Effects of long‐term transdermal hormone replacement therapy on the renin–angiotensin– aldosterone system,plasma bradykinin levels and blood pressure in normotensive postmenopausal women

Aim: This study was designed to investigate the effects of 24‐month long‐term transdermal hormone replacement therapy (HRT) on the circulating levels of components of the renin–angiotensin–aldosterone system (RAAS) and bradykinin, blood pressure (BP) and lipid profile in normotensive postmenopausal women (PMW). Methods: Twenty‐two normotensive PMW were randomized to receive transdermal HRT (continuous 17‐β estradiol patch at 36 µg/day plus cyclic oral medroxyprogesterone acetate 2.5 mg/day for 12 days/month) (n = 12) or control (n = 10). The plasma renin activity (PRA), serum angiotensin‐converting enzyme (ACE) activity, plasma angiotensin (Ang) I, Ang II, aldosterone, bradykinin, and BP were measured before, and 12 and 24 months after, the start of the HRT. Results: In the HRT group, the diastolic BP and mean BP were significantly decreased at 12 and 24 months (both P < 0.05) after the start of therapy, however, no significant change of the systolic BP was noted during the study period. No changes in the RAAS components or lipid profile were noted in either group. The plasma bradykinin levels were significantly reduced at 12 (P < 0.05) and 24 months (P < 0.01), while no changes were observed in the control group. Conclusion: More than 12 months of long‐term transdermal HRT kept diastolic BP, mean BP and plasma bradykinin levels decreased in normotensive PMW, without influencing any of the components of the RAAS. This therapy may allow optimal blood pressure control and prevent elevation of the cardiovascular risk.     

Effects of Bradykinin B2 Receptor Blockade on Infarct Size and Hemodynamics after Myocardial Infarction in Enalapril-treated Rats

Objectives To study the effects of bradykinin （BK） B2 receptor blockade on infarct size and hemodynamics after myocardial infarction （MI） in rats with angiotensin-converting enzyme （ACE） inhibition therapy. Methods MI was produced by ligating the left coronary artery. The effects of enalapril （ 500 μg/kg·day）, enalapril （ 500 μg/kg · day） with BK B2 receptor antagonist Hoe-140 （500 μg/kg · day）, angiotensin Ⅱ （Ang Ⅱ） type 1 （AT1） receptor antagonist losartan （3 mg/kg · day） on infarct size, left ventricular systolic pressure （ LVSP）, cardiac output index （CI） and stroke volume index （SVI） were observed in rats after MI. Treatments were started on the 2nd day after MI and continued for another 6 weeks. Results Enalapril reduced infarct size and improved CI and SVI compared with the untreated MI group （ P 〈 0. 05 ）, and these effects of enalapril were significantly blunted by concomitant treatment with Hoe-140 （P 〈 0. 05）. Losartan was less effective than enalapril. LVSP were unchanged in the three treatment groups. Conclusions BK can reduce infract size and improve hemodynamics in rats following MI. The cardioprotective effects of ACEI partly result from the action of BK exerted through the B2 receptor.     

Issue Information ‐ TOC2

Hereditary angioedema (HAE) is a rare autosomal dominant genetic disorder clinically characterized by recurrent attacks of subcutaneous and mucosal swelling that can result in significant morbidity and even mortality. Several novel therapies introduced since 2008 have dramatically transformed the approach to management. In this review we will discuss the current understanding of the pathophysiology of HAE, diagnostic evaluation of recurrent angioedema without urticaria, and the therapeutic approach to HAE. We advocate taking an integrative approach to care in order to normalize the lives of affected patients.     

Anomaly of the des-Arg9-bradykinin metabolism associated with severe hypotensive reactions during blood transfusions: a preliminary study

BACKGROUND: Severe hypotensive reactions have been described after the transfusion of platelets or red cells through negatively-charged bedside white cell-reduction filters. The possibility of a role for bradykinin (BK) in the genesis of these reactions has been raised. STUDY DESIGN AND METHODS: To understand if an anomaly of BK metabolism is associated with these reactions, the metabolism of BK and des-Arg9-BK was studied in the sera of four patients who presented with a severe hypotensive transfusion reaction. Tests were performed in the absence and the presence of complete in vitro inhibition of angiotensin-converting enzyme (ACE) activity by enalaprilat. RESULTS: In the presence of ACE inhibition (enalaprilat), the half-life (t1/2) of BK measured in the sera of patients who presented with a severe hypotensive transfusion reaction (361 +/- 90 sec) was not significantly different from that measured in the sera of normal controls (249 +/- 16 sec). In the presence of ACE inhibition (enalaprilat), the t1/2 of des-Arg9-BK was significantly greater in patients who presented with a severe hypotensive transfusion reaction (1549 +/- 319 sec) than in normal controls (661 +/- 38 sec) (p < 0.001). CONCLUSION: A metabolic anomaly mainly affecting the degradation of des-Arg9-BK could be responsible for its accumulation in vivo. Des-Arg9-BK could be responsible, at least in part, for severe hypotensive transfusion reactions.     

USE OF NICOTINE, BRADYKININ AND VERATRIDINE TO ELICIT CARDIOVASCULAR CHEMOREFLEXES IN UNANAESTHETIZED RABBITS

1. We have characterized in unanaesthetized rabbits the reflex effects of injecting nicotine into the pericardial sac or left atrium on heart rate, arterial pressure, systemic vascular resistance and the amplitude and frequency of respiration. These effects were compared with those of atrial administration of nicotine and veratridine, and intrapericardial administration of veratridine and bradykinin. 2. Injection of nicotine (6.25-400 micrograms) into the pericardial sac caused dose-dependent falls of heart rate and arterial pressure, and a brief period of hypopnoea. The fall in arterial pressure was mainly due to a fall in systemic vascular resistance. The threshold dose was 25 micrograms. Near maximal falls in heart rate (108 beats/min) and arterial pressure (47 mmHg) occurred at a dose of 200-400 micrograms. The latency between injection and the onset of bradycardia was 3.0 s. 3. The effects of intrapericardial nicotine on arterial pressure and respiration were antagonized in a dose-dependent fashion by intrapericardial mecamylamine (1-100 micrograms/kg) but were unaffected by intrapericardial hyoscine methylbromide (10 micrograms/kg) or vecuronium (1-10 micrograms/kg). The haemodynamic and respiratory effects were abolished by intrapericardial procaine. The haemodynamic effects were increased, though not significantly, by sino-aortic baroreceptor denervation. In decerebrate, artificially ventilated rabbits, bilateral cervical vagotomy converted the hypotensive and bradycardic response into a slowly developing tachycardia without change in arterial pressure. 4. Left atrial injection of nicotine (6.25-100 micrograms) caused bradycardia, a rise in arterial pressure, and prolonged hyperpnoea preceded by transient hypopnoea. After sino-aortic barodenervation it caused profound falls in heart rate and arterial pressure and transient hypopnoea, which were abolished by intrapericardial procaine. 5. Intrapericardial injection of veratridine (50-100 micrograms) had no consistent effect under control conditions. After sino-aortic barodenervation it caused falls in heart rate and arterial pressure which were abolished by intrapericardial procaine. Left atrial injection of veratridine caused highly variable haemodynamic effects. 6. Intrapericardial bradykinin (2.5-25 micrograms) caused rises in both arterial pressure and heart rate. These were abolished by intrapericardial procaine. 7. We conclude that when nicotine is injected into the pericardial sac of conscious rabbits the reflex haemodynamic and respiratory effects are due to the selective activation of neuronal-type nicotinic cholinoceptors on vagal afferents that originate in the epicardium. The reflex effects of left atrial nicotine are probably due to the excitation of a combination of carotid chemoreceptors and cardiac receptors. 8. The effects of nicotine, veratridine and bradykinin that we observed in conscious rabbits were profoundly different from those reported in anaesthetized rabbits.     

Activation of splanchnic and pelvic colonic afferents by bradykinin in mice.

BACKGROUND: Lumbar splanchnic (LSN) and sacral pelvic (PN) nerves convey different mechanosensory information from the colon to the spinal cord. Here, we determined whether these pathways differ also in their chemosensitivity to bradykinin. METHODS: Using a novel in vitro mouse colon preparation, serosal afferents were recorded from the LSN and PN and distinguished based on their mechanosensitivity to von Frey filaments (70-4000 mg) and insensitivity to colonic stretch (1-5 g) or fine mucosal stroking (10 mg). Bradykinin was applied into a ring around mechanoreceptive fields. RESULTS: The LSN and PN afferents had different dynamic responses to mechanical stimuli: PN afferents required lower intensity stimuli, evoked larger responses, and displayed more maintained responses than LSN afferents. Bradykinin (1 micromol L-1) excited 66% (27 of 41) of LSN afferents. Responses to probing were potentiated after bradykinin. The concentration-dependent (EC50: 0.16 micromol L-1) response was reversed by the B2-receptor antagonist HOE-140 (10 nmol L-)). Twelve bradykinin responsive afferents were mechanically insensitive. More LSN serosal afferents responded to bradykinin than PN afferents (11%, P<0.001) , with larger responses (P<0.05). No mechanically insensitive PN afferents were recruited by bradykinin. CONCLUSIONS: Bradykinin potently stimulates most splanchnic serosal afferents via B2-receptors, but few pelvic afferents. Mechanically insensitive afferents recruited by bradykinin are exclusive to the LSN.     

Bradykinin potentiates LH-induced follicular rupture in the rat ovary perfused in vitro

The possible role of bradykinin as a modulator of LH-induced ovulation was investigated using a model of the in-vitro perfused rat ovary. Ovaries from immature rats, primed with pregnant mare's serum gonadotrophin (PMSG; 20 IU), were perfused in vitro for 20 h, starting on the morning of induced proestrus. Stimulation in vitro with luteinizing hormone (LH; 0.1 microgram/ml) resulted in 3.4 +/- 1.2 ovulations per treated ovary, whereas no ovulations occurred in the unstimulated group. Bradykinin (5 microM) added to the perfusion system at 0, 2.5, 5, 7.5 and 10 h gave two ovulations in one ovulating ovary out of five ovaries perfused. When LH was combined with bradykinin, added to concentrations of 1 microM and 5 microM at the above-mentioned five time points, the numbers of ovulations were 12.2 +/- 2.7 and 15.6 +/- 3.7 per treated ovary, respectively. Bradykinin (5 microM), administered as a single dose concomitantly with LH, resulted in no further increase in the ovulation rate (3.6 +/- 1.6). Bradykinin did not affect cyclic AMP or steroid release from unstimulated or LH-stimulated ovaries. These data indicate a role of bradykinin in the ovulatory process of the rat, potentiating LH-induced ovulations.     

Three-dimensional structure of bradykinin in SDS micelles

The conformational properties of bradykinin in five molar excess sodium dodecyl sulfate (SDS) micelles have been examined by two-dimensional nuclear magnetic resonance (NMR) techniques at 500 MHz. Detailed structural information for bradykinin in SDS was obtained from quantitative 2-D nuclear Over-hauser enhancement (n.O.e.) analyses, distance geometry, and restrained molecular mechanics and dynamics calculations. The conformation of bradykinin in SDS micelles, as determined by these methods, is characterized by a β-turn-like structure at residues 6–9. A detailed comparison of the structures derived from distance geometry and restrained molecular mechanics and dynamics is also presented.