Reserpine shows promise in refractory hypertension

The potent sympatholytic agent reserpine provides blood pressure (BP)-lowering benefits to hypertensive individuals whose BP remains uncontrolled on maximal antihypertensive therapy, according to the results of a proof-of-concept study.

“Many studies indicate that resistant hypertension is attributable to excess fluid retention related in large part to high dietary sodium intake and aldosterone excess. In contrast, indirect assessments of sympathetic tone suggest that refractory hypertension (RfHTN) is attributable to heightened sympathetic output and not by persistent excess fluid retention,” the researchers said. [Hypertension 2018;72:e53-e90; Chest 2007;131:453-459; Hypertension 2015;66:126-133; Hypertension 2018;72:343-349; Hypertens Res 2019;42:1708-1715]

To test the hypothesis that RfHTN is neurogenic in aetiology, the researchers identified 21 consecutive patients fully adherent with their antihypertensive regimen. Seven of these patients agreed to participate in the trial, with six (mean age, 49.5 years; 66.7 percent female; mean body mass index, 31.1 kg/m²) completing open-label treatment with reserpine 0.1 mg daily for 4 weeks.

All patients were taking at least five BP-lowering drugs (eg, lisinopril or quinapril, losartan, amlodipine, chlorthalidone, spironolactone or eplerenone, carvedilol or labetalol, hydralazine or minoxidil, clonidine, or guanfacine) at baseline. Comorbidities included congestive heart failure, prior stroke or transient ischaemic attack, diabetes, and dyslipidaemia.

The mean systolic and diastolic automated office BP (AOBP) levels at baseline were 161.5 and 100.0 mm Hg, respectively, while the mean heart rate (HR) was 80.3 beats/minute. After 4 weeks of reserpine therapy, systolic AOBP decreased by 29.3 mm Hg (p=0.023), diastolic AOBP by 22.0 mm Hg (p=0.019) and HR by 12.0 beats/min (p=0.003). [Am J Hypertens 2020;doi:10.1093/ajh/hpaa042]

A similar pattern of results was observed for 24-hour ambulatory BP (ABP) measurements. At week 4, systolic and diastolic ABP levels were lower by 21.8 and 15.3 mm Hg (p=0.010 and p=0.011), respectively. Corresponding reductions in daytime systolic and diastolic ABPs were 23.8 and 17.8 mm Hg (p=0.004 and p=0.005), while those of night-time ABP levels were 21.5 and 13.7 mm Hg (p=0.006 and p=0.004).

Likewise, there were significant reductions seen in 24-hr HR (–10.2 beats/min; p=0.002), awake HR (­–10.5 beats/min; p=0.001) and asleep HR (–9.8 beats/min; p=0.021). None of the patients experienced any adverse effect with use of reserpine during the 4-week treatment period.

“The current results provide important preliminary evidence that antihypertensive treatment failure in the presence of appropriately dosed diuretic therapy, including chlorthalidone and a mineralocorticoid receptor antagonist is attributable, at least in part, to heightened sympathetic output,” the researchers pointed out.

“[B]y failing generally effective antihypertensive regimens, including specifically blocking aldosterone, volume-dependent causes of treatment resistance have likely been overcome, leaving other undertreated aetiologies of treatment resistance, which the current and prior findings suggest may be in large part sympathetic hyperactivity. If so, it is hypothesized that these patients may preferentially benefit from effective sympatholytic therapies, such as long-acting and well-tolerated medications or device-based treatments,” they added.

Additional trials, with larger populations, are warranted to more rigorously test the hypothesis, according to the researchers.