Piers C. G. Nye

Phenoxybenzamine is more effective and less harmful than papaverine in the prevention of radial artery vasospasm.

OBJECTIVES There is an increasing use of arterial conduits for coronary artery bypass grafting, and the radial artery is commonly used as the third graft. The major drawback of the radial artery is its proclivity to spasm. Both papaverine and phenoxybenzamine have been recommended as topical vasodilators in clinical practice. We compared the efficacy of both drugs to prevent radial artery spasm and their ability to preserve endothelial function. METHODS The ability of both drugs to prevent alpha-adrenoreceptor mediated constriction was tested in vitro in an organ bath in radial artery segments obtained from 20 patients. Vessel viability was determined by potassium (K(+)) constriction, and endothelial function was assessed by observing endothelium-dependent relaxation by a synthetic analogue of acetylcholine, carbachol. RESULTS Papaverine consistently abolished and prevented spasm for up to a maximum of 30 min in all segments. In contrast, phenoxybenzamine consistently abolished and prevented radial artery spasm in all segments for at least 6 h. Whereas papaverine damaged the endothelium of 70% of vessels, there was no evidence of endothelial damage in any arterial segments after exposure to phenoxybenzamine. CONCLUSIONS Phenoxybenzamine more effectively prevents alpha-adrenoreceptor mediated spasm of the human radial artery than papaverine. It is also less harmful to the endothelium.

Ca2+ and Mg-ATP activated potassium channels from rat pulmonary artery.

The hyperpolarizatlon-activated current (If) was recorded from single myocytes dissociated from rabbit sinoatrial node. Although If is usually carried by both Na+ and K+, removal of the minor K+ component from physiological saline suppresses inward component. This inward Na+ current through If channel increases on raising the extracellular K+ concentration. The Na+ conductance relative to K+ conductance (PNa/PK), as measured from the reversal potential, increases and saturates near 5 mM K+. This effect is different from the current increase caused by raising the concentration of carrier ion K+, which saturates at 70 mM with a half-maximal value (K1/2) of 10 mM. It is suggested that the If channel has multiple, interactive binding sites for cation permeation.

BIOPHYSICAL PROPERTIES OF CA2- AND MG-ATP-ACTIVATED K+ CHANNELS IN PULMONARY ARTERIAL SMOOTH MUSCLE CELLS ISOLATED FROM THE RAT

A novel class of Ca2+-activated K+ channel, also activated by Mg-ATP, exists in the main pulmonary artery of the rat. In view of the sensitivity of these “KCa,ATP” channels to such charged intermediates it is possible that they may be involved in regulating cellular responses to hypoxia. However, their electrophysiological profile is at present unknown. We have therefore characterised the sensitivity of KCa,ATP channels to voltage, intracellular Ca2+ ([Ca2+]i) and Mg-ATP. They have a conductance of 245 pS in symmetrical K+ and are approximately 20 times more selective for K+ ions than Na+ ions, with a K+ permeability (PK) of 4.6×10−13cm s−1. Ca2+ ions applied to the intracellular membrane surface of KCa,ATP channels causes a marked enhancement of their activity. This activation is probably the result of simultaneous binding of at least two Ca2+ ions, determined using Hill analysis, to the channel or some closely associated protein. This results in a shift of the voltage activation threshold to more hyperpolarized membrane potentials. The activation of KCa,ATP channels by Mg-ATP has an EC50 of approximately 50 μM. Although the EC50 is unaffected by [Ca2+]i, channel activation by Mg-ATP is enhanced by increasing [Ca2+]i. One possible interpretation of these data is that Mg-ATP increases the sensitivity of KCa,ATP channels to Ca2+. It is therefore possible that under hypoxic conditions, where lower levels of Mg-ATP may be encountered, the sensitivity of KCa,ATP channels to Ca2+ and therefore voltage is reduced. This would tend to induce a depolarising influence, which would favour the influx of Ca2+ through voltage-activated Ca2+ channels, ultimately leading to increased vascular tone.

The effect of beta adrenergic blockade on the carotid body response to hyperkalaemia in the cat

Arterial chemoreceptor discharge and ventilation are both significantly increased when the concentration of arterial potassium is raised to a level typical of moderate exercise. However, although the plasma potassium level of exercising, beta-blocked patients rises by more than that of normal subjects, this does not show up in their steady-state ventilatory response, i.e. exercising beta-blocked subjects ventilate no more than exercising controls. The present experiments were designed to test the hypothesis that the apparent failure of beta-blocked subjects to respond to the extra hyperkalaemia that they experience might be accounted for by a reduction in the sensitivity of arterial chemoreceptors to potassium. We used eleven pentobarbitone-anaesthetized, thoracotomized, artificially hyperventilated cats, in which arterial potassium was raised from ca. 4.5 to ca. 7 mM before and during beta blockade by propranolol or atenolol. The steady-state relation between chemoreceptor discharge and arterial potassium was curvilinear, discharge becoming more sensitive to potassium as the concentration of the latter was raised. Beta blockade significantly reduced discharge at all levels of plasma potassium (P less than 0.0001). It also significantly reduced (P less than 0.05) the slope of the response of discharge to a given increase of plasma potassium. Our results show that beta blockade decreases the sensitivity of arterial chemoreceptors to increases in arterial potassium. This may explain why exercising beta-blocked subjects breathe no harder than controls, in spite of the fact that they are more hyperkalaemic.

The effect on breathing of abruptly stopping carotid body discharge.

In bilaterally vagotomized, decerebrate or pentobarbitone anaesthetized cats, intense carotid body discharge (FET O2 ca. 0.075) was abruptly removed by injections centrally of 100% O2-equilibrated Ringer into both external carotid arteries. In an inspiration the injections usually shortened that inspiration, reduced its volume and prolonged the immediately following expiration. Early in expiration they prolonged that expiration, but later in expiration they shortened it. The inspiratory results can be reconciled with von Eulers model of the inspiratory off-switch if the off-switch acts early because a reduction in chemoreceptor input lowers its threshold more rapidly than it reduces the input to it. The threshold falls to half of its final value in about one second. The respiratory centres respond to decreases in carotid body activity nearly as quickly as to increases, and expiration can be altered independently of the preceding inspiration. We present a simple model of the control of expiratory duration.

Effect of oxygen on potassium-excited ventilation in the decerebrate cat

Raising arterial potassium ([K+]a) from ca. 3.5 to 6.5 mM, as occurs in heavy exercise, excites the arterial chemoreceptors and ventilation (VE) in anaesthetised cats. We have previously shown that the excitation of chemoreceptors by potassium is enhanced by hypoxia and abolished by hyperoxia, and here we show, in decerebrate cats, that the potassium-induced increase in VE is also abolished by hyperoxia. 100% oxygen was given abruptly in hypoxia (PETO2 ca. 50 Torr), with inspired gas tensions adjusted to give the same PETO2 and PETCO2 values before all tests on a given animal. Intravenous infusions of 150 mM KCl, which raised [K+]a from 3.9 +/- 0.3 mM to 7.4 +/- 0.3 mM (mean +/- SE), always excited hypoxic VE (42 +/- 8%; P less than 0.01). Hyperoxia, given during KCl infusion, reduced VE to a value not significantly greater (P greater than 0.27) than the hyperoxic value obtained before infusion. These results show that: (i) VE reflects the responses of chemoreceptors to K+, (ii) that abrupt hyperoxia removes the potassium-induced ventilatory drive, and (iii) that, in our experiments, K+ appears to have excited VE only via the peripheral chemoreceptors.

Opposing actions of tolbutamide and glibenclamide on hypoxic pulmonary vasoconstriction

1. We show that cromakalin and diazoxide, drugs that activate ATP-sensitive potassium (KATP) channels, abolish hypoxic pulmonary vasoconstriction (HPV) of isolated, perfused rat lungs. 2. Glibenclamide, an inhibitor of these channels, does not affect HPV, but it reverses the relaxation caused by cromakalim and diazoxide. 3. Tolbutamide, which has effects similar to glibenclamide in other tissues, paradoxically abolishes HPV, an effect reversed by glibenclamide. 4. These results suggest that: (i) pulmonary vessels contain KATP channels which are normally closed and are not opened by levels of hypoxia that cause constriction, (ii) tolbutamide acts on the pulmonary vasculature by a mechanism which differs from that of glibenclamide.

Ventilation and carotid chemoreceptor discharge during venous CO2 loading via the gut

A simple method of loading CO2 into the venous blood of anaesthetized or decerebrate cats is described. Heated humidified gas of high CO2 content is passed retrogradely through the gut. This increases CO2 elimination from the lungs by 1.8 to 3.6 fold, minute ventilation by 1.5 to 2.7 fold and cardiac output by 1.1 to 1.6 fold. This method of venous CO2 loading allows the recording of afferent nerve impulses. We show that it has little effect on the mean discharge frequency of carotid body chemoreceptors when end-tidal gases are held constant, but that it enhances greatly the amplitude of the respiratory oscillation of their discharge.

The effect on breathing of abruptly reducing the discharge of central chemoreceptors

Tris, a powerful CO2 buffer, was injected through one vertebral artery directly at the central chemoreceptive region in bilaterally vagotomized pentobarbitone anaesthetized cats. This was intended to reduce central chemoreceptor drive abruptly. Injections in inspiration shortened that inspiration and prolonged the following expiration. Injections given early in expiration often prolonged that expiration and also the following inspiration, but most injections given in an expiration shortened that expiration and also shortened the following inspiration. Tidal volume (VT) was invariably reduced. A plot of VT against delay from an injection to the termination of inspiration shows that VT falls with a half time of about one second. The changes in the pattern of breathing were similar to those after abrupt removal of carotid body chemoreceptor discharge (Nye et al., 1981) though the latency to the first response of air flow was about 100 msec longer. These observations support the idea that peripheral and central chemoreceptors have similar connections with the respiratory centre.

Human Ventilatory Response to Immersion of the Face in Cool Water

The cardiovascular response to facial cooling in man can be dramatic (3), and this is shown by one exceptional subject studied by us (Figure 1). Here there was an increase in cardiac interval from one second during the control period to seven seconds as the cool water reached the eyes. This response is very pronounced in diving animals (1) and is therefore commonly known as the diving reflex. The bradycardia is accompanied by vasoconstriction which diverts blood flow away from the robust periphery towards the hypoxically sensitive heart and brain. The reflex is most prominent during breath-holding, indeed it may be completely overridden by the act of breathing. An abstract of this work has been published (4).