in humans.

Adult↗
PubMed1994

Effect of hypoxia on arterial potassium concentration at rest and during exercise in man.

Hypoxia has been reported to increase arterial potassium concentration ([K+]a) in anaesthetized cats (Paterson, Estavillo & Nye, 1988). The purpose of this study was to determine whether this phenomenon occurs in humans. The effect of hypoxia on [K+]a was measured in ten male subjects, at rest and during light exercise, before and after 8 weeks of physical training. The [K+]a increased by 0.15 +/- 0.04 mM (mean +/- S.E.M.) at rest, when end-tidal PO2 (PET,O2) was lowered from 100 to 51 +/- 1.6 Torr, and by 0.10 +/- 0.02 mM during exercise, when PET,O2 was lowered from 100 to 66 +/- 6.2 Torr. Physical training did not alter the rise in [K+]a significantly. The magnitude of this effect is small in comparison with that of exercise-induced hyperkalaemia, and is unlikely to be of great physiological significance at moderate levels of hypoxia.

Arteries↗
PubMed1994

Role of Ca2+ in protecting the heart from hyperkalemia and acidosis in the rabbit: implications for exercise.

Catecholamines can offset the negative effect of acidosis and raised extracellular K+ concentration in the isolated rabbit heart when these factors are changed with similar kinetics and concentrations as those observed in exercise. This effect appears to be mediated by changes in Ca2+ handling in the heart. To test the role of Ca2+ in vivo, we studied the interactive effects of infusions of KCl, lactic acid, norepinephrine (NE), and CaCl2 on cardiovascular performance in the anesthetized rabbit. After propranolol, CaCl2 was given during acidosis and hyperkalemia. Acidosis (arterial pH 7.17 +/- 0.3) markedly reduced cardiac performance, and its effects were exacerbated by hyperkalemia (7.3 +/- 0.4 mM). NE reversed the cardiac response to combined acidosis and hyperkalemia. After propranolol, arterial pH and arterial K+ concentration changed more rapidly with acidosis and hyperkalemia, combined with a faster fall in cardiac performance, but CaCl2 offset these negative hemodynamic effects. The rises in plasma Ca2+, NE, and sympathetic activity during exercise may therefore interact to ameliorate the harmful effects of acidosis and hyperkalemia.

Acidosis↗