**3.7 Metabolic syndrome**

36 Antihypertensive Drugs

type Ca2+ channel-blocking activity may be partly associated with control of the glomerular pressure. Indeed, cilnidipine has been demonstrated to dilate both afferent and efferent arteries using the hydronephrotic kidney model of the rat (Konno & Kimura, 2008). Furthermore, in renal injury animal models, cilnidipine reduces glomerular capillary pressure, afferent and efferent arteriolar resistances, urinary albumin excretion, and

In clinical studies, cilnidipine significantly decreased urinary albumin excretion without affecting serum creatinine concentration in hypertensive patients, which is comparable to the angiotensin-converting enzyme inhibitor benazepril. Other studies have shown that the renal protective effect of cilnidipine was greater than that of pure L-type Ca2+ channel blockers. Furthermore, the combination of cilnidipine and valsartan was shown to decrease the albumin/creatinine ratio more markedly than valsartan alone. Recently, the multi-center, open-labeled and randomized trial of Cilnidipine versus Amlodipine Randomized Trial for Evaluation in Renal disease (CARTER) has shown that cilnidipine is superior to amlodipine in preventing the progression of proteinuria in patients with hypertension and chronic renal

Since the first generation of Ca2+ channel blockers were known to suppress cardiac functions such as contractility, sino-atrial automaticity, and atrioventricular conduction at vasodilator doses, pharmaceutical companies have developed new Ca2+ channel blockers with higher vascular selectivity in addition to slow kinetics as a new generation. The blood-perfused canine heart preparation is an excellent model to quantitatively determine cardio-vascular selectivity of Ca2+ channel blockers, and many Ca2+ channel blockers were analyzed using this model (Taira, 1987). Cilnidipine has about 10 times more potent coronary vasodilator action and higher vascular selectivity than nifedipine in this heart preparation. An in vivo experimental study has confirmed that cilnidipine shows anti-anginal effects in the vasopressin-induced angina model (Saitoh et al., 2003). A recent study indicates that cilnidipine relaxes human arteries through Ca2+ channel antagonism and increases production of nitric oxide by enhancement of endothelial nitric oxide synthase in the human

The cardioprotective action of cilnidipine against ischemia has been analyzed in a rabbit model of myocardial infarction, in which cilnidipine decreased the myocardial interstitial norepinephrine levels during ischemia and reperfusion periods, leading to reduction of the myocardial infarct size and incidence of ventricular premature beats (Nagai et al., 2005). Clinically, cilnidipine has been reported to improve left ventricular diastolic function in patients with hypertensive heart disease (Kosaka et al., 2009). These cardioprotective actions are probably associated with suppression of cardiac sympathetic overactivity via blockade of N-type Ca2+ channels and/or anti-oxidative (as described below) effects of cilnidipine,

The brain is known to have an autoregulatory capacity that allows cerebral blood vessels to maintain constant cerebral blood flow by dilating or contracting in response to abrupt

disease when coupled with a renin–angiotensin system inhibitor (Fujita et al., 2007).

glomerular volume as well as plasma norepinephrine levels.

**3.5 Cardiovascular action** 

internal thoracic artery (Fan et al., 2011).

which should be further clarified.

**3.6 Cerebrovascular action** 

Pancreatic insulin secretion from β-cells and glucagon secretion from α-cells in the islets of Langerhans are Ca2+-dependent processes initiated by Ca2+ influx probably through N-type Ca2+ channels. In a study using N-type Ca2+ channel α1B-subunit-deficient homozygous knockout mice fed normal diet, there was improved glucose tolerance without any change in insulin sensitivity, and also body weight gain reduced in the mice fed a high-fat diet (Takahashi et al., 2005). In another study with fructose-fed rats, insulin sensitivity was significantly lower than in controls, and insulin resistance improved significantly after cilnidipine treatment (Takada et al., 2001). These imply that N-type Ca2+ channels play a significant role in glucose homeostasis.

Clinically, it was revealed that cilnidipine significantly reduced 24-hour urinary catecholamines in hypertensive patients with type 2 diabetes, and thereby may improve insulin resistance (Takeda et al., 1999). Also, it is demonstrated that with cilnidipine treatment in patients with obesity, fasting serum immunoreactive insulin (F-IRI) and insulin resistance index as assessed by homeostasis model assessment (HOMA-R) lowered, and serum dehydroepiandrosterone (DHEA) and serum DHEA-sulfate (DHEA-S) increased (Ueshiba & Miyachi, 2002).
