N-type Calcium Channel Blocker Research Articles

The Promise of Cilnidipine in Hypertension with Comorbidities: National Consensus Statement: National Consensus Group Comprises Cardiologists, Nephrologists, and Diabetologists from India in a National Meet at New Delhi held on 22nd May 2022.

The rapidly increasing burden of hypertension is responsible for premature deaths from cardiovascular disease (CVD), renal disease, and stroke, with a tremendous public health and financial burden. Hypertension detection, treatment, and control vary worldwide; it is still low, particularly in low- and middle-income countries (LMICs). High blood pressure (BP) and CVD risk have a strong, linear, and independent association. They contribute to alarming numbers of all-cause and CVD deaths. A major culprit for increased hypertension is sympathetic activity, and further complications of hypertension are heart failure, ischemic heart disease (IHD), stroke, and renal failure. Now, antihypertensive interventions have emerged as a global public health priority to reduce BP-related morbidity and mortality. Calcium channel blockers (CCB) are highly effective vasodilators. and the most common drugs used for managing hypertension and CVD. Cilnidipine, with both L- and N-type calcium channel blocking activity, is a promising 4th generation CCB. It causes vasodilation via L-type calcium channel blockade and inhibits the sympathetic nervous system (SNS) via N-type calcium channel blockade. Cilnidipine, which acts as a dual L/N-type CCB, is linked to a reduced occurrence of pedal edema compared to amlodipine, which solely blocks L-type calcium channels. The antihypertensive properties of cilnidipine are very substantial, with low BP variability and long-acting properties. It is beneficial for hypertensive patients to deal with morning hypertension and for patients with abnormal nocturnal BP due to exaggerated sympathetic nerve activation. Besides its BP-lowering effect, it also exhibits organ protection via sympathetic nerve inhibition and renin-angiotensin-aldosterone system inhibition; it controls heart rate and proteinuria. Reno-protective, neuroprotective, and cardioprotective effects of cilnidipine have been well-documented and demonstrated.

Study on the Analgesic Activity of Peptide from Conus achates.

As a peptide originally discovered from Conus achates by mass spectrometry and cDNA sequencing, Ac6.4 contains 25 amino acid residues and three disulfide bridges. Our previous study found that this peptide possesses 80% similarity to MVIIA by BLAST and that MVIIA is a potent and selective blocker of N-type voltage-sensitive calcium channels in neurons. To recognize the target protein and analgesic activity of Ac6.4 from Conus achates. In the present study, we synthesized Ac6.4, expressed the Trx-Ac6.4 fusion protein, tested Ac6.4 for its inhibitory activity against Cav2.2 in CHO cells and investigated Ac6.4 and Trx-Ac6.4 for their analgesic activities in mice. Data revealed that Ac6.4 had strong inhibitory activity against Cav2.2 (IC50 = 43.6 nM). After intracranial administration of Ac6.4 (5, 10, 20 μg/kg) and Trx-Ac6.4 (20, 40, 80 μg/kg), significant analgesia was observed. The analgesic effects (elevated pain thresholds) were dose-dependent. This study expands our knowledge of the peptide Ac6.4 and provides new possibilities for developing Cav2.2 inhibitors and analgesic drugs.

333 Intraventricular Ziconotide Improves Cognitive Outcomes following Lateral Fluid Percussion Injury in a Rat Model

INTRODUCTION: Traumatic brain injury (TBI) is a major source of morbidity and mortality worldwide. In previous studies, intravenous ziconotide, a selective N-type voltage-gated calcium channel blocker, reduced brain calcium accumulation, improved brain mitochondrial respiration, and improved cognitive and motor outcomes in rodent models of TBI. Attempts to translate intravenous ziconotide therapy to humans were halted due to peripheral side-effects. However, ziconotide is now FDA-approved for treatment of severe pain syndromes when administered intrathecally instead of intravenously. We hypothesize that following TBI intraventricular ziconotide will improve cognitive function in the absence of significant side effects. METHODS: Seventy-seven Sprague-Dawley rats underwent sham (n = 11 males, n = 11 females) or lateral fluid percussion (LFP) injury (n = 21 males, n = 23 females). One-hour post-injury, rats received either an intraventricular injection of saline (n = 22 sham, n = 23 LFP) or ziconotide (n = 21 LFP). A catheter was implanted in the left lateral ventricle and connected to an Alzet micro-osmotic pump to allow for 72 hours of continuous infusion. Cognitive outcomes were evaluated using Morris water maze (MWM; days 10-15). RESULTS: TBI-saline rats performed significantly worse than shams on MWM (p < 0.01). Ziconotide treated rats had an intermediate phenotype on MWM. TBI-saline rats swam a less efficient path than sham animals (p < 0.01); ziconotide path efficiency was not significantly different from shams. Performance on the MWM was likely not related to motor deficits as there was no significant effect of group on mean swimming speed in either males or females. Female sham animals performed significantly better on probe trials compared to TBI-saline (p < 0.05); ziconotide animals were not different from shams. CONCLUSIONS: These findings support centrally delivered Ziconotide as a potential neuroprotective agent to improve cognitive performance following TBI. Further studies are required to characterize the neuroprotective effects of Ziconotide therapy.

N-type calcium channel blockers: a new approach towards the treatment of chronic neuropathic pain

Neuropathic pain (NP) remains maltreated for a wide number of patients by the currently available treatments and little research has been done in finding new drugs for treating NP. Ziconotide (PrialtTM) had been developed as the new drug, which belongs to the class of ω-conotoxin MVIIA. It inhibits N-type calcium channels. Ziconotide is under the last phase of the clinical trial, a new non-narcotic drug for the management of NP. Synthetically it has shown the similarities with ω-conotoxin MVIIA, a constituent of poison found in fish hunting snails (Conus magus). Ziconotide acts by selectively blocking neural N-type voltage-sensitized Ca2+ channels (NVSCCs). Certain herbal drugs also have been studied but no clinical result is there and the study is only limited to preclinical data. This review emphasizes the N-type calcium channel inhibitors, and their mechanisms for blocking calcium channels with their remedial prospects for treating chronic NP.

Systemic, Intrathecal, and Intracerebroventricular Antihyperalgesic Effects of the Calcium Channel Blocker CTK 01512-2 Toxin in Persistent Pain Models.

CTK 01512-2 toxin is a recombinant peptide of the Phα1β version derived from the venom of the Phoneutria nigriventer spider. It acts as an N-type voltage-gated calcium channel (VGCC) blocker and shows a prolonged effect on preventing and reducing nociception. Herein, CTK 01512-2 was tested on two models of persistent pain, the chronic post-ischemia pain (CPIP) and the paclitaxel-induced peripheral neuropathy, to evaluate its systemic, intrathecal, and intracerebroventricular effects on mechanical hypersensitivity and thermal allodynia. Glial cell viability was also investigated using the MTT test. The results showed that CTK 01512-2 intrathecal and systemic treatments reduced the mechanical hypersensitivity induced by CPIP, mainly between 1-4h after its administration. Additionally, intrathecal treatment reduced the CPIP-induced thermal allodynia. In its turn, the intracerebroventricular treatment showed mechanical antihyperalgesic and thermal antiallodynic effects in the paclitaxel-induced peripheral neuropathy. These data reinforce the therapeutic potential of CTK 01512-2 to treat persistent pain conditions and offer a perspective to use the systemic route. Moreover, CTK 01512-2 increased the glial cell viability in the MTT reduction assay, and it may indicate a new approach to managing chronic pain. The results found in this study help to pave new perspectives of pain relief treatments to patients affected by chronic pain.

Nanophotonics Enable Targeted Photothermal Silencing of Nociceptor Neurons.

The sensory nervous and immune systems work in concert to preserve homeostasis. While this endogenous interplay protects from danger, it may drive chronic pathologies. Currently, genetic engineering of neurons remains the primary approach to interfere selectively with this potentially deleterious interplay. However, such manipulations are not feasible in a clinical setting. Here, this work reports a nanotechnology-enabled concept to silence subsets of unmodified nociceptor neurons that exploits their ability to respond to heat via the transient receptor potential vanilloid type 1 (TRPV1) channel. This strategy uses laser stimulation of antibody-coated gold nanoparticles to heat-activate TRPV1, turning this channel into a cell-specific drug-entry port. This delivery method allows transport of a charged cationic derivative of an N-type calcium channel blocker (CNCB-2) into targeted sensory fibers. CNCB-2 delivery blocks neuronal calcium currents and neuropeptides release, resulting in targeted silencing of nociceptors. Finally, this work demonstrates the ability of the approach to probe neuro-immune crosstalk by targeting cytokine-responsive nociceptors and by successfully preventing nociceptor-induced CD8+ T-cells polarization. Overall, this work constitutes the first demonstration of targeted silencing of nociceptor neuron subsets without requiring genetic modification, establishing a strategy for interfering with deleterious neuro-immune interplays.

Electrospinning-modified Pt/CeO2 nano bandage as a promising therapy to reduce secondary brain injury

Traumatic brain injury (TBI) continues to be a major contributor to morbidity, disability, and mortality in all age groups. Initial brain damage is accompanied by acute and irreversible primary damage to the parenchyma, while subsequent secondary brain damage often progresses slowly over months to years, thus providing a window for therapeutic intervention. The most frequent case which happened is excessive oxidative stress and calcium release after brain injury. Although some traditional antioxidants have been clinically approved, the efficacy is far from satisfactory due to their low ROS-scavenging efficiency, instability, toxicity, or inadequate penetration of the blood-brain barrier. Moreover, the combination of Nanozyme based-bandage with Pt/CeO2 atom catalysis with electrospinning nanofibers N-type voltage-gated calcium channel blocker (SNX-185) is predicted to be as promising as a potential novel to reduce secondary injury of TBI. Therefore, the duo could cut down morbidity and mortality rates because of TBI in the future, noninvasively.

Protective Actions of Cilnidipine: Dual L/N-Type Calcium Channel Blocker Against Hypertensive Renal Injury in Rats

Background: Cilnidipine belongs to fourth generation dihydropyridine calcium channel blocker (CCB). It is a dual L & N-type CCB. L- type calcium channels are present on the vascular smooth muscle and N-type calcium channels are present on the presynaptic nerve terminals. Cilnidipine has a vasodilating effect, its action is slow and long lasting. Aim and objectives: Aim of present study was to demonstrate the beneficial effects of cilnidipine on the hypertensive renal injury rats. And our objectives is to assess renal injury parameters (Proteinuria, Creatinine clearance, Renal fibrosis/glomerulosclerosis) in response to chronic NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) treatment in the presence or absence of cilnidipine treatment. Material and methods: Male albino Wister rats were procured from institutional animal house, divided into 4 groups (n=6 in each group). Group1 treated with vehicle (control), group2 treated with cilnidipine, group3 treated with L-NAME, group4 treated with L-NAME & cilnidipine. 24 hour urinary protein and creatinine clearance were measured. Serum urea and creatinine levels are also measured. Urinary and serum Angiotensin II levels were measured. Histopathological examination of kidneys was performed. Results: Our results demonstrate that treatment with cilnidipine (group4) there is reduction in 24hr urinary protein, improvement in creatinine clearance. We observed there was renal glomerulosclerosis and tubular degeneration of kidney tubules in group3 rats and reduction of renal injury in group4 rats. We also found reduced urinary and serum Angiotensin II level in cilnidipine treated (group 4) rats. Conclusion: These findings indicated that cilnidipine act as renoprotective agent and reduces glomerular damage in L-NAME induced hypertensive rats.

Sympathetic modulation by antihypertensive drugs.

Sympathetic modulation by antihypertensive drugs.

EFFECT OF L- AND N-TYPE CALCIUM CHANNEL BLOCKER CILNIDIPINE ON SERUM SOLUBLE (PRO)RENIN RECEPTOR CONCENTRATION

Objective: Cilnidipine (Cil) is an L- and N-type calcium channel blocker that inhibits the release of norepinephrine (NE) from the sympathetic nerve endings. It has inhibitory effects on SNA and the renin-angiotensin-aldosterone system (RAAS), as well as its strong renal and vascular protective effects. (Pro)renin receptor [(P)RR] activates the tissue RAAS and contributes to the pathogenesis of organ damages. The soluble form of (P)RR [s(P)RR] is produced via cleavage of (P)RR, and its blood concentration is a biomarker of organ damage. The present study investigated the effects of Cil on serum s(P)RR concentration, as well as the relationships between the serum s(P)RR concentration and changes in NE and aldosterone (ALDO) levels. Design and method: Patients with essential hypertension were randomly assigned to 2 groups: the Cil treatment (C) group (n = 19) and the amlodipine treatment (A) group (18). Changes in various parameters (urinary, biochemistry, and endocrine data and cardio-ankle vascular index (CAVI), an index of arterial stiffness, during the 6 months-treatment period were compared. Results: In both groups, there was a significant decrease in blood pressure by the treatments, while there was no difference in changes in blood pressure between the two groups. In the C group, urinary albumin excretion and CAVI decreased significantly. There were no changes in s(P)RR levels in both groups. Serum NE levels (rate of decline: 13.6 ± 33.3%) and ALDO levels (18.4 ± 33.6%) significantly decreased in the C group. In the C group, while the decline rate of NE was significantly greater in the low s(P)RR group (24.6 ± 31.4%, n = 9) than in the high s(P)RR group (1.2 ± 33.0%, n = 10), changes in ALDO was not significantly different between the groups. Conclusions: The present study reconfirmed that Cil reduces NE and ALDO levels, and has renal and vascular protective effects. Although changes in serum s(P)RR concentration by Cil were not demonstrated, there was an association between the serum s(P)RR levels and the rate of decline of NE, suggesting involvement of (P)RR expression in the regulation of SNA. Future studies are needed to determine the underlying mechanism of this involvement.

Gellan gum based gastroretentive tablets for bioavailability enhancement of cilnidipine in human volunteers

Cilnidipine, a fourth-generation both L-and N-type calcium channel blocker (CCB) is safe and effective in lowering blood-pressure without reflex tachycardia compared to other dihydropyridine CCBs. However, its low solubility coupled with extensive first-pass metabolism results in very low oral bioavailability. Thus the study aimed to improve oral bioavailability of Cilnidipine by increasing its gastrointestinal transit-time and mucoadhesion. Gastroretentive tablets were prepared by direct-compression technique using gellan gum as hydrogel forming polymer and sodium bicarbonate as gas-generating agent. Statistical optimization was carried out by design approach which showed that gellan gum has significant impact on floating lag time, mucoadhesive strength, % drug release at 1 h and time to release 90% of drug. Drug release study revealed that optimized tablets prolonged drug release for 12 h and followed anomalous-diffusion indicating drug release is by coupling of both diffusion and erosion mechanism. Intragastric behaviour of formulation in human volunteers revealed that radio-opaque tablets remain buoyant in stomach for more than 6 h with sufficient mucoadhesion. Comparative pharmacokinetic profiling in human subjects revealed that relative bioavailability of Cilnidipine GR tablets was enhanced compared to reference tablets. Thus concluded that gastroretentive tablets to be promising strategy for improved oral bioavailability of Cilnidipine for effective treatment of hypertension.

Single-pill combination of cilnidipine, an l-/n-type calcium channel blocker, and valsartan reduces the day-by-day variability of morning home systolic blood pressure in patients with treated hypertension: A sub-analysis of the HOPE-combi survey.

We examined the effects of a fixed‐dose single‐pill combination of cilnidipine (10 mg), an L‐/N‐type calcium channel blocker, and valsartan (80 mg) (SPC of Cil/Val) on the day‐by‐day variability of morning home systolic blood pressure (MHSBP) in 616 patients with treated hypertension for 12 months as a sub‐analysis of the HOPE‐Combi survey, multicentral, post‐marketing, and prospective observational survey. The SPC of Cil/Val was administrated once a day in the morning. The SPC of Cil/Val decreased the standard deviation (SD, from 6.3 ± 4.8 to 5.1 ± 3.8 mmHg, p < .01), coefficient of variation (from 4.3 ± 3.2 to 3.8 ± 2.9%, p < .05), average real variability (ARV, from 7.9 ± 6.6 to 6.3 ± 5.1 mmHg, p < .01), and the difference between maximum and minimum (MMD, from 11.9 ± 9.2 to 9.7 ± 7.2 mmHg, p < .01) of MHSBP. The variability of MHSBP increased with age; however, this was not increased in patients ≥70 years at the baseline. In elderly patients (≥70 years, N = 283), the SPC of Cil/Val decreased the SD (from 6.9 ± 5.6 to 5.6 ± 4.4 mmHg, p < .01), ARV (from 8.6 ± 7.7 to 6.9 ± 5.7 mmHg, p < .05), and MMD (from 13.2 ± 10.7 to 10.7 ± 8.3 mmHg, p < .01) of MHSBP at 12 months; the reduction in these MHSBP variability parameters was comparable to that in adults <70 years. These results suggest that the SPC of Cil/Val is effective in reducing day‐by‐day variability of MHSBP in elderly patients.

Effects of L-/N-Type Calcium Channel Blockers on Angiotensin II-Renin Feedback in Hypertensive Patients.

Objectives Cilnidipine, an L-/N-type calcium channel blocker (CCB), has unique organ-protective properties due to suppression of hyperactivity in the sympathetic nervous system and renin-angiotensin system (RAS). In this study, we hypothesized that cilnidipine might exert a renoprotective effect by suppressing the RAS. Methods A total of 25 hypertensive patients receiving a RAS inhibitor were randomly assigned to a cilnidipine (n = 12) or amlodipine (n = 13) group. The effects of cilnidipine on proteinuria and angiotensin II–renin feedback were assessed. Results After 6 months of treatment, both systolic and diastolic blood pressures were significantly reduced to a similar extent in both groups. The urine albumin-to-creatinine ratio was significantly lower in the cilnidipine group (p < 0.05) than in the amlodipine group. Amlodipine increased plasma angiotensin I and angiotensin II levels (p < 0.05), whereas cilnidipine did not. Interestingly, the cilnidipine group had a higher ratio of angiotensin-(1–7) (Ang-(1–7)) to angiotensin II in plasma than the amlodipine group (p < 0.05). Conclusions The L-/N-type CCB cilnidipine, but not amlodipine, decreased urinary albumin excretion in hypertensive patients. Cilnidipine also increased the ratio of Ang-(1–7) to angiotensin II in plasma, which might be one factor underlying its beneficial effects.

Calcium channels blockers toxins attenuate abdominal hyperalgesia and inflammatory response associated with the cerulein-induced acute pancreatitis in rats

Agents that modulate the activity of high-voltage gated calcium channels (HVCCs) exhibit experimentally and clinically significant effect by relieving visceral pain. Among these agents, the toxins Phα1β and ω-conotoxin MVIIA effectively reduce chronic pain in rodent models. The molecular mechanisms underlying the chronic pain associated with acute pancreatitis (AP) are poorly understood. Hypercalcemia is a risk factor; the role of cytosolic calcium is considered to be a modulator of pancreatitis. Blockade of Ca2+ signals may be useful as a prophylactic treatment of pancreatitis. We explored the pathophysiological roles of three peptide toxins: Phα1β and its recombinant form CTK 01512-2—blockers of TRPA1 receptor and HVCCs and ω-conotoxin MVIIA, a specific blocker of N-type calcium channels in cerulein-induced AP. Cerulein injection elicits AP in rats, evidenced by an increase in hyperalgesic pain, inflammatory infiltration, amylase and lipase secretion, and reactive oxygen species, TNF-α, and p65 NF-κB levels. These effects of cerulein-induced AP were abolished by Phα1β and its recombinant form CTK 01512-2, whereas ω-conotoxin MVIIA had no effect on the induced increase in pancreatic enzyme secretion. Our results demonstrate that Phα1β and CTK 01512-2 toxins—antagonists of HVCCs and TRPA1 receptor presented an effective response profile, in the control of nociception and inflammatory process in the AP model in rats, without causing changes in spontaneous locomotion of the rats.

CGRP Modulates Orofacial Pain through Mediating Neuron-Glia Crosstalk

Calcitonin gene-related peptide (CGRP) plays a crucial role in the modulation of orofacial pain, and we hypothesized that CGRP mediated a neuron-glia crosstalk in orofacial pain. The objective of this study was to elucidate the mechanisms whereby CGRP mediated trigeminal neuron-glia crosstalk in modulating orofacial pain. Orofacial pain was elicited by ligating closed-coil springs between incisors and molars. Trigeminal neurons and satellite glial cells (SGCs) were cultured for mechanistic exploration. Gene and protein expression were determined through immunostaining, polymerase chain reaction, and Western blot. Orofacial pain was evaluated through the rat grimace scale. Our results revealed that the expressions of CGRP were elevated in both trigeminal neurons and SGCs following the induction of orofacial pain. Intraganglionic administration of CGRP and olcegepant exacerbated and alleviated orofacial pain, respectively. The knockdown of CGRP through viral vector-mediated RNA interference was able to downregulate CGRP expressions in both neurons and SGCs and to alleviate orofacial pain. CGRP upregulated the expression of inducible nitric oxide synthase through the p38 signaling pathway in cultured SGCs. In turn, L-arginine (nitric oxide donor) was able to enhance orofacial pain by upregulating CGRP expressions in vivo. In cultured trigeminal neurons, L-arginine upregulated the expression of CGRP, and this effect was diminished by cilnidipine (N-type calcium channel blocker) while not by mibefradil (L-type calcium channel blocker). In conclusion, CGRP modulated orofacial pain through upregulating the expression of nitric oxide through the p38 signaling pathway in SGCs, and the resulting nitric oxide in turn stimulated CGRP expression through N-type calcium channel in neurons, building a CGRP-mediated positive-feedback neuron-glia crosstalk.

Detection of Lipase Activity in Cells by a Fluorescent Probe Based on Formation of Self-Assembled Micelles.

SummaryReliable and sensitive detection of lipase activity is essential for the early diagnosis and monitoring of acute pancreatitis or progression of digestive diseases. However, the available fluorescent probes for detection of lipase activity are only implemented in a hexane-water two-phase system due to the nature of heterogeneous catalysis of lipase, thus limiting their applications in direct imaging of lipase activity in living cells and tissues. Here we designed and synthesized a “turn on” fluorescent probe CPP based on self-assembled micelles for hydrolysis of lipase. The CPP probe exhibits high selectivity and excellent sensitivity for the detection of lipase in such a homogeneous system and is successfully applied for monitoring lipase activity in pancreatic AR42J cells, tissues, and serums. Taken together, the fluorescent CPP probe not only provides a tool for diagnostic potential in pancreatic disease but also demonstrates an application potential for micelle self-assembly-based development of biological probes.

Antidepressant-like and memory-enhancing effects of the N-type calcium channel blocker ziconotide in rats

The lack of oral or injectable formulations of ziconotide (ω-conotoxin peptide), a novel analgesic agent, limits research on potential neurobehavioral protective properties of this substance, including antidepressant-like effects. Here we expose rats to a stress paradigm that induces depression and memory impairment to assess the effects of ziconotide treatment. Ziconotide was administered intracerebroventricular (i.c.v.) to rats undergoing stereotaxic surgery at a single dose (1 μg/rat) or in repeated long-term applications (dosage groups: 0.1, 0.3, and 1 μg/rat). The antidepressant activity and memory-enhancing effects of ziconotide were examined via the forced swimming test, the Morris water maze test, and the passive avoidance learning test. Behavioral results showed that long-term i.c.v. ziconotide administration significantly decreased the immobility time and delayed the latency period to immobility in a dose-dependent manner compared to controls. In the passive avoidance learning test, the latency period increased, and in the Morris water maze test, the platform location latency time decreased. A single dose of ziconotide (1 μg/rat) did not show a significant effect on memory function or depression parameters during the same tests. Animals were sacrificed immediately after behavioral testing, and both hippocampi were removed and prepared for BDNF evaluation. Hippocampal BDNF levels were significantly increased in rats receiving long-term i.c.v. ziconotide compared to controls. Our results suggest that long-term consumption of ziconotide may attenuate the severity of depression-like behavior and could be useful for preventing memory impairments in various learning models by elevating BDNF levels.

Single-pill combination of cilnidipine, an L-/N-type calcium channel blocker, and valsartan effectively reduces home pulse pressure in patients with uncontrolled hypertension and sympathetic hyperactivity: The HOPE-Combi survey.

The home blood pressure (BP) control by a single-pill combination of cilnidipine (an L-/N-type calcium channel blocker; CCB) and valsartan (HOPE-Combi) survey is a multicenter, post-marketing, prospective observational study of a single-pill combination of cilnidipine 10mg and valsartan 80mg (SPC of Cil/Val) in patients with uncontrolled hypertension. We examined the effects of the SPC of Cil/Val on morning home systolic BP (MHSBP) and morning home pulse pressure (MHPP) of 1036 patients with hypertension over 12months. MHSBP decreased by 14.0mm Hg (P<.01), and MHPP decreased by 6.6mm Hg (P<.01). Moreover, morning home pulse rate (MHPR) decreased by 2.1bpm (P<.01). A more progressive and greater decrease in MHSBP (-17.2 vs -10.3mm Hg, P<.01) and MHPP (-7.6 vs -4.9mm Hg, P<.01) was observed in patients with higher MHPR (≥70bpm) than in those with lower MHPR (<70bpm) over the treatment period. In particular, in patients with a wide MHPP (≥70mm Hg), the difference in the MHPP reduction was greater in patients with higher MHPR than in those with lower MHPR (-17.9 vs -13.6mm Hg, P<.01). These results suggested that the SPC of Cil/Val, which possesses the unique sympatholytic characteristics of an L-/N-type CCB, was particularly effective in patients with uncontrolled hypertension and sympathetic hyperactivity.

Effect of L/N-type Calcium Channel Blocker (Cilnidipine) on Oxidative Stress in Nitric Oxide-Deficient Hypertensive Rats

Background: The sympathetic nervous system plays a major role in the renal function through the vasoactive system and the Renin-Angiotensin-Aldosterone System. Even though interest in the renal protective effects of sympathetic blocker has been increased, there are not much data to clarify this efficiency in nitric oxide deficient hypertensive rats. Aim and Objectives: To find out the effect of cilnidipine, L/N-type calcium channel blocker on oxidative stress of kidney in nitric oxide synthase (NOS) inhibited experimental hypertensive rats. Material and Methods: Male Albino Wistar rats (n-24) were randomly allocated into four groups: group 1, control received vehicle; group 2, received Cilnidipine; group 3, received NG-nitro-L-arginine methyl ester hydrochloride (L-NAME); group 4, received L-NAME C All drugs are given orally for 4 weeks. Blood pressure was measured before and after the intervention and twice during intervention for all the rats. On the 29th day, blood was collected and animals were sacrificed and kidneys were collected. Serum and kidney tissue malondialdehyde (MDA) levels are estimated. Results: The results demonstrate that there is a significant increase in Mean Arterial Pressure (MAP) in L-NAME treated rats compared to the control group. Treatment with cilnidipine significantly decreases the MAP in group 4 rats. We also demonstrated the significantly elevated serum and kidney tissue MDA levels in L-NAME treated rat. Treatment with Cilnidipine reduced serum and kidney tissue MDA levels in group 4 rats compared to group 3 rats. Conclusion: The results demonstrate that cilnidipine has suppressive effects against progressive renal injury as evidenced by decreased oxidative stress indicator MDA levels in NO deficient hypertensive rats. This effect is explained by the L/N type calcium channel inhibition of cilnidipine, the L-type calcium channel blocking action lowers blood pressure and N-type calcium channel blocking action leads to suppression of the sympathetic nerve activity and renin-angiotensin-aldosterone system.

Back to basics with receptors and ligands – molecules, mechanisms and medicine

Drug discovery is a complex, substantially long, technology-driven, labour-intensive and inordinately expensive process involving target discovery and validation, lead identification by high-throughput screening, and lead optimization by medicinal chemistry, preclinical evaluation in animal models, pharmacological screening (ADME screen: administration, distribution, metabolism, elimination) and studies of toxicology, specificity, and drug interactions. While comprehensive drug discovery workflows are predominantly undertaken in the big pharma domain, drug discovery in academia must not be discounted. Research relevant to drug discovery in academia is generally at the fundamental level, with a focus on drug mechanisms and the identification and validation of potential therapeutic targets, often in commercially unattractive, but relevant therapeutic areas particularly for the developing world, including rare disorders, parasitic diseases, and in research into natural products. Investigating natural sources for drug leads include compounds from venomous animals; with illustrious examples of success such as captopril (angiotensin converting enzyme inhibitor for the treatment of hypertension), exenatide (a glucagonlike peptide-1 receptor agonist for the treatment of type 2 diabetes) and ziconotide (an N-type calcium channel blocker for intractable pain)