Journal of Hypertension:
Discovering the sympathomodulatory properties of new calcium channel blockers: an exciting but still snaky journey
aClinica Medica, Dipartimento di Scienze della Salute, Università Milano-Bicocca, Monza
bIRCCS Multimedica, Sesto San Giovanni, Milan, Italy
Correspondence to Guido Grassi, Professor, Clinica Medica, University of Milano-Bicocca, Ospedale San Gerardo dei Tintori, Via Pergolesi 33, 20052 Monza, Milan, Italy. Tel: +39 39 2336005; e-mail: firstname.lastname@example.org
The study by Inomata et al., published in the present issue of the Journal of Hypertension, can count as background on four ‘solid’ sets of evidence. First, the finding that sympathetic overdrive represents a hallmark of the essential hypertensive state, documented via the assessment of human adrenergic function throughout the measurement of haemodynamic [heart rate (HR)], biochemical (plasma norepinephrine and/or its urinary metabolites), neurophysiological (efferent postganglionic muscle sympathetic nerve traffic), neurofunctional (systemic and regional norepinephrine spillover and clearance) as well as power spectral variables [2,3]. Second, the evidence that potentiated sympathetic cardiovascular influences concur, together with the blood pressure (BP) overload and other humoral factors, at the development as well as at the progression of cardiac (left ventricular hypertrophy and left ventricular diastolic dysfunction), vascular (arterial and arteriolar structural and functional remodelling and hypertrophy) and renal (renal insufficiency and failure) target organ damage, thereby augmenting the already elevated cardiovascular risk profile of a given hypertensive patient [2–4]. Third, the recognition that sympathetic overdrive is an independent determinant of cardiovascular risk and of cardiovascular-related fatal and nonfatal events in a variety of disease, such as congestive heart failure, renal failure, life-threatening cardiac arrhythmias, obstructive pulmonary disease and acute stroke [5–11]. Finally, the therapeutic need that modulation of the sympathetic overdrive represents a goal of antihypertensive pharmacological or nonpharmacological interventions aimed at reducing the cardiovascular risk not only by lowering elevated BP values, but also by reducing sympathetic cardiovascular influences [2,3,12].
There is, however, another key antecedent to the study by Inomata et al., namely the finding that antihypertensive drugs may display a nonhomogeneous behaviour regarding their effects on sympathetic neural function. Indeed, whereas thiazide diuretics, vasodilating compounds and alpha-adrenergic blockers have been shown to exacerbate the already elevated sympathetic cardiovascular drive of the essential hypertensive patient , beta-blockers, central sympatholytic agents, angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers as well as mineralcorticoid receptor antagonists are capable of reducing (but not of fully normalizing) sympathetic activity . The heterogeneity of the adrenergic effects of antihypertensive drugs is detectable when comparison is made not only between drugs belonging to different pharmacologic classes, but also between compounds within the same class. This is specifically true for calcium channel blockers, because whereas short-acting ‘classical’ compounds exert marked sympathoexcitatory effects, long-acting ‘classical’ drugs may have more favourable effects, resulting in an overall neutral effect on the adrenergic cardiovascular function . The only exception to the already described general behaviour is the calcium channel blocker cilnidipine of the dihydropyridine group, which, by exerting marked inhibitory effects not only on L-type but also on N-type voltage-dependent calcium channels (particularly those located in the central nervous system), decreases the release of norepinephrine from adrenergic nerve endings and also exerts potent central sympathoinhibitory effects [13–15].
In the above-mentioned scenario of information, the study by Inomata et al. reports new data on the effects of azelnidipine vs. amlodipine (both calcium channel blockers of the dihydropiridine group without any effect on N-type calcium channels) on BP (sphygmomanometric and noninvasive tonometric monitoring) as well as on three different indices of adrenergic drive, that is, HR, low-frequency and high-frequency ratio of the HR signal (power spectral bands analysis) and direct microneurographic recording of efferent postganglionic muscle sympathetic nerve traffic in the peroneal nerve. The results of the study, which was performed according to a prospective, randomized, open-label crossover design, provide evidence that for similar BP-lowering effects, azelnidipine markedly reduces the tachycardic and sympathoexcitatory responses (as assessed directly via the microneurographic technique and indirectly at cardiac level via the power spectral analysis of the R–R interval) detected during prolonged treatment with amlodipine. Indeed, the HR and muscle sympathetic nerve traffic values recorded during prolonged treatment with azelnidipine were by 30–35% less than the one recorded during amlodipine treatment and virtually superimposable to the ones seen in the pretreatment condition .
The intriguing results of the study performed by the Japanese investigators  raise a number of questions, which can receive, however, only a partial answer from the research's findings. The first question is whether the data collected can allow to conclude that azelnidipine exerts a ‘true’ sympathoinhibition or rather a ‘simple’ sympathomodulation. The difference between the two words is not only semantic. With the term ‘sympathoinhibition’, we refer to the results of a nonpharmacological or pharmacological intervention which allows to significantly reduce the predrug values of sympathetic activity, thereby showing clearcut decrease in the sympathetic outflow. An example of sympathoinhibition is the one described with cilnidipine which effectively reduces baseline sympathetic drive, as documented in different published studies by the decrease of the low-frequency component of the HR or SBP signal as well as by the reduction in circulating plasma norepinephrine levels [13–15]. In contrast, with the term ‘sympathomodulation’, we refer to the results of a nonpharmacological or pharmacological intervention which allows to maintain the predrug values of sympathetic activity, thereby preventing the sympathoexcitation related to the drug-induced BP fall without causing, however, any further reduction compared with the predrug sympathetic values. This is the case, according to the results of the study by Inomata et al., for azelnidipine which maintains virtually unaltered muscle sympathetic nerve firing rate throughout the treatment weeks despite the drug-induced BP fall. The different behaviour between cilnidipine and azelnidipine implies that the two drugs may have a different potency in reducing sympathetic drive. They may also mean that cilnidipine may display direct sympathoinihbitory effects, by blocking the central nervous system N-type channels, which azelnidipine does not necessarily have . The impact of the difference in the effects of a given drug on adrenergic drive may be relevant, as shown by the potential favourable consequences of a sustained sympathoinhibition, as summarized in the list below. Potential favourable effects of a calcium channel blocker with ‘true’ central sympathoinhibitory effects are as follows:
1. sustained and more homogeneous BP reduction during the 24-h period;
2. decrease in 24-h BP variability;
3. lack of tachycardia, possibly HR-lowering effects;
4. sustained coronary and renal vasodilatation;
5. improvement in insulin sensitivity;
6. pronounced favourable effects on the regression of cardiac and renal end-organ damage.
The considerations made so far allow a final comment on the mechanisms responsible for the sympathomodulatory effects of azelnidipine. Indeed, the authors of the present study  tested the impact of the two drugs treatment on baroreflex sensitivity, as assessed either via the power spectral analysis of the spontaneous HR changes or via the evaluation of the spontaneous muscle sympathetic nerve traffic changes plotted against the concomitant DBP changes. In both instances, however, the sensitivity of the baroreflex was unaffected by the drug, indicating that the sympathomodulation was unrelated to the reflex mechanisms. The mechanism(s) of the azelnidipine-related sympathomodulation thus remain to be defined. An action of the drug on other reflexogenic areas involved in modulation of the central sympathetic outflow, such as cardiopulmonary volume sensitive receptors , cannot be excluded, however.
Conflicts of interest
1. Inomata J-I, Murai H, Kaneko S, Hamaoka T, Ikeda T, Kobayashi D, et al. Differential effects of azelnidipine and amlodipine on sympathetic nerve activity in patients with primary hypertension. J Hypertens
2. Mancia G, Grassi G. The autonomic nervous system and hypertension. Circ Res
3. Grassi G. Sympathetic neural activity in hypertension and related diseases. Am J Hypertens
4. Esler M. Sympathetic nervous system moves toward center stage in cardiovascular medicine: from Thomas Willis to resistant hypertension. Hypertension
5. Cohn JN, Levine TB, Olivari MT, Garberg V, Lura D, Francis GS, et al. Plasma norepinephrine as a guide to prognosis in patients with chronic congestive heart failure. N Engl J Med
6. Brunner-La Rocca HP, Esler MD, Jennings GL, Kaye DM. Effect of cardiac sympathetic nervous activity on mode of death in congestive heart failure. Eur Heart J
7. Sander D, Winbeck K, Klingelhöfer J, Etgen T, Conrad B. Prognostic relevance of pathological sympathetic activation after acute thromboembolic stroke. Neurology
8. Zoccali C, Mallamaci F, Parlongo S, Cutrupi S, Benedetto FA, Tripepi G, et al. Plasma norepinephrine predicts survival and incident cardiovascular events in patients with end-stage renal disease. Circulation
9. Barretto AC, Santos AC, Munhoz R, Rondon MU, Franco FG, Trombetta IC, et al. Increased muscle sympathetic nerve activity predicts mortality in heart failure patients. Int J Cardiol
10. Andreas S, Haarmann H, Klarner S, Hasenfuss G, Raupach T. Increased sympathetic nerve activity in COPD is associated with morbidity and mortality. Lung
11. Penne EL, Neumann J, Klein IH, Bots ML, Blankestein PJ. Sympathetic hyperactivity and clinical outcome in chronic kidney disease during standard treatment. J Nephrol
12. Grassi G. Counteracting the sympathetic nervous system in essential hypertension. Curr Opin Nephrol Hypertens
13. Takahara A. Cilnidipine: a new generation Ca+
channel blocker with inhibitory action on symapthetic neurotransmitter release. Cardiovasc Ther
14. Kishi T, Hirooka Y, Konno S, Sunagawa K. Cilnidipine inhibits symapthetic nerve activity and improves baroreflex sensitivity in patients with hypertension. Clin Exp Hypertens
15. Ogura C, Ono K, Miyamoto S, Ikai A, Mitani S, Sugimoto N, et al. L/T-type and L/N-type calcium-channel blockers attenuate cardiac sympathetic nerve activity in patients with hypertension. Blood Press
16. Wellington K, Scott LJ. Azelnidipine. Drugs
17. Zanchetti A, Mancia G. Cardiovascular reflexes and hypertension. Hypertension
1991; 18 (5 Suppl):III13–III21.
© 2014 Wolters Kluwer Health | Lippincott Williams & Wilkins
What does "Remember me" mean?
By checking this box, you'll stay logged in until you logout. You'll get easier access to your articles, collections,
media, and all your other content, even if you close your browser or shut down your
To protect your most sensitive data and activities (like changing your password),
we'll ask you to re-enter your password when you access these services.
What if I'm on a computer that I share with others?
If you're using a public computer or you share this computer with others, we recommend
that you uncheck the "Remember me" box.
Data is temporarily unavailable. Please try again soon.
Readers Of this Article Also Read