J receptor activity in idiopathic pulmonary hypertension and its expected change in the presence of pulmonary bed vasodilators
Introduction
Idiopathic pulmonary artery hypertension (IPH) is a condition characterized by elevated resting mean pulmonary artery pressures (mPAP) of >20 mm Hg (Thomas et al., 2020) as compared to normal mean pressures of 14.0 ± 3.3 Hg (Kovacs et al., 2009) and patients are breathless on exertion. While this exercise-limiting dyspnea is considered to be multifactorial; examples of which are respiratory muscle dysfunction (Meyer et al., 2005), impaired skeletal muscle function (Manders et al., 2015), mild hyoxemia at rest and during exercise (Hoeper et al., 2007), ventilation/perfusion mismatching and fatigue due to a reduction in the rate of aerobic regeneration of ATP (Sun et al., 2002), yet there is no unifying explanation for its origin (Dumitrescu et al., 2017). Notwithstanding the mechanism of pathogenesis of IPH i.e., the overproduction of vasoconstrictors, there is no information available about the neural pathway whereby the lowering of pulmonary artery pressure by pulmonary bed vasodilators, such as PDE-5 inhibitors, endothelin receptor antagonists, calcium channel blockers, improves the clinical status of IPH patients (Rich, 2009).
We aimed to investigate if in IPH patients the juxta-pulmonary-capillary (J) receptors could have a role to play in this function of pulmonary bed vasodilators. The J receptors are a group of sensory receptors that lie in the pulmonary interstitium in juxtaposition to pulmonary capillaries innervated by vagal afferents and are accessible only via the pulmonary circulation (Paintal, 1969).They are naturally stimulated by any condition that produces interstitial oedema, transient increases in interstitial volume and pressure or raised pulmonary capillary pressure (Anand and Paintal, 1980). The characteristic reflexes elicited by these receptors are accelerated breathing and inhibition of exercise and these have been demonstrated in animals (Deshpande and Devanandan, 1971), in healthy individuals (Raj et al., 1995; Anand et al., 2010) and in patients with cardiac disease (Dehghani et al., 2004; Anand et al., 2009), mitral stenosis (MS) (Anand et al., 2009) and Eisenmenger syndrome patients (ES) (Anand et al., 2014).
J receptors have a very low activation threshold (Anand, 2019) and experimentally their stimulation by phenyl diguanide in animals (Paintal, 1969) and specifically by i.v. lobeline a short acting alkaloid in human subjects, accelerates respiration and in the latter it is accompanied by a variety of characteristic sensations in the upper chest such as an upward rising pressure from chest to throat, choking, being short of breath, a desire to cough or an actual cough (Raj et al., 1995). Subsequent studies established the lobeline-elicited sensations in cardiac disease patients to be akin to dyspnea (Dehghani et al., 2004; Anand et al., 2009). This similarity in the nature of respiratory sensations in response to i.v. lobeline has been demonstrated in healthy individuals by stimulating J receptors naturally i.e. by increasing pulmonary blood inflow, by releasing lower body negative pressure. This manoeuvre is accompanied by a reduction in the amplitude of the H- reflex reflecting a change in the excitability of the motoneurone pool which demonstrates that a reflex inhibition of locomotion would occur when J receptor activity increases by their natural stimulus (Anand et al., 2010).
Our earlier investigations had established that the dose of i.v. lobeline that gave rise to threshold-level respiratory sensations accompanied by respiratory acceleration is related to the level of J receptor activity at the prevailing pulmonary artery pressure i.e., the presence of their natural stimulus. This was reported both in the presence and absence of interstitial edema in MS patients (Anand et al., 2009) and in the presence of raised and lowered pulmonary artery pressure in ES patients (Anand et al., 2014). Since the level of J receptor activity determines the level of their reflexes, the aim of the present study was to determine the level of their activity in IPH patients at their prevailing pulmonary artery pressures by finding the dose of i.v. lobeline that gives rise to threshold levels of respiratory sensations and a respiratory acceleration. This would provide an insight into the influence on J receptor activity of a fall in pulmonary artery pressure when it occurs with pulmonary bed vasodilator medications.
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Patients
The subjects of this study were 6 newly diagnosed patients of idiopathic pulmonary artery hypertension aged 29.6 (±2) years of which 2 were males and 4, females. The study conformed to the Helsinki declaration, was approved by the ethics committee of All India Institute of Medical Sciences, New Delhi and conducted after obtaining informed consent from the patients in the Institute’s cardiac intensive care unit. Patients with severe anaemia (Hb<9gm%), arterial oxygen saturation (SaO2) less that
Results
Table 1 shows that in six treatment naive IPH patients the mean pulmonary artery pressure which demonstrated severe pulmonary artery hypertension was 58.67 mmHg (range 43–73) and mean right atrial pressure was 8.17 ± 3.4 mmHg (range 3–13). Two out of six patients had mild right ventricular dysfunction (Tapse <17 mm). Echocardiography revealed all patients had mild pulmonary regurgitation whereas three out of six had mild tricuspid regurgitation, while two had moderate and one had severe
Discussion
The main finding of this investigation was that mean dose of intravenously injected lobeline that gave rise to threshold level sensations in 6 IPH patients who had a mean PAsP of 58.67 ± 24 mmHg was 31.6 ± 6.1 μg/kg. Their dose is significantly higher than the known dose of 15 μg/kg (range:12−18) of healthy individuals i.e., those with normal range intrapulmonary pressures (Raj et al., 1995; Anand et al., 2011), but it is in the same range as that of untreated patients of mitral stenosis (32.4
Funding source
This Study was funded by Department of Science & Technology (India) Grant # SERB: EMR/2015/000335.
CRediT authorship contribution statement
Ashima Anand: Conceptualization, Methodology, Writing - review & editing, Investigation, Visualization, Funding acquisition. Rajeev Sharma: Investigation, Project administration. Niraj Srivastava: Investigation. Sivasubramanian Ramakrishnan: Conceptualization, Methodology, Supervision, Project administration.
Declaration of Competing Interest
The authors report no declarations of interest.
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- 1
Current address: Rukmani Birla Hospital, Jaipur, India.
- 2
Current address: Department of Physiology, BSA Medical College, Delhi, India.