Approximately 1.3 billion adults globally have hypertension, and are at higher risk of death associated with cardiovascular disease. Adjusted death rate primarily due to high blood pressure is 31.3 per 100,000. The prevalence of drug-resistant hypertension is estimated to be up to 20 % in hypertensive individuals, and is more common in those with chronic kidney disease and obstructive sleep apnea. It occurs in individuals on ≥3 antihypertensive drugs including a diuretic. The addition of spironolactone, as a fourth drug has been found at times to be effective in management of blood pressure. Other strategies include sequential nephron block (e.g., spironolactone + furosemide + amiloride), and use of drugs such as alpha2 agonists, endothelin antagonists, and nonsteroidal mineralocorticoid antagonists. Use of positive airway pressure and pharmacotherapy have been found to be of value in individuals with sleep apnea in lowering blood pressure. In contrast, baroreceptor stimulation and/or renal denervation combined with pharmacotherapy seem to offer little in a way of consistent efficacy of optimally lowering blood pressures. Remarkably, evidence in the literature strongly supports the view that life style changes including regular exercise and appropriate diet combined with pharmacotherapy can lead to positive outcomes in helping to significantly reduce blood pressure. There is also ample data in literature suggesting the non-compliance to antihypertensive medications as a significant barrier to lowering blood pressure in this group. Accordingly, education regarding pharmacotherapy, and appropriate exercise regimen, including changes to diet should underpin any strategy in the management of high blood pressure in this population.

Abstract Piezo are mechanosensitive non‐selective cation channels that are suggested to be involved in vascular development and function. The aim of our study was to determine any sex‐specific contributions of the mechanosensitive Piezo 1 channels on blood vessel wall stiffness. Composite Young modulus (CYM) was determined using pressure myograph experimental approach using third‐order mesenteric arteries (intact and denuded) from Dahl salt‐sensitive male and female normotensive and hypertensive rats (n = 6–8). The effects of Piezo 1 agonist (Yoda 1; 10 μM), and antagonist (GsMTx‐4; 2 μM) were studied in intact and denuded vessels. The distribution of Piezo 1 was identified using immunohistochemistry. In intact blood vessels, there were no differences in CYM between the experimental groups, however, removal of the endothelium unmasked significant increases in CYM in normotensive males and female groups compared to hypertensive males. The presence of Yoda 1 did not affect CYM in any groups. In the intact tissues, GsMTx‐4 led to significant increases in CYM in hypertensive females, and normotensive males and females, but not in hypertensive males. In the denuded vessels, GsMTx‐4, produced a significant increase in CYM but only in the female normotensives. Differential expression of Piezo 1 were found in male versus female blood vessels. Our findings support a greater contribution of Piezo 1 mechanoceptors to vascular biomechanics of male hypertensive compared to male normotensive or female groups. The evidence also points to a possible differential vasoregulatory role for Piezo 1 in endothelial versus vascular smooth cells, with a greater contribution in males than females.

Heart failure (HF) as a syndrome which is normally associated with significant reduction of cardiac output has evolved to include conditions such those of moderate and preserved ejection fraction. While the prevalence of HF in the population is increasing, it is not HF with reduced ejection fraction that is driving the trajectory upward for mortality. There is some evidence to suggest that a better understanding of the pathophysiology, novel pharmacological strategies, devices, as well as remote monitoring of the hemodynamics seem to account for a reduction in the cardiovascular mortality and re-hospitalization in some cohorts with HF. However, the all-cause mortality associated with HF has not been reduced significantly by the current interventions. To explore the potential approaches needed for the strategies and avenues to reduce all-cause mortality in patients with HF, it would be helpful to evaluate the evidence in the literature directed at the care of patients with chronic/acute decompensated HF. It is evident that ambulatory measurements of pressures and volume are pivotal in a better management of HF but unless the interventions extend to an improvement in the renal function, the chances of reducing all-cause mortality seems modest. Therefore, future directions of interventions must not only be directed at close monitoring of pressures and volume simultaneously in HF patients but also at improving renal function. Moreover, it is clear that venous congestion plays a detrimental role in the deterioration of renal function and until measures are in place to reduce it, all-cause mortality will not decrease.

Abstract Changes in vascular biomechanics leading to increase in arterial stiffness play a pivotal role in circulatory dysfunction. Our objectives were to examine sex‐specific pharmacological changes related to the biomechanics and any structural modifications in small resistance arteries of Dahl salt‐sensitive male and female rats. The composite Young modulus (CYM) was determined using pressure myograph recordings, and immunohistochemistry was used for the evaluation of any structural changes in the third‐order mesenteric arteries (n = 6). Animals on high‐salt diet developed hypertension with significant elevation in central and peripheral blood pressures and pulse wave velocity compared to those on regular diet. There were no significant differences observed in the CYM between any of the groups (i.e., males and females) in vehicle‐treated time‐control studies. The presence of verapamil (0.3 μM) significantly reduced CYM in hypertensive males without changes within females compared to vehicle. This effect was abolished by phenylephrine (0.3 μM). BaCl2 (100 μM), ouabain (100 μM), and L‐NAME (0.3 μM) combined significantly increased CYM in vessels from in normotensive males and females but not in hypertensive males compared to vehicle. The increase in CYM was abolished in the presence of phenylephrine. Sodium nitroprusside (0.3 μM), in the presence of phenylephrine, significantly reduced CYM in male normotensive versus hypertensive, with no differences within females. Significant differences were observed in immunohistochemical assessment of biomechanical markers of arterial stiffness between males and females. Our findings suggest sex possibly due to pressure differences to be responsible for adaptive changes in biomechanics, and varied pharmacological responses in hypertensive state.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus has been at the forefront of health sciences research since its emergence in China in 2019 that quickly led to a global pandemic. As a result of this research, and the large numbers of infected patients globally, there were rapid enhancements made in our understanding of Coronavirus disease 2019 (COVID-19) pathology, including its role in the development of uncontrolled immune responses and its link to the development of endotheliitis and endothelial dysfunction. There were also some noted differences in the rate and severity of infection between males and females with acute COVID. Some individuals infected with SARS-CoV-2 also experience long-COVID, an important hallmark symptom of this being Myalgic Encephalomyelitis-Chronic Fatigue Syndrome (ME-CFS), also experienced differently between males and females. The purpose of this review is to discuss the impact of sex on the vasculature during acute and long COVID-19, present any link between ME-CFS and endothelial dysfunction, and provide evidence for the relationship between ME-CFS and the immune system. We also will delineate biological sex differences observed in other post viral infections and, assess if sex differences exist in how the immune system responds to viral infection causing ME-CFS.

PURPOSE: There is strong evidence that genetic factors influence retinopathy of prematurity (ROP), a neovascular eye disease. It has been previously suggested that polymorphisms in the genes involved in beta-adrenergic receptor (ADR beta) pathways could protect against ROP. Antagonists for the ADR beta are actively tested in clinical trials for ROP treatment, but not without controversy and safety concerns. This study was designed to assess whether genetic variations in components of the ADR beta signaling pathways associate with risk of developing ROP. DESIGN: An observational case-control targeted genetic analysis. METHODS: A study was carried out in premature participants with (n = 30) or without (n = 34) ROP and full-term controls (n = 20), who were divided into a discovery cohort and a validation cohort. ROP was defined using International Classification of Retinopathy of Prematurity criteria (ICROP). Targeted sequencing of 20 genes in the ADR beta pathways was performed in the discovery cohort. Polymerase chain reaction (PCR)/restriction enzyme analysis for some of the discovered ROP-associated variants was performed for validation of the results using the validation cohort. RESULTS: The discovery cohort revealed 543 bi-allelic variants within 20 genes of the ADR beta pathways. Ten single-nucleotide variants (SNVs) in 5 genes including protein kinase A regulatory subunit 1 alpha (PRKAR1A), rap guanine exchange factor 3 (RAPQEF3), adenylyl cyclase 4 (ADCY4), ADCY7, and ADCY9 were associated with ROP ( P < .05). The most significant SNV was found in PRKAR1A ( P = .001). Multiple variants located in the 3 '-untranslated region (3 ' UTR) of RAPQEF3 were also associated with ROP ( P < .05). PCR/restriction enzyme analysis of the 3 ' UTR of RAPQEF3 methodologically validated these findings. CONCLUSION: SNVs in PRKAR1A may represent protective factors whereas SNVs in RAPQEF3 may represent risk factors for ROP. PRKAR1 alpha has previously been implicated in retinal vascular development whereas the RAPQEF3 product has a role in the maintenance of vascular barrier function, 2 processes important in ROP. Multicenter validation of these newly discovered risk factors could lead to valuable tools for predicting and preventing the development of severe ROP. (c) 2024 Elsevier Inc. All rights reserved.

Background and Purpose: Piezo are mechanosensitive non-selective cation channels that are suggested to be involved in vascular development and function. The aim of our study was to determine any sex-specific contributions of the mechanosensitive Piezo 1 channels in vascular biomechanics. Experimental Approach: Composite Young modulus (CYM) was determined using pressure myograph experimental approach using third order mesenteric arteries (intact and denuded) from Dahl salt-sensitive male and female normotensive and hypertensive rats (n = 8). The effects of Piezo 1 agonist (Yoda; 10 μ M), and antagonist (GsMTx-4; 2 μ M) were studied. The distribution of Piezo 1 was identified in mesenteric arteries using immunohistochemistry. Key Results: In intact blood vessels, no differences in CYM between the experimental groups were noted, the removal of the endothelium unmasked significant increases in CYM in normotensive males and corresponding females compared to hypertensive males. In the intact tissue, GsMTx-4 led to significant increases in CYM in hypertensive females and normotensive males and females. In contrast, in the denuded vessels, GsMTx-4, produced a significant increase in CYM but only in the female normotensive group. Differential expression of Piezo 1 mechanosensitive ion channels in small mesenteric arteries were also found. Conclusion and Implications: The outcomes from our studies support a greater contributions of Piezo 1 channels to the biomechanics of male hypertensive compared to male normotensive and female hypertensive animals. The evidence also points to a possible differential vasoregulatory role for Piezo 1 channels in endothelial versus vascular smooth cells, with a greater contributions in males than females.

Emerging evidence points to a positive impact of sodium glucose co-transporter 2 (SGLT-2) inhibitors on cardiac structure and function, acutely (as early as 15 days) and chronically (up to 2 years). Accordingly, data from clinical studies appear to support the beneficial effects of this class of drugs on the cardiovascular system. However, the extent to which such effects may directly and/or indirectly be responsible for the beneficial actions of this class of drugs remains unclear. Based on the data in the literature, the actions of SGLT-2 inhibitors on the cardiac tissue in the absence of SGLT-2 co-transporter sites would suggest possible direct effects on calcium/calmodulin-dependent kinase II (CaMKII), voltage-gated, Nav1.5 channels and sodium-calcium exchanger 1 (NCX1), Na+/H+ exchanger (NHX), the late INa associated with calcium transient, the rapid (IKr) and slow (IKs) delayed rectifier K+ currents, phosphorylated levels of myofilament regulatory proteins, xanthine oxidase activity and sarco(endo)plasmic reticulum calcium ATPase and/or intracellular, and/or possible genomic sites in the cardiac myocytes. Collectively, the experimental and clinical evidence as to the effects of SGLT-2 inhibitors on cardiac and vascular tissues appear multifaceted in nature with no consensus for definitive site(s) of actions. It is clear that further investigations both in animals and humans, in vitro and in vivo are needed to shed more light on the true nature of the pharmacological actions of this class of compounds, and the extent of their beneficial effects as reported in a population with heart failure.

BACKGROUND:Increase in vascular stiffness is associated with a higher risk of cardiovascular morbidity and mortality and is likely sex-specific.METHOD:Our objectives were to compare structural and functional alterations in small resistance arteries as related to vascular stiffness from Dahl salt-sensitive male and female rats (n = 8, mean ± s.e.m.).RESULTS:Arterial blood pressure and pulse wave velocity were significantly (P < 0.05) elevated in males (161 ± 3 mmHg; 6.4 ± 0.2 m/s) and females (147 ± 2 mmHg; 5.5 ± 0.1 m/s) on a high (H) salt compared with regular (R) diets but were significantly higher in males (H) than in all others. Significant increases in collagen and smooth muscle cell areas were evident in ultrastructure of mesenteric arteries of hypertensive males compared to normotensive or corresponding females. There were no significant differences in composite Young's modulus (CYM) between groups. Vasoconstriction resulted in significantly higher CYM in male (H: 8.6 ± 1 KPa) than R (4.5 ± 0.8 KPa), and the corresponding females (H: 5.6 ± 0.6 KPa and R: 5 ± 0.9 KPa). In contrast, vasodilation significantly reduced CYM in the male groups (H: 2.5 ± 0.4 KPa and R: 2.7 ± 0.5 KPa) compared with the corresponding values in females (H: 4.2 ± 0.6 KPa and R: 5 ± 0.5 KPa). Moreover, the slope of pressure-volume curves revealed significantly greater distended vascular compliance in male H than R, and the corresponding females.CONCLUSION:Our findings are supportive of a link between high salt intake and elevated blood pressure as being sex specific, likely involving sex-dependent changes in ultrastructure of the vessels, which ultimately may alter the biomechanics, and thus, the haemodynamic functions of both macro-circulation and micro-circulations.

There has been accumulating evidence in the peer-reviewed literature over the past 5 years that sodium–glucose cotransporter 2 (SGLT-2) inhibitors (eg, empagliflozin and dapagliflozin) offer health-associated benefits in patients with heart failure and diabetes.1,2 More recently, the American Heart Association included this class, namely empagliflozin and dapagliflozin, as adjunct therapy to the conventional group of drugs for the treatment of patients with heart failure without diabetes.2,3 The recommendations were made based on the data presented in some recent clinical trials.4 Although the use of this class of drugs produces significant clinical benefits to patients with heart failure without diabetes, the true nature of the mechanism(s) of action remains yet to be fully determined, both in experimental and clinical settings. Among possible mechanisms for the action of this class of drugs (empagliflozin) was inhibition of the Na+–H+ exchanger in cardiac myocytes.5 This suggestion has become an interesting point of discussion. The original suggestion by Baartscheer et al5 was made using freshly isolated rat and rabbit cardiac tissues. The investigators from the same laboratory also reported that empagliflozin inhibited Na+–H+ exchanger in male isolated mouse (CI78B1/6NCr1) cardiac myocytes and also produced coronary vasodilation using the Langendorff perfused heart technique, while not being capable of affecting cardiac function (eg, dP/dt), cardiac energetics, or oxygen consumption.6 Subsequently, work by Chung et al7 reported that no inhibition of Na+–H+ exchanger occurred with empagliflozin in rat cardiac myocytes, and there was no vasodilation of coronary arteries or inhibition of left ventricular contraction using the perfused heart Langendorff technique. A further exchange of dialog in the peer-reviewed literature by investigators of the 2 laboratories still has not led to the resolution of the dichotomies in the outcomes. Accordingly, this has put the 2 observations at a crossroad. Nonetheless, there are some differences in the methodology and experimental approach and the added matter of species differences. It seems that the experimental set-up in the laboratory of Baartscheer et al,5,6 where inhibition with empagliflozin has been effectively noted, uses moderate amounts of bicarbonate in the 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES) solution, and the pH of the buffer is around 7.2 and perhaps subject to some modest oscillations. By contrast, Chung et al7 fixed the pH at 7.4 using HEPES with no bicarbonate in the salt solution. Thus, it is possible that the lower pH and bicarbonate ions may play a role in the final outcomes of the observations in each. An attempt by Zuurbier et al8 to replicate Chung et al's experimental approach showed that empagliflozin did lead to the retardation of intracellular Na+, but at pH 7.4, the inhibitory effect was at the lower end; in addition, rabbit isolated cardiac myocytes were used instead of rat cardiac myocytes, which were used by Chung et al7,9 in their studies. It is possible that the small concentration of bicarbonate in the HEPES buffer may have played a role in lowering the concentration of intracellular Na+. It is interesting to note that Grace et al10 had reported that the Na+–H+ exchanger and Na+ and bicarbonate-dependent mechanisms contributed approximately equally (about 50% each) to proton efflux at internal pH 6.9 during recovery from intracellular acidosis in the isolated ferret hearts. As the internal pH for the experiments described by Zuurbier et al8 reached values below 6.9, it is possible that in a circumstance where bicarbonate is present, the inhibitory effects of empagliflozin may become multifaceted and perhaps significant. However, there is the issue of why empagliflozin did not produce negative inotropic effects in the perfused hearts like that of cariporide (a Na+–H+ exchanger inhibitor).6,7 There is evidence in the literature to indicate that inhibitors of the Na+–H+ exchanger in the isolated perfused working heart can diminish contractions.10,11 This means that if empagliflozin did inhibit Na+–H+ exchanger in the isolated cardiac myocyte cell preparations, the effect did not extend to the inhibition of the excitation–contraction process in the perfused working heart (ie, Langendorff technique).6,7 Nonetheless, there are also ample data to indicate that chronic treatment of animals with heart failure with Na+–H+ exchanger inhibitors leads to beneficial effects. Accordingly, several studies have reported that inhibition of Na+–H+ exchanger in rats and rabbits with myocardial infraction (left coronary artery ligation) leads to a reduction in cardiac hypertrophy and failure.12–15 Engelhardt et al16 have reported positive outcomes after Na+–H+ exchanger inhibition in the prevention of hypertrophy, fibrosis, and heart failure in β1-adrenoceptor transgenic mice. In addition, chronic inhibition of Na+–H+ exchanger in an experimental model (rabbit) of pressure/volume overload has provided outcomes of reduced hypertrophy, cellular remodeling, and retardation of failure.17,18 This highlights a number of dilemmas associated with this debate: (1) the discord in outcomes of the multiple studies involving the effects of empagliflozin on cardiac Na+–H+ exchanger and (2) how to interpret these findings in the context of the evidence of the beneficial effects of empagliflozin in patients with heart failure. First, because multiple species and conditions seem to have been used to describe the effects of empagliflozin in cardiac myocytes on Na+–H+ exchanger, it leaves us no closer to resolving the matter. Second, which is really at the center of this issue, is the lack of inhibitory effects of empagliflozin in contrast to that of cariporide (Na+–H+ exchanger inhibitor) in the isolated perfused heart preparations using the Langendorff technique. Third, there is the lack of evidence in an isolated failing heart preparation without diabetes. Therefore, this makes any suggestion as to the possible beneficial effects of empagliflozin in the heart, and associated with the inhibition of Na+–H+ exchanger, a challenging one. In a recent report by Philippaert et al,19 it was found that empagliflozin was capable of inhibiting the late INa in a mouse model of heart failure, and this inhibitory action was not unique to the mentioned SGLT-2 inhibitor, but was shared with others namely dapagliflozin and canagliflozin. Moreover, empagliflozin was noted to prevent activation of nuclear-binding domain-like receptor 3 (NLRP3) inflammasome and retard the actions of late INa associated with calcium transients in isolated single myocytes. In addition, the presence of empagliflozin reduced the activation of NLRP3 inflammasome, while improving left ventricular excitation–contraction function, after ischemia in vitro.19 Although, in the latter studies, no functional data were presented as to the actions of empagliflozin in chronic failing hearts, the evidence seems to support positive effects of empagliflozin in modulating intracellular calcium by affecting Na+ flux. Accordingly, it will be helpful to determine the functional effects of empagliflozin and other SGLT-2 inhibitors in different models of heart failure in the absence of diabetes so to determine its pharmacological effects. It should be noted that in a study, Trum et al20 reported that empagliflozin significantly impaired pHi recovery, from acidic condition (pHi ∼5.6), comparable with cariporide in the isolated human atrial cardiomyocyte cell preparations, leading to the suggestion of the inhibition of Na+–H+ exchanger in such tissue. However, it will be enlightening to determine whether parallel effects can be shown in human ventricular muscle and whether such effects are primarily due to the direct inhibition of Na+–H+ exchanger in a functioning ventricle. Collectively, the current evidence seems to suggest that empagliflozin may be capable of affecting the concentration of intracellular Na+, but robust evidence that such an effect may produce beneficial cardiac effects in patients with heart failure without diabetes remains to be fully elucidated.

Understanding the pharmacodynamics of cannabinoids is an essential subject due to the recent increasing global acceptance of cannabis and its derivation for recreational and therapeutic purposes. Elucidating the interaction between cannabinoids and the vascular system is critical to exploring cannabinoids as a prospective therapeutic agent for treating vascular-associated clinical conditions. This review aims to examine the effect of cannabinoids on the vascular system and further discuss the fundamental pharmacological properties and mechanisms of action of cannabinoids in the vascular system. Data from literature revealed a substantial interaction between endocannabinoids, phytocannabinoids, and synthetic cannabinoids within the vasculature of both humans and animal models. However, the mechanisms and the ensuing functional response is blood vessels and species-dependent. The current understanding of classical cannabinoid receptor subtypes and the recently discovered atypical cannabinoid receptors and the development of new synthetic analogs have further enhanced the pharmacological characterization of the vascular cannabinoid receptors. Compelling evidence also suggest that cannabinoids represent a formidable therapeutic candidate for vascular-associated conditions. Nonetheless, explanations of the mechanisms underlining these processes are complex and paradoxical based on the heterogeneity of receptors and signaling pathways. Further insight from studies that uncover the mechanisms underlining the therapeutic effect of cannabinoids in the treatment of vascular-associated conditions is required to determine whether the known benefits of cannabinoids thus currently outweigh the known/unknown risks.

This commentary relates to the article by Yoonjee Park et al, on pages 38–45. In this issue of the Journal, Park et al1 prospectively analyzed the incidence of on-set of diabetes mellitus in hypertensive patients receiving either selective or nonselective β-blockers over 60-month time span. This is an important question faced by all health care professionals that attempt to reduce morbidity and mortality in population of patients who suffer from high blood pressure. It is also a complex question. However, the outcomes from the analytics revealed a number of interesting outcomes that require careful thought. Based on the evidence presented, it seems that nonselective β-blockers significantly increased the incidence of diabetes mellitus, whereas the selective β-blockers did not seem to do so. One of the early indications that treatment of hypertensive patients with β-blockers could lead to diabetes was a report by Bengtsson et al.2 The evidence from the latter investigation indicated that treatment with either β-blockers and/or thiazides resulted in the development of diabetes.2 Further evidence was provided by other reports.3–5 It is interesting that the evidence provided from the analysis by Park et al1 indicates that carvedilol but not metoprolol caused significant increase in the new on-set of diabetes mellitus in hypertensive patients. The data from the Carvedilol Or Metoprolol European Trial (COMET) in patients with chronic heart failure indicate that metoprolol rather than carvedilol was the β-blocker that increased the incidence of diabetes mellitus as assessed over 5 years.6 It is possible that the differential outcome is due to ethnicity of the population, as the patients in COMET were of predominantly of European decent, whereas those in the Park et al1 analysis are Asians. It is also possible that the differences in the outcome are related to the underlying nature of the pathophysiology of the cohort investigated. One other important outcome from the analysis by Park et al1 was when the data for patients taking selective and nonselective β-blockers were combined, the dilution in analysis seems to suggest β-blockers as a class which do not significantly lead to the new on-set diabetes mellitus in matched hypertensive patients. This emphasizes the importance of stratification of mixed and nonhomogenous data sets. Hence, it would have also been helpful to determine sex differences in the new on-set of diabetes mellitus with this class of antihypertensive in this population. Furthermore, it seems that body mass index (BMI) was not a determining factor in the development of diabetes in patients treated with β-blockers. BMI has been identified as an independent risk factor in the development of diabetes mellitus in hypertensive patients taking antihypertensive drugs including β-blockers.5,7,8 It is not readily clear why BMI was not a factor in this particular analysis,1 but race may have an influence. The evidence from the analysis by Park et al1 also seems to reveal that the only diuretic that led to the new on-set of diabetes was furosemide, and that the thiazide diuretics did not seem to readily cause the new on-set of diabetes mellitus in this cohort. This is not entirely surprising, as it has been previously suggested that thiazide-induced diabetes mellitus is likely linked to dose, and a lower dose of such a class of drugs would not significantly lead to the new on-set of diabetes.9 It is possible that the database1 contained patients who were predominately being treated with lower doses of the thiazides. The differential effects of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers in causing new on-set of diabetes mellitus were also noted in the analysis.1 This is of interest because in some studies, angiotensin receptor blockers were noted to cause the new on-set of diabetes, whereas ACE inhibitors were believed to have protective effects.10,11 In general, there are many factors that could influence outcomes including baseline fasting plasma, BMI, systolic blood pressure, race, age, heart rate, and history of coronary heart disease.8,12 Of note, there is a dissociation of the development of diabetes mellitus and major adverse cardiovascular and cerebrovascular events (MACCE) in the analysis.1 Although the use of nonselective β-blockers and ACE inhibitors seems to lead to the new on-set of diabetes mellitus, neither class seems to significantly increase the risk of MACCE. By contrast, the use of nitrates seems to lead to significant risk of MACCE without causing new on-set of diabetes mellitus.1 A valid question directed at a better management of the health of hypertensive patients treated with drugs would be if the new on-set of diabetes mellitus was a major contributor of morbidity and mortality. This question has to be scrutinized very carefully. Accordingly, if the new on-set of diabetes mellitus due to antihypertensive therapy is not the enemy that is made out to be then lowering of blood pressure is of a greater importance. A meta-analysis to determine optimal control of high blood pressure in hypertensive patients in Spain has revealed that lowering of blood pressure did not seem to ideal during treatment for many of these individuals.13 If such a parallel is true worldwide, then the uncontrolled elevated blood pressure will clearly have a greater negative health impact than other matters such as the new on-set of diabetes mellitus in patients receiving antihypertensive drugs. An old dogma is whether uncontrolled high blood pressure eventually leads to the development of diabetes mellitus. Although this question remains controversial, a recent study of more than 4 million patients in United Kingdom has revealed some startling findings. It is reported that elevation of 20 mm Hg in systolic blood pressure and 10 mm Hg of higher diastolic blood pressure above the norm would be associated with 58% increase in the new on-set of diabetes mellitus.14 A meta-analysis of 30 prospective observational studies by the same group further revealed a 77% higher risk of new diabetes in adults with 20 mm Hg of higher systolic blood pressure.14 Taken together, such findings would strongly argue for a more optimal as well as better treatment and control of high blood pressure in hypertensive individuals. More importantly, such evidence may well support the notion that uncontrolled high blood pressure in cohorts treated with antihypertensive drugs would put them at the risk of developing diabetes mellitus irrespective of the class of drugs used. A daunting thought. The bigger picture is the fact that based on the World Health Organization data for 2015, approximately 1.1 billion are believed to have high blood pressure as defined by values greater that 140/90 mm Hg (systolic/diastolic) worldwide. High blood pressure is a major risk factor for stroke and coronary heart disease and is killing about 7.5 million people every day. Essentially, high blood pressure has become a leading global burden as a disease, and unless this condition is taken seriously, hypertension is slowly turning into a pandemic of cardiovascular disease around the globe.

An increase in arterial stiffness is associated with a high risk for morbidity and mortality in a state of elevated systemic pressure. The sympathetic nervous system plays an important role in the regulation of vascular tone via activation of β-adrenoceptors. The aim of this investigation was to determine the involvement of β-adrenoceptors in the control of arterial stiffness in a state of hypertension versus normotension. Pulse wave velocity (PWV), an index of vascular stiffness, was assessed in isoflurane-anaesthetized 13-14-week-old male spontaneously hypertensive (SH) and Wistar-Kyoto (WKY) rats. At baseline, PWV was significantly higher in SH (9.2±0.9m/s) compared to WKY rats (6.7±0.4m/s). The stimulation of β2- but not β3-adrenoceptors significantly reduced PWV in SH rats despite comparable reductions in blood pressure. Stimulation of β2- or β3-adrenoceptors did not reduce PWV in WKY rats. The administration of sodium nitroprusside (SNP) also significantly reduced PWV in SH but not WKY rats. Immunofluorescence revealed the expression of β2- and β3-adrenoceptors in endothelial cells and vascular smooth muscle cells of the abdominal aorta. There were no significant differences in the distribution of the expression of β2- and β3-adrenoceptors in endothelial and/or smooth muscle cells in blood vessels of SH compared to WKY rats. The evidence suggests that β2-adrenoceptor stimulation and SNP infusion reduce PWV independently from reduction in blood pressure in a state of high systemic arterial pressure. A reduction in vascular tone of the central arteries may play a key role in decreasing PWV that is elevated due to stiffer arterial wall.

Elevated intravascular pressure is a contributing factor to increased arterial stiffness, and is a risk factor for cardiovascular morbidity and mortality. Assessment of arterial stiffness is of importance in evaluating cardiovascular risk. Pulse wave velocity (PWV) has been broadly used in the assessment of arterial stiffness. We compared three different metrics of arterial stiffness to PWV. Hemodynamic recordings were carried out in anesthetized hypertensive and normotensive rats (n=25; 13-14weeks old). Four parameters were calculated (PWV, elastic modulus (E-inc), stiffness index (), and pressure-strain modulus (E-p)) as metrics of arterial stiffness. Hypertensive in comparison to normotensive rats had significantly higher systolic and diastolic blood pressures. Metric for arterial stiffness were significantly (p<0.002) higher in hypertensive animals: PWV (8.46 +/- 2.01 vs. 6.39 +/- 1.28m/s), E-p (0.246 +/- 0.019 vs. 0.137 +/- 0.010 dyn/cm(2)x10(-6)), E-inc (17.5 +/- 1.8 vs. 10.1 +/- 0.9 dyn/cm(2)x10(-6)), and (2.43 +/- 0.11 vs. 1.98 +/- 0.08) (mean +/- SE). Bland-Altman analysis revealed as the only metric aligned with PWV in hypertensive state. We find in state of reduced arterial compliance associated with high systemic pressure, but not E-inc or E-p is an index of arterial stiffness showing agreement with PWV.

Regional perfusion is reduced and the renin-angiotensin system activated in rats with aortocaval fistula. The effects of captopril (angiotensin-converting enzyme inhibitor), losartan (angiotensin II type 1 receptor antagonist) and PD 123319 (angiotensin II type 2 receptor antagonist) on regional blood flow and vascular conductance were assessed in rats with aortocaval fistula and sham-operated rats. Control of blood flow and vascular conductance by angiotensin II was evaluated by serial bolus injections of captopril, losartan and PD 123319 in anaesthetized rats. In rats with fistula, PD 123319 significantly decreased, whereas captopril and losartan increased, mesenteric blood flow. The decrease in mesenteric blood flow induced by PD 123319 was significantly greater in rats with fistula compared with sham operation. Captopril and PD 123319 significantly decreased renal blood flow compared with losartan, which increased it. In sham-operated rats, captopril and losartan significantly increased, whereas PD 123319 decreased, mesenteric and renal conductance. In rats with fistula, captopril and losartan significantly increased, whereas PD 123319 decreased, mesenteric conductance. The significant increase produced by losartan on mesenteric conductance was greater in rats with fistula compared with sham operation. PD 123319 produced a significantly greater decrease in renal conductance of rats with aortocaval fistula compared with sham-operated rats. Captopril, losartan and PD 123319 did not significantly affect perfusion in the hindquarter in rats with fistula or sham-operated. The renin-angiotensin system is more active in the control of regional haemodynamics in rats with aortocaval fistula and acts as a mechanism of maintaining normal arterial blood pressure in these animals. In rats with fistula, angiotensin II type 1 receptors predominate in regulating regional haemodynamics.

Chronic inflammatory process(es) contributes to changes in vascular function in a variety of diseases. Sympathetic nerve-mediated responses in blood vessels play a pivotal role in regular physiological functions. We tested the hypothesis that sympathetic neuro-effector function will be altered as consequence of inflammatory state. Sympathetic nerve-mediated contractions and alpha adrenergic receptor expressions were evaluated in isolated caudal arteries of rats treated with saline and Complete Freund's adjuvant (CFA). While CFA-treated animals had significantly higher plasma levels of tumor necrosis factor-alpha compared to saline, blood pressure remained unchanged. Immunofluorescence revealed increased expression of ionized calcium adapter binding molecule-1 in the adventitia of blood vessels from CFA-treated animals compared to saline. In isolated arteries, electrical field stimulations between 1.25 and 40Hz resulted in frequency-dependent contractions that wasabolished by tetrodotoxin. Neurogenic contractions from CFA groups were significantly greater than saline. While the presence of alpha1-adrenoceptor antagonist (prazosin) significantly inhibited contractions at lower frequencies of stimulation (1.25-5Hz) in isolated arteries of CFA-treated rats compared to controls, alpha2-adrenoceptor antagonist (rauwolscine) had modest effects. Inhibition of neuronal reuptake by cocaine comparably enhanced field-stimulated responses in vessels of experimental and control animals. Immunofluorescence revealed a difference in expression of alpha1- and alpha2-adrenoceptors in the endothelium of blood vessels of CFA compared to saline controls. Collectively, our observations lend support to enhanced neurogenic contractions in blood vessels of inflamed animals possibly attributing to alterations in responsiveness and/or distribution of post-junctional alpha1-adrenoceptors.

The reasons for the occurrence of the toxic effects of chemicals in the heart include accidental overdose and inappropriate therapeutic use. Chemicals act on many sites in the myocardium to produce toxic effects. Accordingly, substances can adversely influence cell function by producing abnormal inotropic, chronotropic, and/or dromotropic effects, leading to compromised cardiac function and cardiac output. High incidence of cardiac toxicity seems to be associated with certain classes of drugs, namely tricyclic antidepressants, cardioglycosides, β-adrenoceptor blockers, Ca channel antagonists, and anthracyclines. In addition, a host of other chemicals with diverse chemical structures seem to inhibit the rapid delayed rectifier K+ current and to prolong repolarization of cardiac cells. This leads to polymorphic ventricular tachycardia that, at times, can be fatal. In addition, certain toxins that are able to alter ion permeability in cardiomyocytes appear to have profound effects on cardiac function. For example, a group of lipid-soluble, plant-derived toxins, such as grayanotoxin, veratridine, and aconitine, are capable of increasing Na+ permeability in mammalian cardiomyocytes. Toxin-induced alteration of Na+ permeability can lead to destabilization of the resting membrane potential and cause major disruption of cardiac function.

OBJECTIVESThere is evidence indicating that intravenous fatty emulsion (IFE) is beneficial in restoring circulatory function in certain types of drug overdose. The authors investigated the hemodynamic effects of IFE compared to epinephrine in rats treated with propranolol and clonidine.METHODSAnesthetized male Sprague-Dawley rats were instrumented for measurement of hemodynamics. Rats were randomly assigned to one of six groups (n = 6-8), and each received a clonidine infusion (150 μg/kg) or an equivalent volume of normal saline (0.9% NaCl) over 1 hour. Each rat then received normal saline (1.0 mL/kg) or propranolol (15 to 20 mg/kg). Thereafter, each rat received a dose of IFE (20% solution; 1.0 mL/kg) or epinephrine (2.0 μg/kg) or an equivalent volume of normal saline (1.0 mL/kg).RESULTSPropranolol alone or with clonidine significantly (p < 0.05) reduced a number of hemodynamic parameters (mean arterial pressure, 37% to 70%; heart rate, 30% to 51%; cardiac contractility [dP/dtmax], 50% to 67%; and abdominal aortic blood flow, 50% to 83%), while increasing PR intervals (65% to 85%) and QTc intervals (26% to 64%). Saline and epinephrine treatment after propranolol and clonidine combined resulted in no survivors in saline and two out of six in epinephrine group. IFE resulted in significant survival (seven out of eight) for 30 minutes in rats treated with propranolol alone, and propranolol combined with clonidine (seven out of eight).CONCLUSIONSThese data demonstrate that IFE is effective for resuscitating rats overdosed on propranolol combined with clonidine. The effect of IFF is unlikely due to a direct positive inotropic or chronotropic action on the myocardium. IFE is also more effective than epinephrine treatment in this paradigm.