Gene expression profiling of calcium-channel antagonists in the heart of hypertensive and normotensive rats reveals class specific effects

Calcium channel blockers (CCB) differ in their effects on the cardiovascular system with diltiazem being less negatively ionotrop as compared to verapamil. Diltiazem is mainly used to treat supraventricular tachycardia, vasospastic angina and the Raynaud's syndrome. Little is known about the molecular effects of benzothiazepins on cardiac gene expression. We therefore investigated the effects of diltiazem on cardiac gene expression in normotensive and hypertensive rats with left ventricular hypertrophy and compared the results with our previous findings on verapamil and nifedipine. Spontaneously hypertensive (SHR) and normotensive Sprague Dawley (SD) rats were treated with 15 mg/kg diltiazem b.i.d. for 3 days. Total RNA was isolated from surgically removed hearts and the gene expression of ion channels, ion transporters and their associated partners, calcium handling proteins as well as stress and cellular differentiation markers was investigated by RT-PCR. Subsequently, hierarchical gene cluster analysis was performed to decode treatment effects of different classes of CCBs. CCB treatment of normotensive and hypertensive rats revealed class specific effects with diltiazem specifically repressing cardiac genes pertinent for ion homeostasis and excitation-contraction coupling in normotensive but not hypertensive rats. Conversely, verapamil and nifedipine caused predominantly repression of genes to affect ion homeostasis and contractile dysfunction in spontaneously hypertensive rats; nonetheless, genes coding for calcium-handling proteins were up-regulated. Unlike diltiazem treatment of normotensive rats with verapamil and/or nifedipine did not influence cardiac gene expression. The effects of diltiazem on cardiac gene expression provide a molecular rationale for its use in the treatment of vasospastic angina.