Cocrystal Prediction of Nifedipine Based on the Graph Neural Network and Molecular Electrostatic Potential Surface.

Nifedipine (NIF) is a dihydropyridine calcium channel blocker primarily used to treat conditions such as hypertension and angina. However, its low solubility and low bioavailability limit its effectiveness in clinical practice. Here, we developed a cocrystal prediction model based on Graph Neural Networks (CocrystalGNN) for the screening of cocrystals with NIF. And scoring 50 coformers using CocrystalGNN. To validate the reliability of the model, we used another prediction method, Molecular Electrostatic Potential Surface (MEPS), to verify the prediction results. Subsequently, we performed a second validation using experiments. The results indicate that our model achieved high performance. Ultimately, cocrystals of NIF were successfully obtained and all cocrystals exhibited better solubility and dissolution characteristics compared to the parent drug. This study lays a solid foundation for combining virtual prediction with experimental screening to discover novel water-insoluble drug cocrystals.

Tissue oxygen saturation is predictive of lactate clearance in patients with circulatory shock.

BACKGROUND: Tissue oxygen saturation (StO2) decrease could appear earlier than lactate alteration. However, the correlation between StO2 and lactate clearance was unknown. METHODS: This was a prospective observational study. All consecutive patients with circulatory shock and lactate over 3 mmol/L were included. Based on the rule of nines, a BSA (body surface area) weighted StO2 was calculated from four sites of StO2 (masseter, deltoid, thenar and knee). The formulation was as follows: masseter StO2 × 9% + (deltoid StO2 + thenar StO2) × (18% + 27%)/ 2 + knee StO2 × 46%. Vital signs, blood lactate, arterial and central venous blood gas were measured simultaneously within 48 h of ICU admission. The predictive value of BSA-weighted StO2 on 6-hour lactate clearance > 10% since StO2 initially monitored was assessed. RESULTS: A total of 34 patients were included, of whom 19 (55.9%) had a lactate clearance higher than 10%. The mean SOFA score was lower in cLac ≥ 10% group compared with cLac < 10% group (11 ± 3 vs. 15 ± 4, p = 0.007). Other baseline characteristics were comparable between groups. Compared to non-clearance group, StO2 in deltoid, thenar and knee were significantly higher in clearance group. The area under the receiver operating curves (AUROC) of BSA-weighted StO2 for prediction of lactate clearance (0.92, 95% CI [Confidence Interval] 0.82-1.00) was significantly higher than StO2 of masseter (0.65, 95% CI 0.45-0.84; p < 0.01), deltoid (0.77, 95% CI 0.60-0.94; p = 0.04), thenar (0.72, 95% CI 0.55-0.90; p = 0.01), and similar to knee (0.87, 0.73-1.00; p = 0.40), mean StO2 (0.85, 0.73-0.98; p = 0.09). Additionally, BSA-weighted StO2 model had continuous net reclassification improvement (NRI) over the knee StO2 and mean StO2 model (continuous NRI 48.1% and 90.2%, respectively). The AUROC of BSA-weighted StO2 was 0.91(95% CI 0.75-1.0) adjusted by mean arterial pressure and norepinephrine dose. CONCLUSIONS: Our results suggested that BSA-weighted StO2 was a strong predictor of 6-hour lactate clearance in patients with shock.

Accuracy of Mean Value of Central Venous Pressure from Monitor Digital Display: Influence of Amplitude of Central Venous Pressure during Respiration.

Background A simple measurement of central venous pressure (CVP)-mean by the digital monitor display has become increasingly popular. However, the agreement between CVP-mean and CVP-end (a standard method of CVP measurement by analyzing the waveform at end-expiration) is not well determined. This study was designed to identify the relationship between CVP-mean and CVP-end in critically ill patients and to introduce a new parameter of CVP amplitude (ΔCVP= CVPmax - CVPmin) during the respiratory period to identify the agreement/disagreement between CVP-mean and CVP-end.Methods In total, 291 patients were included in the study. CVP-mean and CVP-end were obtained simultaneously from each patient. CVP measurement difference (|CVP-mean - CVP-end|) was defined as the difference between CVP-mean and CVP-end. The ΔCVP was calculated as the difference between the peak (CVPmax) and the nadir value (CVPmin) during the respiratory cycle, which was automatically recorded on the monitor screen. Subjects with |CVP-mean - CVP-end|≥ 2 mmHg were divided into the inconsistent group, while subjects with |CVP-mean - CVP-end| < 2 mmHg were divided into the consistent group.Results ΔCVP was significantly higher in the inconsistent group [7.17(2.77) vs.5.24(2.18), P<0.001] than that in the consistent group. There was a significantly positive relationship between ΔCVP and |CVP-mean - CVP-end| (r=0.283, P <0.0001). Bland-Altman plot showed the bias was -0.61 mmHg with a wide 95% limit of agreement (-3.34, 2.10) of CVP-end and CVP-mean. The area under the receiver operating characteristic curves (AUC) of ΔCVP for predicting |CVP-mean - CVP-end| ≥ 2 mmHg was 0.709. With a high diagnostic specificity, using ΔCVP<3 to detect |CVP-mean - CVP-end| lower than 2mmHg (consistent measurement) resulted in a sensitivity of 22.37% and a specificity of 93.06%. Using ΔCVP>8 to detect |CVP-mean - CVP-end| >8 mmHg (inconsistent measurement) resulted in a sensitivity of 31.94% and a specificity of 91.32%.Conclusions CVP-end and CVP-mean have statistical discrepancies in specific clinical scenarios. ΔCVP during the respiratory period is related to the variation of the two CVP methods. A high ΔCVP indicates a poor agreement between these two methods, whereas a low ΔCVP indicates a good agreement between these two methods.

Ursodeoxycholic Acid (UDCA) Reduces Hepatocyte Apoptosis by Inhibiting Farnesoid X Receptor (FXR) in Hemorrhagic Shock (HS).

BACKGROUND: Hemorrhagic shock (HS) is the most common cause of potentially preventable death after traumatic injury. Acute liver injury is an important manifestation of HS. Apoptosis plays an important role in liver injury. Farnesoid X receptor (FXR) can alleviate liver injury. This study aimed to examine the effects of ursodeoxycholic acid (UDCA) on hepatocyte apoptosis in HS and its relationship with the FXR pathway. METHODS: Mice were randomly divided into 4 groups: sham group, HS group, HS + UDCA group, and FXR (-) + HS + UDCA group. There were 6 mice in each group. As to the model of HS, MAP of 40 ± 5 mmHg was maintained for 1 hour. As to UDCA intervention, UDCA (300mg/kg) was given nasally. Real-time RT-PCR and Western blotting were used to detect changes in the expression level of Caspase-3, Bax, LC3Ⅰ, LC3Ⅱ, Bcl-2, and Beclin-1 in the liver. TUNEL assay was used to detect changes in hepatocyte apoptosis. RESULTS: The expression level of Caspase-3 and Bax in the liver decreased significantly after treatment with UDCA under HS conditions. The expression level of LC3Ⅰ, LC3Ⅱ, Bcl-2, and Beclin-1 in the liver increased significantly after treatment with UDCA under HS conditions. TUNEL positive percentage of liver decreased significantly after treatment with UDCA under HS conditions. In the case of FXR (-), the influence of UDCA was inhibited. CONCLUSION: These results indicated that UDCA could reduce hepatocyte apoptosis during HS through the FXR pathway.

Changes of farnesoid X receptor and Takeda G-protein coupled receptor 5 following biliary tract external drainage in hemorrhagic shock.

Since biliary tract external drainage (BTED) is increasingly used to treat patients with shock, it is necessary to clarify pathophysiological changes following BTED in hemorrhagic shock (HS). The present study aimed to investigate the effect of BTED on farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR-5) expression in HS. A total of 24 Sprague-Dawley rats were randomly allocated to sham, BTED, HS and HS + BTED groups. Rat models of HS were induced by drawing blood from the femoral artery until a mean arterial pressure of 40±5 mmHg was achieved and maintained for 60 min. Rat models of BTED were induced by inserting a catheter into the bile duct. The distal end of the bile duct was ligated, and the catheter was passed through the rat flank to allow external collection of bile. Reverse transcription-quantitative PCR, western blotting and immunohistochemistry were performed to detect changes in expression levels of FXR and TGR-5 in the jejunum, ileum and liver. Expression levels of FXR and TGR-5 increased significantly in jejunum and liver following HS (P<0.05). BTED significantly decreased expression levels of FXR in the liver (P<0.05) and TGR-5 in the jejunum, ileum and liver (P<0.05). In conclusion, expression levels of FXR and TGR-5 increased in HS but BTED decreased expression levels of FXR and TGR-5 in HS.

Novel bioavailability-based risk assessment of Cd in earthworms and leeches utilizing in vitro digestion/Caco-2 and MDCK cells.

In the present study, the oral bioavailability of cadmium (Cd) in earthworms and leeches was investigated through in vitro physiologically based extraction test (PBET) digestion/Caco2 and MDKC cell models. We are the first to create an innovative assessment strategy which has capacity to offer a more precise evaluation of Cd-associated health risks in traditional animal medicines (TAMs), by combinational usage of bioavailable Cd levels, the duration and frequency of the exposure to TAMs obtained by questionnaire data, as well as safety factor of TAMs. Our data showed that the percentage of bioavailability for Caco-2 cells in earthworms and leeches ranged from 3.29 to 14.17% and 4.32 to 12.61%, respectively. The percentage of bioavailability of MDCK cells in earthworms and leeches ranged from 4.83 to 15.74% and 6.53 to 15.04%, respectively. After adjusting by the bioavailability of Cd to target hazard quotient (THQ), excitingly, our findings manifested that the health risks induced by the ingestion of earthworms and leeches were acceptable in the clinic. Our key findings suggest that bioavailability characterization cannot be ruled out and health risks should be assessed on the basis of the bioavailable Cd levels rather than total levels. Our novel strategy provides insight into the bio-accumulation of Cd in organisms as well as a more realistic and accurate assessment of Cd-associated health risks in TAMs, with the main purpose of improving public health by scientifically using TAMs.

MRGPRX2 is critical for clozapine induced pseudo-allergic reactions.

BACKGROUND: Clozapine is one of the most widely used second-generation antipsychotics in clinic. However, allergy-like symptoms such as rash and angioedema have been reported frequently, and the mechanism is still not clear. Mas-related G protein-coupled receptor X2 (MRGPRX2) expressed on mast cells is a crucial receptor for drug induced pseudo-allergic reactions. Therefore, we explored whether the symptoms induced by clozapine were associated with allergic reaction through MRGPRX2. METHODS: The effects of clozapine on pseudo-allergic reactions were evaluated by mast cells degranulation and calcium mobilization assay in vitro, and mice hindpaw swelling, serum histamine detection, avidin and H&E staining assay in vivo. The overexpressed MRGPRX2 cells membrane chromatography (MRGPRX2-HEK293/CMC), MRGPRX2-HEK293 cells calcium mobilization assay and molecular docking were applied to research the correlation between clozapine and MRGPRX2. RESULTS: The study showed that clozapine induced the release of ß-hexosaminidase, histamine and monocyte chemoattractant protein-1 (MCP-1), and trigged calcium mobilization in mast cells. In vivo, clozapine induced paw swelling, degranulation and vasodilation. Furthermore, clozapine could activate the calcium mobilization obviously in MRGPRX2-HEK293 cells, not in NC-HEK293 cells. Clozapine also had a good retention characteristic on MRGPRX2-HEK293/CMC column and the K D value is (2.33 ± 0.21)×10-01M. CONCLUSIONS: Our findings demonstrated that clozapine could induce pseudo-allergic reactions and MRGPRX2 might be the critical receptor for it.

Two-Photon Fluorescent Nanomaterials and Their Applications in Biomedicine.

In recent years, two-photon excited (TPE) materials have attracted great attentions because of their excellent advantages over conventional one-photon excited (OPE) materials, such as deep tissue penetration, three-dimensional spatial selectivity and low phototoxicity. Also, they have been widely applied in lots of field, such as biosensing, imaging, photo-catalysis, photoelectric conversion, and therapy. In this article, we review recent advances in vibrant topic of two-photon fluorescent nanomaterials, including organic molecules, quantum dots (QDs), carbon dots (CDs) and metal nanoclus-ters (MNCs). The optical properties, synthetic methods and important applications of TPE nanomaterials in biomedical field, such as biosensing, imaging and therapy are introduced. Also, the probable challenges and perspectives in the forthcoming development of two-photon fluorescent nanomaterials are addressed.

Cross-sectional study for the clinical application of extracorporeal membrane oxygenation in Mainland China, 2018.

BACKGROUND: To investigate the epidemiology and in-hospital mortality of veno-venous (VV) and veno-arterial (VA) extracorporeal membrane oxygenation (ECMO) in Mainland China throughout 2018. METHODS: Patients supported by ECMO from 1700 tertiary hospitals in 31 provinces from January 1 to December 31, 2018, were selected from the National Clinical Improvement System database. RESULTS: The 1700 included hospitals had 2073 cases of ECMO in 2018, including 714 VV and 1359 VA ECMOs. The average patient age was 50 years (IQR 31-63), and 1346 were male. The average hospital stay was 17 days (IQR 7-30), and the average costs per case was $36,334 (IQR 22,547-56,714). The three provinces with the highest number of ECMO cases were Guangdong, Beijing, and Zhejiang; the southeast coastal areas and regions with higher GDP levels had more cases. Overall in-hospital mortality was 29.6%. Mortality was higher among patients who were male, over 70 years old, living in underdeveloped areas, and who were treated during the summer. Mortality in provinces with more ECMO cases was relatively low. The co-existence of congenital malformations, blood system abnormalities, or nervous system abnormalities increased in-hospital mortality. CONCLUSIONS: Mortality and medical expenses of ECMO among patients in China were relatively low, but large regional and seasonal differences were present. Risk factors for higher in-hospital mortality were older age, male sex, in underdeveloped areas, and treatment during the summer. Additionally, congenital malformations and blood system and nervous system abnormalities were associated with in-hospital mortality.

Progress of mechanical power in the intensive care unit.

Mechanical power of ventilation, currently defined as the energy delivered from the ventilator to the respiratory system over a period of time, has been recognized as a promising indicator to evaluate ventilator-induced lung injury and predict the prognosis of ventilated critically ill patients. Mechanical power can be accurately measured by the geometric method, while simplified equations allow an easy estimation of mechanical power at the bedside. There may exist a safety threshold of mechanical power above which lung injury is inevitable, and the assessment of mechanical power might be helpful to determine whether the extracorporeal respiratory support is needed in patients with acute respiratory distress syndrome. It should be noted that relatively low mechanical power does not exclude the possibility of lung injury. Lung size and inhomogeneity should also be taken into consideration. Problems regarding the safety limits of mechanical power and contribution of each component to lung injury have not been determined yet. Whether mechanical power-directed lung-protective ventilation strategy could improve clinical outcomes also needs further investigation. Therefore, this review discusses the algorithms, clinical relevance, optimization, and future directions of mechanical power in critically ill patients.

Effect of mean arterial pressure change by norepinephrine on peripheral perfusion index in septic shock patients after early resuscitation.

BACKGROUND: The peripheral perfusion index (PI), as a real-time bedside indicator of peripheral tissue perfusion, may be useful for determining mean arterial pressure (MAP) after early resuscitation of septic shock patients. The aim of this study was to explore the response of PI to norepinephrine (NE)-induced changes in MAP. METHODS: Twenty septic shock patients with pulse-induced contour cardiac output catheter, who had usual MAP under NE infusion after early resuscitation, were enrolled in this prospective, open-label study. Three MAP levels (usual MAP -10 mmHg, usual MAP, and usual MAP +10 mmHg) were obtained by NE titration, and the corresponding global hemodynamic parameters and PI were recorded. The general linear model with repeated measures was used for analysis of variance of related parameters at three MAP levels. RESULTS: With increasing NE infusion, significant changes were found in MAP (F = 502.46, P < 0.001) and central venous pressure (F = 27.45, P < 0.001) during NE titration. However, there was not a significant and consistent change in continuous cardiac output (CO) (F = 0.41, P = 0.720) and PI (F = 0.73, P = 0.482) at different MAP levels. Of the 20 patients enrolled, seven reached the maximum PI value at usual MAP -10 mmHg, three reached the maximum PI value at usual MAP, and ten reached the maximum PI value at usual MAP +10 mmHg. The change in PI was not significantly correlated with the change in CO (r = 0.260, P = 0.269) from usual MAP -10 mmHg to usual MAP. There was also no significant correlation between the change in PI and change in CO (r = 0.084, P = 0.726) from usual MAP to usual MAP +10 mmHg. CONCLUSIONS: Differing MAP levels by NE infusion induced diverse PI responses in septic shock patients, and these PI responses may be independent of the change in CO. PI may have potential applications for MAP optimization based on changes in peripheral tissue perfusion.

Innovative health risk assessments of heavy metals based on bioaccessibility due to the consumption of traditional animal medicines.

Few studies reported the extent of heavy metal accumulation in traditional Chinese medicines (TCMs). Currently, oral bioaccessibility of lead (Pb), cadmium (Cd), arsenic (As), mercury (Hg), and copper (Cu) present in traditional animal medicines was investigated with physiologically based extraction test-extracted in vitro model. We are the first to develop a health risk assessment strategy by combinational analysis of bioaccessible heavy metal levels to calculate target hazard quotient (THQ), target hazard index (THI) and cancer risk (CR), which has capacity to evaluate the heavy metal associated heath risk of traditional animal medicines. To precisely acquire a realistic risk assessment, questionnaire data was adopted to measure the frequency and duration of the exposure to traditional animal medicines, and the safety factor was highlighted as well. Our data revealed that the bioaccessibility of Hg was the lowest among the five heavy metals. After the adjustment with the bioaccessibility of each heavy metal to target hazard index (THI) values, excitingly, the results manifested that the consumption of traditional animal medicines might not exert an unacceptable health risk in a broad community. In addition, the CR values of As and Pb indicated that the risk of developing cancers was quite lower than their acceptable levels in the clinic.

Nutritional outcomes after radiotherapy target volume reduction for nasopharyngeal cancer: a Phase III trial.

Aim: This study aimed to assess the nutritional status of patients with locoregionally advanced nasopharyngeal cancer, for whom intensity-modulated radiotherapy (IMRT) was planned using their pre- or post-induction chemotherapy (IC) nasopharyngeal gross tumor volume. Materials & methods: 212 cases of stage III-IVb nasopharyngeal cancer were randomized into groups A (n = 97) and B (n = 115). IMRT was planned for groups A and B using pre-IC and post-IC images, respectively. Results: There was a significant decrease in the nutritional parameters of group B compared with those of group A during radiotherapy. Multivariate analysis indicated that the T stage and nasopharyngeal gross tumor volume IMRT-planning protocol were prognostic factors of poor nutritional status. Conclusion: Decreasing the IMRT target volume through IC can improve nutritional status.

Ursodeoxycholic Acid (UDCA) Promotes Lactate Metabolism in Mouse Hepatocytes through Cholic Acid (CA) - Farnesoid X Receptor (FXR) Pathway.

BACKGROUND: Persistent hyperlactatemia is associated with greater mortality in shock. Liver is the main site of lactate metabolism. METHOD: In the first part, freshly isolated hepatocytes were incubated in 10% fetal bovine serum William's E medium supplemented with 10 mM lactate. Cells were then exposed to 100 µM ursodeoxycholic acid (UDCA), with no addition (control) for 2, 4, 6, 8 h. In the second part, hepatocytes were treated with Silencer select siRNA targeting FXR or scramble siRNA. The siRNA treatment was repeated twenty four hours later, and the cells were used in the experiments twenty-four hours after the second treatment. Then hepatocytes were incubated in 10% fetal bovine serum William's E medium supplemented with 10 mM lactate. Cells were then exposed to 100 µM UDCA for 2, 4, 6, 8 h. Lactate concentration was determined by ABL80 automatic blood gas analyzer. RESULTS: UDCA increased ability of hepatocytes to remove lactate. After the knockdown of FXR, effects caused by UDCA were weakened. CONCLUSION: These results demonstrate that UDCA promotes lactate metabolism in mouse hepatocytes through CA-FXR pathway.

Synthesis and biological evaluation of novel biphenyl-furocoumarin derivatives as vasodilator agents.

A series of novel biphenyl-furocoumarin derivatives were synthesized based on the nuclear structure of imperatorin and identified by IR, 1H NMR, 13C NMR and MS, and evaluated for their ability to relax vessel on isolated rat mesenteric artery, basilar artery and renal artery, respectively. The majority of compounds demonstrated potent vasodilatation, and compound 8e expressed the highest activity (EC50 = 0.56 µM) in MA. Compounds with fluorine at 2-position of 5-phenyl get better activity than others with chlorine or bromine, and the compounds containing a bulky structure had relatively low activity, such as 8c (EC50 = 22.39 µM) in MA. As a follow-up, 8e, 10e, and 8c were docked into L-calcium channel (PDB code: 3G43) to explain the difference in the activity of the compounds.

Resuscitation incoherence and dynamic circulation-perfusion coupling in circulatory shock.

OBJECTIVE: Poor tissue perfusion/cellular hypoxia may persist despite restoration of the macrocirculation (Macro). This article reviewed the literatures of coherence between hemodynamics and tissue perfusion in circulatory shock. DATA SOURCES: We retrieved information from the PubMed database up to January 2018 using various search terms or/and their combinations, including resuscitation, circulatory shock, septic shock, tissue perfusion, hemodynamic coherence, and microcirculation (Micro). STUDY SELECTION: The data from peer-reviewed journals printed in English on the relationships of tissue perfusion, shock, and resuscitation were included. RESULTS: A binary (coherence/incoherence, coupled/uncoupled, or associated/disassociated) mode is used to describe resuscitation coherence. The phenomenon of resuscitation incoherence (RI) has gained great attention. However, the RI concept requires a more practical, systematic, and comprehensive framework for use in clinical practice. Moreover, we introduce a conceptual framework of RI to evaluate the interrelationship of the Macro, Micro, and cell. The RI is divided into four types (Type 1: Macro-Micro incoherence + impaired cell; Type 2: Macro-Micro incoherence + normal cell; Type 3: Micro-Cell incoherence + normal Micro; and Type 4: both Macro-Micro and Micro-cell incoherence). Furthermore, we propose the concept of dynamic circulation-perfusion coupling to evaluate the relationship of circulation and tissue perfusion during circulatory shock. CONCLUSIONS: The concept of RI and dynamic circulation-perfusion coupling should be considered in the management of circulatory shock. Moreover, these concepts require further studies in clinical practice.

Refined assessment of heavy metal-associated health risk due to the consumption of traditional animal medicines in humans.

Little is known about the extent of heavy metal accumulation in traditional Chinese medicines (TCMs). In this study, the levels of lead (Pb), cadmium (Cd), arsenic (As), and mercury (Hg) in traditional animal medicines were monitored using inductively coupled plasma mass spectroscopy (ICP-MS). Additionally, for the first time, a heavy metal risk assessment strategy was used to evaluate the potential risks of traditional animal medicines by calculating estimated daily intake (EDI), target hazard quotient (THQ), and cancer risk (CR). To obtain a refined risk assessment, the frequency of exposure to traditional animal medicines was determined from questionnaire data, and the safe factor for TCM was applied. Based on the standard levels for leech, it was found that earthworm, hive, scorpion, and leech accumulated high levels of heavy metals. The combined THQ (cTHQ) values indicated that ingestion of most traditional animal medicines would not pose a risk to the health of either male or female human beings. However, it was indicated that attention should be paid to the potential risk associated with cicada slough, earthworm, scorpion, turtle shells, and hive. Among heavy metals, As and Hg contributed to a major extent to the risk to human health. The CR assessment for Pb and As indicated that, with the exception of earthworm, the cancer risk was less than the acceptable lifetime risk for both males and females. Owing to the higher body weight, both THQ and CR were generally lower for males than for females.

Design, synthesis, and evaluation of new series of Imperatorin analogs with potential vasodilatory activity.

Two series of imperatorin analogs were synthesized based on our previous research and evaluated for their vasodilatation activities on in vitro rat mesenteric artery, basilar artery, and renal artery ring models. Target compounds were characterized by infrared, 1H NMR, and mass spectra. Most derivatives possessed significant vasodilatory activity on the mesenteric artery, and compound 3a exhibited favorable and broad vasodilatation activities on three kinds of rat artery ring models. The pharmacological results indicated that introducing nitrogen-contained ring in side chain or large steric hindrance at the distal end could increase the vasodilatory activity. Further, replacement of oxygen atom (-O-) in the skeleton of furocoumarin derivatives with nitrogen (-NH-) could cause the decrease of vasodilatory activity. The molecular docking also indicated that compound 3a showed a best affinity with α-1C receptor (PDB ID: 3G43). All these results suggested compound 3a would be a potential vasodilatory agent for hypertension.