Intracellular angiotensin-(1-12) changes the electrical properties of intact cardiac muscle.

In the present work, the influence of intracellular injection of angiotensin-(1-12) [Ang-(1-12)] on the electrical properties of the intact left ventricle of Wistar Kyoto rats was investigated with electrophysiological methods. Particular attention was given to the role of chymostatin on the effect of the peptide. The results indicated that intracellular administration of the peptide elicited a depolarization of the surface cell membrane and an increase of duration of the action potential followed by the generation of early afterdepolarizations. The increment of action potential duration caused by Ang-(1-12) (100 nM) was due to a decrease of total potassium current recorded from single cardiomyocytes using the whole cell configuration of pCAMP. The decrease of potassium current was related to the activation of protein kinase C (PKC) because the specific inhibitor of kinase C, Bis-1 (10-9 M), abolished Ang-(1-12) effects on the potassium current. The question of whether the effect of Ang-(1-12) was related to the formation of Ang II by chymase was investigated.The results revealed that the intracellular administration of chymostatin, a chymase inhibitor (10-9 M) abolished the effect of intracellular Ang-(1-12) on the potassium current. Moreover, intracellular Ang II (100 nM), by itself, reduced the potassium current, an effect decreased by intracellular valsartan (100 nM). Valsartan (10-9 M) dialyzed into the cell abolished the effect of Ang-(1-12) (100 nM). These observations demonstrate that the effect of Ang-(1-12) on potassium current was related to the formation of Ang II and that the peptide has arrhythmogenic properties.

Therapeutic targets in liver transplantation: angiotensin II in nonsteatotic grafts and angiotensin-(1-7) in steatotic grafts.

Numerous steatotic livers are discarded as unsuitable for transplantation because of their poor tolerance of ischemia-reperfusion(I/R). The injurious effects of angiotensin (Ang)-II and the benefits of Ang-(1-7) in various pathologies are well documented. We examined the generation of Ang II and Ang-(1-7) in steatotic and nonsteatotic liver grafts from Zucker rats following transplantation. We also studied in both liver grafts the effects of Ang-II receptors antagonists and Ang-(1-7) receptor antagonists on hepatic I/R damage associated with transplantation. Nonsteatotic grafts showed higher Ang II levels than steatotic grafts, whereas steatotic grafts showed higher Ang-(1-7) levels than nonsteatotic grafts. Ang II receptor antagonists protected only nonsteatotic grafts against damage, whereas Ang-(1-7) receptor antagonists were effective only in steatotic grafts. The protection conferred by Ang II receptor antagonists in nonsteatotic grafts was associated with ERK 1/2 overexpression, whereas the beneficial effects of Ang-(1-7) receptor antagonists in steatotic grafts may be mediated by NO inhibition. Our results show that Ang II receptor antagonists are effective only in nonsteatotic liver transplantation and point to a novel therapeutic target in liver transplantation based on Ang-(1-7), which is specific for steatotic liver grafts.

Characterization of vascular reactivity in dorsal hand veins after oral rosiglitazone treatment in healthy subjects.

OBJECTIVE: In clinical studies with diabetic patients thiazolidinediones have been shown to restore abnormal vascular function which might be attributed to improved blood sugar control or to restoration of vascular endothelium and smooth muscle responsiveness. The present study was undertaken to investigate whether rosiglitazone modulates vascular responsiveness to different vasoactive agents and exerts renin-angiotensin-system (RAS)-inhibiting properties in healthy subjects in vivo. METHODS: 24 healthy male subjects were randomized to receive either rosiglitazone or placebo. Venoconstrictor responses to angiotensin II (Ang II) and phenylephrine, and endothelium-dependent response to histamine and insulin, and endothelium-independent response to glyceroltrinitrate were compared using the dorsal hand vein compliance method. Effects on the RAS were investigated by plasma level determinations of Ang II and angiotensin-(1-7). Treatment effects on the systemic arterial system were investigated by standardized pulse-wave-analysis. RESULTS: Rosiglitazone significantly inhibited venoconstrictor responses to Ang II by 19% (-70% vs. -51% constriction, p = 0.034) and in the presence of rosiglitazone the ED80 for phenylephrine was increased (ED80: 317 A+/- 86 ng vs. 531 A+/- 102 ng; p = 0.010). Rosiglitazone treatment was without effect on endothelium-dependent dilation, blood pressure, pulse-wave-velocity and plasma angiotensin peptide levels. CONCLUSIONS: The data of the present study in veins of healthy subjects are consistent with data from in vitro and animal studies supporting a direct effect of rosiglitazone on venous tone by modulation of the vascular smooth muscle response via AT1-receptor-downregulation.

Distribution of angiotensin-(1-7) and ACE2 in human placentas of normal and pathological pregnancies.

This work was designed to study the expression of the vasodilator peptide angiotensin-(1-7) [Ang-(1-7)] and its generating enzyme (ACE2) in the uteroplacental interface. Placentas were obtained from 11 early pregnancy failures (5 miscarriages and 6 ectopic pregnancies), 15 normotensive, and 10 preeclamptic gestations. In placental villi, the main sites of immunocytochemical expression of Ang-(1-7) and ACE2 were the syncytiotrophoblast, cytotrophoblast, endothelium and vascular smooth muscle of primary and secondary villi. Syncitial Ang-(1-7) expression in samples obtained from miscarriages and ectopic pregnancies was increased compared to normal term pregnancy [2.0 (2.0-2.25 for the 25 and 75% interquartile range) vs 1.3 (1.0-1.9), p<0.01]. In the maternal stroma, Ang-(1-7) and ACE2 were expressed in the invading and intravascular trophoblast and in decidual cells in all 3 groups. Ang-(1-7) and ACE2 staining was also found in arterial and venous endothelium and smooth muscle of the umbilical cord. The expression of Ang-(1-7) and ACE2 was similar in samples obtained from normal term or preeclamptic pregnancies, except for increased expression of ACE2 in umbilical arterial endothelium in preeclampsia [0.5 (0.5-0.8) vs 0.0 (0.0-0.0), p<0.01]. The uteroplacental location of Ang-(1-7) and ACE2 in pregnancy suggests an autocrine function of Ang-(1-7) in the vasoactive regulation that characterizes placentation and established pregnancy.

Effect of estrogen on neprilysin expression in uterus and kidney of Sprague-Dawley normotensive and heterozygous (mRen2)27-transgenic hypertensive rats.

The present study was designed to determine whether estrogen modulates the angiotensin processing enzymes in membrane homogenates obtained from uterus and kidney cortex and medulla of Sprague-Dawley (SD) and heterozygous (mRen2)27-transgenic hypertensive (Tg(+)) female rats treated with or without 17beta-estradiol (E2). We evaluated estrogen's influence on neprilysin (NEP), an endopeptidase that forms angiotensin-(1-7) [Ang-(1-7)] and on aminopeptidase (AMP), which degrades Ang-(1-7). Renal tissue from normotensive and hypertensive male rats was also evaluated. E2 up-regulated NEP mRNA in the uterus of both SD and Tg(+) and this was associated with increased NEP activity in the uterus of SD (0.31+/-0.03 nmol/min/mg versus 0.18+/-0.04 nmol/min/mg of protein, p<0.05) and Tg(+) (0.26+/-0.04 nmol/min/mg versus 0.13+/-0.02 nmol/min/mg of protein, p<0.05) female). E2 had no significant effect on NEP activity in cortex and medulla of hypertensive and normotensive female. In female animals, cortical NEP activity is two-fold higher than medullary; in males there is a four-fold higher cortical NEP activity as compared to medulla. In male animals, medullary NEP was significantly lower than females with or without E2 treatment; no gender specific effect was found in cortex. E2 treatment also caused a two-fold increase in AMP activity in the uterus and 1.6-fold decrease in kidney cortex of SD and Tg(+) female (p<0.05). Our studies indicate that NEP may be a primary candidate for increased Ang-(1-7) processing in the uterus with estrogen treatment; kidney NEP, on the other hand, showed no modulation by estrogen, suggesting that down regulation of other processing enzymes, like AMP and ACE, may come into play in the kidney with estrogen replacement. In addition, these studies showed that there is tissue-specific regulation of NEP with estrogen treatment that is strain independent.

Inability to induce hypertension in normotensive rat expressing AT(1) receptor antisense.

Our previous studies have shown that neonatal delivery of angiotensin type 1 receptor antisense (AT(1)R-AS) in a retroviral vector prevents spontaneously hypertensive rats from developing hypertension for life but has no effect on blood pressure (BP) in normotensive animals. Based on these results, we hypothesized that AT(1)R-AS transduction in normotensive rats would protect them from developing experimental hypertension. The present study was designed to evaluate this hypothesis. A single intracardiac administration of AT(1)R-AS by a retroviral-mediated delivery system (LNSV-AT(1)R-AS) in 5-day-old normotensive Sprague-Dawley rats resulted in long-term expression of the AT(1)R-AS without an effect on basal BP. However, angiotensin II (Ang II)-induced BP, dipsogenic responses, and renovascular contractility were significantly attenuated in the LNSV-AT(1)R-AS-treated rats. Chronic infusion of low-dose Ang II (55 ng. kg(-)(1). min(-)(1)) in LNSV-alone-treated rats caused a modest increase in BP, profound increase in cardiac hypertrophy, and increased vascular contractility. In contrast, the LNSV-AT(1)R-AS-treated rats were protected from developing these changes after Ang II infusion. These data establish that LNSV-AT(1)R-AS pretreatment protects healthy rats from developing Ang II-dependent hypertension.

Clinical characteristics of patients with premature lower extremity atherosclerosis associated with familial early cardiovascular disease and/or cancer.

AIM: In the past decade we experienced a steady growth in the number of young smokers with severe premature lower extremity atherosclerosis (PLEA) and high frequency of familial cardiovascular disease (Fam CVD). The widely used Framingham risk score does not include Fam CVD among predictors of incident CVD. METHODS: We studied 370 patients younger than 55 with severe PLEA (45% females, 96% smokers) treated between 1998 and 2004. Overall, 312 (85%) patients reported a positive history of Fam CVD; 217 (59%) had family history of premature CVD (FamP-CVD), and 29% had history of early malignancies in family members <60 years (Fam Mal <60). RESULTS: Patients with FamP-CVD compared to those without FamP-CVD had similar prevalence of traditional risk factors, and concentrations of metabolic and inflammatory parameters, however had greater prevalence of clinical coronary artery disease (P=0.03), cerebrovascular disease (P=or<0.01) or both (P<0.01). Patients with both FamP-CVD and Fam Mal <60 (n=58) when compared to those with neither (n=92), had greater frequency of dyslipidemia (P=0.02) and coronary revascularizations (P=0.02). Patients with Fam P-CVD had 3-fold higher odds of prevalent CVD compared to those without Fam P-CVD. This association was independent of demographic and cardiovascular risks. CONCLUSIONS: In patients with PLEA, familial premature CVD may predict early clinical manifestations of systemic atherosclerosis, independently of traditional risk factors. Patients with family history of early malignancies had similar clinical characteristics, including prevalence of CVD.

Inhibition of early atherogenesis by losartan in monkeys with diet-induced hypercholesterolemia.

BACKGROUND: Angiotensin II may contribute to atherogenesis by facilitating the proliferative and inflammatory response to hypercholesterolemia. This study determined, in a primate model of diet-induced atherosclerosis, the effect of AT(1) blockade on fatty-streak formation, plasma lipids, and surrogate markers of vascular injury. METHODS AND RESULTS: Male cynomolgus monkeys fed a diet containing 0.067 mg cholesterol/kJ for 20 weeks were given losartan (180 mg/d, n=6) or vehicle (n=8) for 6 weeks starting at week 12 of the dietary regimen. Arterial pressure, heart rate, plasma total and lipoprotein cholesterol concentrations, and lipoprotein particle sizes and subclass distributions were unaffected by treatment. Losartan caused significant (P<0.05) increases in plasma angiotensin II and angiotensin-(1-7). Compared with vehicle-treated controls, losartan reduced the extent of fatty streak in the aorta, the coronary arteries, and the carotid arteries by approximately 50% (P<0.05). A significant (P<0.05) reduction in the susceptibility of LDL to in vitro oxidation, serum levels of monocyte chemoattractant protein-1, and circulating monocyte CD11b expression were also associated with losartan treatment. In addition, serum levels of vascular cell adhesion molecule-1 and E-selectin did not change during treatment but increased after discontinuation of losartan. Serum C-reactive protein, platelet aggregability, and white cell counts were not modified by losartan. CONCLUSIONS: This study demonstrates for the first time an antiatherogenic effect of AT(1) receptor blockade in nonhuman primates. Losartan inhibited fatty-streak formation through mechanisms that may include protection of LDL from oxidation and suppression of vascular monocyte activation and recruitment factors.

Association of angiotensinogen M235T and A(-6)G gene polymorphisms with coronary heart disease with independence of essential hypertension: the PROCAGENE study. Prospective Cardiac Gene.

OBJECTIVES: We examined the relationship between the angiotensinogen (AGT) gene M235T polymorphism, the variant promoter of the AGT gene A(-6)G and the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism and coronary heart disease (CHD) in native Gran Canaria Island habitants, who have the highest rates of CHD in Spain. BACKGROUND: Some studies subject that the ACE (I/D) polymorphism could be associated with CHD, while AGT (M235T) has been related to essential hypertension. METHODS: We studied 304 subjects with angiographic evidence of coronary artery disease and a clinical diagnosis of myocardial infarction or unstable angina and 315 age- and gender-matched controls. Blood was drawn and DNA extracted. Angiotensin-converting enzyme (I/D) gene polymorphism was analyzed by polymerase chain reaction (PCR) and AGT gene polymorphisms by restriction fragment length polymorphism-PCR and mutagenically-separated PCR. RESULTS: The ACE (I/D) polymorphism showed no association with CHD, whereas the frequency distribution of AGT (M235T) genotypes among patients and controls (235T: 29.1% and 19.0%; M235T: 48.5% and 50.2%; M235: 22.4% and 30.8%, respectively) was statistically different (p = 0.005) and not related to the presence of essential hypertension. Similar results were observed with the AGT A(-6)G polymorphism. In multiple logistic regression analysis, CHD odds ratio associated with 235T and M235 homozygotes were 1.7 (1.1 to 2.6) and 0.54 (0.36 to 0.82), respectively. CONCLUSIONS: This study shows that genetic variation of the AGT (M235T), but not the ACE (I/D), genotypes contributes to the presence of CHD independently of blood pressure profile in a subset of the Spanish population with a high prevalence of cardiovascular disease.

Neurogenic actions of angiotensin II.

It has become increasingly evident that blood-borne angiotensin II has major effects upon brain cardiovascular centers. With the discovery of an angiotensin I-forming enzyme or isoenzymes in the central nervous system of mammals, alternative concepts have emerged regarding the role of this peptide in the regulation of central adrenoreceptor activity, pituitary function, and hydromineral metabolism. These concepts are reviewed, and a framework for future research is suggested by the author.

Do primary dysfunctions in neural control of arterial pressure contribute to hypertension?

This article is a summary of the physiological and clinical evidence that links the cause of essential hypertension to the brain. We stress the potential importance of a biochemical disturbance in the central role of angiotensin II in the regulation of arterial pressure. While the evidence is compelling, we acknowledge the need for further complete studies on this timely subject.

Bidirectional transport of angiotensin II binding sites in the vagus nerve.

We previously showed that specific angiotensin II (Ang II) binding sites are present in the canine nodose ganglion and peripheral vagus nerve, and that unilateral removal of the nodose ganglion results in loss of binding in the ipsilateral nucleus tractus solitarii and the dorsal motor nucleus of the vagus. An association of Ang II binding sites with both afferent and efferent vagal fibers is consistent with actions of the peptide on cardiac vagal tone and the baroreceptor reflex. To investigate possible transport of Ang II binding sites, quantitative in vitro receptor autoradiography was used to visualize binding after double ligation of the peripheral process of the cervical vagus nerve. One ligature was tied 0.2 to 0.5 cm distal to the nodose ganglion; the second ligature was tied on the same nerve 1.0 to 1.5 cm from the nodose ganglion. Twenty-four hours later, high-affinity Ang II binding sites (Ka = 0.46 +/- 0.08 nM) accumulated at the first ligature (the side nearest the nodose ganglion), indicating anterograde transport. Since accumulations of similar affinity sites were seen distal to the second ligature, retrograde transport of binding sites also occurred. These data reveal the existence of a mechanism for the bidirectional axonal transport of Ang II binding sites in the cervical portion of the vagus nerve.

Altered neural control of cardiovascular function in sodium-depleted dogs.

Sodium restriction affects sympathetic control mechanisms by blunting of the reflex pressor response to carotid sinus hypotension, which is reversible by section of vagal afferents. To obtain more direct evidence, sympathetic nerve activity was recorded from a renal nerve (RNA) in 16 normal (NS) and 13 sodium-depleted (SD) dogs anesthetized with morphine-pentobarbital. Integrated RNA was measured during changes in mean arterial pressure (MAP) produced by i.v. infusion of sodium nitroprusside (100 micrograms/kg/min) or phenylephrine (20 micrograms/kg/min). The classical inverse relationship between MAP and integrated RNA was found before and after bilateral vagotomy (VAGT) in both NS and SD dogs. However, RNA in SD dogs, expressed as % of maximal neural firing, was significantly less at any blood pressure level when compared to NS dogs. In addition, the critical pressure (point at which RNA ceased) was reduced in SD vs NS dogs (p less than 0.002). The decreased sympathetic neural firing in SD dogs was abolished after bilateral VAGT, confirming the pronounced buffering effects of vagal afferents on RNA in salt-depleted dogs.

Collagen metabolism and reversal of aortic medial hypertrophy in spontaneously hypertensive rats treated with methyldopa.

Collagen synthesis, content, and concentration were determined in the hypertrophied intima media of thoracic aortas from 10-, 15-, and 20-week-old spontaneously hypertensive rats (SHR). Although the rates of aortic collagen synthesis declined with age, the dry weight of the intima media and the total collagen content increased proportionally. Collagen concentration thus remained unchanged. Methyldopa was administered orally to SHR when they were 12 to 15 weeks of age, when their body weight were identical to the untreated group. Blood pressure and the degree of aortic medial hypertrophy, judged by medial dry weight per kilogram body weight, were significantly lower compared with untreated SHR. Collagen synthesis was likewise decreased to a mean rate not significantly higher than age-matched normotensive Wistar-Kyoto controls. This reduction in collagen synthesis, however, was not sufficient to decrease measurably the total collagen content of the aortas compared with untreated SHR. Since medial dry weights were lower in the treated rats, collagen concentration in aortas from SHR given methyldopa for 3 weeks was actually increased. The increase in collagen concentration also suggests that medial hypertrophy was reversed.

Central opiate system modulation of the area postrema pressor pathway.

Angiotensin II, when given into the vertebral arteries, acts at the area postrema to augment central sympathetic vasomotor activity. The mechanism of action is unknown but recent evidence implicates an interaction with the opiate system. In dogs anesthetized with chloralose either alone or in combination with morphine, naloxone blunted the pressor response to vertebrally administered angiotensin II by 50%. Addition of morphine to dogs anesthetized with chloralose only doubled the pressor response to identical doses of angiotensin II. On the other hand, the magnitude of the pressor responses to intravenously infused angiotensin II were unaltered by either naloxone or morphine. Likewise, responses to norepinephrine given vertebrally and intravenously were not similarly affected. Therefore, naloxone-induced changes in vascular responsiveness were not responsible for the altered sensitivity of the area postrema to angiotensin II following blockade of endogenous opiates. The data suggest that there exists a previously unrecognized interaction of the endogenous opiate system in the medulla in mediating the pressor effects of angiotensin II at the level of the area postrema.

Location of the area postrema pressor pathway in the dog brain stem.

Electrical stimulation of the dog's area postrema (AP) induces a response that mimics the pressor response produced by intravertebral infusion of low-dose angiotensin II, which causes an increase in mean arterial pressure associated with transient tachycardia and increased peripheral resistance. The present study investigated in morphine-chloralose anesthetized dogs whether: 1) the characteristics of the AP pressor response are influenced by the presence of carotid sinus afferents; 2) structures rostral to the medulla influence the AP pressor response; and 3) the pressor pathway is initiated by neurons within the AP. Since bilateral cervical sinovagal denervation, which potentiated the phenylephrine pressor response, did not affect the pressor response to AP stimulation, the data provide evidence for an inhibitory influence exerted upon the central baroreflex mechanism by the AP pressor mechanism. The unaltered AP pressor response after midcollicular transection suggests that the efferent pathway is contained within the brain stem caudal to the pons. Finally, the elimination of the pressor response following kainic acid microinjection into the AP provides evidence that the AP pressor mechanism is initiated by neurons within the AP, rather than by fibers of passage from other pressor centers. These results suggest that the AP produces its facilitation of central sympathetic vasomotor outflow via a pathway contained within the medulla.

Effects of chronic intraventricular sodium on blood pressure and fluid balance.

To examine if chronic sodium loading on the brain produces sustained increases in blood pressure, water intake, and sodium excretion, hypertonic (0.5 M and 1.5 M) and isotonic (0.15 M) NaCl solutions were infused into the third ventricle of Sprague-Dawley rats at a rate of 5.5 microliters/hr for 7 days. Intracerebroventricular infusion of 1.5 M NaCl significantly increased systolic blood pressure during the entire infusion period (+23 +/- 5 mm Hg on day 1 and +15 +/- 2 mm Hg on day 7, n = 10, mean +/- SEM). Blood pressure rose insignificantly in the 0.5 M NaCl group, whereas it remained at the baseline levels in the 0.15 M NaCl group. The increases in water intake (day 2), positive water balance (day 2), and negative sodium balance (day 3) were observed in the 1.5 M NaCl group. On day 7, the 1.5 M NaCl group showed hyponatremia and low plasma osmolality and had higher plasma norepinephrine but not vasopressin compared with the 0.15 M NaCl group. In another series of study, depressor response to intravenous hexamethonium (20 mg/kg) in the 1.5 M NaCl group was greater than that in the 0.15 M NaCl group on both day 1 and 7. The depressor response to d(CH2)5Tyr(Me)-arginine vasopressin (10 micrograms/kg) in the 1.5 M NaCl group was greater on day 1 but not on day 7. These results indicate that sustained sodium stimulus on the central nervous system causes mild hypertension and alters water and sodium balance. The sympathetic nervous system but not vasopressin may play an important role in the chronic phase of central NaCl-induced hypertension.

Neurogenic hypertension produced by lesions of the nucleus tractus solitarii alone or with sinoaortic denervation in the dog.

The cardiovascular effects of bilateral lesions of the nucleus tractus solitarii (NTS) were compared with those of subsequent sinoaortic denervation in the same dogs. Destruction of the lateral but not the medial component of the NTS between + 0.5 and 3 mm anterior to the obex produces mild hypertension and tachycardia, not always sustained for more than 2 weeks. Rises in pressure were accompanied by increased lability which was not present regularly in all dogs but correlated with the baseline level of arterial pressure. On the other hand, sinoaortic denervation following lateral NTS lesions produced the first demonstration of fulminant hypertension in the dog, which led to death within hours. These data suggest that, while NTS lesions in the dog probably only partially interrupt central baroreceptor pathways, the addition of sinoaortic denervation completely disrupts baroreceptor inputs to the central nervous system, thus releasing central sympathetic outflow completely from baroreceptor inhibition.

Angiotensin-(1-7) dilates canine coronary arteries through kinins and nitric oxide.

Angiotensin-(1-7) [Ang-(1-7)] was recently recognized to have novel biological functions that are distinct from those of Ang II. In these studies, we determined the vasoactive effects of Ang-(1-7) together with the endothelium-dependent mediator(s) of these responses in canine coronary arteries. Isometric tension was measured in intact canine coronary artery rings suspended in organ chambers perfused with 95% O2/5% CO2 at 37 degrees C. Ang-(1-7) caused significant concentration-dependent vascular relaxation (2.73 +/- 0.58 micromol/L, EC50) of rings precontracted with the thromboxane A2 analogue U46,619. Pretreatment with the nitric oxide synthase inhibitor N(omega)-nitro-L-arginine (1 mol/L) abolished the vasodilator response to Ang-(1-7), whereas treatment with the cyclooxygenase inhibitor indomethacin (10 micromol/L) was without effect. The vasodilator response produced by Ang-(1-7) was blocked by 75% with the bradykinin B2 receptor antagonist Hoe 140 (1 micromol/L) or by 80% with the nonselective Ang II antagonist [Sar1,Thr8]-Ang II (1 micromol/L). In contrast, the selective AT1 or AT2 Ang II antagonists CV 11974 (1 micromol/L), and PD 123319 (1 micromol/L), respectively, were ineffective in inhibiting the Ang-(1-7)-elicited vasodilation. Furthermore, pretreatment of the coronary rings with 2 micromol/L Ang-(1-7) markedly potentiated the bradykinin response. These results suggest that Ang-(1-7) elicits coronary vasodilation that is specifically mediated by the endothelium-dependent release of nitric oxide. These responses involve a B2 bradykinin receptor and a non-AT1, non-AT2, angiotensin receptor. These data suggest that increases in circulating levels of Ang-(1-7) accompanying long-term administration of converting enzyme inhibitors or Ang II receptor blockers may contribute to the cardioprotective actions of these drugs.

Neurovascular mechanisms and sodium balance in the pathogenesis of hypertension.

Physiological studies have clarified the role that the brain has in the interplay between salt balance and hypertension. Neural mechanisms and endocrine secretions play a pivotal role in the adaptation of mammals to changes in the intake and excretion of sodium. Maneuvers that alter the concentration of sodium in the plasma modify the sensitivity of baroreceptor reflexes and alter vascular reactivity. These changes may be mediated in part by the release of vasopressin. The research also suggests that the brain indirectly modulates the ability of the vascular endothelium to release vasoactive factors. Collectively, these studies illustrate the multiple effects of the sodium ion on the peripheral neural and central endocrine mechanisms that participate in the regulation of arterial pressure.