Neuroadrenergic effects of calcium channel blockers

The interest concerning a link between the antihypertensive profile of calcium antagonists and the sympathetic nervous system dates back almost 20 years when, for the first time, a group of Swiss investigators advanced the hypothesis that adrenergic neural factors might be involved in determining the blood pressure-lowering effects of these drugs [1]. In recent years, there has been renewed interest, with the well-known ‘calcium antagonists controversy’ leading some investigators to identify one of the main mechanisms responsible for the unfavourable effects of the short-acting formulations of dihydropyridines in an activation of the sympathetic nervous system [2–4]. A number of authoritative reviews, meta-analyses and original studies have provided continuous fuel to the scientific debate [5–13]. However, in the last few years, this has seen the appearance of new concepts and ideas. In the current issue of the journal, Ruzicka et al. [14] provide intriguing results that may represent an important step forward in our understanding of the complex relationships between calcium channels blockers and neuroadrenergic drive. Dihydropyridines: sympathoexcitatory or sympathoinhibitory drugs? In spontaneously hypertensive rats, intracerebroventricular administration of nifedipine elicits a marked decrease in blood pressure and heart rate [15]. These systemic haemodynamic effects are coupled with a clear-cut reduction in sympathetic neural outflow to the kidneys, whose temporal patterns appear to differ according to the pharmacological characteristics of the different dihydropyridines used [5,15–17]. However, the main message generated from these studies is that this group of calcium channel blockers, when directly administered into the brain, may lower, rather than increase, sympathetic cardiovascular drive [18]. This effect has been shown: (i) to depend on the blockade of L-type Ca2+ channels in brain areas [6,15–18]; (ii) to take place at drug concentrations lower than those required for achieving an inhibition of calcium ions influx into vascular smooth muscle cells [5,15–18]; and (iii) to be related to the ability of these compounds to cross the blood–brain barrier, a feature that appears to be closely associated with the lipophilic properties of the different agents. Sympathoinhibitory effects have been also described following peripheral administration of dihydropyridines, particularly when prolonged for several days at low dosage (i.e. in a condition in which an attenuated direct arterial vasodilation is coupled with a central sympathoinhibitory action) [19,20]. Taken together, these findings suggest that the effects of calcium channels blockers on adrenergic cardiovascular drive are heterogeneous in nature, depending on a number of factors (Table 1), including not only their pharmacologic or pharmakinetic profile, but also the balance between the indirect peripheral (sympathoexcitatory) and the direct central (sympathoinhibitory) effects of the drug itself.Table 1: Factors potentially affecting the sympathetic effects of calcium channel blockersThe sympathetic responses to calcium antagonists also depend, on another key factor (i.e. the phase of treatment in which they are investigated). Conclusive evidence indeed exists indicating that acute administration of calcium antagonists or other blood pressure-lowering agents (even beta-blockers or central sympatholytic drugs) almost invariably triggers a sympathoexcitation [13,21,22]. However, this response appears to be virtually absent or markedly attenuated during prolonged antihypertensive drug treatment. In the case of calcium antagonists, it is likely that this depends on the ability of the compounds to cross the blood–brain barrier and thus to exert a direct depressor (and sympathoinhibitory) effect on the vasomotor centre during a chronic treatment. Are the sympathetic responses to dihydropyridines age-related? The study by Ruzicka et al. [14] addresses two intriguing questions by examining whether and to what extent the adrenergic responses to dihydropyridines administration (i) are qualitatively and/or quantitatively different in young versus old hypertensive patients and (ii) are responsible for the referred greater efficacy of dihydropyridine compounds in patients aged older than 60 years. Indeed, the study basically tested the hypothesis that neurohumoral mechanisms (including the adrenergic ones) might be responsible for the greater efficacy of calcium channel blockers in aged individuals [1,23]. To this aim, Ruzicka et al. [14] evaluated the long-term effects of either low-dose nifedipine gastrointestinal therapeutic systems (GITS) or placebo on a number of haemodynamic neurohumoral and neurophysiologic variables, including efferent postganglionic muscle sympathetic nerve traffic [14]. The study provides a number of intriguing results. First, it shows that dihydropyridines have no clear-cut blood pressure-lowering effects in young patients, which is at variance from what the study shows in older individuals in whom the systo-diastolic blood pressure reduction amounts, on average, to 10 ± 3/7 ± 2 mmHg. Second, the study results provide a sound pathophysiological rationale for the above-mentioned age-related differences in the blood pressure-lowering effects of this class of drugs. Indeed, when the data are compared with those collected during placebo treament, an increase (albeit modest) is shown in the sympathetic nerve firing rate in younger but not older individuals. Finally, the study findings do not support the previously advanced hypothesis [1,23] that the greater efficacy of dihydropyridines in the elderly depends on the renin profile, with no relationship being found between the changes in angiotensin II levels and the concomitant blood pressure reductions. Questions on the floor A number of questions remain unanswered with respect to the results of the study. For example, the mechanism(s) responsible for the age-related difference in the sympathetic responses to dihydropyridines remain unclear. Ruzicka et al. [14] may be correct in excluding a participation of reflexes stemming from arterial baroreceptors. However, they cannot rule out the possibility that the difference in the responses depends on the participation of cardiopulmonary volume receptors, which contribute to a major extent to the reflex modulation of sympathetic drive [24]. It also remains unknown whether the same results would be obtained if baseline blood pressure values were superimposable in the two groups. Indeed, the lower blood pressure values displayed by younger individuals per se may represent a factor responsible for the age-related difference in the antihypertensive (and neuroadrenergic) effects of calcium channels blockers. This explanation is supported by the evidence that nifedipine, as well as verapamil, has no effects on blood pressure values in normotensive subjects [25].