Potent Blood Pressure Lowering Research Articles

Calcium channel blockers for hypertension: old, but still useful

Calcium channel blockers (CCBs) constitute a heterogeneous class of drugs that can be divided into dihydropyridines (DHPs) and non-DHPs. DHP-CCBs are subcategorized into four generations based on the duration of activity and pharmacokinetics, while non-DHP-CCBs are subcategorized into phenylethylamine and benzodiazepine derivatives. DHP-CCBs are vascular-selective and function as potent vasodilators, whereas non-DHP-CCBs are cardiac-selective and are useful for treating tachyarrhythmia, but reduce cardiac contractility and heart rate. Traditional DHP-CCBs (nifedipine) mainly block L-type calcium channels, whereas novel CCBs block N-type (amlodipine) and/or T-type channels (efonidipine) in addition to L-type channels, leading to organ-protective effects. DHP-CCBs have a potent blood pressure–lowering effect and suppress atherosclerosis and coronary vasospasm. Diltiazem, a non-DHP-CCB, is highly effective for vasospasm control. CCBs reduce left ventricular hypertrophy and arterial stiffness. Amlodipine, a DHP-CCB, reduces blood pressure variability. L/N- and L/T-type CCBs combined with renin-angiotensin system blockers reduce proteinuria and improve kidney function compared with L-type CCBs. According to large-scale trials, DHP-CCBs reduce cardiovascular events in patients with isolated systolic hypertension, as well as in elderly and high-risk patients. Accordingly, CCBs are indicated for hypertension in elderly patients, isolated systolic hypertension, angina pectoris, and coronary vasospasm. Non-DHP-CCBs are contraindicated in high-grade heart block, bradycardia (<60 beats per minute [bpm]), and heart failure with reduced ejection fraction (HFrEF). DHP-CCBs should be used with caution in patients with tachyarrhythmia, HFrEF, and severe leg edema, and non-DHP-CCBs should be used carefully in those with constipation. Each CCB has distinct pharmacokinetics and side effects, underscoring the need for meticulous consideration in clinical practice.

COMPARISON OF CLINICAL BENEFITS BETWEEN TELMISARTAN AND OTHER ANGIOTENSIN RECEPTOR BLOCKERS IN HYPERTENSION PATIENTS WITH COMBINATION THERAPY: MULTICENTER REAL-WORLD STUDY

Objective: Background Telmisartan have potent blood pressure lowering effect as well as the other pleiotrophic effects including PPAR-??/?? dual activation. In large clinical studies, telmisartan demonstrated the comparable clinical benefits with angiotensin converting enzyme inhibitor. However, there were few studies of direct comparison between telmisartan and the other angiotensin receptor blockers (ARBs). This study aimed to compare the cardiovascular and renal protective effect between telmisartan and the other ARBs in patients with the advanced hypertension who required two or more anti-hypertensive drugs. Design and method: This study used the Observation Medical Outcomes Partnership-Common Data Model database of three tertiary hospitals in Korea. 19,247 Patients were prescribed at least two antihypertensive drugs including ARBs, were selected from January 1, 2017 to December 31, 2019. 3,437 patients in the telmisartan group and 15,810 patients in the other ARB group were matched 1:1 through propensity score matching. Major adverse cardiovascular event (MACE), heart failure (HF) hospitalization and new-onset dialysis were compared for 3,386 patients in each group. Result: Before the matching, there was a higher proportion of patients with a history of myocardial infarction (MI) in the telmisartan group compared to the other ARB group. After the matching, average on-treatment blood pressure was similar between two groups. Over a three-year period, the incidence of MACE and HF hospitalization did not differ significantly between the two groups. Compared to the other ARB group, the telmisartan group had a lower incidence of new-onset dialysis (1.3% vs 1.9%, p-value = 0.04). However, this difference was not statistically significant in the multivariable Cox regression model. Conclusions: Telmisartan has similar cardiovascular and renal protective effects to other ARBs in patients with advanced hypertension who are taking at least two anti-hypertensive medications. Figure. Kaplan-Meier curves showing the incidence of MACE and dialysis in the telmisartan group and the other ARB group.

Sodium-Glucose Cotransporter-2 Inhibitors-Miracle Drugs for the Treatment of Chronic Kidney Disease Irrespective of the Diabetes Status: Lessons from the Dedicated Kidney Disease-Focused CREDENCE and DAPA-CKD Trials.

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) and end-stage kidney disease worldwide. In Japan, the proportion of new patients requiring dialysis due to DKD has remained unchanged over the past five years. Early diagnosis and treatment are extremely important for the prevention of DKD progression. Albuminuria is the most promising biomarker currently available for diagnosing DKD and predicting its prognosis at an early stage; however, it has relatively poor specificity and sensitivity for DKD. Measuring the serum levels of tumor necrosis factor receptors (TNFRs; TNFR1 and TNFR2) is an alternative for predicting the prognosis of patients with CKD, irrespective of their diabetes status. Cardiorenal risk factor management and renin-angiotensin system inhibitor usage are effective in slowing the DKD progression, although the residual risk remains high in patients with DKD. Recently, two classes of antihyperglycemic agents, sodium-glucose cotransporter 2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists, in addition to nonsteroidal selective mineralocorticoid receptor antagonists, which are less potent blood pressure-lowering and potassium-sparing agents, have emerged as cardiorenal disease-modifying therapies for preventing the DKD progression. This review focused on the SGLT2 inhibitor-based therapeutic strategies that have demonstrated cardiorenal benefits in patients with type 2 diabetes.

A novel soluble guanylyl cyclase activator, BR 11257, acts as a non-stabilising partial agonist of sGC

The soluble guanylyl cyclase (sGC) plays a key role in NO/cGMP signalling and is widely recognised to be important in different disease pathomechanisms. The discovery of sGC agonists provides a new opportunity to stimulate the NO/cGMP pathway. One class of compounds are the heme-independent sGC activators, which are thought to bind to oxidised or heme-free sGC. This enzyme is preferentially formed under disease situations accompanied by oxidative stress. Accordingly, this binding mode of sGC activators has quite some appeal for the clinical use of sGC activator drugs in diseases with high oxidative stress burden. However, none of the previous sGC activators, most of them dicarboxylic acid derivatives, has passed clinical trials to date, also because of the potent blood pressure lowering effects. In the current study, we investigate the effects of a new monocarboxylic drug BR 11257 in vitro and in vivo. Activity measurements with purified enzyme indicated gentle sGC activation for BR 11257 resembling a partial agonistic behaviour. In thermal shift measurements, we observed an unexpected difference between BR 11257 and the sGC activators from the dicarboxylic acid type. While activators from the dicarboxylic acid type had a highly thermostabilising influence on sGC, this effect was absent with BR 11257. We hypothesize that the key interaction partner for thermostabilisation is the second carboxylic acid in BAY 60-2770 which is missing in BR 11257. The absence of this thermodynamic receptor stabilisation and the partial agonism may be advantageous to overcome limitations of this class of drugs by avoiding excessive hypotension.

Improvements in Left Atrial Appendage Velocities Following Transcatheter Aortic Valve Replacement

Background: The natriuretic peptide family consists of atrial and b-type natriuretic peptide (ANP, BNP) and C-type natriuretic peptide (CNP). ANP and BNP are mainly produced in the heart and possess potent blood pressure lowering as well as natriuretic and diuretic actions through guanylyl cyclase receptor A (GC-A) and cGMP activation. Meanwhile, CNP is an endothelium and renal derived hormone of which its mature biological active form, CNP22, has the most robust cardiorenal anti-remodeling properties via GC-B activation and generation of cGMP compared to GC-A. Recently we reported that heart failure (HF) patients have increased plasma and markedly elevated urinary levels of a larger CNP molecular form, CNP53, which also is biologically active and generates cGMP through the GC-B receptor. Notably, preliminary studies have demonstrated that CNP53 is more biologically active and has renal enhancing actions in vivo, compared to CNP22. However, it remains unclear if CNP53’s biological and renal actions differ from that of BNP in vivo. Objectives: To define the cardiorenal and cGMP generating actions of CNP53, GC-B agonist, compared to BNP, a GC-A agonist, in vivo. Hypothesis: We hypothesize that CNP53 has cardiorenal and cGMP actions in vivo, but will exhibit less hypotension than BNP. Methods: Vehicle (V), an equimolar dose of BNP or CNP53 (Phoenix Pharmaceuticals, CA) was infused intravenously into anesthetized normal rats. Mean arterial blood pressure (MAP), glomerular filtration rate (GFR) and urinary sodium (Na) excretion were assessed. Plasma and urinary cGMP was determined by radioimmunoassay. Data are presented as Mean6SE. *p!0.05 between all groups. Results: During CNP53 and BNP infusion, plasma cGMP (V: 961, CNP53: 9164, BNP: 190637*, pmol/ml) and urinary cGMP excretion (V: 3366, CNP53: 176628, BNP: 5096124*, pmol/min) significantly increased compared to vehicle. Moreover, GFR (V: 4.860.3, CNP53: 5.760.2, BNP: 7.260.5*, ml/min/kg) and urinary Na excretion (V: 0.860.1, CNP53: 1.460.2, BNP: 2.460.1*,uEq/min) also significantly increased with CNP53 and BNP compared to vehicle. Notably, BNP had the greatest drop in MAP compared to vehicle and CNP53 (DMAP V: 2.06 3.0, CNP53: -4.062.7, BNP: -11.363.8*, mmHg). Conclusion: We report CNP53 exerts favorable cardiorenal and cGMP actions without excessive hypotension as seen with BNP. These findings support an emerging concept that CNP53 may be an alternative therapeutic strategy for HF, especially in the setting of hypotension, and this warrants further investigation.

Therapeutic Insights for Heart Failure: In Vivo Comparison Between a Guanylyl Cyclase Receptor A and a Novel Guanylyl Cyclase Receptor B Activator

The natriuretic peptide family consists of atrial and b-type natriuretic peptide (ANP, BNP) and C-type natriuretic peptide (CNP). ANP and BNP are mainly produced in the heart and possess potent blood pressure lowering as well as natriuretic and diuretic actions through guanylyl cyclase receptor A (GC-A) and cGMP activation. Meanwhile, CNP is an endothelium and renal derived hormone of which its mature biological active form, CNP22, has the most robust cardiorenal anti-remodeling properties via GC-B activation and generation of cGMP compared to GC-A. Recently we reported that heart failure (HF) patients have increased plasma and markedly elevated urinary levels of a larger CNP molecular form, CNP53, which also is biologically active and generates cGMP through the GC-B receptor. Notably, preliminary studies have demonstrated that CNP53 is more biologically active and has renal enhancing actions in vivo, compared to CNP22. However, it remains unclear if CNP53’s biological and renal actions differ from that of BNP in vivo. To define the cardiorenal and cGMP generating actions of CNP53, GC-B agonist, compared to BNP, a GC-A agonist, in vivo. We hypothesize that CNP53 has cardiorenal and cGMP actions in vivo, but will exhibit less hypotension than BNP. Vehicle (V), an equimolar dose of BNP or CNP53 (Phoenix Pharmaceuticals, CA) was infused intravenously into anesthetized normal rats. Mean arterial blood pressure (MAP), glomerular filtration rate (GFR) and urinary sodium (Na) excretion were assessed. Plasma and urinary cGMP was determined by radioimmunoassay. Data are presented as Mean±SE. *p<0.05 between all groups. During CNP53 and BNP infusion, plasma cGMP (V: 9±1, CNP53: 91±4, BNP: 190±37*, pmol/ml) and urinary cGMP excretion (V: 33±6, CNP53: 176±28, BNP: 509±124*, pmol/min) significantly increased compared to vehicle. Moreover, GFR (V: 4.8±0.3, CNP53: 5.7±0.2, BNP: 7.2±0.5*, ml/min/kg) and urinary Na excretion (V: 0.8±0.1, CNP53: 1.4±0.2, BNP: 2.4±0.1*,uEq/min) also significantly increased with CNP53 and BNP compared to vehicle. Notably, BNP had the greatest drop in MAP compared to vehicle and CNP53 (ΔMAP V: 2.0± 3.0, CNP53: -4.0±2.7, BNP: -11.3±3.8*, mmHg). We report CNP53 exerts favorable cardiorenal and cGMP actions without excessive hypotension as seen with BNP. These findings support an emerging concept that CNP53 may be an alternative therapeutic strategy for HF, especially in the setting of hypotension, and this warrants further investigation.

Abstract 19094: Antihypertensive Properties of Subcutaneous M-ANP, a Novel Designer Atrial Natriuretic Peptide, in a Canine Model of Chronic Angiotensin-II Induced Hypertension

Introduction: Blood pressure (BP) control remains low despite combination therapy in resistant hypertension (RH). Thus, there is an unmet need for novel strategies targeting RH. Recently we have reported that M-ANP, a novel Mayo engineered ANP-based peptide, possesses greater and more sustained biological actions compared to ANP and is more resistant to neprilysin degradation. The current study was designed to investigate for the first time the efficacy of a single daily subcutaneous (SQ) injection of M-ANP using a chronic canine model of hypertension induced by angiotensin II (Ang-II). Hypothesis: We hypothesize that a daily SQ M-ANP injection would have potent BP lowering and renal enhancing properties in our chronic hypertensive canine model. Methods: We induced hypertension in canines (n=5) by continuous Ang II (80 ng/kg/min) osmotic mini-pump administration for 24 days. Continuous 24 hour mean BP (MBP) was measured by telemetry and a 24 hour urine collection was used to assess urinary volume, sodium (Na) and cGMP, the second messenger for the ANP system. M-ANP was administered SQ for 5 days (10μg/kg/day). Data are mean±SE. ΨP&lt;0.05 Ang II Day 16 vs. baseline; *P&lt;0.05 Ang II Day 16 vs. M-ANP (Table 1). Results: Chronic Ang II administration resulted in model of severe hypertension, with an increase in MBP from 112±2 to 157±2 mmHg (day 16). As seen in Table 1, M-ANP significantly reduced MBP, significantly increased plasma cGMP as well as urinary cGMP excretion, urinary volume rate (UV) and urinary Na excretion (UNa), without significant changes in heart rate (HR). Furthermore, there was a trend for plasma ANP to increase and plasma aldosterone to decrease with SQ M-ANP injection. Conclusions: This study demonstrates for the first time that chronic SQ administration of M-ANP reduces BP, activates plasma cGMP, and increases UV and UNa, without significant changes in HR in an experimental model of chronic hypertension.

Clinical Science of Calcium Channel Blocker to Inhibit Hypertensive Vascular Injury

Calcium channel blockers are the strongest and most widely used antihypertensive drugs in Japan. Calcium channel blockers dilate both artery and arteriole that increases end-organ perfusion, thus possessing few side effects especially for the elderly hypertensive patients. The safety of calcium channel blockers was well established. In this paper, important clinical evidence supporting the effectiveness of calcium channel blockers and improving cardiovascular endpoints will be reviewed. Calcium channel blockers protect end-organs from hypertensive vascular injury. In addition, calcium channel blockers show non-inferiority to angiotensin converting enzyme inhibitors, angiotensin receptor blockers and diuretics regarding cardiovascular endpoints. Furthermore, calcium channel blockers may have superiority to betablockers. Although cardiovascular protection by calcium channel blockers largely depends on their potent blood pressure lowering ability, including central blood pressure, calcium channel blockers can manifest blood pressure-independent vascular protection. Thus, calcium channel blockers are basic antihypertensive drugs, and constitute the treatment of choice to obtain target blood pressure for most hypertensive patients, especially for high-risk population and those with resistant hypertension. An intense treatment of hypertension with adequate doses of calcium channel blockers is mandatory to improve cardiovascular prognosis.

Efonidipine, Another Beauty Relieving the Pressure

Refer to the page 231-238 In a variety of observational studies from the population level to various clinical situations, it is well known that, a lower heart rate is considered to be better.1) However, in Anglo-Scandinavian Cardiac Outcomes Trial study, a vice versa was demonstrated showing an inferior protection for stroke by atenolol and bendroflumethiazide to amlodipine and perindopril.2) Despite of several explanations on those contradictory findings, findings such as the pharmacodynamics actions, an explanation solely provided by the slow heart rate seems to be, at least from a statistical viewpoint, the most powerful.3) In the study by Komukai et al.4) efonidifine, a dihydropiridine calcium antagonist on the actions of L-type as well as T-type calcium channels, showed a significant reduction in the heart rate as well as in the blood pressure. It is characterized by rapid onset and durable which is independent of the administration time. In the previous study by Oh et al.5) efonidipine also showed similar efficacy, in regards to, slowing down the heart rate by approximately 11% in the mild to moderate hypertension patients. Komukai et al.4) postulated that heart rate reduction could be partially explained by slowly fading antihypertensive action, which was demonstrated by a non-linear fitting model, based periodic function. In essential hypertension, slowing down the heart rate by atenolol is rather closely related to the worsening of central hemodynamics. Moreover, there is no evidence supporting the hypothesis that the slower heart rate is better, in any direct comparison study. Recently, a 12 month follow up study for the patient with diabetic nephropathy done by Sasake et al.6) showed that efonidipine was better in reducing arterial stiffness than amlodipine, through the actions on aldosterone, renal function, and oxidative stress. Unfortunately, the blood pressure and the heart rate data were not demonstrated well enough to detect the difference between the groups. Putting those altogether, there seems to be a possibility that intrinsic pharmakodynamic properties of efonidipine could compensate or overcome the potential or relative disadvantage caused by a deceased heart rate on the arterial stiffness. Due to ethical issues, a study replacing heart rate slowing drugs for beta-blocker in the coronary artery disease is currently not allowed. Therefore, the beta-blocker therapy for coronary artery disease is not to be replaced by other rate slowing drugs, according to the current evidences. Even with a significant reduction in the secondary composite end points in the MorBidity-mortality EvAIUaTion of the /f inhibitor ivabradine in patients with coronary artery disease and left ventricULar dysfunction (BEAUTIFUL) study subgroup of heart rate of 70 beat per minute or greater, it is needless to say that the efficacy of ivabradine is not to be extrapolated to the essential hypertension patients.7) But at the same time, at least, ivabradine data did suggest that the harmful effects, demonstrated by atenolol, might not be universal to all the beta-blockers.7) Mechanism of of efonidipine on the sinus node is quite similar to that of ivabradine.8) Considering potential efficacy on the arterial stiffness, the BEAUTIFUL-like action in addition to modest antihypertensive efficacy, provided by efonidipine, is something throbbing. Especially studies for central hemodynamics and a direct comparison study would be very interesting. Another interesting hypothesis, regarding efonidipine, is that the dissociation of the durability on blood pressure and the heart rate could be an alternative to the trade-off between potent blood pressure lowering and the reflex tachycardia common in other dihydrophyridine calcium antagonists. Since the 24 hours blood pressure reduction is partly contributed by nocturnal blood pressure reduction, modest efonidipine efficacy on nocturnal blood pressure needs to be considered for individualized patient care.

A Novel Atrial Natriuretic Peptide Based Therapeutic in Experimental Angiotensin II Mediated Acute Hypertension

M-atrial natriuretic peptide (ANP; M-ANP) is a novel next generation 40 amino acid peptide based on ANP, which is highly resistant to enzymatic degradation and has greater and more sustained beneficial actions compared with ANP. The current study was designed to advance our understanding of the therapeutic potential of M-ANP in a canine model of acute angiotensin II-induced hypertension with elevated cardiac filling pressures and aldosterone activation. We compare M-ANP with vehicle and equimolar human B-type natriuretic peptide, which possesses the most potent in vivo actions of the native natriuretic peptides. M-ANP significantly lowered mean arterial pressure and systemic vascular resistance. Importantly, despite a reduction in blood pressure, renal function was enhanced with significant increases in renal blood flow, glomerular filtration rate, diuresis, and natriuresis after M-ANP infusion. Although angiotensin II induced an acute increase in pulmonary capillary wedge pressure, M-ANP significantly lowered pulmonary capillary wedge pressure, pulmonary artery pressure, and right atrial pressure. Further, M-ANP significantly suppressed angiotensin II-induced activation of aldosterone. These cardiovascular and renal enhancing actions of M-ANP were accompanied by significant increases in plasma and urinary cGMP, the second messenger molecule of the natriuretic peptide system. When compared with human B-type natriuretic peptide, M-ANP had comparable cardiovascular actions but resulted in a greater natriuretic effect. These results suggest that M-ANP, which is more potent than ANP in normal canines, has potent blood pressure lowering and renal enhancing properties and may, therefore, serve as an ANP based therapeutic for acute hypertension.

Spironolactone and resistant hypertension

True resistant hypertension is relatively frequent, yet effective treatment is often difficult to identify. In a new study, de Souza and colleagues demonstrate the potent blood pressure lowering effect of low-dose spironolactone in patients with evident resistant hypertension. This finding should have broad clinical implications in the effective management of a notoriously challenging condition.

Hemodynamic Effects of the Nitric Oxide Donor DETA/NO in Mice

(Z)‐1‐[N‐(2‐aminoethyl)‐N‐(2‐ammonioethyl)amino]diazen‐1‐ium‐1,2‐diolate (DETA/NO) is a recently synthesized member of NO‐releasing, polyamine zwitterions, the so‐called NONOates, that spontaneously liberate NO in aqueous solutions. The aim of this study was to determine the hemodynamic effects of DETA/NO in normotensive and hypertensive mice. Male Swiss Outbred mice were implanted with TA11PA‐C20 blood pressure devices (Data Sciences International, USA). After recovery (7–10 days), blood pressure was monitored for 10 days while mice were receiving saline (0.1 ml/20 g/day, s.c.). Mice were then treated every four hours for 1 day with either DETA/NO 60 mg/kg i.p. or the inactive metabolite, diethylenetriamine 38 mg/kg (molar equivalent) i.p. After a 2 week wash‐out period, mice were treated with adrenocorticotrophic hormone (ACTH: 500 µg/kg/day, s.c.) for 10 days and re‐challenged with DETA/NO or diethylenetriamine. Results were expressed as mean ± SEM. After 10 days of saline treatment, baseline systolic and diastolic blood pressure (BP) were similar for animals subsequently receiving DETA/NO or the amine (123 ± 1/95 ± 3 and 124 ± 1/92 ± 0.2 mmHg) respectively. DETA/NO induced a profound fall in BP [Systolic: 74 ± 4 mmHg (− 40 ± 3%); Diastolic: 46 ± 4 mmHg (− 52 ± 4%)] and an increase in heart rate [729 ± 33 bpm (32 ± 2%)] within the first 80 minutes. Diethylenetriamine had no effect. ACTH treatment increased BP in both groups (137 ± 16/108 ± 12 and 161 ± 1/142 ± 1 mmHg) respectively. DETA/NO induced a profound fall in blood pressure [Systolic: 92 ± 11 mmHg (− 32 ± 7%); Diastolic: 68 ± 10 mmHg (− 35 ± 10%)] and an increase in heart rate [613 ± 36 bpm (18 ± 6%)] within the first 80 minutes. Again diethylenetriamine had no significant effect. There was no significant effect on body weight with any treatment. Thus DETA/NO has potent blood pressure lowering effects in both normotensive and hypertensive mice.

Vasopeptidase Inhibition Has Potent Effects on Blood Pressure and Resistance Arteries in Stroke-Prone Spontaneously Hypertensive Rats

The antihypertensive agent omapatrilat represents a novel approach to antihypertensive therapy, namely vasopeptidase inhibition. Omapatrilat (BMS-186716) concomitantly inhibits neutral endopeptidase and angiotensin-converting enzyme, leading to protection from degradation of natriuretic and other hypotensive peptides in addition to interruption of the renin-angiotensin system. Although the potency of omapatrilat on reduction of blood pressure has been reported, its effects on resistance artery structure and function were unknown. We tested omapatrilat in stroke-prone spontaneously hypertensive rats (SHRSP), a malignant model of hypertension, with the hypothesis that it would improve the structure and endothelial function of mesenteric resistance arteries. Ten-week-old SHRSP were treated orally for 10 weeks with omapatrilat (40 mg/kg per day). Mesenteric arteries (lumen <300 microm) were studied on a pressurized myograph. After 10 weeks, untreated SHRSP had a systolic blood pressure of 230+/-2 mm Hg that was significantly reduced (P<0.05) by omapatrilat (145+/-3 mm Hg). Omapatrilat treatment improved endothelium-dependent relaxation of resistance arteries as elicited by acetylcholine (10(-5) mol/L) but had no significant effect on endothelium-independent relaxation produced by a nitric oxide donor (sodium nitroprusside). This suggested that there existed endothelial dysfunction in SHRSP that was corrected by vasopeptidase inhibition, probably in part caused by the potent blood pressure-lowering effect of omapatrilat. Media width and media/lumen ratio were significantly decreased (P<0.05) by omapatrilat, and a trend (P=0.07) to increase lumen diameter was observed. Vascular stiffness (slope of the elastic modulus versus stress curve) was unaltered by omapatrilat. In conclusion, omapatrilat, acting as a potent antihypertensive agent, may improve structure and endothelial function of resistance arteries in SHRSP, a severe form of genetic hypertension.

The effects of dietary evening primrose, black currant, borage and fungal oils on plasma, hepatic and vascular tissue fatty acid composition in the spontaneously hypertensive rat

Hypertension is associated with alterations in the metabolism of ω-6 polyunsaturated fatty acids (PUFA) in tissues. Compositional changes in tissue fatty acids may affect cellular properties such as ion permeability and receptor interactions important to blood pressure regulation. Recent evidence suggests that the ω-6 PUFA, gamma-linolenic acid (GLA), is a potent blood pressure lowering nutrient. In this study, the effects of dietary oils enriched with GLA (evening primrose, black currant, borage and fungal) on plasma, hepatic and vascular tissue fatty acid composition were determined in spontaneously hypertensive rats. The oils increased the composition of GLA and dihomogamma-linolenic acid in hepatic, aortic and renal arterial tissue (p<0.05). Arachidonic acid levels were also increased in the liver (p<0.05). The data suggest that alterations in the fatty acid profiles of hepatic and vascular tissue induced by GLA-enriched oils may be responsible for the favorable blood pressure lowering effect of GLA.

Signal transduction: activation of the guanylate cyclase-cyclic guanosine-3'-5' monophosphate system by hormones and free radicals.

Intracellular communication and transmission of messages for many hormones and free radicals occur after the hormones and free radicals bind to their receptors by enhancing the activity of guanylate cyclase, the enzyme that catalyzes the conversion of guanosine triphosphate to the intracellular messenger cyclic guanosine-3'-5' monophosphate (cyclic GMP). The guanylate cyclase-linked receptors exist intracellularly (ie, cytoplasmic) and in membrane-bound forms. Enhancement of guanylate cyclase by hormones or free radicals increases intracellular cyclic GMP, which closes cation channels in the kidney while activating cation channels in the retina and olfactory cilia, either directly or by cyclic GMP-dependent protein kinase. Cyclic GMP also has potent blood pressure lowering properties. Cyclic GMP promotes growth by increasing DNA, RNA, and protein synthesis. Overactivity of this system is observed in Traveler's diarrhea, whereas underactivity occurs in Chediak-Higashi syndrome in which lysosomal enzyme release and chemotaxis are defective and can be corrected in vitro by addition of cyclic GMP.

Dual angiotensin converting enzyme/thromboxane synthase inhibitors.

A variety of compounds were prepared to determine whether dual angiotensin converting enzyme (ACE)/thromboxane synthase (TxS) inhibition could be obtained in the same molecule. These compounds would be used to explore the concept that a dual inhibitor would have superior antihypertensive activity in the spontaneous hypertensive rat compared to an ACE inhibitor. Potent in vitro dual ACE and TxS inhibition was obtained in the same molecule with five series of compounds. Potent blood pressure lowering in the SHR was observed after oral administration of 8b and 11. However, a correlation between blood pressure lowering and the A1 pressor response inhibition was not observed. The blood pressure-lowering actions of enalapril were significantly potentiated by concurrent administration of 3, a thromboxane synthase inhibitor. Analysis of the area under the curve for 24 h showed nearly a doubling of the blood pressure-lowering effect.

Effect of pramipexole, a dopamine‐1/dopamine‐2 receptor agonist, on sodium excretion and blood pressure in spontaneously hypertensive rats

1. Abnormalities of the renal dopaminergic system have been implicated in the pathogenesis of hypertension in the spontaneously hypertensive rat (SHR). 2. Both DA-1 and DA-2 receptors are present in renal tubules and blood vessels. DA-1 receptors mediate the renal vasodilatory and natriuretic effects of DA but the contribution of DA-2 receptors to these effects is not known. 3. We therefore studied the effect of a novel and selective DA-1 and DA-2 agonist, pramipexole, on MAP, glomerular filtration rate (GFR), urine flow (V), absolute (UNaV) and fractional sodium (FeNa) excretion in 9-18-week-old SHR. Wistar-Kyoto rats (WKY) served as control. 4. Pramipexole given intravenously (1, 10, 100 micrograms kg body wt-1 min-1) decreased MAP in a dose-related manner to a greater extent in SHR (n = 5) than WKY (n = 6) such that at the highest dose of pramipexole, MAP was similar in both groups. Pramipexole did not alter GFR in either WKY or SHR. Pramipexole increased V in a dose-related manner in both WKY and SHR. At 100 micrograms pramipexole kg body wt-1 min-1, V increased eightfold in both SHR and WKY. In contrast, pramipexole increased UNaV to a greater extent in WKY (5.1-fold) than SHR (3.7-fold). 5. These studies show a differential effect of pramipexole on renal function and MAP in SHR and WKY. Pramipexole has a more potent blood pressure lowering effect in SHR than in WKY. However, the natriuretic effect of pramipexole was greater in the WKY than in the SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

ChemInform Abstract: SYNTHESIS AND BLOOD PRESSURE LOWERING ACTIVITY OF BENZYLIC ETHERS OF 2‐DIETHYLAMINOETHANOL AND A RELATED DIAMINE

AbstractWährend die Verbindung (I) eine stark blutdrucksenkende Wirkung aufweist, besitzer die strukturell ähnlich aufgebauten Benzyläther (II) und (III) sowie das Diamin (IV) eine geringere Wirksamkeit.

Synthesis and Blood Pressure Lowering Activity of Benzylic Ethers of 2-Diethylaminoethanol and a Related Diamine

Based upon the unpublished finding that 3′-hydroxy-4′-(β-diethylaminoethoxy)-3′,4′-dihydroseselin possessed a potent blood pressure lowering effect in the cat at a dose of 1 mg/kg, the present study examined the activities of several related compounds. These compounds were derived by dissection of the parent compound to give four benzylic ethers of 2-diethylaminoethanol and a diamine, derived by replacing the ether oxygen of the parent compound with an N—CH3 function. The simplest compounds were the benzyl and 2,6-dimethoxybenzyl ethers of the aminoalcohol. Closely related to the benzyl compound was a congener with a hydroxymethyl group on the benzylic carbon. The β-diethylaminoethyl ether of 4-chromanol was the most complex of the ethers. The blood pressure measurements were carried out on male cats and compared to papaverine hydrochloride as a standard. In all cases, the most potent blood pressure lowering activity resided in the parent compound, which was not greatly superior to the diamine but substantially more active than the other compounds.