bluuebunny/crossref_metadata_2025 huggingface dataset:
Plasma norepinephrine and dihydroxyphenylglycol in essential hypertension.
Authors: Ludwig J , Gerlich M , Halbrügge T , Graefe K H
Published: June 2012

The aim of the present study was to examine whether essential hypertension is associated with altered plasma concentrations of dihydroxyphenylglycol, the principal presynaptic metabolite of norepinephrine. Forearm venous plasma dihydroxyphenylglycol and norepinephrine were determined at rest and during graded orthostasis in 47 normotensive control subjects and 58 outpatients with essential hypertension. There was no group difference in age. At supine rest as well as during sitting and standing, hypertensive subjects had plasma norepinephrine concentrations similar to those in normotensive control subjects, but plasma dihydroxyphenylglycol concentrations were higher than those in normotensive control subjects. Both groups showed a linear relation between plasma dihydroxyphenylglycol (ordinate) and plasma norepinephrine (abscissa). The resulting regression line was steeper (p less than 0.02) and its ordinate intercept higher (p less than 0.01) in hypertensive than in control subjects. Eleven normotensive and 14 hypertensive subjects were also tested 3 hours after desipramine (1.5 mg/kg orally) was administered to inhibit neuronal norepinephrine reuptake. The drug did not alter plasma norepinephrine, but did reduce plasma dihydroxyphenylglycol and did abolish plasma dihydroxyphenylglycol responses to upright posture in both groups of subjects. The mean plasma dihydroxyphenylglycol concentration observed in the presence of desipramine again was higher in the hypertensive than in the control group (p less than 0.01) and closely agreed, in both groups, with the dihydroxyphenylglycol concentration given by the ordinate intercept of the dihydroxyphenylglycol versus norepinephrine regression line in the absence of desipramine.(ABSTRACT TRUNCATED AT 250 WORDS)
Hemodynamic and hormonal effects of neutral endopeptidase inhibitor SCH 39370 in sheep.
Authors: Charles C J , Espiner E A , Cameron V A , Richards A M , Yandle T G , Sybertz E J
Published: June 2012

Whole body clearance of atrial natriuretic factor is due to both receptor uptake and enzymatic degradation initiated by neutral endopeptidase 24.11. The effects of neutral endopeptidase inhibition have been studied in seven sodium-replete sheep using SCH 39370, a specific and potent inhibitor of neutral endopeptidase, in the presence or absence of exogenous hormone [rat ANF-(101-126), 2.4 pmol/kg/min for 2 hours]. SCH 39370 alone (2.5 mg/kg bolus) increased plasma atrial natriuretic factor and plasma cyclic GMP levels, lowered arterial pressure for periods beyond changes in plasma atrial natriuretic factor or cyclic GMP, and suppressed both plasma aldosterone and cortisol levels when compared with vehicle injections. The effects of SCH 39370 were similar to or exceeded those of atrial natriuretic factor infusions, which induced significantly greater increases in plasma atrial natriuretic factor (p = 0.01). Neither agent alone was natriuretic. When SCH 39370 and atrial natriuretic factor were given together, plasma cyclic GMP but not atrial natriuretic factor levels were increased (p = 0.013) compared with atrial natriuretic factor infusion alone, and the half-life was prolonged (p = 0.002) in the presence of SCH 39370. The hypotensive response was greater than that induced by atrial natriuretic factor alone (p = 0.03) but not different from SCH 39370 alone. Inhibitory effects of SCH 39370 on aldosterone levels were similar in the presence of absence of exogenous atrial natriuretic factor.(ABSTRACT TRUNCATED AT 250 WORDS)
G protein-mediated ion channel activation.
Authors: Breitwieser G E
Published: June 2012

Guanine nucleotide binding proteins couple a wide variety of receptors to ion channels via both "direct" or membrane-delimited and "indirect" second messenger-mediated pathways. This tutorial summarizes current approaches to defining the mechanisms of guanine nucleotide binding protein-mediated ion channel activation. Two well-characterized ion channels in the heart, namely, the beta-adrenergic receptor-activated calcium channel and the muscarinic receptor-activated potassium channel, are used to illustrate the criteria that can distinguish between direct and indirect guanine nucleotide binding protein-transduced pathways.
Atrial natriuretic factor receptor subtypes in the rat central nervous system.
Authors: Konrad E M , Thibault G , Schiffrin E L , Cantin M
Published: June 2012

In this study we investigated the presence and anatomical location of atrial natriuretic factor (ANF) receptor subtypes in the rat central nervous system using in vitro autoradiographic and cross-linking techniques. 125I-ANF-(Ser99-Tyr126) served as a labeled ligand, whereas ANF-(Ser99-Tyr126) and two peptides endowed with selectivity for ANF-C receptor--namely, C-ANF (des-[Gln116-Gly120] ANF-[Asp102-Cys121]-NH2) and ANF-(Phe106-Ile113)-NH2--were used as displacing agents. Distribution studies revealed the presence of specific ANF binding sites in a number of central nervous system areas examined. C-ANF at 10(-6) M competed for 125I-ANF binding to a much lower extent than ANF in many of those structures, whereas ANF-(106-113)-NH2 at 10(-6) M did not have a significant effect on the radioligand binding except in the choroid plexus, pia-arachnoid, and olfactory bulb. Analysis of the competition curves revealed that in the choroid plexus, pia-arachnoid, olfactory bulb, subfornical organ, area postrema, and habenular nucleus, ANF interacts with its binding sites with high affinity (IC50, 0.46-0.77 nM). In contrast, C-ANF and ANF-(106-113)-NH2 competed for 125I-ANF binding with high potency (IC50, 2-16 nM) in the choroid plexus and pia-arachnoid only, where they were able to displace 60-70% of the radioligand binding. 125I-ANF cross-linking to olfactory bulb membranes resolved a specific 120-kDa band corresponding to the high molecular weight receptor but did not disclose a specifically labeled band corresponding to the low molecular mass receptor.(ABSTRACT TRUNCATED AT 250 WORDS)
Quinapril, an angiotensin converting enzyme inhibitor, prevents cardiac hypertrophy during episodic hypertension.
Authors: Julius S , Li Y , Brant D , Krause L , Taylor D
Published: June 2012

Six control dogs, six dogs treated with 1.5 mg/kg b.i.d. quinapril, and six dogs treated with 8 mg/kg q.d. minoxidil underwent 6 hours daily of hindquarter compression for 9 weeks. Minoxidil significantly decreased baseline blood pressure (-17 mm Hg; p less than or equal to 0.01), whereas quinapril decreased baseline blood pressure 11 mm Hg but not significantly (p = 0.15). Hindquarter compression elicited blood pressure increases in all three groups (control +18, quinapril +13, minoxidil +19 mm Hg). After 9 weeks, left ventricular mass in control dogs increased 22% (p less than 0.004); a similar increase was seen in minoxidil-treated dogs (+22%, p less than 0.0001) but not in the quinapril-treated group (+4%, p less than 0.15). The increase in left ventricular mass in control dogs was concentric (increased epicardial volume only), whereas in the minoxidil group, the hypertrophy was eccentric (both epicardial and endocardial volumes increased). The minimal hypertrophy in the quinapril group was concentric (no change in epicardial, but a decrease in endocardial volume). Quinapril had little hypotensive effect, but prevented the development of left ventricular hypertrophy, whereas minoxidil did not prevent hypertrophy in spite of its hypotensive effect. The mechanism of this differential effect of direct vasodilation versus converting enzyme inhibition on left ventricular hypertrophy is not fully elucidated. The results with quinapril suggest that some antihypertensive agents may positively affect left ventricular hypertrophy in spite of the absence of a large effect on baseline blood pressure or on blood pressure reactivity.
Renin promoter SV40 T-antigen transgenic mouse. A model of primary renal vascular hyperplasia.
Authors: Jacob H J , Sigmund C D , Shockley T R , Gross K W , Dzau V J
Published: June 2012

Transgenic mice containing a ren-2 promoter T-antigen fusion construct (TAG+) develop renal vascular hypertrophy and hyperplasia associated with markedly suppressed renal renin mRNA, renal renin content, and plasma renin concentration. These animals are normotensive. In the present study, the renal and cardiovascular systems are characterized, revealing some surprising findings. Not only are the TAG+ mice normotensive in the face of pronounced renal pathology but also in the presence of an increase in plasma volume. These data raise interesting questions about blood pressure physiology and renal function of the TAG+ mice. Blood nitrogen urea of the TAG+ animal was markedly elevated and plasma creatinine level was in the normal range, indicating prerenal azotemia without renal failure. These findings are consistent with impaired renal perfusion with secondary volume expansion probably as the result of vascular hyperplasia. These transgenic animals provide a unique genetic model for studying the physiology of primarily renal vascular hyperplasia as well as blood pressure control in a low renin state.
Role of anteroventral third ventricle and vasopressin in renal response to stress in borderline hypertensive rats.
Authors: Hatton D C , Jones S Y , Johnson A K , DiBona G F
Published: June 2012

The borderline hypertensive rat is the first filial offspring of the spontaneously hypertensive rat and the Wistar-Kyoto rat. In response to acute environmental stress (air jet), the borderline hypertensive rat exhibits a diuretic response, whereas the parental strains exhibit an antidiuretic response (spontaneously hypertensive rat) or no change in urine flow rate (Wistar-Kyoto rat). This study sought to investigate the role of the periventricular tissue surrounding the anteroventral third ventricle and vasopressin release in the diuretic response of the borderline hypertensive rat to acute environmental stress. Sixteen-week-old borderline hypertensive rats who had consumed a 1% NaCl diet for 10-12 weeks were given either electrolytic lesions of the anteroventral portion of the third ventricle or sham lesions. When exposed to acute environmental stress 4 weeks later, the increase in volume of dilute urine seen in the sham-lesion rats was not observed in the lesion rats. Plasma vasopressin concentration was decreased by acute environmental stress in the sham-lesion rats (15.2 +/- 4.0 to 10.9 +/- 1.7 pg/ml, p less than 0.05) but was unchanged in the lesion rats (12.3 +/- 2.0 to 13.4 +/- 4.0 pg/ml). In a separate group of intact borderline hypertensive rats, a constant intravenous infusion of vasopressin prevented the diuretic response to acute environmental stress. The results suggest that acute environmental stress produces a diuresis in the borderline hypertensive rats via a decrease in plasma vasopressin concentration that is dependent on the integrity of the periventricular tissue of the anteroventral portion of the third ventricle.
Insulin resistance and blood pressure regulation in obese and nonobese subjects. Special lecture.
Authors: Rocchini A P
Published: June 2012

A review is presented of the potential ways in which insulin resistance and hypertension may be linked. Although controversy exists as to the role insulin resistance and hyperinsulinemia play in the pathogenesis of hypertension, data are presented from both obese and nonobese subjects that strongly suggests that selective insulin resistance and hypertension are directly related. Because insulin resistance may be both tissue and pathway specific, it is possible that the degree to which insulin resistance is tissue specific determines whether hypertension will develop in specific individuals or animals.
Modulation of endothelin effects on blood pressure and hematocrit by atrial natriuretic peptide.
Authors: Valentin J P , Gardner D G , Wiedemann E , Humphreys M H
Published: June 2012

Infusion of endothelin has been observed to increase hematocrit, and the peptide also stimulates release of atrial natriuretic peptide (ANP) both in vitro and in vivo. We studied the relation of these two actions of endothelin in anesthetized, bilaterally nephrectomized Sprague-Dawley rats. Infusion of endothelin (25 ng/kg/min) for 45 minutes produced a modest increase in blood pressure of 12% from a baseline of 99 +/- 5 mm Hg and an increase in hematocrit of 8.0 +/- 0.6%, reflecting a reduction in plasma volume of 13.1 +/- 0.9%. These changes each exceeded greatly those observed after 45 minutes of vehicle infusion. Plasma protein concentration, however, increased only by 4.2 +/- 0.6%, suggesting protein extravasation, which was confirmed by finding an endothelin-dependent increase in the accumulation of Evans blue dye in heart, skeletal muscle, and intestine, but not liver, lung, brain, or testis. Endothelin infusion increased plasma immunoreactive ANP concentration from 196 +/- 50 to 722 +/- 203 pg/ml (p less than 0.02), and a close correlation existed between the increase in plasma immunoreactive ANP and immunoreactive endothelin concentrations as a result of the infusion (r = 0.84, p less than 0.01). Pretreatment of rats with rabbit anti-rat ANP antiserum did not affect baseline variables but led to an exaggerated increase in blood pressure (25.3 +/- 2.9%, p less than 0.002 versus endothelin alone). No change in hematocrit occurred. Thus, the increase in plasma immunoreactive ANP concentration resulting from endothelin infusion mediates the increase in hematocrit through an increase in vascular permeability to whole plasma.(ABSTRACT TRUNCATED AT 250 WORDS)
Hypertension-induced changes of platelet-derived growth factor receptor expression in rat aorta and heart.
Authors: Sarzani R , Arnaldi G , Chobanian A V
Published: June 2012

Hypertension-associated growth of vascular smooth muscle cells might be mediated in vivo by platelet-derived growth factor (PDGF). Our previous investigations in hypertensive rats failed to demonstrate changes in aortic steady-state mRNA levels of PDGF A or B chains. The current studies were performed to determine whether hypertension might affect the expression of PDGF receptors. We studied PDGF alpha- and beta-receptor gene expression by Northern analysis using human and rat cDNA probes. Studies of tissue distribution revealed that PDGF beta-receptor mRNA was most abundant in total aorta and aortic media, whereas the PDGF alpha-receptor mRNA was most abundant in the lung and was expressed at low levels in aortic tissue. Deoxycorticosterone acetate (DOCA)-salt hypertension induced a threefold increase in aortic steady-state PDGF beta-receptor mRNA levels. Aortic PDGF beta-receptor expression also was higher in spontaneously hypertensive rats (SHRs) when compared with age-matched normotensive Wistar-Kyoto (WKY) controls. Aortic PDGF alpha-receptor steady-state mRNA levels were unchanged in DOCA-salt hypertension and were expressed at similar levels in WKY rats and SHRs. Unlike the findings with aorta, cardiac PDGF beta- and alpha-receptor and PDGF B-chain expressions were unchanged in the DOCA-salt model and were decreased in SHRs. These findings indicate that hypertension can increase aortic steady-state mRNA levels for PDGF beta-receptor. They also indicate that tissue-specific expression of the genes of the PDGF ligand/receptor system are differentially regulated in hypertension.
Role of endothelium-derived relaxing factor in regulation of vascular tone and remodeling. Update on humoral regulation of vascular tone.
Authors: Tolins J P , Shultz P J , Raij L
Published: June 2012

In addition to preserving the permselectivity of the vascular wall and providing an antithrombogenic surface, the vascular endothelium contributes importantly to the regulation of vasomotor tone. Indeed, the endothelium participates in the conversion of angiotensin I to angiotensin II; the enzymatic inactivation of several plasma constituents such as bradykinin, norepinephrine, serotonin, and ADP; and the synthesis and release of vasodilator substances such as prostacyclin and the recently discovered endothelium-derived relaxing factor (EDRF). The diffusible EDRF released from the endothelium is nitric oxide or a substance closely related to it such as nitrosothiol. The endothelium also synthesizes and releases vasoconstrictive factors, including products derived from arachidonic acid metabolism and the recently discovered peptide endothelin. An increasing body of evidence from experimental and clinical studies indicates that EDRF and endothelium-derived contracting factors play an important role in vascular physiology and pathology. It has become apparent that the balance of these factors may be a major determinant of systemic and regional hemodynamics. Moreover, through generally opposite effects on growth-related vascular changes, contracting factors such as endothelin and relaxing factors such as EDRF also may be important determinants of the vascular response to injury in various disease states such as atherosclerosis and hypertension. It is clear that the vascular endothelium is a complex and dynamic organ. Understanding endothelium function in normal physiology and disease states is of potential clinical importance and should be the focus of future investigation.
Renal arteriolar diameters in spontaneously hypertensive rats. Vascular cast study.
Authors: Kimura K , Tojo A , Matsuoka H , Sugimoto T
Published: June 2012

The relation between the arteriolar diameters and hypertensive glomerulosclerosis was studied by using microvascular casts and histological evaluation. Spontaneously hypertensive rats 4 weeks of age were divided into three groups: nontreated, captopril (40 mg/kg/day)-treated, and trichlormethiazide (1 mg/kg/day) with hydralazine (20 mg/kg/day)-treated. Wistar-Kyoto rats served as controls. At 6 weeks old, the captopril-treated rats showed a lower blood pressure and a larger afferent arteriolar diameter compared with the control rats. At 20 weeks old, the nontreated group exhibited hypertension and a lower arteriolar diameter ratio (afferent to efferent, 0.89 versus 1.22 in control group) because of afferent constriction and efferent dilatation, seen equally in the outer and inner cortexes. Glomerulosclerosis was accentuated only in the inner cortex of the nontreated group (score, 63 versus 29 in control group). In the two treated rat groups, the blood pressure was reduced and arteriolar diameter ratios were similar to those in the control group (1.18 and 1.26). The sclerosis score in the trichlormethiazide with hydralazine-treated rats (score, 26) was lower than in the nontreated rats but not the captopril-treated rats (score, 36). These results indicated that 1) in the hypertensive rats, despite a reduced diameter ratio, glomerulosclerosis was more severe in the inner cortex; 2) two therapies reduced blood pressure and reversed the arteriolar changes, but a decrease in glomerulosclerosis was seen only in the trichlormethiazide with hydralazine-treated rats; and 3) for development of glomerulosclerosis, factors other than hemodynamics may be important in addition to intraglomerular pressure.
Heterogeneity of renin alleles in outbred Dahl salt-sensitive (Brookhaven) rats.
Authors: O'Dowd B F , Rapp J P
Published: June 2012

Selectively outbred Dahl salt-sensitive (DS) and salt-resistant (DR) rats were compared with the inbred Dahl salt-sensitive (SS/Jr) and salt-resistant (SR/Jr) rats developed from the original Brookhaven stocks by J.P. Rapp. The animals were evaluated for genotype at the renin locus. The inbred strains are uniformly homozygous for their respective alleles, s in SS/Jr and r in SR/Jr. DR rats were also uniformly homozygous for the r renin allele. In DS rats, however, three renin alleles were segregating. In addition to the s and r alleles, a third allele, designated the z allele, was found. The gene frequencies in DS rats were s = 0.690, r = 0.284, and z = 0.026. Continued use of DS and DR rats in most experimental work is inappropriate because of genetic heterogeneity in the DS stock.
Postexercise hypotension is not sustained in normal and hypertensive humans.
Authors: Somers V K , Conway J , Coats A , Isea J , Sleight P
Published: June 2012

Blood pressure falls after a single session of exercise. The duration for which this fall in blood pressure persists is not known. Sustained hypotension after a single session of exercise may have important implications in the treatment of patients with mild hypertension. We studied 24 subjects (12 normotensive subjects and 12 patients with mild or borderline hypertension). Blood pressure was measured in the laboratory for 30 minutes before and for an hour after graded bicycle exercise to maximal voluntary capacity. Subjects then left the hospital and measured their blood pressures at home (three measurements every 2 hours) following a strict measurement protocol for the rest of the day (usually between 8 and 12 hours). These home blood pressure measurements were compared with home blood pressure measurements recorded at the same times on a nonexercise control day. At 30 minutes after the graded maximal exercise test, the hypertensive patients experienced a fall in blood pressure from 142 +/- 3.5/93 +/- 6.5 mm Hg (mean +/- SEM) to 124 +/- 4.5/79 +/- 2.8 mm Hg (p less than 0.01). For the normotensive subjects, blood pressure after exercise fell from 117 +/- 3.1/70 +/- 2.1 mm Hg to 109 +/- 3.1/62 +/- 2.8 mm Hg (p less than 0.01). Despite these striking blood pressure reductions for the second half hour after exercise, blood pressure measurements recorded at home were not significantly different on the exercise and control days in either group. We conclude that although a single bout of exercise lowers blood pressure for a short (1-hour) period, this hypotension is not sustained.
Intrahypothalamic clonidine infusion prevents NaCl-sensitive hypertension.
Authors: Jin H K , Yang R H , Wyss J M , Chen Y F , Oparil S
Published: June 2012

We have previously shown that dietary NaCl supplementation increases blood pressure and sympathetic nervous system activity in association with decreased norepinephrine release and increased alpha 2-adrenergic receptor number in the anterior hypothalamic area of salt-sensitive spontaneously hypertensive rats (SHR-S) but not in salt-resistant spontaneously hypertensive rats (SHR-R) or Wistar-Kyoto (WKY) rats. Further, acute microinjection of clonidine into the anterior hypothalamic area produced depressor responses that were augmented by high salt feeding in SHR-S but not in SHR-R or WKY rats. The current study tested the hypothesis that chronic infusion of clonidine into the anterior hypothalamic area prevents salt-sensitive hypertension in SHR-S. Beginning at age 7 weeks, immediately before initiation of 1% or 8% salt diets, clonidine (2 ng/min) or saline vehicle was infused into the anterior hypothalamic area or femoral vein of male SHR-S via osmotic minipump for 20 days. In SHR-S fed an 8% salt diet, chronic microinfusion of clonidine into the anterior hypothalamic area offset the hypertensive effect of the dietary salt supplementation and reduced the enhancing effects of dietary salt on left ventricular weight and plasma norepinephrine levels. In contrast, chronic microinfusion of clonidine into the anterior hypothalamic area did not significantly affect any of these measures in 1% salt-fed SHR-S. Intravenous infusion of clonidine at the rate used for the anterior hypothalamic area infusion did not alter any of these measures in 8% salt-fed SHR-S.(ABSTRACT TRUNCATED AT 250 WORDS)
Simplified captopril renography in diagnosis and treatment of renal artery stenosis.
Authors: Setaro J F , Saddler M C , Chen C C , Hoffer P B , Roer D A , Markowitz D M , Meier G H , Gusberg R J , Black H R
Published: June 2012

To improve the diagnosis and forecast the response to surgery or renal angioplasty in patients with hypertension and renal artery stenosis, we employed a simplified captopril renography protocol in conjunction with renal arteriography in 94 clinically selected patients. Fifty hypertensive patients (group 1) with a high clinical likelihood of renovascular hypertension were evaluated using a simplified captopril renography protocol and renal angiography on the arterial side. Criteria for normal captopril renal scintigrams were established based on this original cohort and validated in an additional 44 clinically comparable patients (group 2). Renal revascularization or nephrectomy was performed in 39 patients, and success of the procedure was determined in the 34 patients for whom 3-month follow-up was available. In the 94 patients, 44 (47%) had renal artery stenosis. Simplified captopril renography was 91% sensitive and 94% specific in identifying or excluding renal artery stenosis in the combined group, with no difference in the diagnostic utility between groups 1 and 2, or in those with renal insufficiency (n = 38) or those with bilateral disease (n = 17). Scintigraphic abnormalities induced by captopril were strongly associated with cure or improvement in blood pressure control following revascularization or nephrectomy (15 of 18), while the lack of captopril-induced changes was associated with failure of such intervention (13 of 16) (p = 0.0004). We conclude that simplified captopril renography is highly sensitive and specific in the diagnosis of renal artery stenosis in a clinically selected high-risk population and that the test accurately predicts the success or failure of therapeutic intervention.
Evidence for a renomedullary vasodepressor system in rabbits and dogs.
Authors: Christy I J , Woods R L , Courneya C A , Denton K M , Anderson W P
Published: June 2012

Renal perfusion was increased in anesthetized rabbits and dogs by using an extracorporeal circuit. When left kidney perfusion pressure was raised in rabbits (145-240 mm Hg), arterial pressure fell by 1.34 +/- 0.20 mm Hg/min. Pretreatment of the rabbits with 2-bromoethylamine hydrobromide, which destroyed the renal medulla, abolished the fall in arterial pressure (-0.08 +/- 0.08 mm Hg/min) in response to increased renal perfusion pressure. In dogs (with blockade of autonomic ganglia by pentolinium, converting enzyme inhibition [captopril/enalaprilat], and surgical renal denervation), increasing renal perfusion pressure to 170-220 mm Hg resulted in a fall in arterial pressure by 0.32 +/- 0.03 mm Hg/min (or by 28.9 +/- 3.1 mm Hg over a 90-minute period). Mean arterial pressure did not change significantly in identically prepared dogs not subjected to increased renal perfusion pressure, whereas pretreatment of dogs with bromoethylamine abolished the hypotensive response to increased renal perfusion pressure. Thus, the hypotensive response to increased renal perfusion was dependent on the presence of an intact renal medulla, but hypotension still occurred in the presence of converting enzyme inhibition, autonomic ganglion blockade, and renal denervation. The results provide in vivo evidence in two species that a vasodepressor factor from the renal medulla is released in response to increased renal perfusion.
Zinc metallopeptidase inhibitors. A novel antihypertensive treatment.
Authors: Carretero O A , Scicli A G
Published: June 2012

Inhibitors of two zinc metallopeptidases, angiotensin I converting enzyme (ACE) and neutral metalloendopeptidase-24.11 (EP-24.11), are antihypertensive agents. In this issue of Hypertension, Genden and Molineaux report that yet another peptidase inhibitor, metalloendopeptidase-24.15, EC 3.4.24.15 (EP-24.15), lowers blood pressure in normotensive rats. In this editorial we discuss the possible role of kinins as common mediators of part of the vasodepressor action of these peptidase inhibitors. Genden and Molineaux report that the marked fall in blood pressure caused by the EP-24.15 inhibitor is almost abolished by a kinin receptor antagonist, supporting the hypothesis that kinins play a role in the regulation of normal blood pressure. We have confirmed that the EP-24.15 inhibitor used by these investigators lowers blood pressure. Up to now, EP-24.15 has not been implicated in in vivo metabolism of kinins. Although a number of kininases have been identified, our own previous work indicated that the metabolic pathway responsible for clearing kinins from the circulation involves the action of kininase II (angiotensin I converting enzyme) and renal peptidases. Nevertheless, the main metabolic pathway involved some other unidentified enzyme, since in these experiments disappearance of kinins from the circulation was only marginally reduced by a "cocktail" of inhibitors of ACE, EP-24.11, and carboxypeptidase N. It could be that EP-24.15 is involved in kinin metabolism. However, a number of questions need to be answered with regard to the mechanism by which the EP-24.15 inhibitor lowers blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)
Sympathoadrenal control by paraventricular hypothalamic beta-endorphin in hypertension.
Authors: Jin C B , Rockhold R W
Published: June 2012

The paraventricular hypothalamus regulates autonomic nerve outflow and is innervated with beta-endorphin-immunoreactive nerve terminals. This study examined the effects of beta-endorphin microinjected into the paraventricular hypothalamus on blood pressure, heart rate, and plasma catecholamine and glucose concentrations in conscious, unrestrained spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats at the age of about 9 weeks. Thirty minutes after paraventricular hypothalamic injection of [125I] beta-endorphin (3.5 micrograms), most of the recovered radioactivity was detectable within +/- 0.5 mm from the injection site in the coronal, sagittal, and horizontal planes. Unilateral paraventricular hypothalamic injections of beta-endorphin (1 and 0.1 microgram/0.1 microliter) increased blood pressure and heart rate in both strains in a dose-independent manner with significantly greater increases in SHR. Plasma catecholamine and glucose concentrations were measured 15, 30, and 60 minutes after beta-endorphin injection. Norepinephrine concentrations were not significantly altered in WKY rats but increased in SHR. Epinephrine concentrations increased in both strains with significantly greater increases in SHR. Increases in catecholamine concentrations were not dose-related. Glucose concentrations also increased in both strains with significantly greater increases in SHR only at the lower dose. Ganglionic blockade with pentolinium significantly reduced beta-endorphin-induced pressor and tachycardiac responses in SHR. Pretreatment of the paraventricular hypothalamus with naltrexone (1.1 micrograms) in SHR blocked the initial pressor and tachycardiac responses to beta-endorphin (0.1 microgram) and blunted increases in epinephrine and glucose levels. When the animals were anesthetized with alpha-chloralose 2-5 days after the study in conscious animals, there were no differences in blood pressure or heart rate between strains after beta-endorphin (0.1 microgram) injection. The results indicate that conscious SHR show enhanced cardiovascular and sympathoadrenal responses to beta-endorphin injected into the paraventricular hypothalamus, suggesting that alterations in the activity of the paraventricular hypothalamic beta-endorphin system can modulate the development of hypertension in SHR.
Boiled coffee and blood pressure. A 14-week controlled trial.
Authors: van Dusseldorp M , Smits P , Lenders J W , Thien T , Katan M B
Published: June 2012

The question of whether long-term elimination of coffee from the diet lowers blood pressure has not been settled. Consumption of Scandinavian-style "boiled coffee" is associated with coronary heart disease. However, little is known about the effect of brewing method on the blood pressure-raising potential of coffee. We have studied the effects on blood pressure and heart rate of total elimination of coffee and tea in comparison with drinking boiled coffee consumed as such, or boiled coffee consumed after filtration through paper filter. Thirty-one women and 33 men first consumed 6 cups/day of boiled and filtered coffee for 17 days. Then they were randomly divided into three groups, which for the next 79 days received either unfiltered boiled coffee (caffeine content 860 mg/l), boiled-and-filtered coffee (887 mg caffeine/l), or no coffee, the latter being replaced by fruit juice and mineral water. Total elimination of coffee did not significantly affect blood pressure or heart rate relative to boiled-and-filtered coffee. In subjects who drank boiled coffee, mean ambulant systolic blood pressure rose significantly relative to those who consumed boiled-and-filtered coffee (mean difference +/- SEM, 3.1 +/- 1.1 mm Hg, p = 0.006). This response showed a tendency to be stronger for women (4.5 +/- 1.8 mm Hg) than for men (1.7 +/- 1.2 mm Hg). We conclude that elimination of filtered coffee has no substantial long-term effect on blood pressure, but consumption of unfiltered boiled coffee may cause a slight but significant rise in systolic blood pressure.
Left ventricular blood flow during aortic pressure reduction in hypertensive dogs.
Authors: Smolich J J , Weissberg P L , Friberg P , Broughton A , Korner P I
Published: June 2012

We measured left ventricular blood flow with radioactive microspheres during aortic pressure reduction in 10 open-chest, anesthetized dogs with left ventricular hypertrophy due to chronic hypertension and in 10 matched normotensive dogs. Heart rate and left atrial pressure were held constant, and autonomic reflexes were abolished with ganglionic blockade. Aortic diastolic pressure was lowered from baseline to 90, 75, and 60 mm Hg with an arteriovenous fistula. During aortic pressure reduction, a stepwise decline in the endocardial-to-epicardial flow ratio in hypertrophied hearts from 1.23 +/- 0.04 at baseline to 0.96 +/- 0.09 at a diastolic pressure of 75 mm Hg parallelled that in normal hearts and was not associated with any deterioration in left ventricular performance. However, a further fall in the endocardial-to-epicardial flow ratio to 0.76 +/- 0.10 at a diastolic pressure of 60 mm Hg in hypertrophied hearts exceeded that in normal hearts (0.92 +/- 0.05, p less than 0.05) and was accompanied by evidence of left ventricular isovolumic and end-systolic dysfunction. We conclude that in hearts with pressure-overload left ventricular hypertrophy, aortic pressure reduction causes a transmural blood flow redistribution from subendocardial to subepicardial muscle layers. At moderately low aortic pressures, this redistribution is more pronounced than in normal hearts and is associated with functional evidence of myocardial ischemia.
Differential regulation of angiotensin peptide levels in plasma and kidney of the rat.
Authors: Campbell D J , Lawrence A C , Towrie A , Kladis A , Valentijn A J
Published: June 2012

We compared the effects of the converting enzyme inhibitor perindopril on components of the renin-angiotensin system in plasma and kidney of male Sprague-Dawley rats administered perindopril in their drinking water at two doses (1.4 and 4.2 mg/kg) over 7 days. Eight angiotensin peptides were measured in plasma and kidney: angiotensin-(1-7), angiotensin II, angiotensin-(1-9), angiotensin I, angiotensin-(2-7), angiotensin III, angiotensin-(2-9), and angiotensin-(2-10). In addition, angiotensin converting enzyme activity, renin, and angiotensinogen were measured in plasma, and renin, angiotensinogen, and their respective messenger RNAs were measured in kidney; angiotensinogen messenger RNA was also measured in liver. In plasma, the highest dose of perindopril reduced angiotensin converting enzyme activity to 11% of control, increased renin 200-fold, reduced angiotensinogen to 11% of control, increased angiotensin-(1-7), angiotensin I, angiotensin-(2-7), and angiotensin-(2-10) levels 25-, 9-, 10-, and 13-fold, respectively; angiotensin II levels were not significantly different from control. By contrast, for the kidney, angiotensin-(1-7), angiotensin I, angiotensin-(2-7), and angiotensin-(2-10) levels did not increase; angiotensin II levels fell to 14% of control, and angiotensinogen fell to 12% of control. Kidney renin messenger RNA levels increased 12-fold, but renal renin content and angiotensinogen messenger RNA levels in kidney and liver were not influenced by perindopril treatment. These results demonstrate a differential regulation of angiotensin peptides in plasma and kidney and provide direct support for the proposal that the cardiovascular effects of converting enzyme inhibitors depend on modulation of tissue angiotensin systems. Moreover, the failure of kidney angiotensin I levels to increase with perindopril treatment, taken together with the fall in kidney angiotensinogen levels, suggests that angiotensinogen may be a major rate-limiting determinant of angiotensin peptide levels in the kidney.
Effect of energy-restricted diet on sympathetic muscle nerve activity in obese women.
Authors: Andersson B , Elam M , Wallin B G , Björntorp P , Andersson O K
Published: June 2012

Twenty obese women aged 45-65 years with borderline hypertension were allocated randomly to either a group with an energy-restricted diet or to a control group. Body weight, blood pressure, urinary sodium, and urinary excretion of norepinephrine and plasma volume were recorded. Resting muscle sympathetic nerve activity was measured in the peroneal nerve by tungsten microelectrodes and expressed as bursts per minute. These measurements were repeated after 3 days of semistarvation and after a body weight reduction of 7% while each patient's weight was in a steady state. After 3 days of semistarvation, only body weight was reduced, whereas after the long-term energy intake restriction, there were reductions of body weight (79.9 +/- 3.4 versus 74.1 +/- 3.4 kg; p less than 0.001), diastolic blood pressure (93 +/- 3 versus 86 +/- 4 mm Hg; p = 0.01), and muscle sympathetic nerve activity (49 +/- 2 versus 42 +/- 3 bursts/min; p less than 0.05). Other variables were unchanged. There were no changes in body weight, blood pressure, or muscle sympathetic nerve activity in the control group. We conclude that body weight decrease in obesity results in a reduction of blood pressure that is at least partially caused by a reduction of sympathetic vasoconstrictor activity.
Alcohol, high blood pressure, and serum gamma-glutamyl transpeptidase level.
Authors: Yamada Y , Ishizaki M , Kido T , Honda R , Tsuritani I , Ikai E , Yamaya H
Published: June 2012

The influence of the level of serum gamma-glutamyl transpeptidase, a biological marker of alcohol consumption, on elevations of blood pressure and on the development of hypertension related to increases in alcohol consumption was determined in a cross-sectional study of 1,492 middle-aged male workers and in a subsequent 5-year follow-up study of 1,393 workers. Blood pressure levels, as well as the prevalence and incidence of hypertension, were higher in the subjects with serum gamma-glutamyl transpeptidase levels above 50 units/l than in those with normal levels. These differences were more marked in drinkers who consumed 30 ml or more of alcohol per day. Thus, elevated serum gamma-glutamyl transpeptidase activity may identify drinkers at higher risk for the development of alcohol-related hypertension.
Mechanism of neurally induced monkey mesenteric artery relaxation and contraction.
Authors: Toda N , Okamura T
Published: June 2012

Physiological importance in vasodilator innervation alleviating noradrenergic neurogenic vasoconstriction has not been clarified. Isolated monkey mesenteric artery strips denuded of the endothelium responded to nerve stimulation by electrical pulses or nicotine with a contraction, which was potentiated by Ng-nitro-L-arginine, a nitric oxide synthesis inhibitor, but not by the D-enantiomer. The potentiation was abolished by L-arginine. NG-Nitro-L-arginine did not potentiate the response to exogenous norepinephrine nor did it increase the release of [3H]norepinephrine from adrenergic nerves electrically stimulated. The contraction was reversed by treatment with phentolamine and guanethidine to a relaxation, which was abolished by NG-nitro-L-arginine. The inhibition was reversed by L- but not D-arginine. The relaxant response was not influenced by atropine, timolol, or indomethacin. These findings strongly suggest the importance of reciprocal nitric oxide-related (nitroxidergic) vasodilator and noradrenergic vasoconstrictor innervation in the regulation of monkey arterial tone.
Accelerated secretion of brain natriuretic peptide from the hypertrophied ventricles in experimental malignant hypertension.
Authors: Kohno M , Horio T , Yoshiyama M , Takeda T
Published: June 2012

Plasma concentrations of immunoreactive (ir) atrial (ANP) and brain (BNP) natriuretic peptides were measured in the prehypertensive and hypertensive phases in spontaneously hypertensive rats (SHR) and in the malignant phase of hypertension caused by deoxycorticosterone acetate (DOCA)-salt in SHR. The secretory rate of ANP and BNP were examined in the perfusion of isolated beating heart before and after atrial removal. Plasma irANP and irBNP in mature SHR were higher than those of control Wistar-Kyoto (WKY) rats, whereas ANP and BNP values in young SHR did not differ from those of control WKY rats. DOCA-salt treatment for 8 weeks markedly increased blood pressure, ventricular weight, and plasma irANP and irBNP in SHR. ANP and BNP values were positively correlated with ventricular weight in DOCA-salt SHR. The secretory rate of ANP and BNP from the perfused whole heart were much higher in DOCA-salt SHR than other rat groups. A large amount of BNP was secreted from the hypertrophied ventricles in DOCA-salt SHR. In contrast, ANP was mainly secreted from the atrium in all rat groups. High-performance liquid chromatography profiles of extract in plasma showed that a major component of irANP and irBNP corresponded to synthetic rat ANP-(1-28) and rat BNP-45, respectively. Results suggest that both rat ANP-(1-28) and rat BNP-45 are markedly increased in plasma in DOCA-salt-induced malignant hypertension of SHR and that the major source of circulating BNP is the hypertrophied ventricles in this model.
Effects of renin-angiotensin system blockade in guinea pigs.
Authors: Véniant M , Clozel J P , Hess P , Fischli W
Published: June 2012

The goal of the present study was to compare the hemodynamic and biochemical effects of the renin inhibitor Ro 42-5892, the angiotensin converting enzyme inhibitor cilazapril, and the angiotensin II receptor blocker EXP132, the aldehyde derivative of DuP 753. The three drugs were evaluated in guinea pigs, previously treated with furosemide, using their maximal effective doses. Cilazapril decreased arterial blood pressure more than Ro 42-5892 and EXP132. In contrast, Ro 42-5892 and EXP132 had similar effects. The larger decrease of arterial pressure induced by cilazapril was not due to a larger decrease of angiotensin II in plasma and was not influenced by cyclooxygenase inhibition with indomethacin or by bradykinin antagonism with Hoe 140. After binephrectomy, most of the blood pressure-lowering effect of Ro 42-5892 disappeared. In contrast, cilazapril was still markedly effective, pointing to extrarenal effects. We conclude that in furosemide-treated guinea pigs, as opposed to previously published animal models, the decrease of arterial pressure induced by angiotensin converting enzyme inhibitors may be partly due to extrarenal effects not related to the renin-angiotensin system.
C-type natriuretic peptide inhibits thrombin- and angiotensin II-stimulated endothelin release via cyclic guanosine 3',5'-monophosphate.
Authors: Kohno M , Horio T , Yokokawa K , Kurihara N , Takeda T
Published: June 2012

We examined the inhibitory effect of porcine C-type natriuretic peptide (CNP) on endothelin-1 secretion stimulated by thrombin and angiotensin II (Ang II) in cultured porcine endothelial cells. The results were compared with the effects of atrial (ANP) and brain (BNP) natriuretic peptides. Thrombin and Ang II produced a concentration-dependent stimulation of immunoreactive endothelin-1 secretion, and porcine CNP-22 potently inhibited this stimulated secretion in a concentration-dependent manner. CNP-22 had a stronger inhibitory effect than either porcine ANP(1-28) or porcine BNP-26. In addition, CNP potently increased the cellular level of cyclic guanosine 3',5'-monophosphate (GMP), with the inhibition of immunoreactive endothelin-1 secretion in response to thrombin and Ang II being paralleled by the increase in the cyclic GMP level. The increase of cyclic GMP produced by CNP was also greater than that due to porcine ANP(1-28) or porcine BNP-26. The immunoreactive endothelin-1 in the culture medium had two components on high-performance liquid chromatography; the major one corresponded to endothelin-1 (1-21) and the minor one to big endothelin-1 (porcine 1-39). Treatment with CNP did not affect this profile. Our results suggest that CNP probably inhibits the endothelin-1 secretion stimulated by thrombin and Ang II through a cyclic GMP-dependent process. The increase of cyclic GMP levels and the inhibition of immunoreactive endothelin-1 secretion produced by CNP appear to be greater than those produced by ANP or BNP.
Pressure natriuresis in rats during blockade of the L-arginine/nitric oxide pathway.
Authors: Johnson R A , Freeman R H
Published: June 2012

The natriuretic response was studied in anesthetized rats during the intravenous infusion of L-arginine analogues to inhibit the production of endothelium-derived nitric oxide. In an initial experimental series, rats were administered saline vehicle or vehicle containing 300 mumol/kg body wt N omega-monomethyl-L-arginine, N omega-nitro-L-arginine methyl ester, N omega-monomethyl-D-arginine, or L-arginine. Infusion of the competitive inhibitors N omega-monomethyl-L-arginine and N omega-nitro-L-arginine methyl ester significantly increased mean arterial pressure to 155 +/- 3 and 145 +/- 5 mm Hg, respectively, compared with a mean arterial pressure of 118 +/- 3 mm Hg determined in the vehicle control group. Sodium excretion averaged 3.27 +/- 1.08 and 2.52 +/- 0.78 mu eq/min in the N omega-monomethyl-L-arginine- and N omega-nitro-L-arginine methyl ester-treated rats, respectively, and each was significantly higher than the basal sodium excretion of 0.20 +/- 0.05 mu eq/min in the vehicle-treated control animals. Plasma renin activity was significantly lower in the N omega-monomethyl-L-arginine- and N omega-nitro-L-arginine methyl ester-treated groups than in the vehicle-treated group. Neither L-arginine nor N omega-monomethyl-D-arginine administration significantly altered any of the measured variables compared with vehicle alone. In a second experimental series, an adjustable snare was placed around the suprarenal aorta for the purpose of controlling renal perfusion pressure independently of increases in the systemic mean arterial pressure initiated by infusion of N omega-nitro-L-arginine methyl ester (75 mumol/kg i.v.).(ABSTRACT TRUNCATED AT 250 WORDS)