Changes In Systemic Arterial Pressure Research Articles

Impact of hypertension on mean transvalvular gradients in aortic stenosis Lessons learned from in silico modelling

Abstract Introduction The influence of hypertension on the diagnostic assessment of aortic stenosis (AS) severity is unclear, yet clinically relevant. To clarify the effect of hypertension on transvalvular gradients, requires a better understanding of the impact that blood pressure change has on mean flow rate. Also, the effect of various degrees of AS severity, the valve geometry and intrinsic left ventricular contractile function (elastance) on this interaction, needs to be clarified. Existing clinical research on this topic is limited by not incorporating the full complement of factors that influences the directionality and magnitude of mean transvalvular gradient change for any given change in blood pressure. Purpose To use validated flow dynamics modelling grounded in fundamental physics principles to create a digital platform where various parameters can be manipulated to quantify the effects of bloodpressure change on mean transvalvular gradients in various pathological states. Methods A validated, zero-dimensional electro-hydraulic analogue computer model of the human cardiovascular circulatory system was generated. It was used to assess the impact of blood pressure changes on left ventricular pressure and transvalvular gradients at various flow rates, left ventricular elastances, a range of aortic valve areas and for different aortic valve morphologies. Results Mean transvalvular gradients are flow dependent. The impact of hypertension on mean flow rate (MFR), and hence on mean gradient (MG), is influenced by the aortic valve area as well as the underlying left ventricular elastance (Figure 1). Subsequently, the relationship between MFR and MG could be modelled (Figure 2). Generally, for a given change in systemic arterial pressure, the impact on MG will be the most marked for lower flow rate states such as is expected in more severe degrees of AS and for worse intrinsic left ventricular (LV) contractility. Furthermore, for a constant hemodynamic valve area, the hydraulic valve orifice area was found to be smaller in rheumatic AS compared to degenerative AS. This results in less susceptibility to blood pressure induced changes in mean transvalvular gradient. Similarly, the size of the aortic root was found to be inversely related to the susceptibility to induce a change in mean gradient for a change in blood pressure. Conclusion The interaction between hypertension and mean gradients in AS is complex. The current work places previous recommendations in perspective by quantifying the magnitude of the effect that a change in blood pressure has on mean gradient in various pathophysiological states. By doing so it provides more granularity into this multifaceted interaction compared to previously oversimplified deductions from clinical studies. The findings of this study creates a basic science framework based on first principles that dictates the scope of parameters that should be considered in future clinical research on the topic.Modelling 1Modelling 2

The acute hemodynamic effects of sodium lactate infusion: increased cardiac output and decreased afterload in a randomized trial in pigs

Abstract Background Lactate is traditionally acknowledged as a by-product of anaerobic glucose metabolism. Recently, however, lactate has been proven to be a preferred oxidative substrate for stressed myocardium. Studies have shown that exogenous lactate infusion provides beneficial hemodynamic effects including increased cardiac output (CO). Nevertheless, the exact mechanism of action underlying the hemodynamic effects of lactate infusion has not been fully elucidated. Aim To identify the cardiovascular mechanisms behind the acute hemodynamic effects of exogenous sodium lactate infusion in an experimental model of healthy human-sized pigs. Methods We performed a randomized, assessor-blinded crossover study in eight female 60 kg pigs. In randomized order, the pigs received an infusion with 1 M sodium lactate for two hours and a control infusion with iso-osmolar and isovolumetric sodium chloride for two hours. The two infusion periods were separated by a one-hour washout period. We measured CO and pulmonary pressures hourly with a pulmonary artery catheter. A pressure-volume admittance catheter was inserted in the left ventricle to assess measures of cardiac efficiency, contractility, afterload, and preload. Hemodynamic measures as arterial blood pressure, heart rate, and mixed venous saturation (SvO2) were measured hourly as well. The study followed the principles of laboratory animal care (NIH Publication no. 85-23 revised 1985) and national and European legislations. Results Lactate levels increased by 9.9 mmol/L (95% CI 9.1 to 11.0) and CO increased by 2.0 L/min (95% CI 1.2 to 2.8) during lactate infusion as compared with the control period (figure 1). During lactate infusion, ejection fraction increased by 16.0 percentage points (95% CI 1.9 to 31.0) and heart rate by 21 bpm (95% CI 9 to 32) compared with control. Arterial elastance decreased by -1.1 mmHg/ml (95% CI -2.1 to -0.18). Lactate infusion also increased cardiac efficiency, SvO2, arterial pH, and arterial glucose concentration significantly. The infusion of lactate led to no changes in systemic arterial pressure nor pulmonary pressures including pulmonary artery wedge pressure. Also, no changes were found in left ventricle end systolic elastance (contractility). Futhermore, no change in left ventricle end-diastolic volume or -pressure (preload) were observed during lactate infusion compared with the control (figure 2). Conclusion High dose lactate infusion increased cardiac output by reducing afterload. No changes in left ventricular contractility or -preload were observed.Fig 1:Lactate concentration and COFig 2:Changes of endpoint parameters

H1 and H2 antihistamines pretreatment for attenuation of protamine reactions after cardiopulmonary bypass: a randomized-controlled study.

Protamine administration post-cardiopulmonary bypass (CPB) can potentially cause hemodynamic instability. Histamine released from mast cells is believed to be responsible for hypotension after protamine administration. The aim of this study was to examine the effects of pretreatment with H1 and H2 antihistamines on changes in systemic arterial pressure following protamine administration. This study was a randomized, triple-blinded, placebo-controlled study, conducted at a university hospital. Forty adult patients undergoing elective coronary artery bypass grafting (CABG) or single valve surgery were included. The patients were randomly allocated (20 patients in each group) to receive a single dose of combined chlorpheniramine 10 mg and ranitidine 50 mg or normal saline intravenously immediately after separation from CPB prior to protamine administration. Trajectory changes in systolic blood pressure (SBP), mean arterial pressure (MAP), and vasoactive-inotropic score (VIS) from baseline until 35 minutes following protamine administration (24-time points) were compared between the two groups. Serial serum tryptase levels were also obtained at baseline, 30 and 60 minutes after protamine was given. Forty patients were included in the analysis. Demographic and baseline blood pressure were similar between the two groups. At 30 minutes after protamine administration, there were no significant differences in both crude SBP [mean difference: -7.1 mmHg, 95% confidence interval (CI), -1.1 to 15.3 mmHg, P=0.09] and SBP after adjustment for the European System for Cardiac Operative Risk Evaluation (EuroSCORE II), CPB time, and VIS (mean difference: -3.9 mmHg, 95% CI, -11.9 to 4.0 mmHg, P=0.33). There were also no significant differences in crude MAP (mean difference: -2.1 mmHg, 95% CI, -6.9 to 2.7 mmHg, P=0.39) and adjusted MAP (mean difference: -0.7 mmHg, -5.9 to 4.4 mmHg, P=0.78) between the two groups. None of the patients in both groups had a significant increase in serum tryptase from baseline. No differences in median serum tryptase levels at baseline, 30 and 60 minutes were demonstrated between the two groups. Pretreatment with H1 and H2 antihistamines does not attenuate blood pressure responses to protamine administration in patients after CPB. Mechanisms other than histamine release from mast cells might be responsible for protamine-induced cardiovascular changes. ClinicalTrials.gov NCT03583567.

In-silico modelling of the impact of hypertension on the mean transvalvular gradients in aortic stenosis.

The influence of hypertension on the diagnostic assessment of aortic stenosis (AS) severity is unclear, yet clinically relevant. To clarify the effect of hypertension on transvalvular gradients, requires a better understanding of the impact that blood pressure change has on mean flow rate. Also, the effect of various degrees of AS severity, the valve geometry and intrinsic left ventricular contractile function (elastance) on this interaction, needs to be clarified. The current work aims to assess this interaction and the magnitude of these effects. A validated, zero-dimensional electro-hydraulic analogue computer model of the human cardiovascular circulatory system was generated. It was used to assess the impact of blood pressure changes on left ventricular pressure and transvalvular gradients at various flow rates, left ventricular elastances, a range of aortic valve areas and for different aortic valve morphologies. The magnitude of the impact of hypertension induced changes on the mean gradient (MG) is influenced by the mean flow rate, the AS severity, the hydraulic effective valve orifice area and the left ventricular elastance. Generally, for a given change in systemic arterial pressure, the impact on MG will be the most marked for lower flow rate states such as is expected in more severe degrees of AS, for worse intrinsic left ventricular (LV) contractility, shorter ejection times and lower end diastolic LV volumes. Given the above conditions, the magnitude of the effect will be more for a larger aortic sinus diameter, and also for a typical degenerative valve morphology compared to a typical rheumatic valve morphology. The interaction between hypertension and mean gradients in AS is complex. The current work places previous recommendations in perspective by quantifying the magnitude of the effect that the changes in blood pressure has on mean gradient in various pathophysiological states. The work creates a framework for the parameters that should be considered in future clinical research on the topic.

SPARC ‐ Anatomical Analysis and Optogenetic Stimulation of TRPV1+ Sensory Fibers in the Renal Cortex

Hypertension is a major health concern throughout the world and is the leading contributor to cardiovascular‐related deaths. While drug‐based treatments exist, many patients are drug‐resistant while others do not adhere to their prescribed treatment. To combat these obstacles, clinical trials are currently underway investigating the efficacy of renal denervation (RDN) for the treatment of hypertension. While recent clinical trials support the concept that RDN is efficacious, it is nonspecifically destructive in nature, ablating both sympathetic (efferent) and sensory (afferent) renal nerves. Previous experiments from our group showed via afferent‐specific renal denervation that sensory nerves drive the development and maintenance of the DOCA‐Salt model of hypertension in rats. However, the roles that specific subtypes of sensory renal nerves play in regulating cardiovascular function in a non‐pathophysiological state remain to be elucidated. With this objective in mind, we use large volume tissue clearing and imaging techniques, as well as kidney‐targeted optogenetic modulation of TRPV1+ sensory fibers to better understand the anatomy and function of this subtype of sensory renal nerves.While previous anatomical studies of sensory renal nerves have focused on the innervation of the pelvic wall, here we report a close anatomical relationship between renal glomeruli and sensory fibers. To the best of our knowledge, this has not been quantified previously. Approximately half of the glomeruli analyzed are in close proximity to CGRP+ and/or TRPV1+ sensory fibers. These fibers occasionally appear to penetrate Bowman’s capsules, and they often follow a periglomerular path, contrasting the arteriolar interactions describing sympathetic fibers. Based on these observations and the expression profiles of these sensory fibers, our working hypothesis is that they sense changes in glomerular function, such as glomerular pressure. Further ongoing experiments will directly test this hypothesis.Furthermore, experiments investigating the roles of TRPV1+ renal sensory fibers in cardiovascular regulation and renal function are in progress. Using a custom‐designed optogenetic kidney cup, LED stimulation is applied to the renal cortex in transgenic mice that express channel rhodopsin in TRPV1+ nerve fibers. To define the functions of these fibers, we measure mean arterial pressure and cortical blood flow as physiological outputs of their optogenetic activation. Unilateral optogenetic stimulation applied to the cortex of the mouse kidney results in a decrease in renal cortical blood flow, no change in systemic arterial pressure, and therefore an increase in renal resistance. These results suggest that glomerular TRPV1+ renal sensory fibers may function in a novel sympathoexcitatory reflex.Support or Funding InformationNIH SPARC Award 1U01DK116320‐02, 2018‐2019 MnDRIVE Fellowship

Acetaminophen increases pulmonary and systemic vasomotor tone in the newborn rat.

Acetaminophen is widely prescribed to both neonates and young children for a variety of reasons. In adults, therapeutic usage of acetaminophen induces systemic arterial pressure changes and exposure to high doses promotes tissue toxicity. The pulmonary vascular effects of acetaminophen at any age are unknown. Hypothesizing that, early in life, it promotes vasomotor tone changes via oxidative stress, we tested the in vitro acetaminophen effects on intrapulmonary and carotid arteries from newborn and adult rats. We measured the acetaminophen dose-response in isometrically mounted arteries and pharmacologically evaluated the factors accounting for its vasomotor effects. Acetaminophen induced concentration- and age-dependent vasomotor tone changes. Whereas a progressive increase in vasomotor tone was observed in the newborn, the adult arteries showed mostly vasorelaxation. Inhibition of endogenous nitric oxide generation with L-NAME and the use of the peroxynitrite decomposition catalyst FeTPPS (Fe(III)5,10,15,20-tetrakis(4-sulfonatophenyl)porphyrinato chloride) mostly abolished the drug-induced increase in newborn pulmonary vasomotor tone CONCLUSIONS: In newborn rats, acetaminophen increases pulmonary vasomotor tone via peroxynitrite generation. Given its therapeutic usage, further clinical studies are warranted to assess the acetaminophen effects on the newborn pulmonary and systemic vascular resistance.

METHOD FOR DETERMINING THE UPPER LIMIT OF CEREBRAL AUTOREGULATION IN RATS

The main objective of the phenomenon of cerebral autoregulation is to maintain a constant cerebral blood flow rate with changes in systemic arterial pressure in the range of 50 mmH up to 150 Mmhg. To study this phenomenon, there are two approaches: dynamic and static. The dynamic approach is known to the study autoregulation, can indirectly characterize this phenomenon with the help of calculated indicators, and the described static methods can characterize only the lower limit of autoregulation of cerebral blood flow.The aimof the study was to develop a method for determining the value of pressure at the “breakdown” point of the upper limit of cerebral hemodynamics autoregulation.Materials and methods. The experiment was carried out on male rats of the Wistar line weighing 200–250 g, kept in standard vivarium conditions. The essence of the method of establishing the upper “breakdown” point of the autoregulatory mechanisms of cerebral circulation is pumping blood from the femoral artery to both carotid arteries by means of a peristaltic pump, while controlling the pressure and cerebral blood flow velocity. In order to avoid blood loss as a result of blood flow redistribution, external carotid arteries were ligated. The pressure was measured by the direct method. Since the pressure is created by the resistance of the cerebral vessels, it can be measured at the entrance by specially modeled carotid catheters. Cerebral blood flow velocity was measured by an ultrasound doppler scanner using MDK-Minimax Doppler v .2.1 program. To establish the possibility of using this method in the study of the influence of substances on the autoregulation of cerebral circulation, the effect of nicergoline on this phenomenon was studied. The drug was administered as a suspension intragastrally to rats 1 hour before metering.The results and discussionof the experiment showed that in intact rats the “breakdown” point of the upper limit of autoregulation was recorded at 165.0 ± 3.4 Mmhg (M ± m). Statistical processing of the obtained data indicates the normal distribution of the sample and the validity of the developed method. The introduction of nicergoline led to the increase in pressure at which there was a “breakdown” of the autoregulation mechanisms to 181.7 ± 4.7 Mmhg, which was significantly higher than the values of the intact group.Conclusion. As a result of the experiment on male rats, a valid method was developed for determining the blood pressure value at the highest point of “breakdown” of cerebral hemodynamics autoregulation and it was established that nicergoline shifts the functioning limit of the autoregulation phenomenon to higher values.

ARTERIAL HYPERTENSION AT SPORT ACTIVITIES IN MIDDLE AGE AND ELDERLY SPORTSMEN

Aim. To analyze the changes of systemic arterial pressure (BP) before and after sport load, incl. the diagnosis of arterial hypertension (AH) and antihypertensive treatment, in veteran sportsmen. Material and methods. Questionnaires were applied for the main cardiovascular risk factors assessment, and BP measurement upright resting (before warming up exercises) and just after the load in 108 competitive sportsmen 40-72 y.o. In the study, the previously set diagnosis of systemic hypertension was taken in consideration and its treatment type. Results. Among all participants, 41% had increased systolic BP (SBP) and 29,6% — diastolic (DBP) at baseline. After exercises, increase of SBP was found in 41% and DBP — in 50,9%. During competition, baseline increase of SBP had 61,8% of all participants, increased DBP — 35,3%. After competition, increase of SBP was found in 67,6% sportsmen, of DBP — 41,2%. Among those with no AH diagnosis, 30,6% had SBP >139 mmHg at baseline, and 42% — after warming up. In sportsmen with already diagnosed AH, raised SBP before warming up was found in 56%, after — 60%. The tendency was even more prominent during competitions. In AH sportsmen, the characteristics of BP change at sport loads did not differ significantly by the type and regularity of antihypertension drugs intake. Conclusion . Almost a half of adult and elderly sportsmen have AH diagnosis, and of those less than a half do take regular antihypertensive therapy. Most of veteran sportsmen experience raised BP before and after sport load, including those taking regular therapy and a third of those not diagnosed with AH.

Autoregulation of cerebral blood flow in severe diffuse axonal brain injury: the role of neuroanatomical factors

The study aim was to assess the effect of anatomical injuries to deep brain structures on the extent and duration of ACBF abnormalities in a model of severe diffuse axonal injury (DAI). The study demonstrated that brain injury in the projection of a dopaminergic structure (substantia nigra) and a cholinergic structure (nucleus basalis of Meynert region) was more common in patients with impaired ACBF and was associated with a longer duration of the impairment. The obtained data may indicate the presence of central (neurogenic) pathways of cerebral vessel tone regulation; traumatic injury of the pathways leads to a more severe and prolonged period of impaired ACBF. Probably, injury to these regulatory structures in some patients has an indirect effect on the course of intracranial hypertension. Further experimental and clinical studies in this direction are needed to elucidate all elements of neurogenic regulation of cerebral vessel tone and ACBF mechanisms.

ANGIOTENSIN CONVERTING ENZYME INHIBITION ACTIVITY OF DAIDZEIN

Daidzein produces antihypertensive and beneficial cardiovascular effects, although the mechanisms for these effects are not known. We examined whether genistein inhibits the in vivo responses to angiotensin I or enhances the responses to bradykinin in anaesthetized rats as a result of angiotensin-converting enzyme inhibition. We have also studied the in vitro effects produced by genistein on the angiotensin-converting enzyme activity. We measured the changes in systemic arterial pressure induced by angiotensin I in doses of 0.05 to 10 µg/kg, by angiotensin II in doses of 0.025 to 5 µg/kg, and to bradykinin in doses of 0.03 to 10 µg/kg in anaesthetized rats pretreated with vehicle (controls), or a single i.v. dose of daidzein 25 mg/kg, or a single i.v. dose of enalapril 2 mg/kg. Plasma angiotensin-converting enzyme activity was determined in controls and daidzein-treated rats using a fluorometric method. The effects of genistein (3–300 µmol/l) on in vitro angiotensin-converting enzyme activity were assessed by adding daidzein to plasma samples and measuring angiotensin-converting enzyme activity. We found significant lower angiotensin-converting enzyme activity in plasma samples from rats pretreated with daidzein compared with those found in the control group (84.23±7.4 his-leu nmol/min/ml and 100.45±9.2 his-leu nmol/min/ml, respectively; P = 0.01). The incubation of daidzein with plasma samples showed that daidzein decreased the angiotensin-converting enzyme activity in plasma in a concentration-dependent manner (P=0.01). These findings indicate that daidzein inhibits the angiotensin-converting enzyme in vivo and in vitro and may explain, at least in part, the antihypertensive and beneficial vascular effects produced by daidzein.Keyword: Angiotensin, Daidzein, Bradykinin, Arterial pressure.Â

Enhanced angiotensin-converting enzyme activity and systemic reactivity to angiotensin II in normotensive rats exposed to a high-sodium diet

A high salt diet is associated with reduced activity of the renin–angiotensin–aldosterone system (RAAS). However, normotensive rats exposed to high sodium do not show changes in systemic arterial pressure. We hypothesized that, despite the reduced circulating amounts of angiotensin II induced by a high salt diet, the cardiovascular system's reactivity to angiotensin II is increased in vivo, contributing to maintain arterial pressure at normal levels. Male Wistar rats received chow containing 0.27% (control), 2%, 4%, or 8% NaCl for six weeks. The high-sodium diet did not lead to changes in arterial pressure, although plasma levels of angiotensin II and aldosterone were reduced in the 4% and 8% NaCl groups. The 4% and 8% NaCl groups showed enhanced pressor responses to angiotensin I and II, accompanied by unchanged and increased angiotensin-converting enzyme activity, respectively. The 4% NaCl group showed increased expression of angiotensin II type 1 receptors and reduced expression of angiotensin II type 2 receptors in the aorta. In addition, the hypotensive effect of losartan was reduced in both 4% and 8% NaCl groups. In conclusion these results explain, at least in part, why the systemic arterial pressure is maintained at normal levels in non-salt sensitive and healthy rats exposed to a high salt diet, when the functionality of RAAS appears to be blunted, as well as suggest that angiotensin II has a crucial role in the vascular dysfunction associated with high salt intake, even in the absence of hypertension.

Cardiopulmonary hemodynamic responses to the small injection of hemoglobin vesicles (artificial oxygen carriers) in miniature pigs

Intravenous injection of liposomes into pigs reportedly induces anaphylactoid reactions at a small dose, resulting in circulatory disorder. Hemoglobin vesicles (HbVs) are artificial oxygen carriers encapsulating Hb solution in liposomes. It is not known how pigs respond to HbV injection. We aimed to analyze the cardiopulmonary responses to small injections of HbV and empty vesicle (EV) and compare them with a conventional liposome (CL) with a different lipid composition containing phosphatidylglycerol (PG). PG is known to induce an anaphylactoid reaction in pigs. Nine male miniature pigs were used for HbV, EV, and CL injections. The anesthetized pig received 0.05 and 0.5 mL/kg of a test fluid for the first and second injection with a 70 min interval. Results show that CL repeatedly induced significant increases in systemic and pulmonary arterial pressures and vascular resistances and decreases in heart rate and cardiac output (CO). HbV and EV at the first injection-induced pulmonary hypertension, with significantly smaller changes in systemic arterial pressure and CO. No remarkable response was visible at the second injection in spite of a larger dosage. Only CL repeatedly induced thrombocytopenia, leukocytopenia, and plasma thromboxane B(2) increase resulting from complement activation, although HbV and EV showed smaller changes. Transmittance electron micrograph of pulmonary intravascular macrophages (PIMs) showed phagocytosis of HbV, indicating the possibility that nonspecific phagocytosis by PIMs relates to the responses observed after the first injection. HbV does not induce a significant anaphylactoid reaction in pigs compared with CL because of the different lipid composition.

Glomerular hyperfiltration: a marker of early renal damage in pre-diabetes and pre-hypertension

Glomerular hyperfiltration is a characteristic functional abnormality in insulin-dependent diabetes mellitus and occurs in the large majority of young Type 1 diabetic patients. Hyperfiltration is hypothesized to be a precursor of intraglomerular hypertension leading to albuminuria. Glomerular filtration rate (GFR) then falls progressively in parallel with a further rise in albuminuria which may lead, in the long run, to end-stage renal failure. Experimental and clinical studies have shown that glomerular hyperfiltration can occur also in hypertension. However, whether hyperfiltration occurs also in early stages of hyperglycaemia and high blood pressure, such as in pre-diabetes and pre-hypertension, is not well known. In this issue of the Journal, Okada and Coll studied a large Japanese population showing that in pre-diabetic and pre-hypertensive subjects, the prevalence of hyperfiltration is proportional to the level of glucose and blood pressure, respectively. One main problem with the diagnosis of hyperfiltration is that no generally accepted definition is available due to the strong inverse correlation of GFR with age. To overcome this limitation, Okada et al. calculated the upper normal limit of GFR in a large healthy Japanese sample divided into 10-year age groups, providing ageand sex-specific reference values. For hyperfiltration to develop, the concomitant action of a variety of pathogenetic factors are needed including increased body mass index, hyperinsulinaemia, activation of the sympathetic nervous system, hyperleptinaemia, increased oxidative stress, inflammatory cytokines, etc. Another mechanism accounting for increased GFR in obese persons is increased NaCl intake. In addition, a significant role of increased Na reabsorption in the pathophysiology of glomerular hyperfiltration in obesity and hypertension has been described. Pharmacological agents with action on the renin–angiotensin system are effective in reducing glomerular hypertension which accounts for their efficacy in preventing progression of microalbuminuria in diabetes and hypertension. According to current guidelines, only low GFR and microalbuminuria or proteinuria should be considered as markers of renal dysfunction. Due to the strong association between hyperfiltration and risk of microalbuminuria found in diabetes and hypertension, hyperfiltration should be regarded as a precursor of nephropathy in these clinical conditions. More extensive use of markers of early organ damage may help clinicians to reach a more timely decision about the initiation of treatment and thus delay cardiovascular complications. Hyperglycaemia and high blood pressure in people with hyperfiltration should be treated earlier to prevent the progression of renal dysfunction to chronic kidney disease. Increased GFR, also called hyperfiltration, is a proposed mechanism for renal injury in several clinical conditions. According to the Brenner theory [1], low nephron number at birth explains why some individuals are prone to developing progressive renal damage later in life when other risk factors become operative. At the single-nephron level, hyperfiltration is hypothesized to be a precursor of intraglomerular hypertension leading to albuminuria. Increased glomerular capillary hydraulic pressure may be due to changes in systemic arterial pressure and/or changes in efferent and afferent arteriolar resistances. In the absence of therapeutic interventions, GFR then falls progressively in parallel with a further rise in albuminuria which may lead, in the long run, to end-stage renal failure (Figure 1). Human models of renal injury are in keeping with this pathogenetic view. Glomerular hyperfiltration has been observed in patients with unilateral renal agenesis [2], congenitally reduced nephron number [3] and acquired reduction in renal mass [4]. These individuals are prone to developing proteinuria early in life in association with glomerular sclerosis. It is suggested that this model of renal injury may apply to the early diabetic or hypertensive kidney.

Measuring high pressure baroreceptor sensitivity in the rat

IntroductionThe high pressure baroreceptor reflex rapidly buffers changes in systemic arterial pressure in response to postural changes, altered gravitational conditions, diseases, and pharmacological agents. Drug-induced exaggeration of changes in heart rate and in systemic arterial pressure is a leading cause of adverse events and of patients terminating use of drugs, particularly in the aging population. This paper presents a facile method for monitoring the high pressure baroreceptor reflex in rats, and presents an alternative to quantifying the magnitude of this reflex using 2 dependent variables, heart rate and systemic arterial pressure, rather than merely change in heart rate. MethodsTwenty-four rats were allocated to 3 groups: group I anesthetized with 100mg/kg thiopental, group II anesthetized with 2% isoflurane given by inhalation, group III anesthetized with thiopental but pretreated for 2weeks with 2μg/kg aldosterone given SQ bid. After induction to anesthesia, hair was clipped from the ventral aspect of the neck, and petrolatum was applied to the skin to permit an air-tight seal with a glass funnel attached to a source of variable and controllable negative pressure. Systemic arterial pressure, ECG, heart rate, and a force of suction applied to the neck were all recorded continuously. ResultsAfter baseline recordings, a force of −20mmHg was applied for 20s over the carotid artery. In rats receiving thiopental, the average changes in heart rate and systemic arterial pressure following the application of −20mmHg neck suction were 30±11bpm and 45±14mmHg, respectively. The ratios of change in heart and change in systemic arterial pressure to application of negative force over the carotid sinus are 1.5±0.6bpm/mmHg and 0.7±04mmHg/mmHg, respectively. Mean values for heart rate and for mean systemic arterial pressure during baseline and after application of neck suction for 20s showed little to no decrease (i.e., blunting) in rats anesthetized with isoflurane or pretreated with aldosterone. DiscussionThus this methodology was able to detect, in rats, blunting of baroreceptor function for at least 2 perturbations of this important homeostatic control system.

Res-Erection of Viagra as a Heart Drug

In 1998, the world was formally introduced to Viagra (sildenafil), the first oral agent to be approved in the United States for the treatment of erectile dysfunction. Developed by Pfizer chemists, sildenafil inhibited phosphodiesterase type 5 (PDE5), one of the 11-member superfamily of enzymes that hydrolyze cyclic nucleotide monophosphates and among the first discovered that was selective for cGMP. PDE5 had been identified more than 2 decades earlier, first as a protein that bound cGMP and later as one that hydrolyzed it (the binding function turning out to be a mechanism to regulate activity).1 Sildenafil induces vasorelaxation by blocking PDE5-cGMP hydrolysis, raising cGMP levels in smooth muscle to activate protein kinase G (also known as cGK). In platelets, this blunts thrombosis; together, the effects suggested a potential use for coronary vascular disease and hypertension. Pfizer initiated trials targeting coronary ischemia, but, although antianginal effects were disappointing, the study gave a whole new meaning to the term “side effect,” effectively hijacking sildenafil from cardiovascular development to a rather different indication. Article see p 8 There were still some cardiovascular studies performed, but essentially all were limited assessments of volunteer populations, mostly normal and at rest and some with cardiovascular disease; the results were interpreted to support safety for patients taking the drug. In particular, blood pressure changes were slight if present at all, and cardiac function appeared unaltered. Well into the mid 2000s, PDE5 was thought to be expressed in selective vascular beds, lung and corpus cavernosum being dominant, and to have a minor cardiovascular profile elsewhere, with a negligible role in the heart. Sildenafil reemergence as …

Chronic Treatment with Quercetin does not Inhibit Angiotensin‐Converting Enzyme In Vivo or In Vitro

The precise mechanisms explaining the anti-hypertensive effects produced by quercetin are not fully known. Here, we tested the hypothesis that chronic quercetin treatment inhibits the angiotensin-converting enzyme (ACE). We examined whether quercetin treatment for 14 days reduces in vivo responses to angiotensin I or enhances the responses to bradykinin in anaesthetised rats. We measured the changes in systemic arterial pressure induced by angiotensin I in doses of 0.03-10 μg/kg, by angiotensin II in doses of 0.01-3 μg/kg, and to bradykinin in doses of 0.03-10 μg/kg in anaesthetised rats pre-treated with vehicle (controls), or daily quercetin 10 mg/kg intraperitoneally for 14 days, or a single i.v. dose of captopril 2 mg/kg. Plasma ACE activity was determined by a fluorometric method. Plasma quercetin concentrations were assessed by high performance liquid chromatography. Quercetin treatment induced no significant changes in the hypertensive responses to angiotensin I and angiotensin II, as well in the hypotensive responses to bradykinin (all p>0.05). Conversely, as expected, a single dose of captopril inhibited the hypertensive responses to angiotensin I and potentiated the bradykinin responses (all p<0.01), while no change was found in the vascular responses to angiotensin II (all p>0.05). In addition, although we found significant amounts of quercetin in plasma samples (mean=206 ng/mL), no significant differences were found in plasma ACE activity in rats treated with quercetin compared with those found in the control group (50±6 his-leu nmol/min/mL and 40±7 his-leu nmol/min/mL, respectively; p>0.05). These findings provide strong evidence indicating that quercetin does not inhibit ACE in vivo or in vitro and indicate that other mechanisms are probably involved in the antihypertensive and protective cardiovascular effects associated with quercetin.

Gene Delivery of Cytochrome P450 Epoxygenase Ameliorates Monocrotaline-Induced Pulmonary Artery Hypertension in Rats

Pulmonary arterial hypertension (PAH) is a life-threatening disease that leads to progressive pulmonary hypertension, right heart failure, and death. Endothelial dysfunction and inflammation were implicated in the pathogenesis of PAH. Epoxyeicosatrienoic acids (EETs), products of the cytochrome P450 epoxygenase metabolism of arachidonic acid, are potent vasodilators that possess anti-inflammatory and other protective properties in endothelial cells. We investigated whether gene delivery with the human cytochrome P450 epoxygenase 2J2 (CYP2J2) ameliorates monocrotaline (MCT)-induced pulmonary hypertension in rats. Significant pulmonary hypertension developed 3 weeks after the administration of MCT, but gene therapy with CYP2J2 significantly attenuated the development of pulmonary hypertension and pulmonary vascular remodeling, without causing changes in systemic arterial pressure or heart rate. These effects were associated with increased pulmonary endothelial NO synthase (eNOS) expression and its activity, inhibition of inflammation in the lungs, and transforming growth factor (TGF)-β/type II bone morphogenetic protein receptor (BMPRII)-drosophila mothers against decapentaplegic proteins (Smads) signaling. Collectively, these data suggest that gene therapy with CYP2J2 may have potential as a novel therapeutic approach to this progressive and oftentimes lethal disorder.

Skeletal muscle blood flow responses to hypoperfusion at rest and during rhythmic exercise in humans

We evaluated the contribution of changes in systemic arterial pressure and local vasodilation to blood flow restoration in contracting human muscles during acute hypoperfusion. Healthy subjects (n=10) performed rhythmic forearm exercise (10% and 20% of maximum) while a balloon in the brachial artery located above the elbow was inflated. Each trial included 3 min of rest, exercise, exercise with balloon inflation, and exercise after balloon deflation. Forearm blood flow (FBF) was measured using Doppler ultrasound. Blood pressure on both sides of the balloon was measured using a brachial artery catheter (distal pressure), and Finometer for proximal (systemic) arterial pressure. Balloon inflation during exercise reduced distal arterial pressure, and FBF fell 37-41%. There was also a surprising acute increase in forearm vascular resistance (distal pressure/FBF). This was followed by recovery of distal arterial pressure and forearm vasodilation that caused a marked (approximately 75%) restoration of flow that was not associated with significant changes in systemic arterial pressure. During validation trials (n=6) at rest and with exercise both balloon and brachial artery diameters were stable when the balloon was inflated. Our findings indicate that at these exercise intensities 1) the restoration of FBF during exercise with hypoperfusion relied primarily on local dilator responses in conjunction with restoration of distal perfusion pressure likely as a result of increased collateral flow around the elbow, and 2) a loss of pulsatile flow and elastic recoil in the forearm may have contributed to the acute increase in vascular resistance seen at the onset of hypoperfusion.

Isoflavone genistein inhibits the angiotensin-converting enzyme and alters the vascular responses to angiotensin I and bradykinin

Genistein produces antihypertensive and beneficial cardiovascular effects, although the mechanisms for these effects are not known. We examined whether genistein inhibits the in vivo responses to angiotensin I or enhances the responses to bradykinin in anaesthetized rats as a result of angiotensin-converting enzyme inhibition. We have also studied the in vitro effects produced by genistein on the angiotensin-converting enzyme activity. We measured the changes in systemic arterial pressure induced by angiotensin I in doses of 0.03 to 10 µg/kg, by angiotensin II in doses of 0.01 to 3 µg/kg, and to bradykinin in doses of 0.03 to 10 µg/kg in anaesthetized rats pretreated with vehicle (controls), or a single i.v. dose of genistein 25 mg/kg, or daily genistein 25 mg/kg i.v for two days, or a single i.v. dose of captopril 2 mg/kg. Plasma angiotensin-converting enzyme activity was determined in controls and genistein-treated rats using a fluorometric method. The effects of genistein (3–300 µmol/l) on in vitro angiotensin-converting enzyme activity were assessed by adding genistein to plasma samples and measuring angiotensin-converting enzyme activity. We found significant lower angiotensin-converting enzyme activity in plasma samples from rats pretreated with genistein compared with those found in the Control group (77.7 ± 8.1 his-leu nmol/min/ml and 108.7 ± 8.4 his-leu nmol/min/ml, respectively; P = 0.01). The incubation of genistein with plasma samples showed that genistein decreased the angiotensin-converting enzyme activity in plasma in a concentration-dependent manner ( P < 0.01). These findings indicate that genistein inhibits the angiotensin-converting enzyme in vivo and in vitro and may explain, at least in part, the antihypertensive and beneficial vascular effects produced by genistein.

Cardiovascular responses to rat/mouse hemokinin-1, a mammalian tachykinin peptide: Systemic study in anesthetized rats

Rat/mouse hemokinin-1 is a mammalian tachykinin peptide whose biological functions have not been well characterized. In the present study, an attempt has been made to investigate the effect and mechanism of action of rat/mouse hemokinin-1 on systemic arterial pressure after intravenous (i.v.) injections in anesthetized rats by comparing it with that of substance P. Our data showed that injection of rat/mouse hemokinin-1 (0.1, 0.3, 1, 3 and 10 nmol/kg) lowered systemic arterial pressure dose-dependently. This effect was significantly blocked by pretreatment with SR140333 (a selective tachykinin NK1 receptor antagonist) and the NO synthase inhibitor L-NAME (Nomega-nitro-L-arginine methyl ester hydrochloride), respectively, but was not affected by bilateral vagotomy or the muscarinic receptor blocker atropine. Compared to rat/mouse hemokinin-1, a dose of 3 nmol/kg of substance P caused biphasic changes in systemic arterial pressure (depressor and pressor responses). The results suggest that the mechanism of the depressor response caused by substance P was similar to rat/mouse hemokinin-1 in that it was inhibited by SR140333 and L-NAME, respectively, but that there was a component of the cardiovascular change induced by rat/mouse hemokinin-1 (but not substance P) that was attenuated by SR48968 (a selective tachykinin NK2 receptor antagonist). The depressor response induced by rat/mouse hemokinin-1 (i.v.) might be explained primarily by the action on endothelial tachykinin NK1 receptors to release endothelium-derived relaxing factor (NO) and this effect was not affected by vagal components. In addition, rat/mouse hemokinin-1 could not induce the pressor response through stimulation of sympathetic ganglion like substance P in anesthetized rats.