Hypertension is the leading remediable risk factor for cardiovascular disease, affecting more than 1 billion people worldwide, and is responsible for more than 10 million preventable deaths globally each year. While hypertension can be successfully diagnosed and treated, only one in seven persons with hypertension have controlled blood pressure. To meet the challenge of improving the control of hypertension, particularly in low- and middle-income countries, the authors developed the Standardized Hypertension Treatment and Prevention Project, which involves a health systems–strengthening approach that advocates for standardized hypertension management using evidence-based interventions. These interventions include the use of standardized treatment protocols, a core set of medications along with improved procurement mechanisms to increase the availability and affordability of these medications, registries for cohort monitoring and evaluation, patient empowerment, team-based care (task shifting), and community engagement. With political will and strong partnerships, this approach provides the groundwork to reduce high blood pressure and cardiovascular disease-related morbidity and mortality.

Scope-Diabetic embryopathy, a consequence of diabetic pregnancy is associated with increase in embryonic oxidative stress and apoptosis which lead to severe embryonic damage at early stage of organogenesis.Methods and results-This study investigated if resveratrol, found in red grapes and blueberries, may prevent diabetes-induced oxidative stress and apoptosis in embryos and have beneficial effects in diabetic dams. A rodent model of diabetic embryopathy was used. Diabetes was associated with lowered reduced glutathione levels (26.98%), increased total thiol (100.47%) and lipid peroxidation (124.73%) in embryos, and increased blood sugar (384.03%), cholesterol (98.39%) and triglyceride (1025.35%) in diabetic dams. Increased apoptosis (272.20%) was also observed in the embryos of diabetic dams. Administration of resveratrol (100 mg/kg b. wt.) during pregnancy prevented both oxidative stress and apoptosis in embryos. Resveratrol reduced embryonic maldevelopment by improving embryo weight (41.23%), crown rump length (16.50%) and somite number (11.22%). It further improved the glucose (33.32%) and lipid (cholesterol 41.74%, triglyceride 60.64%) profile of the diabetic dams which also represents the protective role of resveratrol in diabetes.Conclusion-Resveratrol was found to prevent embryonic oxidative stress and apoptosis. It also improved glucose and lipid profile of diabetic dams indicating the beneficial effects in diabetic pregnancy.

Hypertension is a major cause of cardiovascular disease and deaths worldwide especially in low- and middle-income countries. Despite the availability of safe, well-tolerated, and cost-effective blood pressure (BP)-lowering therapies, <14% of adults with hypertension have BP controlled to a systolic/diastolic BP <140/90 mm Hg. We report new hypertension treatment guidelines, developed in accordance with the World Health Organization Handbook for Guideline Development. Overviews of reviews of the evidence were conducted and summary tables were developed according to the Grading of Recommendations, Assessment, Development, and Evaluations approach. In these guidelines, the World Health Organization provides the most current and relevant evidence-based guidance for the pharmacological treatment of nonpregnant adults with hypertension. The recommendations pertain to adults with an accurate diagnosis of hypertension who have already received lifestyle modification counseling. The guidelines recommend BP threshold to initiate pharmacological therapy, BP treatment targets, intervals for follow-up visits, and best use of health care workers in the management of hypertension. The guidelines provide guidance for choice of monotherapy or dual therapy, treatment with single pill combination medications, and use of treatment algorithms for hypertension management. Strength of the recommendations was guided by the quality of the underlying evidence; the tradeoffs between desirable and undesirable effects; patient’s values, resource considerations and cost-effectiveness; health equity; acceptability, and feasibility consideration of different treatment options. The goal of the guideline is to facilitate standard approaches to pharmacological treatment and management of hypertension which, if widely implemented, will increase the hypertension control rate world-wide.

Abstract-Nerves that contain calcitonin gene-related peptide (CGRP) are components of the sensory nervous system.Although these afferent nerves have traditionally been thought to sense stimuli in the periphery and transmit the information centrally, they also have an efferent vasodilator function. Acute administration of a CGRP receptor antagonist increases the blood pressure (BP) in several models of hypertension, which indicates that this potent vasodilator plays a counterregulatory role to attenuate the BP increase in these settings. To determine the role of this peptide in the long-term regulation of cardiovascular function, including hypertension, we obtained mice that have a deletion of the ␣-calcitonin gene-related peptide (␣-CGRP) gene. Although the ␤-calcitonin gene-related peptide (␤-CGRP) gene is intact in these mice, ␣-CGRP is by far the predominant species of CGRP produced in dorsal root ganglia (DRG) sensory neurons. Initially, we examined the effect of deletion of the ␣-CGRP on baseline BP and ␤-CGRP and substance P mRNA expression. Systolic BP was significantly higher in the knockout mice (nϭ7) compared with wild-type in both male (160Ϯ6.1 vs 125Ϯ4.8 mm Hg) and female (163Ϯ4.8 vs 135Ϯ33 mm Hg) mice. Next, groups (nϭ7) of knockout and wild-type mice had catheters surgically placed in the right carotid artery for mean arterial pressure recording. With the animals fully awake and unrestrained, the knockout mice displayed an elevated mean arterial pressure compared with wild-type in both male (139Ϯ4.9 vs 118Ϯ4.9 mm Hg) and female (121Ϯ3.4 vs 107Ϯ3.1 mm Hg) mice. Northern blot analysis of DRG RNA samples confirmed the absence of ␣-CGRP mRNA in the knockout mice. Substance P mRNA content in DRG was unchanged between the 2 groups; however, ␤-CGRP mRNA levels were reduced 2-fold in the knockout mice. These results indicate for the first time that ␣-CGRP may be involved in the long-term regulation of resting BP and suggest that these mice are particularly sensitive to challenges to BP homeostasis because of the loss of a compensatory vasodilator mechanism. Key Words: peptides Ⅲ blood pressure Ⅲ mice Ⅲ genes C alcitonin gene-related peptide (CGRP) is a 37-amino acid vasoactive neuropeptide that is widely distributed in the central and peripheral nervous systems in mammals. 1,2 ␣-CGRP is produced by the tissue-specific alternative splicing of the primary transcript of the calcitonin/␣-CGRP gene and is synthesized almost exclusively in neuronal tissues. 3,4 There is a second CGRP gene, ␤-CGRP, which does not produce calcitonin. 5 Again, expression of ␤-CGRP is limited almost exclusively to specific neuronal sites. 4,5 The 2 CGRP genes, ␣ and ␤ in the rat and I and II in humans, differ in their protein sequences by 1 and 3 amino acids, respectively, and their biological activities are quite similar in most vascular beds. 6,7 The dorsal root ganglia (DRG) is a prominent site of CGRP synthesis that contains the cell bodies of primary afferent neurons that terminate peripherally on blood vessels and other tissue...

The role of sensory innervation in the regulation of liver physiology and the pathogenesis of cholestatic liver disease are undefined. Biliary proliferation has been shown to be coordinately controlled by parasympathetic and sympathetic innervation of the liver. The aim of our study was to address the role of the sensory neuropeptide calcitonin gene-related peptide (a-CGRP) in the regulation of cholangiocyte proliferation during cholestasis induced by extrahepatic bile duct obstruction (BDL). Our study utilized a knockout (KO) mouse model, which lacks the sensory neuropeptide a-CGRP. Wildtype (WT) and a-CGRP KO mice were subjected to sham surgery or BDL for 3 and 7 days. In addition, immediately after BDL, WT and KO mice were administered the CGRP receptor antagonist (CGRP 8-37 ) for 3 and 7 days by osmotic minipumps. Liver sections and isolated cholangiocytes were evaluated for proliferation markers. Isolated WT BDL (3 days) cholangiocytes were stimulated with a-and b-CGRP and evaluated for proliferation and cAMP-mediated signaling. Lack of a-CGRP inhibits cholangiocyte proliferation induced by BDL at both 3 and 7 days. BDL-induced cholangiocyte proliferation in WT mice was associated with increases of circulating a-CGRP levels. In vitro, a-and b-CGRP stimulated proliferation in purified BDL cholangiocytes, induced elevation of cAMP levels, and stimulated the activation of cAMPdependent protein kinase A and cAMP response element binding protein DNA binding. In conclusion, sensory innervation of the liver and biliary expression of a-CGRP play an important role in the regulation of cholangiocyte proliferation during cholestasis.

Calcitonin gene-related peptide (CGRP), a potent vasodilator primarily synthesized in dorsal root ganglia (DRG) neurons, has been shown to decrease vascular resistance and thus regulate blood flow to a variety of organs in rats. Serum CGRP levels in the human have been reported to increase with pregnancy and decrease postpartum. It has been suggested that female sex steroid hormones play a role in cardiovascular function, but the mechanisms are unknown. In this study, we examined the effects of estradiol-17beta (E(2)) and progesterone (P(4)) on the expression of CGRP in DRG in adult rats both in vivo and in vitro. Ovariectomized (ovx) animals were injected s.c. with 5 microg E(2), 4 mg P(4), or 5.0 microg E(2) + 4 mg P(4) in 0.5 ml sesame oil or with oil only, and groups of 4 rats were killed at 0, 24, or 48 h. DRGs were then removed and analyzed for CGRP mRNA and immunoreactive (i-)CGRP content by Northern blotting and RIA, respectively. Primary cultures of DRG neurons from adult female rats were used to assess the effects of varying doses of E(2) (1, 10, 100 nM), P(4) (10, 100, 1000 nM), or E(2) (10 nM) + P(4) (100 nM) in the absence or presence of nerve growth factor (NGF; 20 ng/ml); and CGRP mRNA content in the cells and i-CGRP in the medium were quantitated at 24 or 48 h after incubation. Results of in vivo studies showed that E(2) caused a significant increase in CGRP mRNA at 24 h (1.8-fold) and in i-CGRP levels both at 24 h (2. 8-fold) and at 48 h (3.4-fold) in DRG of ovx rats. P(4) also stimulated expression of both CGRP mRNA and i-CGRP. In the in vitro studies, either E(2) or P(4) alone or the two in combination were without effect on CGRP expression in cultured DRG neurons at all the doses tested. However, in the presence of NGF, both CGRP mRNA and peptide levels were significantly enhanced by E(2), P(4), and E(2)+P(4) in a time-dependent (2.0- to 2.8-fold at 24 h, 3.0- to 5. 0-fold at 48 h) and dose-dependent manner, with maximal effects achieved at 1.0 nM (E(2)) and 100 nM (P(4)) at 24 h of incubation. In summary, both E(2) and P(4), either alone or in combination, stimulate CGRP peptide synthesis in DRG neurons through increasing CGRP mRNA. The effects of these steroid hormones are mediated through amplifying the NGF-induced synthesis of CGRP in these neurons. Thus, we propose that the cardiovascular functions of female sex steroid hormones may be mediated, at least in part, by the up-regulation of neuronal CGRP synthesis, via NGF-mediated mechanisms.

Calcitonin gene-related peptide (CGRP) is a potent vasodilator neuropeptide. We previously demonstrated that neuronal CGRP expression is significantly increased in deoxycorticosterone (DOC)-salt hypertensive rats. To determine the hemodynamic role of CGRP in this setting, we used CGRP8-37, a specific CGRP receptor antagonist. DOC-salt hypertension was induced in Sprague-Dawley rats. To control for DOC pellet implantation, left nephrectomy, and/or saline drinking water, we also studied four normotensive groups. Four week after the initiation of each protocol, all rats had intravenous (for drug administration) and arterial (for continuous mean arterial pressure monitoring) catheters surgically placed and were studied in the conscious, unrestrained state. Baseline mean arterial pressure was higher in the DOC-salt than normotensive rats (175 +/- 5 versus 119 +/- 4 mm Hg, P < .001). Vehicle administration did not alter mean arterial pressure in any group, and CGRP8-37 administration (bolus doses of 3.2 x 10(4) or 6.4 x 10(4) pmol/L) did not change mean arterial pressure in the four normotensive groups. However, CGRP8-37 administration to the DOC-salt rats rapidly and significantly increased mean arterial pressure at both the lower dose (9 +/- 1 mm Hg, P < .001) and higher dose (14 +/- 1 mm Hg, P < .001). In addition, the increase in mean arterial pressure between the two CGRP8-37 doses was also significant (P < .01), indicating a dose-dependent response. We conclude that the increase in neuronal CGRP expression in DOC-salt hypertension plays a compensatory vasodilator role to attenuate the elevated blood pressure. These results provide the first conclusive evidence that CGRP plays a direct role in DOC-salt hypertension.

Patients with humoral hypercalcemia of malignancy display markedly increased serum calcium levels, reduced blood pressure, and tachycardia. The causative agent, humoral hypercalcemia of malignancy factor [also called PTH-related protein (PTHrp)] has been shown to interact with PTH receptors in bone and kidney. We compared human PTHrp-(1-34) with rat PTH-(1-34) for the effects of each peptide on cardiovascular function in unrestrained conscious rats. Both PTHrp and PTH decreased blood pressure in a dose-dependent manner over the concentration range of 0.3-30 micrograms/kg. PTHrp was approximately 3-fold more potent than PTH, producing up to a 50 mm Hg decrease in pressure within 2 min at 10 micrograms/kg. Both peptides increased heart rate more than 70 beats/min at this dose. However, PTH appeared to exert greater efficacy and potency than PTHrp in increasing heart rate in vivo. In the isolated and perfused rat heart, PTHrp and PTH produced positive chronotropic and positive inotropic effects as well as increased coronary flow. PTHrp was more potent and more effective than PTH. The time courses of these effects in the perfused heart preparations indicated that both peptides produced maximal effects within 1 min, with all responses returning to baseline within 10 min. In isolated helical strips of rat aorta, PTHrp and PTH relaxed norepinephrine-contracted tissues in a concentration-dependent fashion. A functional endothelium was not required for the relaxing effects of either peptide. These studies indicate that PTHrp and PTH decrease blood pressure by relaxing vascular tissue in an endothelium-independent manner. Also, these peptides directly increased heart rate, contractility, and coronary flow. Since PTHrp has recently been found in normal human cells, these studies suggest the possibility of PTHrp as a regulator or modulator of cardiovascular function.