Repeated inspiratory occlusions acutely impair myocardial function in rats

Abstract

Repeated episodes of hypoxia and sympathetic activation during obstructive sleep apnoea are implicated in the initiation and progression of cardiovascular diseases, but the acute effects are unknown. We hypothesized that repeated inspiratory occlusions cause acute myocardial dysfunction and injury. In 22 spontaneously breathing pentobarbital-anaesthetized rats, inspiration was occluded for 30 s every 2 min for 3 h. After ∼1.5 h, mean arterial pressure started to fall; heart rate between occlusions was stable throughout, consistent with only transient increases in sympathetic activity during each occlusion. Three hours of occlusions resulted in ventricular diastolic dysfunction (reduced peak rate of change of ventricular pressure and slower relaxation). Post-occlusions, the left ventricular contractile response to dobutamine was blunted. After 1 h of recovery, left ventricular pressure generation had returned to values no different from those in sham animals in 5 of 9 of the animals. Cardiac myofibrils from rats subjected to occlusions had depressed calcium-activated myosin ATPase activity, indicating myofilament contractile dysfunction that was not due to breakdown of contractile proteins. Haematoxylin and eosin-stained cross-sections revealed multifocal areas of necrosis within the septum and both ventricles. Repeated inspiratory occlusions, analogous to moderately severe obstructive sleep apnoea, acutely cause global cardiac dysfunction with multifocal myocardial infarcts.

A new method to produce obstructive sleep apnoea in conscious unrestrained rats

“…The intrathoracic pressure changes seen here during apnoea are similar to those reported by others in anaesthetized (Simpson et al 2008) and conscious rats (Farré et al 2007). However, the heart rate changes seen in our conscious rats are very different from those observed in anaesthetized rats (e.g.…”

“…The response observed by us during apnoea resembles that seen in diving rats (McCulloch et al 1997). This response may help reduce cardiac oxygen demand, improve myocardial perfusion and prevent cardiac necrosis, which can be induced by repetitive apnoeas (Simpson et al 2008). The bradycardia seen during apnoea may also help prevent abnormally low stroke volumes during forced expiration, when little blood enters the right ventricle.…”

“…However, the heart rate changes seen in our conscious rats are very different from those observed in anaesthetized rats (e.g. Sun et al 2006;Simpson et al 2008), although they are similar to those seen in conscious sleeping dogs (Schneider et al 2000) and seen ocasionally in human patients with sleep apnoea (Guilleminault et al 1983). Intense bradycardia can be seen during apnoea in anaesthetized mice (Iiyori et al 2005) and anaesthetized dogs (Hamlin et al 1966); therefore, it seems that anaesthesia interferes with the bradycardic response to apnoea in rats.…”

Moderate and severe hypoxia elicit divergent effects on cardiovascular function and physiological rhythms

“…; Simpson et al . ) severe hypoxia. Whether hypoxia is caused by breathing low oxygen (∼ F I O 2 < 0.10) or the application of a respiratory load, the resultant hypoxic outcome is equivalent to what would be observed physiologically at an elevation of >6500 m above sea level (ranging between the peaks of Mount Kilimanjaro to Mount Everest).…”

Phylogeny in Sleep Medicine

“…Through artificial occlusion of the airway and exposure to repetitive hypoxemia, induced sleep apnea in dog, rat, and mice preparations has been used to demonstrate the physiologic effects of sleep apnea [85][86][87][88]. These mammalian studies have shed new light on, for example, the cardiovascular and neurochemical consequences of sleep apnea [89,90], but model organisms have not been forthcoming in determining the genetic basis for the mechanisms of this disorder.…”