Comment on: "Effect of Combining Obtusifolin and Amlodipine on Their Antihypertensive Effects and its Potential Mechanism".

Metabolic considerations in the approach to diabetic hypertensive patients

The antihypertensive, diuretic, and toxicological effects of S‐8666 were studied in rats. At doses of more than 60 mg/kg/day, p.o., S‐8666 was antihypertensive in DOCA‐salt hypertensive rats with a potency corresponding to 1/20 of that of trichlormethiazide. The antihypertensive effect was dose‐dependent, and, at the higher doses, S‐8666 had a more potent depressor effect than trichlormethiazide. The antihypertensive activity of S‐8666 was shown predominantly by the S‐(−)‐enantiomer, with the R‐(+)‐enantiomer being only slightly active. A similar dose‐dependent antihypertensive effect was shown by furosemide, tienilic acid, or indacrinone, but the therapeutic index (LD50/minimum effective dose) of S‐8666 was the highest among them. The acute diuretic and natriuretic effects of S‐8666 after oral administration of 60–200 mg/kg to DOCA‐salt hypertensive rats correlated well with its antihypertensive effect, although such diuretic and natriuretic effects in normotensive rats had no effect on blood pressure. S‐8666, like trichlormethiazide, showed a prophylactic effect on the development of hypertension in DOCA‐salt hypertensive rats, salt‐loaded spontaneously hypertensive rats (SHR), and salt‐loaded Dahl‐S rats, though it was much less potent. Moreover, the combination of S‐8666 with captopril in SHR enhanced the depressor effect of captopril like hydrochlorothiazide. These results indicate that S‐8666 can be an effective nonthiazide diuretic for use as an antihypertensive agent.

(1) Background: Arterial stiffness is closely and bi-directionally related to hypertension and is understood as both a cause and a consequence of hypertension. Several studies suggest that antihypertensive drugs may reduce arterial stiffness. Therefore, effective prescription of antihypertensive drugs should consider both blood pressure and arterial stiffness. The aim of this protocol is to provide a review comparing the effects of different types of antihypertensive drug interventions on the reduction of arterial stiffness in hypertensive subjects. (2) Methods: The literature search will be performed through the MEDLINE, EMBASE, Cochrane Central Register of Controlled Trials, Cochrane Database of Systematic Reviews, and Web of Science databases. Randomised clinical trials assessing the effect of antihypertensive drug interventions on arterial stiffness measured in subjects with hypertension will be included. A frequentist network meta-analysis will be performed to determine the comparative effects of different antihypertensive drugs. (3) Results: The findings of this study will be published in a peer-reviewed journal. (4) Conclusions: This study will provide evidence for health care professionals on the efficacy of different antihypertensive drugs in decreasing arterial stiffness; in addition, it will analyse the efficacy of the drugs not only in terms of arterial stiffness but also in terms of blood pressure treatment.

Hypertension and osteoporosis are common comorbidities among elderly individuals. Drug therapy has been widely used in clinical practice as the preferred antihypertensive treatment. Therefore, antihypertensive drugs have become some of the most commonly prescribed drugs in healthcare settings. However, antihypertensive drugs have different effects on bone metabolism. The results of animal and clinical studies on the effects of antihypertensive drugs on osteoporosis or fracture risk are controversial and have aroused widespread concern among clinicians. Recent studies found that angiotensin receptor blockers, selective β-adrenergic receptor blockers, and thiazide diuretics might improve bone trabecular number and bone mineral density by stimulating osteoblast differentiation, reducing osteoclast generation, and other mechanism. Furthermore, nonselective β-adrenergic receptor blockers and dihydropyridine calcium channel blockers were found to have no significant relationship with bone mineral density or bone strength, and α-adrenergic receptor blockers and loop diuretics might increase fracture risk by decreasing bone mineral density. This article aimed to review previous animal experiments, clinical studies, and meta-analyses focusing on the effects of different antihypertensive drugs on bone metabolism, and to provide a new approach for the prevention and treatment of osteoporosis.

The effects of several antihypertensive drugs on bone mineral density (BMD) and micro-architectural changes in ovariectomized (OVX) mice were investigated. Eight-week-old female C57/BL6 mice were used for this study. Three days after ovariectomy, mice were treated intraperitoneally with nifedipine (15 mg/kg), telmisartan (5 mg/kg), enalapril (20 mg/kg), propranolol (1 mg/kg) or hydrochlorothiazide (12.5 mg/kg) for 35 consecutive days. Uterine atrophy of all mice was confirmed to evaluate estrogen deficiency state. BMD and micro-architectural analyses were performed on tibial proximal ends by micro-computed tomography (micro-CT). When OVX mice with uterine atrophy were compared with mice without atrophy, BMD decreased (P < 0.001). There were significant differences in BMD loss between different antihypertensive drugs (P = 0.005). Enalapril and propranolol increased BMD loss in mice with atrophied uteri compared with control mice. By contrast, thiazide increased BMD in mice with uterine atrophy compared with vehicle-treated mice (P = 0.048). Thiazide (P = 0.032) and telmisartan (P = 0.051) reduced bone loss and bone fraction in mice with uterine atrophy compared with the control. Thiazide affects BMD in OVX mice positively. The reduction in bone loss by thiazide and telmisartan suggest that these drugs may benefit menopausal women with hypertension and osteoporosis.

Cardiovascular effects of antihypertensive drugs — Involvement in the therapeutic choice

Indapamide, a non-thiazide antihypertensive diuretic agent, has been widely coadministered with other classes of antihypertensive agents to reach target systolic blood pressure. Indapamide is extensively metabolized by cytochromes P450. Interaction of indapamide and other antihypertensive drugs are unknown. We investigated the effects of other antihypertensive drugs on the metabolism and pharmacokinetics of indapamide in vitro and in vivo. Indapamide metabolism was studies in vitro using human liver microsomes pretreated with or without different concentrations of CYP-selective inhibitors and seven major antihypertensive drugs, felodipine, nifedipine, nitrendipine, telmisartan, irbesartan, valsartan and puerarin. Furthermore, the pharmacokinetics of indapamide was determined by HPLC-MS/MS to evaluate the effects of felodipine coadministered on the bioavailability of indapamide in rats in vivo. The Km and Vmax of indapamide metabolism were 114.35 ± 3.47 μM and 23.13 ± 6.61 μmol/g/min. The metabolites of indapamide, hydroxyl-indapamide and dehydrogen-indapamide, were followed. CYP3A4 and CYP2C19 were involved in indapamide metabolism in human live microsomes. In addition, felodipine, nifedipine and nitrendipine significantly inhibited indapamide metabolism with the maximum inhibitory rates of 82.6%, 72% and 95%, respectively. Felodipine significantly elevated indapamide plasma concentration and prolonged its half-life. Combination therapy of indapamide and felodipine might lead to the alteration of indapamide metabolism and pharmacokinetics. The consequence of such an interaction that may include increased effectiveness and side effect needs to be tudeis in human.

Black people have a greater prevalence of elevated blood pressure leading to excess morbidity and mortality. To systematically review the effects of different antihypertensive drugs on mortality, morbidity and blood pressure black adults with elevated blood pressure. Medline, Embase, LILACS, African Index Medicus, the Cochrane Library November 2003; Pubmed September 2003 to March 2004. Searches were conducted without language restriction. Randomised controlled trials of drugs versus placebo (blood pressure outcomes) or versus placebo or other drugs (morbidity and mortality outcomes). Two reviewers independently extracted data unblinded. Disagreements were resolved by discussion. Authors were contacted twice to obtain missing information. Full reports or abstracts from more than 2900 references of papers yielded 30 trials considering 53 interventions with 8 classes of antihypertensive drugs in 20,006 black patients from Africa, the Caribbean, and the United States of America, aged 18 to >80 years. In one large trial the main morbidity and mortality outcomes did not differ significantly between initial treatment drug classes when drugs were added to reach goal blood pressures. However, the comparison ACE Inhibitors vs diuretic favoured the diuretic for stroke 1.40 [1.17 to 1.68]; combined CHD 1.15 [1.02 to 1.30] and combined CVD 1.19 [1.09 to 1.30] and the comparison alpha blocker vs diuretic favoured the diuretic for combined CVD 1.40 [1.25 to 1.57]. In addition, all comparisons for heart failure favoured diuretic (1.47 [1.24 to 1.74] vs calcium blocker; 1.32 [1.11 to 1.58] vs ACE Inhibitor; and 2.18 [1.73 to 2.74] vs alpha blocker. The results also showed a greater occurrence of diabetes with diuretics. No significant differences were detected between placebo and beta adrenergic blockers in the reduction of systolic blood pressure (weighted mean difference [95% CI], -3.52 [-7.50 to 0.46] mm Hg). In addition, ACE inhibitors did not significantly differ from placebo in achievement of goal diastolic blood pressure (risk difference [95% CI], 5% [-10% to 21%]). Calcium blockers, diuretics, centrally acting agents, alpha adrenergic blockers and angiotensin II antagonists were all more effective than placebo in reducing blood pressure in the pooled analyses. Only calcium blockers remained effective in all prespecified subgroups, including baseline diastolic blood pressure >109 mm Hg. When first-line drugs from different classes are compared in the treatment of black people, there is no evidence of differential effects on most mortality and morbidity outcomes. Those morbidity differences that were found favoured diuretics. Drugs differ in their ability to reduce blood pressure in black people. Calcium blockers were the only drug class that reduced blood pressure in all subgroups of black people including those with severe hypertension. Beta-blockers, angiotensin receptor blocker, alpha blockers and ACE Inhibitors were least good at reducing blood pressure in black adults.

This review examines the effects of various antihypertensive drugs on blood lipids, lipoproteins, and apolipoproteins. A large number of studies have documented the elevation of total cholesterol, triglycerides, low density lipoprotein (LDL) cholesterol, and very-low density lipoprotein (VLDL) cholesterol with many thiazide-type diuretic drugs, albeit mainly in short term studies. When added to thiazide diuretics, both beta 1-selective and non-selective beta-blocking drugs elevate total triglycerides and VLDL triglycerides, lower high density lipoprotein (HDL) cholesterol and raise the ratio of total cholesterol to HDL cholesterol ratio. Most non-selective beta-blockers have similar effects when used as monotherapy, but the beta 1-selective agents appear not to affect HDL cholesterol in monotherapy. Prazosin appears free of adverse lipid effects and has improved lipid-lipoprotein concentrations in many studies. Preliminary data on several other drugs also suggest a favourable lipid profile and additional study is warranted - among these are guanabenz, clonidine, pindolol, labetalol, indapamide, and guanfacine. Elevations in serum triglycerides are often ignored on various counts, but triglycerides have been found to be a strong risk factor in European studies and in women over the age of 50 years in the Framingham study. Despite the unfavourable short term effects of diuretics, the theoretical risk of the lipid-lipoprotein changes remains unclear because HDL cholesterol and the total cholesterol to HDL cholesterol ratio are often unchanged. For this and other reasons, a long term trial comparing thiazide-type diuretics with drugs with the most favourable lipid-lipoprotein profile is needed. Until this is accomplished, in most settings diuretic-based regimens are still preferred initially since they are of proven, if limited, efficacy against the cardiovascular complications of hypertension.

This paper reviews published data concerning the effects of antihypertensive drugs on the development of atherosclerosis in experimental animal models with hyperlipoproteinaemia. Emphasis is placed on the influence of calcium channel antagonists on this process, and the potential mechanisms responsible for the effect. In addition, studies of the action of beta-receptor antagonists on atherogenesis are also summarized. The results indicate that several antihypertensive drugs may inhibit or retard experimentally-induced atherogenesis, even in normotensive animals, although the mechanisms for the effects remain poorly understood.

BackgroundWe systematically reviewed Mendelian randomization (MR) studies and summarized evidence on the potential effects of different antihypertensive drugs on health.MethodsWe searched PubMed and Embase for MR studies evaluating the effects of antihypertensive drug classes on health outcomes until 22 May 2024. We extracted data on study characteristics and findings, assessed study quality, and compared the evidence with that from randomized controlled trials (RCTs).ResultsWe identified 2643 studies in the search, of which 37 studies were included. These studies explored a wide range of health outcomes including cardiovascular diseases and their risk factors, psychiatric and neurodegenerative diseases, cancer, immune function and infection, and other outcomes. There is strong evidence supporting the protective effects of genetically proxied antihypertensive drugs on cardiovascular diseases. We found strong protective effects of angiotensin-converting enzyme (ACE) inhibitors on diabetes whereas beta-blockers showed adverse effects. ACE inhibitors might increase the risk of psoriasis, schizophrenia, and Alzheimer’s disease but did not affect COVID-19. There is strong evidence that ACE inhibitors and calcium channel blockers (CCBs) are beneficial for kidney and immune function, and CCBs showed a safe profile for disorders of pregnancy. Most studies have high quality. RCT evidence supports the beneficial effects of ACE inhibitors and CCBs on stroke, diabetes, and kidney function. However, there is a lack of reliable RCTs to confirm the associations with other diseases.ConclusionsEvidence of the benefits and off-target effects of antihypertensive drugs contribute to clinical decision-making, pharmacovigilance, and the identification of drug repurposing opportunities.

Aims: To synthesize and evaluate the available scientific evidence on the efficacy of antihypertensive drugs on arterial stiffness in patients with hypertension by using a network meta-analysis approach. Methods: A systematic search of the MEDLINE (via PubMed), Scopus, and Web of Science databases was conducted to identify experimental studies addressing the effect of different antihypertensive drugs on arterial stiffness parameters (pulse wave velocity [PWV] and augmentation index [AIx]) in adults with hypertension. Comparative evaluation of the effect of antihypertensive drugs was performed by conducting a standard pairwise meta-analysis and a network meta-analysis for direct and indirect comparisons between antihypertensive drugs and placebo/other antihypertensive drugs. Analyses were performed including studies of any duration and only studies longer than 6months length. Results: Seventy-six studies were included in the main analysis and considering only studies longer than 6months length, thiazide diuretics, ACEIs, ARBs, the ACEI/ARB combination, the ACEI/CCB combination, and the ARB/CCB combination showed a higher effect on reducing PWV, and ACEIs and ARBs on reducing AIx. Conclusion: Our research provides evidence that antihypertensive medications are an effective way to treat arterial stiffness in adults with hypertension. Based on our findings, patients with hypertension who have greater levels of arterial stiffness may benefit from using thiazide diuretics, ACEIs, ARBs, the ACEI/ARB combination, the ACEI/CCB combination, and the ARB/CCB combination. Systematic Review Registration: PROSPERO (CRD42021276360).

Abnormal glucose metabolism is a common disease of the endocrine system. The effects of drugs on glucose metabolism have been reported frequently in recent years, and since abnormal glucose metabolism increases the risk of microvascular and macrovascular complications, metabolic disorders, and infection, clinicians need to pay close attention to these effects. A variety of common drugs can affect glucose metabolism and have different mechanisms of action. Hypertension is a common chronic cardiovascular disease that requires long-term medication. Studies have shown that various antihypertensive drugs also have an impact on glucose metabolism. Among them, α-receptor blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and calcium channel blockers can improve insulin resistance, while β-receptor blockers, thiazides and loop diuretics can impair glucose metabolism. The aim of this review was to discuss the mechanisms underlying the effects of various antihypertensive drugs on glucose metabolism in order to provide reference information for rational clinical drug use.

Background; Hypertension is the major leading risk factor for atherosclerosis and other diseases, especially renal and cardiovascular disorders, including myocardial infarction, stroke, and heart failure. Blood pressure may be influenced by either genetic and/or lifestyle factors including nutrition, smoking, high blood glucose and high body-mass index. Global mortality due to hypertension is currently over 30 million and may increase to 40 million annually by 2030. Objectives: This research work was designed to evaluate the antihypertensive and electrolyte modulatory effect of ethanol extract of Terminalia catappa leaf following L-NAME induced hypertension in male Wistar rats. Methods: In this present work, thirty- five (35) Wistar male rats was allowed to acclimatize for a period of 7 days, in a well-ventilated room at room temperature and relative humidity of 29°C and 70% respectively with 12 hours natural light-dark cycle Hypertension was induced by intraperitoneal administration of L-NG-nitro arginine methyl ester (L-NAME) (40 mg/kgb.wt/day in distilled water. Treatment was carried out as follows: group 1 (normal control) received only the vehicle (Normal saline) orally, group 2 (hypertensive control) received L-NAME (40 mg/kgb wt/day) intraperitoneally for 2 successive weeks; group 3 ( standard control) L-NAME (40 mg/kgb .wt/day) +20mg/kg b.wt /day of amlodipine while group 4 and 5 (reference groups) received L-NAME + extract of T. catappa (200 and 400 mg/kg b .wt/day respectively for 2 successive weeks. Blood was collected by cardiac puncture under plane sterile tubes for serum electrolytes and lipid profile. Results: The result displayed that T. catappa leaf produced a significant (p&lt;0.05) decrease in serum Na+, K+, Ca2+, Cl- ion concentration when compared with normotensive and hypertensive. The extract significantly (p&lt;0.05) increased serum HDL and triacyl glycerides, but lowered the serum LDL, total –cholesterol when compared with normotensive, hypertensive and standard control. Conclusion: It can be inferred from this present work that extract of Terminalia catappa might inhibit predisposition to hypertension and/ or contain some bioactive compounds with antihypertensive effect and might be useful in the management of pathological conditions associated with cardiovascular dysfunction possibly by deactivation of either the brain renin–angiotensin–aldosterone system (RAAS) or sympathetic nervous system.

Antihypertensive and vasorelaxant effects on KRN2391 in spontaneously hypertensive rats