Hypertension is a frequent condition encountered during kidney disease development and a leading cause in its progression. Hallmark factors contributing to hypertension constitute a complexity of events that progress chronic kidney disease (CKD) into end-stage renal disease (ESRD). Multiple crosstalk mechanisms are involved in sustaining the inevitable high blood pressure (BP) state in CKD, and these play an important role in the pathogenesis of increased cardiovascular (CV) events associated with CKD. The present review discusses relevant contributory mechanisms underpinning the promotion of hypertension and their consequent eventuation to renal damage and CV disease. In particular, salt and volume expansion, sympathetic nervous system (SNS) hyperactivity, upregulated renin–angiotensin–aldosterone system (RAAS), oxidative stress, vascular remodeling, endothelial dysfunction, and a range of mediators and signaling molecules which are thought to play a role in this concert of events are emphasized. As the control of high BP via therapeutic interventions can represent the key strategy to not only reduce BP but also the CV burden in kidney disease, evidence for major strategic pathways that can alleviate the progression of hypertensive kidney disease are highlighted. This review provides a particular focus on the impact of RAAS antagonists, renal nerve denervation, baroreflex stimulation, and other modalities affecting BP in the context of CKD, to provide interesting perspectives on the management of hypertensive nephropathy and associated CV comorbidities.
Increased stiffness of large arteries in chronic kidney disease (CKD) has significant clinical implications. This study investigates the temporal development of thoracic aortic dysfunction in a rodent model of CKD, the Lewis polycystic kidney (LPK) rat. Animals aged 12 and 18 weeks were studied alongside age-matched Lewis controls (total n = 94). LPK rodents had elevated systolic blood pressure, left ventricular hypertrophy and progressively higher plasma creatinine and urea. Relative to Lewis controls, LPK exhibited reduced maximum aortic vasoconstriction (Rmax) to noradrenaline at 12 and 18 weeks, and to K(+) (12 weeks). Sensitivity to noradrenaline was greater in 18-week-old LPK vs. age matched Lewis (effective concentration 50%: 24 × 10(-9) ± 78 × 10(-10) vs. 19 × 10(-8) ± 49 × 10(-9), P < 0.05). Endothelium-dependent (acetylcholine) and -independent (sodium nitroprusside) relaxation was diminished in LPK, declining with age (12 vs. 18 weeks Rmax: 80 ± 8% vs. 57 ± 9% and 92 ± 6% vs. 70 ± 9%, P < 0.05, respectively) in parallel with the decline in renal function. L-Arginine restored endothelial function in LPK, and L-NAME blunted acetylcholine relaxation in all groups. Impaired nitric oxide synthase (NOS) activity was recovered with L-Arginine plus L-NAME in 12, but not 18-week-old LPK. Aortic calcification was increased in LPK rats, as was collagen I/III, fibronectin and NADPH-oxidase subunit p47 (phox) mRNAs. Overall, our observations indicate that the vascular abnormalities associated with CKD are progressive in nature, being characterized by impaired vascular contraction and relaxation responses, concurrent with the development of endothelial dysfunction, which is likely driven by evolving deficits in NO signaling.
Palm oil esters are high molecular weight esters oil that has been newly synthesized by University Putra Malaysia researchers. It has received a lot of attention for its pharmaceutical and chemical application. The aim of this study is to study the effects of the palm oil esters with different HLB surfactant mixture on the ternary diagrams behaviour and to confine the various systems resulted from these combinations. These systems include traditional emulsion, gel area, transpernat micro-emulsion area, O/W and W/O emulsions. In this study, pseudoternary phase diagrams of water, POEs and non-ionic surfactant mixture of several HLB values were constructed using water titration method. The resultant mixtures collected after each addition and mixing of water were analysed visually, along with conductivity, dilution in water and dye test (methylene blue) to classify them as O/W emulsion (transparent and opaque) or W/O (opaque) and liquid or gel. As a conclusion, palm oil esters were found to be suitable for the formulation of different types of emulsion. Additionally, different HLB value of non-ionic surfactant(s) exhibited different pseudoternary phase diagram characteristics. Keywords: palm oil esters, Tween, Span, Pseudoternary phase diagram, O/W emulsion
In the present study, L. ferrugineus methanol extract (LFME) was evaluated for its blood pressure lowering effect in anesthetized normotensive Sprague Dawley (SD) rats and its spasmogenic effect in isolated guinea pig ileum. The possible mechanism(s) of action were also investigated. LFME was obtained by Soxhlet extraction. The rats were fasted overnight and anesthetized with sodium pentobarbitone (60 mg/kg i.p.). LFME was administered in i.v. boluses in the concentrations of 25, 50, 100 and 200 mg/kg respectively, with concomitant monitoring of mean arterial pressure (MAP). It was found that LFME dose-dependently reduced MAP. An i.v. bolus injection of atropine significantly decreased the blood pressure lowering effect of LFME. Similarly, L-NAME (Nω-nitro-L-arginine methyl ester) significantly lowered both the MAP and the action duration. Conversely, no significant change in MAP was seen following i.v. injections of neostigmine, hexamethonium, prazosin and propranolol. LFME also produced a dose-dependent contractile effect in guinea pig ileum. This contraction was significantly reduced in atropine pre-incubated tissue segments, yet it was significantly enhanced in the presence of neostigmine. No appreciable change in the ability of LFME to contract guinea pig ileum was seen in the presence of hexamethonium. Accordingly, it can be postulated that LFME possesses a marked hypotensive effect that can be attributed to stimulation of muscarinic receptors and/or stimulation of nitric oxide (NO) release. Moreover, LFME retains a considerable spasmogenic action due to its cholinergic properties. The hypotensive and spasmogenic effects of LFME justify its traditional uses.
This study investigated the impact of acute renal denervation (ARD) on sodium and water excretory responses to i.v. infusion of norepinephrine (NE) and angiotensin II (Ang II) in anesthetized spontaneously hypertensive rats (SHR). Anesthetized SHR were acutely denervated and NE or Ang II was continuously infused for 1hr. A screw‐controlled snare was placed around the aorta above the renal arteries and systemic blood pressure was regulated to avoid any increments in the renal perfusion pressure (RPP) in response to the vasoactive stimuli. Three 20min urine clearances were collected to measure urine flow rate (V) and sodium excretion (U Na V). The administration of NE or Ang II to innervated SHR produced marked (P<0.05) antidiuresis/antinatriuresis response compared to innervated saline treated SHR. Lower (P<0.05) diuresis/natriuresis response was observed in denervated NE treated SHR compared to denervated saline treated rats. There was a larger (P<0.05) diuresis/natriuresis response to ARD in Ang II treated SHR compared to denervated saline treated counterparts. NE retains its typical antidiuretic/antinatriuretic action in denervated SHR. Data demonstrated that the antidiuretic/antinatriuretic action of Ang II depends on the presence of intact renal innervation. It can also be suggested that Ang II facilitates the NE release from renal sympathetic nerve by a presynaptic action.
Abstract ID 96015Poster Board 465 The relationship between metabolic syndrome and vascular dysfunction is a prominent factor in the development of cardiovascular diseases. Previous data from our laboratory demonstrated functional and structural abnormalities within the aortic vasculature of the high-fat diet (HFD)-streptozotocin (STZ)-induced diabetes mellitus (HFD-D) rat model of metabolic syndrome. We further showed that a direct association between altered metabolic profile and deficits in endothelium-dependent relaxation exists. In the present study, changes in nitric oxide (NO) pathway, a critical determinant of endothelium-dependent relaxation, and their association with impaired metabolic parameters in HFD-D rats was investigated. Five-week-old male Wistar albino rats (n = 24) were fed with either HFD (45 kcal% fat) or control diet (10 kcal% fat) for 10 weeks. On week 6, 40 mg/kg STZ and saline were injected (i.p.) into the HFD and control groups, respectively. By week 10, tail systolic blood pressure (SBP) was recorded, and metabolic data were collected. Subsequently, the rats were euthanized, and blood, liver, and kidney samples were collected. Maximal NO-dependent vasorelaxation was assessed in abdominal aortic rings precontracted with phenylephrine (1 μM) and preincubated with the nitric oxide synthase (NOS) inhibitor Nω-nitro-L-arginine methyl ester (L-NAME, 10 μM). Collected measures also included fasting blood glucose (FBG), plasma total cholesterol (TC), plasma triglyceride (TG), plasma high-density lipoprotein (HDL), plasma creatinine (Cr), urinary protein: urinary creatinine (UPC), liver index (LI), and kidney index (KI). HFD-D rats had higher SBP, FBG, TG, Cr, UPC, LI and KI, lower HDL and unchanged TC compared with controls. Maximal NO-induced vasorelaxation (NO Rmax) was markedly blunted in the HFD-D rats compared with controls. NO Rmax showed negative correlations with FBG, TG, Cr, UPC, LI, and KI, while positive correlations were observed with HDL and TC. No significant correlation was found between NO Rmax and SBP. Our previous demonstration of impaired endothelial-dependent relaxation in metabolic syndrome is likely contributed to by a parallel impairment in NO-induced vasorelaxation. It is also plausible that deficits in NO-dependent vasorelaxation stem from the disturbed metabolic function observed in this model. Further research is warranted to provide a comprehensive mechanistic explanation to the above findings. This study was funded by the Alfaisal University Internal Research Grant (IRG-20307), Riyadh, Saudi Arabia.
Among the various NSAIDs used in the treatment of joint pain and osteoarthritis, ibuprofen, a propionic acid derivative, has been widely used for these purposes. In the present investigation, we modified and validated an HPLC method to obtain an accurate, sensitive and precise procedure to be exploited in the quantification of ibuprofen concentrations without interference from other ingredients present in the formulation. The HPLC method reported by Owen et al. (1987) was modified to fulfill our objectives, since the mobile phase used by the authors did not efficiently separate the drug peak from those of the formulation excipients. The modified mobile phase comprised 5 mM of disodium hydrogen phosphate adjusted to pH 3 with concentrated orthophosphoric acid, methanol and acetonitrile at ratios of 28:20:52, respectively. The method was found to be specific, precise, accurate and reproducible when carried out on intra-day and inter-day basis. The limit of detection and quantification were determined to be 0.03125 μg/mL and 0.0625 μg/mL, respectively. The data collectively showed that the current HPLC method is sufficiently sensitive to detect low concentration ranges of ibuprofen present in poor-transference topical delivery systems. Keywords: HPLC, Ibuprofen, Modification and Validation, NSAID.
Background Artificial intelligence (AI) is revolutionizing medical education; however, its limitations remain underexplored. This study evaluated the accuracy of three generative AI tools—ChatGPT-4, Copilot, and Google Gemini—in answering multiple-choice questions (MCQ) and short-answer questions (SAQ) related to cardiovascular pharmacology, a key subject in healthcare education. Methods Using free versions of each AI tool, we administered 45 MCQs and 30 SAQs across three difficulty levels: easy, intermediate, and advanced. AI-generated answers were reviewed by three pharmacology experts. The accuracy of MCQ responses was recorded as correct or incorrect, while SAQ responses were rated on a 1–5 scale based on relevance, completeness, and correctness. Results ChatGPT, Copilot, and Gemini demonstrated high accuracy scores in easy and intermediate MCQs (87–100%). While all AI models showed a decline in performance on the advanced MCQ section, only Copilot (53% accuracy) and Gemini (20% accuracy) had significantly lower scores compared to their performance on easy-intermediate levels. SAQ evaluations revealed high accuracy scores for ChatGPT (overall 4.7 ± 0.3) and Copilot (overall 4.5 ± 0.4) across all difficulty levels, with no significant differences between the two tools. In contrast, Gemini’s SAQ performance was markedly lower across all levels (overall 3.3 ± 1.0). Conclusion ChatGPT-4 demonstrates the highest accuracy in addressing both MCQ and SAQ cardiovascular pharmacology questions, regardless of difficulty level. Copilot ranks second after ChatGPT, while Google Gemini shows significant limitations in handling complex MCQs and providing accurate responses to SAQ-type questions in this field. These findings can guide the ongoing refinement of AI tools for specialized medical education.
Background/Aims: Chronic kidney disease (CKD) is associated with large artery remodeling, endothelial dysfunction and calcification, with angiotensin II (Ang II) a known driver of these pathologies. We investigated long-term Ang II type 1 receptor inhibition with valsartan on aortic function and structure in the Lewis polycystic kidney (LPK) rat model of CKD. Methods: Mixed sex LPK and Lewis control (total n = 28) treated (valsartan 60 mg/kg/day p.o. from 4 to 18 weeks) and vehicle groups were studied. Functional responses to noradrenaline (NA), potassium chloride and endothelium-dependent and independent relaxations were investigated in vitro using acetylcholine hydrochloride (ACh) and sodium nitroprusside (SNP), respectively. Effects of the nitric oxide synthase (NOS) substrate L-arginine, NOS inhibitor L-NAME and cyclooxygenase inhibitor indomethacin on ACh responses were examined. Results: In the LPK, valsartan reduced systolic blood pressure and urinary protein, ameliorated exaggerated sensitivity to NA, and normalized endothelium-dependent (ACh-Rmax; 91 ± 7 vs. 59 ± 6%, p = 0.0001) and independent dysfunction (SNP-Rmax; 99 ± 1 vs. 82 ± 7%, p = 0.040), as well as improving NO-dependent relaxation (Rmax; -51 ± 6 vs. -26 ± 9%, p = 0.008). Valsartan also reduced aortic wall hypertrophy, elastin disruption/fragmentation, calcification, media cystic degeneration, and levels of matrix metalloproteinase 9. Conclusions: This study highlights the role of Ang II in driving vascular manifestations of CKD and indicates that early treatment can significantly limit pathological changes.
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