Long-lasting Hypotensive Effect Research Articles

Histamine H3 receptor antagonist/nitric oxide donors as novel promising therapeutic hybrid-tools for glaucoma and retinal neuroprotection

Glaucoma is a degenerative optic neuropathy in which the degeneration of optic nerve and blindness occur. The main cause is a malfunction of ciliary processes (protrusions of the ciliary bodies) resulting in increased intraocular pressure (IOP). Ocular hypertension (OHT) causes ischemic events leading to retinal ganglion cell (RGC) depletion and blindness.Histaminergic and nitrergic systems are involved in the regulation of IOP. Therefore, we developed novel hybrid compounds that target histamine H3 receptor (H3R) with nitric oxide (NO) releasing features (ST-1989 and ST-2130). After H3R binding was proven in vitro, we investigated their effects in two OHT models in New Zealand White rabbits. Compound ST-1989 showed the highest NO elevation, together with antioxidative and anti-inflammatory features partly superior to the co-administered H3R antagonist (ciproxifan) and NO donor (molsidomine). This hybrid compound demonstrated IOP reduction in both OHT models induced by intravitreal injection of hypertonic saline and carbomer into the anterior chamber of the eye, respectively. Ocular perfusion and photoreceptor neuroprotection were evaluated in a model of ischemia/reperfusion (I/R) of the ophthalmic artery induced by repeated sub-tenon injections of endothelin-1 (ET-1), twice a week for six weeks. Compound ST-1989 counteracts retinal degeneration reducing ophthalmic artery resistance index and increasing photoreceptor responses, thus rescuing RGCs.Our results indicate that compound ST-1989 is a promising molecule with long-lasting hypotensive effects and good effectiveness in reducing inflammation, oxidative stress, and RGCs apoptosis. In conclusion, these hybrid compounds could be a novel strategy to combat glaucomatous blindness and RGC depletion for ocular diseases involving retinal damage.

Azelnidipine treatment reduces the expression of Cav1.2 protein

AimsAzelnidipine, a third-generation dihydropyridine calcium channel blocker (DHP CCB), has a characteristic hypotensive effect that persists even after it has disappeared from the plasma, which is thought to be due to its high hydrophobicity. However, because azelnidipine is unique, it might have other unknown effects on L-type Cav1.2 channels that result in the long-lasting decrease of blood pressure. The aim of this study was to investigate the potential quantitative modification of Cav1.2 by azelnidipine. Main methodsHEK293 cells were used to express Cav1.2 channels. Immunocytochemical analysis was performed to detect changes in the surface expression of the pore-forming subunit of the Cav1.2 channel, Cav1.2α1c. Western blotting analysis was performed to evaluate changes in expression levels of total Cav1.2α1c and Cavβ2c. Key findingsThe surface expression of Cav1.2α1c was markedly reduced by treatment with azelnidipine, but not with other DHP CCBs (amlodipine and nicardipine). Results obtained with a dynamin inhibitor and an early endosome marker suggested that the reduction of surface Cav1.2α1c was not likely caused by internalization. Azelnidipine reduced the total amount of Cav1.2α1c protein in HEK293 cells and rat pulmonary artery smooth muscle cells. The reduction of Cav1.2α1c was rescued by inhibiting proteasome activity. In contrast, azelnidipine did not affect the amount of auxiliary Cavβ2c subunits that function as a chaperone of Cav1.2. SignificanceThis study is the first to demonstrate that azelnidipine reduces the expression of Cav1.2α1c, which might partly explain its long-lasting hypotensive effect.

Effects of Angiotensin II type I receptor shRNA on blood pressure and left ventricular remodeling in spontaneously hypertensive rats.

This study was designed to investigate the effects of the Angiotensin II type I receptor (AT1R) shRNA on blood pressure and left ventricular remodeling in spontaneously hypertensive rats. Ten Wistar Kyoto (WKY) rats were used as a normal blood pressure control group, and 20 spontaneously hypertensive rats (SHR) were randomly divided into the experimental and hypertension control groups. The rats in the experimental group were injected with AT1R shRNA recombinant adenovirus (Ad5-AT1R-shRNA) via a tail vein, and the rats in the other two groups were injected with recombinant adenovirus (Ad5-EGFP). The systolic blood pressure (SBP) at rat arteria caudalis was measured before and after the injection, and the heart, kidney, aorta, and adrenal tissues were obtained two days after repeated injection to observe the distribution of Ad5-AT1R-shRNA under a fluorescence microscope. Before the injection of Ad5-AT1R-shRNA, the blood pressure of the experimental group and the hypertension control group was significantly higher than that of the normal blood pressure control group (P<0.01). After two injections, the blood pressure in the experimental group decreased significantly, and the duration of blood pressure reduction reached 19 days. In the experimental group, the kidney, heart, aorta, and adrenal gland tissues showed vigorous fluorescence expression under the fluorescence microscope. Repeated administration of Ad5-AT1R-shRNA has a long-lasting hypotensive effect on SHR and can significantly improve ventricular remodeling.

Signs of proliferative process after laser treatment of advanced glaucoma

To evaluate the condition of SFOT in dynamics with Visante OCT after one-step combined laser technique consisting of modified selective laser activation of the trabecula (MSLAT) and DGP in advanced POAG patients with normalized IOP who have pronounced pigmentation of the trabecular meshwork and stage II pseudoexfoliation syndrome (PES). OCT scans of 117 patients (117 eyes) were analyzed before laser treatments and after 1, 3, 6, 12 and 24 months. The study included 62 patients (62 eyes) comprising the main group who underwent MSLAT + DGP, and the control group consisting of 55 patients (55 eyes) who only underwent DGP. Visante OCT scans revealed that parameters of the filtration bleb (FB) and intrascleral cavity (ISC) in the main study group were more stable than in the control group during the whole follow-up. In the main study group there were less incorporations in the ISC and they had lower optical density, compared with the control group where there were denser incorporations in the ISC which gradually increased in count. According to Visante OCT, the growing count and the increase in density of incorporations in the ISC can be defined as adverse signs of an active proliferative process in SFOT. A one-step MSLAT with DGP help achieve both a long-lasting hypotensive effect, and decrease of active proliferative process signs in SFOT.

Временный «жидкий» имплантат при врожденной глаукоме (отдаленные результаты)

The aim of the work was to analyze the long-term results of using a temporary “liquid” implant in the surgery of congenital glaucoma in children. The basis of the developed method of filtrative antiglaucomatous surgery (Patent of Ukraine No. 45099 of 2009) – viscosinusotrabeculotomy – has been set the task of reducing the risk of developing intra- and postoperative complications, reducing the scarring rate and maintaining the newly created ways of the intraocular fluid outflow, which in general will increase the effectiveness of surgical treatment of congenital glaucoma in children. 54 children (91 eyes) with simple congenital glaucoma at the age of 1 to 36 months were operated on average (8.7 ± 8.2) months. The persistent and long-lasting hypotensive effect achieved due to viscosinusotrabeculotomy in children with developed and far-advanced stages of congenital glaucoma stops the processes of stretching of the membranes of the eye and stabilizes their size, which in general allows preserving and visual functions improving, in infancy – creating conditions for their formation.

Energy-dependent effect trial of photobiomodulation on blood pressure in hypertensive rats.

The main purpose of this work was to construct an energy-dependent response curve of photobiomodulation on arterial pressure in hypertension animal model. To reach this objective, we have used a two-kidney one clip (2K-1C) rat model. Animals received acute laser light irradiation (660nm) on abdominal region using different energy (0.6, 1.8, 3.6, 7.2, 13.8, 28.2, 55.8, and 111.6J), the direct arterial pressure was measured by femoral cannulation, and systolic arterial pressure (SAP), diastolic arterial pressure (DAP), heart rate (HR), and time of effect were obtained. Our results indicated that 660nm laser light presents an energy-dependent hypotensive effect, and 28.2J energy irradiation reached the maximum hypotensive effect, inducing a decreased SAP, DAP, and HR (decrease in SAP: - 19.23 ± 1.82mmHg, n = 11; DAP: - 9.57 ± 2.23mmHg, n = 11; HR: - 39.15 ± 5.10bpm, n = 11; and time of hypotensive effect: 3068.00 ± 719.00s, n = 11). The higher energy irradiation evaluated (111.6J) did not induce a hypotensive effect and induced an increase in HR (21.69 ± 7.89bpm, n = 7). Taken together, our results indicate that red laser energy irradiation from 7.2 to 55.8J is the effective therapeutic window to reduce SAP, DAP, MAP, and HR and induce a long-lasting hypotensive effect in rats, with effect loss at higher energy irradiation (111.6J).

Hypotensive effects of resistance exercise with continuous and intermittent blood flow restriction

The aim of this study was to compare the acute effects of low-intensity (LI) resistance exercise (RE) with continuous blood flow restriction (CBFR) and intermittent blood flow restriction (IBFR) on systolic blood pressure (SBP), diastolic blood pressure (DBP), and mean arterial pressure (MAP). After a one-repetition maximum test, 10 normotensive recreationally trained men performed three experimental protocols. In the three RE protocols, increases in SBP, DBP, and MAP were observed immediately after exercise, but the effect sizes (ESs) were greater for the LI + CBFR and high-intensity protocols. There were hypotensive effects on SBP, DBP, and MAP in all three protocols; however, the effects on MAP lasted longer for the LI + IBFR and LI + CBFR protocols. These long-lasting hypotensive effects on DBP and MAP occurred in all three protocols. Thus, we conclude that the post exercise hypotensive effects on SBP, DBP, and MAP appear to occur in all three RE protocols, with the effect on SBP being longer in the LI + IBFR and LI + CBFR protocols.

Modern methods of minimally invasive glaucoma surgery

Over the years, glaucoma surgery has improved from iridectomy by A. Graefe and traumatizing procedures performed without magnification tools or microsurgical instrument to high-technology interventions that are not only microscopic, but also pathogenetically oriented. Various modifications of trabeculectomy, initially introduced by J. Cairns back in 1968, had been the gold standard for several decades and were notable for pronounced and stable hypotensive effects. However, there was also a strong association with such complications as choroidal detachment and hyphema, thus, boosting the development of so called nonfistulizing surgeries. Of the latter, the most widely used are non-penetrating procedures, including deep sclerectomy and viscocanalostomy. Although very safe, they appear unable to produce a truly long-lasting hypotensive effect. Moreover, just as fistulizing trabeculectomy, non-penetrating procedures damage the limbus and adjacent conjunctiva reducing the possibility of a second intervention. This fact together with other drawbacks mentioned above, on the one hand, and technical progress, on the other, were essential prerequisites for the appearance of a new type of surgery - minimally invasive glaucoma surgery (MIGS). Parameters that should be met for a procedure to be considered minimally invasive are debated. The main requirement has, however, been established: ab interno approach through a corneal incision. As surgical tools are enhanced and new techniques arise, options for glaucoma treatment widen greatly, ensuring our future move to higher level standards in the field. This review contains all recent data on minimally invasive techniques currently in use in glaucoma surgery or those under investigation. The authors have also analyzed effectiveness reports and present their conclusions regarding the current state of MIGS worldwide.

Long-lasting Hypotensive Effect in Renal Hypertensive Rats Induced by Nitric Oxide Released From a Ruthenium Complex

In this study, we investigated the effect of the ruthenium complex [Ru(terpy)(bdq)NO] (TERPY) on the arterial pressure from renal hypertensive 2 kidney-1 clip (2K-1C) rats, which was compared with sodium nitroprusside (SNP). The most interesting finding was that the intravenous bolus injection of TERPY (2.5, 5.0, 7 mg/kg) had a dose-dependent hypotensive effect only in 2K-1C rats. On the other hand, SNP (35 and 70 μg/kg) presented a similar hypotensive effect in both normotensive (2K) and 2K-1C although the effect of 70 μg/kg was >35 μg/kg. The injection of the nonselective NO-synthase inhibitor N-nitro-L-arginine methyl ester (L-NAME) increased the arterial pressure in 2K and 2K-1C rats with a similar magnitude. After infusion of L-NAME, the hypotensive effect induced by TERPY and SNP was potentiated in both 2K and in 2K-1C rats. The administration of the superoxide scavenger 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl increased the hypotensive effect induced by TERPY or SNP in both 2K and 2K-1C rats. The hypotensive effect induced by TERPY was longer than that produced by SNP. Taken together, our results show that the TERPY has a long-lasting hypotensive effect, which has a dose dependence and higher magnitude in 2K-1C compared with in 2K rats. In comparison with SNP, TERPY is less potent in inducing arterial pressure fall, but it presents a much longer hypotensive effect.

Pharmacological characterization of KR-30988, a novel non-peptide AT1 receptor antagonist, in rat, rabbit and dog.

The pharmacological profile of KR-30988, a non-peptide AT1-selective angiotensin receptor antagonist, has been investigated by use of a variety of experimental models in-vitro and in-vivo. KR-30988 inhibited the specific binding of [125I][Sar1, Ile8]-angiotensin II to the recombinant AT1 receptor from man with a potency similar to that of losartan (IC50 values, the concentrations of drugs displacing 50% of specific binding, 13.6 and 12.3 nM, respectively), but did not inhibit the binding of [125I]CGP 42112A to recombinant AT2 receptor from man (IC50 >10 microM for both drugs). Scatchard analysis showed that KR-30988 interacted competitively with recombinant AT1 receptor from man in the same manner as losartan. In functional studies with rat and rabbit aorta, KR-30988 noncompetitively inhibited the contractile response to angiotensin II (pD2, = -log EC50 (where EC50 is the dose resulting in 50% of a reference contraction), 8.64 and 7.73, respectively) with a 20-85% decrease in the maximum contractile responses, unlike losartan. In pithed rats intravenous KR-30988 resulted in a non-parallel shift to the right of the dose-pressor response curve to angiotensin II (ID50 value, the dose inhibiting the pressor response to angiotensin II by 50%, 0.09 mg kg(-1)) with a dose-dependent reduction in the maximum responses; in this antagonistic effect KR-30988 was 20 times (approx.) more potent than losartan (ID50 1-74 mg kg(-1)). In conscious renal hypertensive rats oral administration of KR-30988 produced a dose-dependent and long-lasting (>24 h) anti-hypertensive effect; the potency was six times that of losartan (ED30 values, the dose reducing mean arterial blood pressure by 30 mmHg, 0.48 and 2.97 mg kg(-1), respectively). In conscious furosemide-treated dogs oral administration of KR-30988 produced a dose-dependent and long-lasting (>8 h) hypotensive effect with a rapid onset of action (time to Emax, the maximum effect, 1-2 h); KR-30988 was eight times more potent than losartan (ED20, the dose reducing mean arterial blood pressure by 20 mm Hg, 1.04 and 7.96 mg kg(-1), respectively). These results suggest that KR-30988 is a potent, orally active selective AT1 receptor antagonist with a mode of insurmountable antagonism.

Antihypertensive activities of royal jelly protein hydrolysate and its fractions in spontaneously hypertensive rats.

Angiotensin I-converting enzyme (ACE) inhibitory and hypotensive effects of 7 peptide fractions (Frs) of royal jelly protein hydrolysate (RJPH) were studied in comparison with those of RJPH alone. Fr 4 and Fr 5 were the highest in ACE inhibitory activity and yield, respectively. Molecular weights (MWs) of RJPH and Fr 1-Fr 7 were distributed from 100 to 5,000 and those of Fr 1-Fr 7 increased in order from Fr 1 to Fr 7. RJPH, Fr 3 and Fr 4 at doses of 10, 30 and 100mg/kg i.v. and Fr 5 and Fr 6 at doses of 30 and 100mg/kg i.v. caused transiently significant hypotensive effects in spontaneously hypertensive rats (SHR). Fr 3, Fr 4, Fr 5 and Fr 6 at a dose of 1,000mg/kg also caused significant hypotensive effects 3h, 4-5h, 7-8h and 8h after oral administration in SHR, respectively. RJPH caused a long-lasting hypotensive effect in proportion to the magnitude of the MWs of RJPH fractions. The hypotensive pattern of RJPH was similar to the combined pattern of Fr 3-Fr 6. From these results, it can be concluded that the long-lasting hypotensive effect of oral administration of RJPH is dependent on the MWs of its ACE inhibitory peptides and the time required to digest them.

Targeting Small Arteries of Hypertensive Status with Novel ATP-Sensitive Potassium Channel Openers&amp;#

The excessive contraction of small arteries under high blood pressure is the main contributor to the pathological change of hypertension. Current anti-hypertensive drugs, which lack a selective effect on small arteries in a hypertensive state, may cause many adverse effects. We have developed a novel opener of ATP-sensitive potassium channels, iptakalim, the vasorelaxing action of which is determined by the hypertensive status of small arteries. In conscious stroke-prone, spontaneously hypertensive rats and "two-kidneys, one-clip" renal hypertensive dogs, this compound produced long-lasting hypotensive effects, with no tolerance. Furthermore, it exerted a protective effect against hypertensive damage to target organs. Given its potency and fewer side effects, iptakalim hydrochloride is a promising drug for the treatment of hypertension.

Anti-Hypertension Effect of Vanylidilol: A Phenylaldehyde α/β-Adrenoceptor Blocker with Endothelium-Dependent and K+ Channels Opening-Associated Vasorelaxant Activities

The antihypertensive effect of vanylidilol, a new α/β-adrenoceptor antagonist with endothelium-dependent and K⁺-channel-opening activities, was investigated in normotensive and hypertensive Wistar rats. Vanylidilol competitively antagonized (–)isoproterenol-induced positive chronotropic effects, inotropic effects, and tracheal relaxation effects in isolated rat right atria, left atria, and guinea pig tracheal strips in a concentration-dependent manner. Vanylidilol’s apparent pA₂ values were 6.36 ± 0.08 (right atria), 6.41 ± 0.07 (left atria), and 6.31 ± 0.06 (trachea). Vanylidilol also produced a competitive antagonism of phenylephrine-induced contraction in the isolated rat aorta with pA₂ values of 6.79 ± 0.18. In the radioligand binding assay, vanylidilol inhibited [³H]CGP-12177 binding to rat ventricle and lung tissues and [³H]prazosin binding to brain membranes with Ki values of 535.17, 2,066.69, and 431.11, respectively. In isolated rat thoracic aorta, vanylidilol’s vasorelaxant effects on phenylephrine (10 µmol/l)-induced contractions were attenuated by removing endothelium and by the presence of L-N^G-nitro arginine methyl ester (L-NAME; 100 µmol/l), methylene blue (10 µmol/l), 1H-[1,2,4]oxadiazolol[4,3,-a] quinoxalin-1-one (ODQ; 10 µmol/l), tetraethylammonium (10 mmol/l), glibenclamide (1 µmol/l), apamin (1 µmol/l), and charybdotoxin (0.1 µmol/l). In addition, vanylidilol, in an equally antagonistic activity, inhibited phenylephrine-induced phasic and tonic contractions. Intravenous vanylidilol further reduced mean blood pressure in pentobarbital-anesthetized normotensive Wistar rats in a dose-dependent manner. The oral administration of vanylidilol to conscious spontaneously hypertensive rats had a long-lasting hypotensive effect on the heart rate and decreased it in a dose-dependent manner. Furthermore, vanylidilol’s vasodilator effect can be attributed in part to the release of NO or NO-related substance from vascular endothelium, while the endothelium-independent mechanism involved in vanylidilol’s relaxation is probably linked to the activation of the K⁺ channels and the α-adrenoceptor blocking activity in these vessels.

Pharmacological profiles and clinical effects of azelnidipine, a long-acting calcium channel blocker.

Azelnidipine (Calblock) is a newly developed dihydropyridine-type calcium antagonist for the treatment of hypertension. In hypertensive animals, a single oral administration of azelnidipine caused a slowly developed and long-lasting hypotensive effect with a little reflex tachycardia. The extent of tachycardia was less with azelnidipine than with other agents of the same class. Long-term administrations of azelnidipine produced a stable antihypertensive effect with a slight decrease in heart rate. The hypotensive effect was preceded by an increase in plasma drug concentration and it persisted even after plasma drug concentration declined to very low levels. In the isolated arteries, the calcium blocking action developed gradually after treatment with azelnidipine and survived for a long period of time after the drug was removed from the bathing solution. These data suggest that the high affinity to vascular tissue contributes to the long-lasting hypotensive effects of this agent. The results from clinical studies in hypertensive patients indicated that once daily administration of azelnidipine achieved stable, 24-h control of blood pressure with no change or a slight decrease in heart rate. Clinical studies also showed a low incidence of adverse events such as headache, facial flush, dizziness, and palpitations. These characteristics make azelnidipine a new generation calcium antagonist that can be used for the treatment of hypertension.

In vivo receptor binding of benidipine and amlodipine in mesenteric arteries and other tissues of spontaneously hypertensive rats

The present study was undertaken to characterize the in vivo 1,4-dihydropyridine (DHP) receptor binding of long-acting 1,4-DHP calcium channel antagonists in the mesenteric artery and other tissues of SHR. In vivo specific binding of (+)-[ 3H]PN 200–110 in the SHR mesenteric artery was significantly (36.6–49.7 %) reduced 1–8 h after oral administration of benidipine (1.84 μmol/kg). A greater reduction in (+)-[ 3H]PN 200–110 binding in the mesenteric artery was observed at a higher dose (5.53 μmol/kg) of this drug. This dose of benidipine also reduced significantly the in vivo specific (+)-[ 3H]PN 200–110 binding in the aorta but not in the myocardium and cerebral cortex. Following oral administration of amlodipine (17.6 μmol/kg), a significant (51.7–94.2 %) reduction in (+)-[ 3H]PN 200–110 binding was seen at 1–18 h in the mesenteric artery and at 1–12 h in the aorta. Only a slight reduction in myocardial and cerebral cortical (+)-[ 3H]PN 200–110 binding was seen following amlodipine administration. In contrast, oral administration of nifedipine (28.9 μmol/kg) reduced markedly in vivo (+)-[ 3H]PN 200–110 binding in all the tissues of SHR at 1–6 h, and the degree and time-course of the reduction did not differ significantly among the tissues. The area under the curve (AUC) for the receptor occupancy vs time was calculated from the reduction rate (%) of in vivo specific (+)-[ 3H]PN 200–110 binding. The ratios of the AUCmesenteric artery to AUCaorta or AUCmesenteric artery to AUCmyocardium after oral administration of benidipine and amlodipine were greater than the corresponding value for nifedipine. The degree and time-course of arterial receptor occupancy by benidipine and amlodipine agreed well with those of their hypotensive effects in the conscious SHR. In conclusion, the present study demonstrates that benidipine and amlodipine may occupy, in a more selective and sustained manner, 1,4-DHP receptors in arterial tissues than in other tissues of SHR, and thus, such receptor binding specificity may be responsible for the long-lasting hypotensive effects of these drugs.

Mature adrenomedullin concentrations in plasma during pregnancy

Objective: Adrenomedullin is a novel peptide that exerts a potent, dose-dependent and long-lasting hypotensive effect. In human plasma, adrenomedullin consists of two molecular forms: mature and immature. Immature adrenomedullin is much less bioactive than mature adrenomedullin. Although a gradual increase in plasma adrenomedullin has been reportedly observed as pregnancy progressed, mature adrenomedullin has not been examined. The aim of this study was to elucidate the plasma level of mature adrenomedullin in pregnant women. Methods: We measured the concentrations of mature adrenomedullin in ten pregnant women in the first trimester, ten pregnant women in the third trimester, and ten non-pregnant controls with the immunoradiometric assay. Results: The mean concentration of mature adrenomedullin was significantly increased in pregnant women in the first trimester compared to age-matched non-pregnant subjects (p < 0.05). The mean concentration of mature adrenomedullin was significantly increased in pregnant women in the third trimester compared with pregnant women in the first trimester (p < 0.005). Conclusion: Our study demonstrated that concentrations of mature adrenomedullin were elevated in pregnant women compared with non-pregnant women and its concentration in the third trimester was significantly higher than that in the first trimester.

Mature adrenomedullin concentrations in plasma during pregnancy

Objective: Adrenomedullin is a novel peptide that exerts a potent, dose-dependent and long-lasting hypotensive effect. In human plasma, adrenomedullin consists of two molecular forms: mature andimmature. Immature adrenomedullin is much less bioactive than mature adrenomedullin. Although a gradual increase in plasma adrenomedullin has been reportedly observed as pregnancy progressed, mature adrenomedullinhas not been examined. The aim of this study was to elucidate the plasma level of mature adrenomedullin in pregnant women.Methods: We measured the concentrations of mature adrenomedullin inten pregnant women in the first trimester, ten pregnant women in the third trimester, and ten non-pregnant controls with the immunoradiometric assay.Results: The mean concentration of matureadrenomedullin was significantly increased in pregnant women in the first trimester compared to age-matched non-pregnant subjects (p < 0.05). The mean concentration of mature adrenomedullin wassignificantly increased in pregnant women in the third trimester compared with pregnant women in the first trimester (p < 0.005).Conclusion: Our study demonstrated that concentrationsof mature adrenomedullin were elevated in pregnant women compared with non-pregnant women and its concentration in the third trimester was significantly higher than that in the first trimester.

In vivo measurement of 1,4-dihydropyridine receptors in mesenteric arteries of spontaneously hypertensive rats and effect of nifedipine and cilnidipine.

The present study was undertaken to measure 1,4-dihydropyridine (DHP) receptor binding sites in vivo in the mesenteric artery and other tissues of spontaneously hypertensive rats (SHR) and to examine the effect of nifedipine and cilnidipine. Specific in vivo binding of (+)-[3H]PN 200-110 in the SHR mesenteric artery was dose dependently reduced by oral administration of nifedipine at relatively low doses. Oral administration of cilnidipine (6.09 micromol/kg) significantly reduced the specific in vivo binding of (+)-[3H]PN 200-110 in the mesenteric artery, aorta, and myocardium. A significant reduction in (+)-[3H]PN 200-110 binding was seen at 1-12 h in the mesenteric artery and at 1-7 h in the aorta and myocardium. In contrast, oral administration of nifedipine (28.9 micromol/kg) markedly reduced in vivo (+)-[3H]PN 200-110 binding in all tissues of SHR at 1-6 h, and the degree and time course of the reduction did not differ much among the tissues. The area under the curve (AUC) for receptor occupancy vs. time was calculated from the reduction rate (%) of specific in vivo (+)-[3H]PN 200-110 binding. The ratio (1.4 or 1.7) of the AUC(mesenteric artery) to AUCaorta or AUCmyocardium after oral administration of cilnidipine was greater than the corresponding value (1.1) for nifedipine. In conclusion, the present study demonstrates that cilnidipine, but not nifedipine, may occupy 1,4-DHP receptors in the small artery in a more selective and sustained manner than in other tissues of SHR, and thus such receptor binding specificity may be responsible for the long-lasting hypotensive effect of this drug.

Vatanidipine hydrochloride: a new long-lasting antihypertensive agent

Vatanidipine is a novel dihydropyridine (DHP)-type calcium channel blocker with slow-onset pharmacological actions, which are probably due to both its slow uptake into vascular tissues and resistance in its approach to the calcium channel binding site. Vatanidipine once incorporated into vascular tissues is not easily released, even by repeated washing, thus resulting in a long-lasting action of the agent. A slow-onset and long-lasting hypotensive action was observed in various experimental hypertensive models. Clinical trials using human subjects with essential hypertension indicated that vatanidipine exerts an antihypertensive effect with a slow onset and long duration. In spite of its potent hypotensive effect, the incidence of adverse effects by vatanidipine administration has been reported to be lower than that in cases of nitrendipine. In addition to its vasodilatory effects, vatanidipine efficiently suppressed noradrenaline release from sympathetic nerve endings, thus suggesting this agent exhibits a beneficial effect in the treatment of hypertensive patients, in which the reflex activation of peripheral sympathetic nerves is unfavourable to antihypertensive therapy. In a double-blind study, vatanidipine did not show reflex tachycardia, despite producing a potent and long-lasting hypotensive effect, in contrast to the administration of nitrendipine. In an animal study, vatanidipine exhibited a protective effect against cerebrovascular lesions, through a mechanism independent of its hypotensive effect. In addition, a renoprotective effect was also observed in experimental hypertensive models. In cholesterol-fed rabbits, vatanidipine exerted an anti-atherosclerotic action, which is probably attributable to the inhibitory action of the agent on low-density lipoprotein oxidation. In essential hypertensive patients, the plasma levels of cholesterol and triglyceride decreased after vatanidipine treatment, thus suggesting that this agent may have a therapeutic potential in preventing such vascular diseases as atherosclerosis. Taken together, vatanidipine appears to be a novel and useful antihypertensive agent, which can both prevent target-organ damage and reduce cardiovascular morbidity and mortality.

Actions of L-NAME and methylene blue on the hypotensive effects of clonidine and rilmenidine in the anesthetized rat.

The antihypertensive mechanism of alpha2-adrenoceptor agonists, such as clonidine and rilmenidine, is not completely elucidated, although it is probably due to reduction of sympathetic tone mediated by stimulation of central alpha2-adrenoceptors. Because activation of alpha2-adrenoceptors on endothelial cells induces release of endothelium-derived relaxing factor (EDRF), we determined whether nitric oxide (NO) release is involved in the antihypertensive action of clonidine and rilmenidine. In chloralose-anesthetised Wistar rats, systolic and diastolic arterial blood pressures were recorded on a polygraph. Intravenous injection of clonidine or rilmenidine (control group) caused a rapid increase of arterial blood pressure. followed by a long-lasting hypotensive effect. The hypotensive effects, estimated as the area enclosed by the decrease in diastolic pressure during the 20 min after clonidine and rilmenidine injections, were 574+/-60 and 410+/-59 mm Hg/min, respectively. The delta decrease in diastolic arterial blood pressure observed 20 min after intravenous injections of clonidine and rilmenidine was 48+/-5 and 34+/-3 mm Hg, respectively. Clonidine and rilmenidine injected 5-10 min after intravenous pretreatment with L-NAME (2 and 1 mg/kg) or methylene blue (10 mg/kg) induced hypotensive effects that were significantly smaller than that observed for the control group. These results suggest that the antihypertensive effects of clonidine and rilmenidine also may be modulated by the NO-cyclic guanosine monophosphate (cGMP) pathway at the level of the central nervous system and/or at the vascular peripheral circulation.