Commentary: Antihypertensive treatment fails to control blood pressure during Exercise

Exercise-induced hypertension (EIHt) in humans is a clinical observation that has a 5-year prognosis to develop into essential hypertension; when observed during moderate exercise intensity it is an independent risk factor for cardiovascular events and mortality¹. To my knowledge, Hart et al.² evaluated for the first time, whether patients on anti-hypertensives with controlled hypertension at rest exhibit EIHt during exercise. Since a hypersensitive metaboreflex was recently confirmed to be a major factor in the hypertensive response to exercise in patients with untreated hypertension³ and in SHR rats⁴, investigators have been evaluating the exercise pressor reflex sensitivity of the recruited subjects using a post-exercise ischemia (PEI) challenge, following isometric handgrip exercise. During the progressive increase in the intensity of dynamic exercise the increase in pressure among subjects of i) controlled; ii) uncontrolled; and iii) untreated resting hypertension was similar, but was significantly greater than in normotensive controls. Similarly, all three subject groups exhibited an exaggerated exercise pressor reflex (EPR) during PEI. Although not specifically mentioned, the investigators recruited age, gender, and aerobic capacity matched groups, which though small in number, addressed the question of differences in arterial stiffness⁵. Hence, in my opinion, the investigators correctly suggest that their findings indicate that the successful pharmaceutical control of resting blood pressure requires further evaluation during moderate to maximal exercise in a clinical setting.

During dynamic and/or resistance exercise, the autonomic neural control of blood pressure is multi-faceted and involves the sympathetic and parasympathetic nervous systems⁶. From the present study, numerous questions arise about the multitude of anti-hypertensive medications including angiotensin-converting enzyme inhibitors (ACEi), angiotensin receptor blockers (ARB), calcium channel blockers (CCB), α & β blockers and diuretics regarding their selectivity of action, lipid solubility and their distribution, actions and efficacy within the systemic and cerebral circulation. In the discussion, the investigators refer to a comprehensive review, which deliberates that the exaggerated sympathetic nerve activity (SNA) of the metaboreflex is a result of an impaired functional sympatholysis⁷, a mechanism by which the transduction of the SNA resulting in vasoconstriction is weakened with increased intensity of exercise. In addition, the investigator’s data revealed that regardless of whether the resting hypertension was pharmaceutically controlled, uncontrolled, or untreated, each of the groups exhibited EIHt during moderate to maximal exercise intensities, compared to the resting normotensive’s physiological blood pressure response to exercise.

It is well established that the physiologic autonomic neural control of arterial blood pressure during progressive increases in dynamic exercise intensity from rest to maximal exercise require an integration between i) central command (a feed forward mechanism originating from the higher brain centers); ii) the exercise pressor reflex (a feed-back mechanism originating from the skeletal muscle afferents sensing mechanical and metabolic stresses); iii) the arterial baroreflex (a negative feed-back mechanism originating from the carotid sinus and the aortic arch for regulating blood pressure); and iv) cardiopulmonary baroreceptors (a feed-back mechanism from stretch receptors located in the heart and lungs sensing central blood volume)⁶. Animal experiments have identified that integration of the autonomic neural inputs occur centrally within the Nucleus Tractus Solitarius (NTS) and involve inflammatory processes and nitric oxide (NO)^{8, 9}. During the progressive increase in exercise intensity, the mean arterial blood pressure (MAP) increases in direct proportion to the exercising muscles’ demand for oxygen. We have demonstrated that the operating point (OP) of the arterial baroreflex (ABR) control of blood pressure is reset upwards and rightwards in direct relation to the increase in exercise intensity from rest to near maximal exercise¹⁰, i.e. physiologic hypertension. More recently, we have identified that by using a central and peripheral ACE inhibitor to reduce the production of free radicals and their scavenging of central NO from the ANG II/ AT1 receptor binding in the central Renin-Angiotensin System (RAS), in humans, the exercise intensity related increases in central muscle SNA outflow were reduced¹¹.

Is it possible that investigations into rescuing central NO to buffer the increased central SNA outflow of the hypersensitive exercise pressor reflex will prove more translational and beneficial for correcting EIHT, rather than investigating a multitude of specific mechanisms that are collectively identified as “functional sympatholysis”?