In the early years the focus was on the Regulation of Sympathetic Nerve Activity in Humans. We have generated new concepts and insights into the pathophysiology of hypertension; heart failure and obstructive sleep apnea. We characterized how the convergence of multiple sensory afferent signals is integrated centrally. We defined as “Reciprocal Dysautonomia” an interaction between baroreceptors and chemoreceptors whereby decreased baroreceptor activity enhances the chemoreceptor response and vice versa. This concept clarifies basic mechanisms by which carotid sinus nerve stimulation in patients with drug resistant hypertension or heat failure may be beneficial.

The work evolved to an understanding that Cardiac Sensory Afferents are Major Regulators of the Autonomic System. We pioneered the concept that the heart is a sensory organ. Low-pressure mechanosensory vagal endings in the heart suppress sympathetic activity, enhance parasympathetic activity, and thus become important blood volume and blood pressure regulators. We were first to establish their role in humans and support the concept of neurocardiogenic syncope. We localized the distribution of these sensory endings in the posterior-inferior wall of the left ventricle thus explaining the preponderance of bradycardia and hypotension in patients with inferior wall myocardial infarction as well as the syncope of patients with aortic stenosis.

In the past 3 decades the reductive extension of our work targeted the Molecular Determinants of Sensory Signaling from Baro and Chemoreceptors. Using patch-clamping techniques we discovered Rheoreceptors in the carotid sinuses and identified paracrine-endothelial, and autocrine ionic and oxidative processes that are powerful modulators of neurosensory activity, as well as increased reactive oxygen derived free radicals, that suppress baroreceptors in hypertension and atherosclerosis. Patch-clamping glomus cells of the carotid bodies allowed us to uncover new ionic determinants of sensitivity to hypoxia and low pH. This work provided a mechanistic background in support of clinical trials of carotid sinus nerve stimulation and carotid body resection in hypertensive patients.

In our persistent quest for the mechanosensitive transducer we pursued: Evolutionary Conserved Mechanosensitive Molecules that Define Neuronal Sensitivities. We found that mechanosensitive channels initially identified in C. elegans were conserved and expressed in baroreceptor neurons in mammalian. They belong to the DEG/ENaC family of non-voltage gated cation channels which contributes also to acid sensitivity of chemoreceptors. Using gene deletion strategies and molecular overexpression of the channels, we found that deletion of ASIC2, the mechanosensitive subunit in mice created a hypertensive phenotype. Moreover, overexpression of ASIC3, the acid sensitive subunit caused increased chemoreceptor activity, and contributed to genetic hypertension in the SHR model.

Three neuro sensors with important translational significance were identified and reported recently.

1. The volume-regulated anion channel (LRRC8) in nodose neurons is acid pH sensitive and provides protective post ischemic preconditioning. (2017 JCI Insight)
2. The mechanosensors PIEZO1 and 2 are important determinants of blood pressure and the baroreflex. (2018 Science)
3. TMEM16B is a CCK sensitive Cl- channel in intestinal nodose neurons that determines weight gain and energy expenditures. (2019 JCI Insight)

A most promising relatively novel direction in our laboratory research has been the Neurohumoral Proinflammatory Modulation of the Innate Immune System in Hypertension. In the last 7 years we uncovered in the genetic model of SHR, prior to the onset of hypertension, abnormalities related to Toll Receptor (TLR) activation and nicotine proinflammatory cholinergic receptors. Hence, our concept of a genetic abnormality in the innate immune system of SHR is linked to the autonomic system. A third provocative result is that SHR bone-marrow transfer into irradiated F1 populations (hybrid SHR/WKY) does not evoke hypertension but appears to induce a significant increase in aortic adventitial adiposity and inflammatory processes. This uncoupling of hypertension from the inflammatory process will require a reassessment of our current understanding.