Fluvastatin, an HMG-CoA reductase inhibitor, protects LDL from oxidative modification in hypercholesterolemic rabbits

The antioxidative effect of fluvastatin sodium (fluvastatin) on low-density lipoprotein (LDL) was evaluated in vivo and in vitro. Since ex vivo measurement of the LDL oxidizability is reported to reflect the response of the atherosclerotic process, LDL isolated from rabbits fed a high cholesterol diet for 4 weeks with or without fluvastatin, pravastatin or alpha-tocopherol administration was oxidized by copper ions to estimate conjugated diene formation. Fluvastatin but not pravastatin significantly prolonged the lag time of LDL oxidized by copper ions ex vivo without affecting plasma cholesterol levels at a dose of 3 mg/kg after four weeks of treatment. Alpha-tocopherol-treated rabbits showed dramatically elongated LDL oxidation lag time at a dose of 150 mg/kg. In order to assess the mechanism, the content of alpha-tocopherol, a major endogenous antioxidant in LDL was measured, and we found that only LDL isolated from alpha-tocopherol-treated rabbits contained a significantly larger amount of alpha-tocopherol than that from high cholesterol control rabbits. To elucidate the mechanism further, the effect of fluvastatin on conjugated diene formation during copper-induced LDL oxidation in vitro was studied. Fluvastatin not only prolonged lag time, but also suppressed the rate of LDL oxidation, both in a dose dependent manner above 1 microM, while pravastatin showed no effect. These results suggest the direct antioxidative effect of fluvastatin on LDL oxidation in vivo. Since oxidation of LDL is an important step in the initiation and progression of atherosclerosis, fluvastatin may reduce the risk of this condition not only by lowering plasma cholesterol but also by protecting LDL from oxidation.     

Activation of protein kinase C by the dihydropyridine calcium channel blocker, felodipine

Felodipine, a dihydropyridine Ca2+ channel blocker, appears to have intracellular sites of action in addition to its ability to attenuate voltage-dependent Ca2+ channels in smooth muscle cells. In vitro, felodipine inhibits several calmodulin-dependent enzymes such as myosin light chain kinase, cyclic nucleotide phosphodiesterase and caldesmon kinase [Walsh MP, Sutherland C and Scott-Woo GC, Biochem Pharmacol 37: 1569-1580, 1988]. Such effects may partially explain the relaxant effects of felodipine and related dihydropyridines on vascular smooth muscle. We have examined the effects of felodipine on the activity of another important enzyme which has been implicated in the regulation of the contractile state of smooth muscle, protein kinase C. We chose to use a physiologically relevant substrate of protein kinase C for these studies, viz. platelet P47 protein, rather than the more commonly used lysine-rich histone which is probably not a physiologically important substrate. Protein kinase C and P47 were purified from human platelets and their important structural and functional properties were characterized. Felodipine and the p-chloro analogue of felodipine enhanced both the rate and extent of P47 phosphorylation by protein kinase C. Half-maximal activation was observed at 9.5 microM felodipine and 8.5 microM p-chloro analogue. Activation by felodipine was dependent upon the presence of phospholipid but did not require diacylglycerol. These observations suggest that the pharmacological actions of felodipine and related dihydropyridines may involve activation of protein kinase C in addition to their known effects on voltage-dependent Ca2+ channels and calmodulin-dependent enzymes.     

The effects of HMG-CoA reductase inhibitor on vascular progenitor cells

Circulating bone marrow-derived vascular progenitor cells contribute to angiogenesis, atherosclerosis, and the response to vascular injury. These vascular progenitor cells consist of two cell groups, endothelial progenitor cells (EPCs) and smooth muscle progenitor cells (SMPCs). Although HMG-CoA reductase inhibitors (statins) have been reported to inhibit atherosclerosis partially by increased EPCs, the effects of statins on SMPCs are unclear. Therefore, we investigated the relationship between EPCs and SMPCs and whether pravastatin has atheroprotective effects on SMPCs. Peripheral mononuclear cells (MNCs) were isolated and cultured on fibronectin-coated dishes in SMPC medium. MNCs were stained with acetylated low density lipoprotein and lectin, or alpha-smooth muscle actin, and cell numbers were counted. mRNA expression and vascular endothelial growth factor (VEGF) protein synthesis of MNCs were evaluated. Pravastatin significantly increased the number of EPC and decreased the number of SMPC. mRNA expression of VEGF, endothelial nitric oxide synthase, VEGF receptor-2 (KDR), and Akt were up-regulated, and VEGF secretion was increased by pravastatin. The present study demonstrated that pravastatin has promotive effects on the differentiation from MNCs to EPC cells, while inhibitory effects to SMPC cells. Our findings suggest a previously unreported mechanism of the effect of statin therapy on vascular progenitor cells.     

Effects of felodipine (a dihydropyridine calcium channel blocker) and analogues on calmodulin-dependent enzymes

We have examined the effects on the activities of three calmodulin-dependent enzymes (cAMP phosphodiesterase, caldesmon kinase and myosin light chain kinase) of the dihydropyridine Ca2+ channel blocker felodipine and three analogues (p-chloro, oxidized and t-butyl) exhibiting different pharmacological potencies. The cAMP phosphodiesterase was inhibited completely by felodipine and the p-chloro analogue with IC50 values of 3.7 and 1.5 microM respectively. The oxidized and t-butyl analogues were relatively ineffective in inhibiting cAMP phosphodiesterase. Felodipine and the p-chloro analogue inhibited the basal (Ca2+/calmodulin-independent) activity of cAMP phosphodiesterase as well as the calmodulin-stimulated activity. Calmodulin was relatively ineffective in preventing inhibition of cAMP phosphodiesterase by felodipine and the p-chloro analogue. These observations suggest that felodipine may act directly on the phosphodiesterase as well as through calmodulin. Felodipine and the p-chloro analogue inhibited Ca2+/calmodulin-dependent caldesmon kinase with similar potencies (IC50 = 17.4 microM), whereas the oxidized and t-butyl analogues caused no inhibition. Similarly, felodipine and the p-chloro analogue inhibited myosin light chain kinase activity whether the isolated 20 kD light chain (IC50 = 12.6 microM) or intact myosin (IC50 = 11.0 microM) was used as substrate. Inhibition in each case was prevented by excess calmodulin. The oxidized and t-butyl derivatives caused little or no inhibition. Finally, the effects of felodipine and the three analogues on two processes which are dependent on myosin phosphorylation were examined, namely the actin-activated Mg2+-ATPase activity of myosin and the assembly of myosin filaments. Felodipine and the p-chloro analogue inhibited the actin-activated Mg2+-ATPase activity of smooth muscle myosin (IC50 = 25.1 microM). The oxidized and t-butyl analogues exhibited no inhibition. Similarly, felodipine and the p-chloro analogue blocked myosin filament assembly induced by low concentrations of calmodulin, whereas the oxidized and t-butyl analogues did not. Again, inhibition of the actin-activated myosin Mg2+-ATPase and myosin filament assembly by felodipine and the p-chloro analogue could be reversed by raising the calmodulin concentration. These observations suggest that some of the pharmacological actions of felodipine on smooth muscle may involve inhibition of calmodulin-dependent enzymes which are functionally involved in the regulation of smooth muscle contraction.     

Pharmacologic effects of Wy 27569: a combined calcium channel blocker and thromboxane synthetase inhibitor

Wy 27569 (1,4 dihydro-2-[imidazol-1-yl-methyl]-6-methyl-4- [3-nitrophenyl] pyridine-3,5, dicarboxylic acid 3-ethyl 5-methyl diester) is a combined calcium channel blocker and thromboxane synthetase inhibitor. This article reports the in vivo and in vitro pharmacological studies demonstrating these properties. Wy 27569 evoked rightward shifts and depressed the maximum of calcium dose response curves in potassium depolarised rat aortas [concentration required to inhibit the response by 50% (IC50) = 7.3 nM]. The calcium channel blocker nitrendipine exhibited a similar profile to, although more potent than, Wy 27569 (IC50 = 0.28 nM). Comparison of the data obtained in aortas with the effects of these compounds in electrically stimulated isolated ventricle strips (IC50 for Wy 27569 = 8.3 microM, IC50 for nitrendipine = 0.41 microM) suggests that Wy 27569, like nitrendipine, is a vascular selective calcium channel blocker. Wy 27569 and the thromboxane synthetase inhibitor dazoxiben inhibited the collagen-stimulated production of thromboxane B2 (TXB2, IC50 = 3.9 and 2.8 microM, respectively) and, over the same concentration range, enhanced the production of immunoreactive 6 keto prostaglandin F1 alpha (6 keto-PGF1 alpha) by human platelet rich plasma. Single doses of Wy 27569 (0.3-10 mg kg-1 p.o.) or dazoxiben (3-10 mg kg-1 p.o.) evoked a dose-related reduction of TXB2 and enhancement of immunoreactive 6 keto PGF1 alpha levels in rat plasma and serum. Nitrendipine (0.3-10 mg kg-1 p.o.) had no significant effect on either eicosanoid.(ABSTRACT TRUNCATED AT 250 WORDS)     

Antihypertensive effects of CS-905, a novel dihydropyridine Ca++ channel blocker

CS-905 is a novel dihydropyridine calcium blocker. A single oral administration of CS-905 or nicardipine at doses of 0.3-3.0 mg/kg produced a dose-dependent reduction of blood pressure in conscious SHR. CS-905, when administered orally in conscious SHR, was more than 3 times as potent as nicardipine. Unlike the hypotensive effect of nicardipine, that of CS-905 has a gradual onset and is long-lasting, with little increase in heart rate. An intravenous administration of CS-905 also produced a hypotension with a slow onset and long duration in SHR, but CS-905 was 3 times less potent than nicardipine by intravenous administration. This difference may be attributed to the first pass effect, which was associated with nicardipine but not with CS-905. The blood pressure lowering effects of CS-905 was most potent in DOCA-salt hypertensive rats, followed by SHR, RHR and normotensive rats, in this order. CS-905 is expected to be an antihypertensive agent that is effective on a once a day regimen in clinical settings.     

Hypolipidaemic and antiatherosclerotic effects of plumbagin in rabbits

Plumbagin (2-methyl-5-hydroxy, 1:4 naphthoquinone) isolated from the roots of Plumbago zeylanica when administered to hyperlipidaemic rabbits, reduced serum cholesterol and LDL-Chol. by 53 to 86 percent and 61 to 91 percent respectively. It lowered cholesterol/phospholipid ratio by 45.8 percent and elevates the decreased HDL-Chol significantly. Further, Plumbagin treatment prevented the accumulation of cholesterol and triglycerides in liver and aorta and regressed atheromatous plaques of thoracic and abdominal aorta. Plumbagin treated hyperlipidaemic subjects excreted more fecal cholesterol and phospholipids. In conclusion-Plumbagin feeding brings about a definite regression of atheroma and prevents the accumulation of cholesterol and triglycerides in liver and aorta.     

Inhibitory effects of fluvastatin, a new HMG-CoA reductase inhibitor, on the increase in vascular ACE activity in cholesterol-fed rabbits.

1. The effects of fluvastatin, a new 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor, on the vascular angiotensin converting enzyme (ACE) activity in hyperlipidaemic rabbits were compared with those of enalapril, an ACE inhibitor. 2. Rabbits were fed a 1.5% cholesterol containing diet or normal diet for 16 weeks and treated with either fluvastatin or enalapril in the diet at the respective doses of 2 and 10 mg kg-1 day-1. The total cholesterol, triglyceride and phospholipid levels in serum were significantly increased in rabbits fed the high cholesterol diet. Treatment with fluvastatin but not enalapril resulted in a decrease in serum lipids. 3. The vascular ACE activities assessed via the cleavage rate from synthetic substrate in the aortic arches and upper thoracic aortae were increased by 8 to 10 times when the rabbits were made hyperlipidaemic. Fluvastatin as well as enalapril significantly lowered the tissue ACE in the aortae. 4. The ACE activities in serum did not alter in hyperlipidaemic rabbits either in the presence or absence of fluvastatin. The serum ACE activity was lowered by enalapril. 5. The lipid peroxide in serum as well as the plaque area in the thoracic aorta was significantly increased in the cholesterol diet-fed rabbits. Treatment with fluvastatin or enalapril reduced both serum lipid peroxide and plaque formation. The relaxant responses to acetylcoholine (ACh) were significantly suppressed in the cholesterol-fed rabbits. Treatment with fluvastatin or enalapril significantly reversed the suppression of ACh-induced relaxation. 6. It seems that the reduction of vascular ACE is not coupled to lipids and ACE activity in serum, but rather to lipid peroxidation. Thus, the decrease in vascular ACE activity by fluvastatin as well as the lipid-lowering effect may reduce the risk of atherosclerosis progression in the vasculature.     

Comparison of different HMG-CoA reductase inhibitors

Summary The HMG-CoA reductase inhibitors have been shown to cause marked reduction of cholesterol and offer a new and effective approach to treatment of hyperlipoproteinemia. Three agents, pravastatin (P), lovastatin (L) and simvastatin (S), have been studied with reference to long-term lipid-lowering effect, tolerance and clinical safety. Following a dietary lead-in period of at least 6 weeks in every case, patients with primary hypercholesterolemia were enrolled from participants of short-term controlled studies which after completion were extended as open studies. Treatment was administered over 6 months with 20 mg S (84 patients), L (42 patients) or P (23 patients) twice daily. Total cholesterol was decreased with S by 30.2% of basal, with L by 25.5%, and with P by 28.2%. The decrease in apolipoprotein B was 28.4%, of basal, with S 16.4% and in P 19.2%. Triglycerides were lowered by 19.6% of basal with S by 17.4%, with L, and by 6.4% with HDL-cholesterol increased in the S group by 23% of basal, by 9.7% in the L group, and by 8.0% in the P group. No serious clinical or laboratory abnormalities were observed. In the S group headache (3.6% of patients), abdominal discomfort (2.4%), sleeping disturbances (3.6%), and muscle pain (2.4%) were reported. In the L group headache (7.1%), abdominal discomfort (4.8%), sleep disorders (4.8%), and muscle pain (4.8%) were observed. In the P group one patient complained of abdominal discomfort (8.7%) and one of sleep disorders (8.7%). Increases in CPK were observed in the S group (4.8% of patients) and in the L group (11.9%). Increases in SGPT was measured in the S group (3.6% of patients), in the L group (7.1 %) and in the P group (4.4% ). None of the patients had to stop therapy because of adverse events. Clinical experience suggest that simvastatin is the inhibitor with the highest efficacy regarding cholesterol lowering, whereas pravastatin seems to the inhibitor that is best tolerated. However, more data are required for comparison of the complete profiles of these three compounds.     

Scientific rationale for combination of a calcium channel antagonist and an HMG-CoA reductase inhibitor: a new approach to risk factor management

Cardiovascular disease is the leading cause of morbidity and mortality throughout the developed world. Risk factors for cardiovascular disease commonly coexist, which multiplies the overall or absolute risk of clinical events. Furthermore, evidence from observational and intervention trials suggest that the numerical risk associated with factors such as cholesterol level and blood pressure increases continuously. These findings concur with results from large-scale clinical trials showing that clinical benefits can be achieved with lowering cholesterol levels, irrespective of the initial levels. Cardiovascular risk factors have been shown to adversely influence vascular endothelial function. In particular, reduced bioavailability of endothelial-dependent nitric oxide production as a result of enhanced oxidative stress represents a common pathological mechanism of cardiovascular risk factors. This contributes to the observation that risk factors increase the overall risk of clinical events in an apparent additive fashion. Treatment guidelines now reflect these advances in our knowledge of risk factors by encouraging approaches that aim to reduce absolute risk, rather than addressing single risk factors in isolation. In response to this, a single pill combination of a calcium channel antagonist and an HMG-CoA reductase inhibitor (statin) has emerged as a means of addressing the suboptimal rates of goal attainment for concomitant hypertension and dyslipidaemia. Moreover, it can be viewed as a new therapeutic approach that seeks to comprehensively manage risk factors and enhance cardiovascular protection for patients at risk. Both experimental and clinical studies indicate that this approach is effective for reducing both the pathophysiological markers of atherosclerotic disease and its clinical consequences. This article provides an overview of the evidence for this new approach and recommends applications for use in clinical settings.     

Pharmacokinetics of barnidipine hydrochloride,a new dihydropyridine calcium channel blocker,in the rat,dog and human

1. The pharmacokinetics of a new calcium antagonist barnidipine hydrochloride, a stereochemically pure enantiomer, was studied after intravenous and oral dosing to the rat and dog, and oral to man.

2. After intravenous dosing, plasma concentrations of barnidipine hydrochloride declined bi-exponentially with the terminal half-lives of 0·6?h in the rat and 4·1?h in the dog. The blood clearance was 5·21/h/kg in the rat and 3·31/h/kg in the dog, and was comparable with hepatic blood flow in both species.

3. After oral dosing, plasma concentrations of barnidipine hydrochloride peaked rapidly (0·3-0·4?h in the rat and dog, 1·0–1·6?h in man). C_max and AUC rose non-linearly with increasing doses in all three species.

4. The absolute bioavailability was low (11–18% in the rat and 6–9% in the dog), suggesting a marked first-pass metabolism.     

Inhibition of cholesterol absorption by HMG-CoA reductase inhibitor

Summary In subjects with familial hypercholesterolemia cholesterol absorption efficiency was insignificantly reduced during a short-term more consistently during longterm pravastatin treatment. A cholesterol feeding had no effect on LDL cholesterol level but reduced absorption efficiency during a long-term lovastatin treatment.     

Synthesis and antihyperlipidemic efficiency of berberine-based HMG-CoA reductase inhibitor

From more than 100 simulation-designed compounds, 8-alkyl-berberine derivatives with a long aliphatic chain (n?=?10–20) were chosen and successfully synthesized to evaluate their antihyperlipidemic activity. With elongating the aliphatic chain, the inhibition of derivatives to HMG-CoA reductase (HMGR) and the LD₅₀ increased gradually. Especially, 8-hexadecyl-berberine (4D) with 8.0?μmol/l significantly inhibited HMGR, even higher than lovastatin. Then, the inhibition gradually decreased with the aliphatic chain further elongating. Animal experiments showed that all tested derivatives could improve blood lipid level to different degree. Similarly, compound 4D showed the best lipid-reducing efficiency especially for TC and LDL-c level which were near to those of the normal control, and could recover the liver damage caused by the high-fat and high-cholesterol diet. The interaction between the receptor and the ligand indicated that the improved antihyperlipidemic efficiency of 4D was exerted by a dual mechanism of inhibiting HMGR activity similar with statins and lowering the level of low density lipoprotein-cholesterol (LDL-c) similar with berberine. Thus, it might be a potential antihyperlipidemic drug candidate.     

Pleiotropic effects of HMG-CoA reductase inhibitors

HMG-CoA reductase, in addition to being the rate-limiting enzyme in the cholesterol biosynthetic pathway, is involved in the regulation of receptors for low-density lipoprotein (LDL)-cholesterol. Clinical studies in men and women demonstrate that inhibitors of HMG-CoA reductase (statins), by reducing plasma cholesterol, may limit the development of atherosclerosis and reduce the risk of mortality and ischemic events. Preclinical evidence suggests that under controlled conditions of plasma cholesterol lowering, statins may have ancillary properties or pleiotropic effects, which may directly limit atherosclerosis progression. In this review, pleiotropic effects have been defined as 'ancillary properties of statins, which result in hepatic and/or vascular changes that may or may not be a consequence of inhibition of HMG-CoA reductase.' Beyond the LDL lowering activity of statins, improvements have been noted in endothelial dysfunction through direct stimulation of expression of such vasodilators as nitric oxide and/or reduction in vasoconstrictors. Factors associated with atherogenesis, such as monocyte adhesion to endothelial cells, macrophage production of proinflammatory molecules and matrix metalloproteases, smooth muscle cell proliferation and migration and macrophage-induced oxidation of LDL particles have also been reduced by various statins. It is unclear whether the observed pleiotropic effects are independent of LDL-cholesterol lowering or inhibition of HMG-CoA reductase, and whether they are clinically relevant; however, one can conclude that the pleiotropic effects appear to be a class effect of statins and can be attenuated by addition of the post-reductase product, mevalonate.     

Natriuretic effect of barnidipine, a long-acting dihydropyridine calcium channel blocker, in patients with essential hypertension

OBJECTIVE: To evaluate the effect of barnidipine hydrochloride, a long-acting dihydropyridine calcium channel blocker on urinary sodium excretion in patients with essential hypertension. PATIENTS: Twelve patients (2 males, 10 females) with mild to moderate essential hypertension. METHODS: A single-blinded study. After the control (placebo) period, 10 to 15 mg barnidipine hydrochloride was administered for 7 days, followed by a post-treatment (placebo) period. Daily changes in blood pressure, urinary volume, and urinary electrolyte excretions were evaluated. Plasma levels of atrial natriuretic peptide (ANP) and aldosterone were also determined in each period. Daily sodium intake was kept at 120 mEq. RESULTS: Blood pressure decreased from 161 +/- 4/92 +/- 2 mmHg to 146 +/- 4/85 +/- 2 mmHg (p<0.05) after 7-day-treatment with barnidipine. Barnidipine significantly increased urinary sodium excretion; the change was evident on the first day of administration (control period 41 +/- 3 mEq/day, and first day 59 +/- 3 mEq/day, p < 0.05). Drug discontinuation transiently decreased sodium excretion to 35 +/- 3 mEq/day. Cumulative sodium balance after 7-day-treatment reached 47 +/- 19 mEq. Urine volume, potassium excretion, and creatinine excretion did not change during the treatment period. The plasma levels of ANP tended to increase, but those of aldosterone did not change with barnidipine. CONCLUSION: Barnidipine administration for a week decreased the blood pressure and made the sodium balance negative by increasing the urinary sodium excretion in patients with essential hypertension. The natriuretic effect of this drug could contribute at least in part to its antihypertensive effect.     

Beneficial renal effects of CS-905, a novel dihydropyridine calcium blocker, in SHR

CS-905 is a potent dihydropyridine calcium blocker that has a gradual and long-lasting antihypertensive action with little tachycardia in SHR. In this study, we investigated chronic and acute effects of CS-905 on renal functions in SHR. To examine the chronic effects, 23 week-old male SHR were treated with CS-905 (1 or 3 mg/kg/day, p.o.) or 0.3% CMC (carboxymethylcellulose). After the 15 week-treatment, the agent dose-relatedly lowered systolic blood pressure measured 24 hr after the final administration (184 +/- 2 and 173 +/- 3 mmHg at 1 and 3 mg/kg/day vs. 218 +/- 4 mmHg for the control group). Natriuresis and the reduction of urinary protein excretion were also observed in the CS-905 treated groups. Urinary NAG (N-acetyl-beta-D-glucosaminidase) activity tended to decrease, but not significantly. Histopathological changes observed in the SHR kidney were reduced by chronic treatment with CS-905. On a single oral administration in 38 week-old SHR, CS-905 caused natriuresis at a dose of 3 mg/kg, but did not affect urinary protein excretion and urinary NAG activity. These effects of CS-905 on renal functions may be beneficial in the treatment of hypertension.     

HMG-CoA reductase inhibitor, fluvastatin, has cholesterol-lowering independent "direct" effects on atherosclerotic vessels in high cholesterol diet-fed rabbits.

Recent clinical studies suggest that some of the beneficial effects of 3-hydroxy-3-metylglutaryl coenzyme A (HMG-CoA) reductase inhibitors on the incidence of myocardial infarctions and ischemic strokes may be through their non-cholesterol-lowering "direct" effects on atherosclerotic vessels. We designed this study to test the hypothesis that fluvastatin inhibits atheroma formation and increase plaque stability independent of cholesterol-lowering effects.Rabbits were fed 0.5% high-cholesterol diet for 12 weeks (progression phase) and then fed the high-cholesterol diet either containing or not containing fluvastatin 2mg/kg per day for additional 8 weeks (treatment phase). Rabbits fed normal diet were used as control.Plasma total and LDL-cholesterol concentrations did not differ during the treatment phase of the experiment. Atherosclerotic changes (plaque formation, lipid- and macrophage-rich intimal thickening, the increase in MCP-1, IL-8, TNF-alpha, IL-1beta, M-CSF, MMP-1, MMP-9, MMP-12, and ACE mRNA expression, and the increase in plasma MCP-1 levels) were observed in the high-cholesterol diet group (HC). All of these changes were less in the fluvastatin-treated group (HC+Flu) than in HC. There was no significant difference in aortic collagen (type I and type IV) mRNA expression between groups. Furthermore, fluvastatin increased the extracellular matrix content (collagen) and vascular smooth muscle cell composition in the atherosclerotic lesion, leading to the increase in plaque stability score (collagen+smooth muscle cell area)/(macrophage+lipid deposition area) in HC+Flu.Fluvastatin not only reduced atherogenesis but also to stabilized vulnerable atheromatous plaques in atherosclerotic rabbits, presumably through the macrophage recruitment and activation in the aortic lesion, at a low dose without cholesterol-lowering effects.     

Central and peripheral effects of the dihydropyridine calcium channel activator BAY K 8644 in the rat

Following intraperitoneal (i.p.) administration BAY K 8644 (0.5−4 mg/kg) induced an increase in blood pressure associated with bradycardia, increased tail-flick latency in response to radiant heat, decreased locomotion, induced muscle contraction, postural changes and also reduced reflex activity. Only the postural changes and reduced locomotion were seen after intracerebroventricular administration (5–20 μg/kg), suggesting that the other effects are mediated peripherally. All the above effects were antagonised by the calcium channel blocker nifedipine. BAY K 8644 (4 mg/kg i.p.) also significantly increased homovanillic acid and 3,4-dihydroxyphenylacetic acid concentrations in the cortex and striatum, an effect which could also be reversed by nifedipine. Apart from inducing hypotension and tachycardia, nifedipine alone had no effect on any of the above parameters. The analgesic-like activity of BAY K 8644 observed in the tail-flick test appears to be related to its vasoconstrictor effects as the peripherally acting vasodilator phenylephrine had similar analgesic activity. These results show that both central and peripheral dihydropyridine-sensitive calcium channels mediate the effects of BAY K 8644. Although a physiological role for the dihydropyridine-sensitive voltage-operated calcium channel in the CNS remains to be demonstrated, activation fo these channels can clearly have functional effects.