Functional sympatholysis is impaired in hypertensive humans

Abstract

In healthy individuals, sympathetic vasoconstriction is markedly blunted in exercising muscles to optimize blood flow to the metabolically active muscle fibres. This protective mechanism, termed functional sympatholysis, is impaired in rat models of angiotensin-dependent hypertension. However, the relevance of these findings to human hypertension is unknown. Therefore, in 13 hypertensive and 17 normotensive subjects we measured muscle oxygenation and forearm blood flow (FBF) responses to reflex increases in sympathetic nerve activity (SNA) evoked by lower body negative pressure (LBNP) at rest and during moderate-intensity rhythmic handgrip exercise. In the normotensives, LBNP caused decreases in oxygenation and FBF (−16 ± 2% and −23 ± 4%, respectively) in resting forearm but not in exercising forearm (−1 ± 2% and −1 ± 3%, respectively; P < 0.05 vs. rest). In the hypertensives, LBNP evoked decreases in oxygenation and FBF that were similar in the resting and exercising forearm (−14 ± 2% vs. −12 ± 2% and −20 ± 3% vs. −13 ± 2%, respectively; P > 0.05), indicating impaired functional sympatholysis. In the hypertensives, SNA was unexpectedly increased by 54 ± 11% during handgrip alone. However, when SNA was experimentally increased during exercise in the normotensives, sympatholysis was unaffected. Treatment for 4 weeks with the angiotensin receptor blocker irbesartan, but not with the thiazide-type diuretic chlorthalidone, restored sympatholysis in the hypertensives. These data provide the first evidence that functional sympatholysis is impaired in hypertensive humans by a mechanism that appears to involve an angiotensin-dependent increase in sympathetic vasoconstriction in the exercising muscles.

Figures

Figure 1. Functional sympatholysis in normotensive and hypertensive subjects

A, original recordings of forearm muscle oxygenation (HbO2+MbO2) and SNA responses to lower body negative pressure (LBNP) applied at rest and during rhythmic handgrip. In both subjects, LBNP evoked similar increases in SNA at rest and during handgrip exercise. In the normotensive subject, this increase in SNA produced a large decrease in muscle oxygenation at rest and an attenuated decrease in oxygenation during handgrip, indicating functional sympatholysis. In the hypertensive subject, the LBNP-induced increases in SNA evoked similar decreases in muscle oxygenation at rest and during handgrip, indicating impaired sympatholysis. Complete forearm vascular occlusion after the exercise produced the maximal decrease in muscle oxygenation that was used to determine the total labile signal (TLS). B, summary data showing the changes in muscle oxygenation and SNA in response to LBNP at rest and during handgrip in normotensive (n= 15) and hypertensive (n= 13) subjects. *P < 0.05 vs. rest.

Figure 2. Pressor and sympathoexcitatory responses to rhythmic handgrip alone in normotensive and hypertensive subjects

Summary data showing MAP, HR and SNA (expressed as burst frequency and change from resting baseline) during the first 3 min of rhythmic handgrip at 30% MVC. In the normotensive subjects (n= 15), this moderate level of handgrip characteristically increased HR without changing MAP or SNA. In contrast, in the hypertensive subjects (n= 13) handgrip evoked a similar increase in HR that was accompanied by atypical progressive increases in MAP and SNA. *P < 0.05 vs. normotensive; †P < 0.05 vs. min 0 (rest).

Figure 3. Functional sympatholysis in normotensive subjects with artificially elevated SNA from the onset of exercise

A, an original recording of forearm muscle oxygenation (HbO2+MbO2) and SNA responses to graded LBNP applied at rest and during handgrip in a normotensive subject. At rest, LBNP produced graded increases in SNA and decreases in muscle oxygenation. LBNP at −20 mmHg was applied at the beginning of handgrip to artificially elevate SNA and mimic the exercise-induced sympathoexcitation observed in the hypertensive subjects. When LBNP was then further lowered to −30 mmHg during handgrip, SNA increased further without reducing muscle oxygenation, indicating preserved functional sympatholysis. B, summary data showing the progressive increase in SNA evoked by handgrip plus simultaneous application of LBNP at −20 mmHg in normotensive subjects (n= 6). *P < 0.05 vs. min 0 (rest). C, summary data showing the changes in muscle oxygenation and SNA in response to LBNP at −30 mmHg at rest and during handgrip (n= 6). *P < 0.05 vs. rest.

Figure 4. Functional sympatholysis in hypertensive subjects treated with an AT1 receptor blocker

Summary data showing the changes in muscle oxygenation, FBF and SNA in response to LBNP at rest and during handgrip in hypertensive subjects (n= 7) studied at baseline (no drug), after treatment with irbesartan for 4 weeks and after drug washout for 4 weeks. *P < 0.05 vs. rest; †P < 0.05 vs. no drug or washout.

Figure 5. Functional sympatholysis in hypertensive subjects treated with a thiazide-type diuretic

Summary data showing the changes in muscle oxygenation, FBF and SNA in response to LBNP at rest and during handgrip in 5 hypertensive subjects studied before and after treatment with chlorthalidone for 4 weeks.