497drug as fi rst line treatment leading to reduction of the number of drugs required for
adequate treatment as well the number of visits by the patient to the health-care
facility for monitoring of blood pressure. The overall effect would be improvements
in quality of health care and cost savings.
Prediction of Antihypertensive Activity of Rostafuroxin
Two mechanisms, among others, are associated with essential HPN and related
organ damage: mutant α-adducin variants and high concentrations of endogenous
ouabain. An antihypertensive agent, rostafuroxin, selectively inhibits these mecha-
nisms in rodents. A study has investigated the molecular and functional effects of
mutant α-adducin, ouabain, and rostafuroxin in hypertensive rats, human cells, and
cell-free systems and demonstrated that both mutant α-adducin variants and the
ouabain–Na,K-ATPase (Na + - and K + -dependent adenosine triphosphatase) complex
can interact with the Src-SH2 (Src homology 2) domain, increasing Src activity and
the Src-dependent Na,K-ATPase phosphorylation and activity (Ferrandi et al. 2010 ).
Wild-type α-adducin or Na,K-ATPase in the absence of ouabain showed no interac-
tion with the Src-SH2 domain. Rostafuroxin disrupted the interactions between the
Src-SH2 domain and mutant α-adducin or the ouabain–Na,K-ATPase complex and
blunted Src activation and Na,K-ATPase phosphorylation, resulting in blood pres-
sure normalization in the hypertensive rats.
The translatability of these data to humans was also shown in a pharmacoge-
nomic clinical trial, which investigated the relationship between variants of genes
encoding enzymes for ouabain synthesis (lanosterol synthase) and HSD3B1
(hydroxy-δ-5-steroid dehydrogenase, 3β- and steroid δ-isomerase 1), ouabain trans-
port and adducin activity, and the responses to antihypertensive medications
(Lanzani et al. 2010 ). The genetic profi le defi ned by these variants predicted the
antihypertensive effect of rostafuroxin, a sodium pump blocker, but not that of losar-
tan or hydrochlorothiazide. The magnitude of the rostafuroxin antihypertensive
effect was twice that of antihypertensive drugs recently tested in phase II clinical
trials. One-quarter of patients with primary HPN display these variants of adducin
or concentrations of endogenous ouabain and would be expected to respond to ther-
apy with rostafuroxin. Because the mechanisms that are inhibited by rostafuroxin
also underlie HPN-related organ damage, this drug may also reduce the cardiovas-
cular risk in these patients beyond that expected by the reduction in systolic blood
pressure alone. The results open up the possibility of improved patient stratifi cation,
as they allow predictions to be made about the effectiveness of rostafuroxin (but not
that of any other antihypertensive drugs) in patients carrying key gene variants.
Role of Pharmacogenetics in Management of Hypertension
Genetic factors may infl uence the response to antihypertensive medication. A num-
ber of studies have investigated genetic polymorphisms as determinants of cardio-
vascular response to antihypertensive drug therapy. Hypertensive patients with the
460 W allele of the α-adducin gene have a lower risk of myocardial infarction and
Role of Diagnostics in Personalized Management of Cardiovascular Disease