Genetic influences on cardiovascular responses to an acoustic startle stimulus in rats

1. The aim of the present study was to assess the cardiovascular differences among five inbred rat strains (n=16 per strain), including spontaneously hypertensive rats (SHR), Wistar Kyoto (WKY) rats, Wistar Furth (WF) rats, Fischer (F344) rats and Lewis (Lew) rats and the usual outbred Wistar (W) rat strain (n=25). 2. These strains were compared under resting conditions for blood pressure (BP) and heart rate (HR) levels and for their baroreceptor-HR reflex sensitivity. In addition, their responses to an acoustic startle stimulus were measured. 3. A consistent rise in BP was observed among the groups as a result of the noise stimulus. This rise in systolic BP (SBP) averaged (+/-SEM) 37 +/- 2 mmHg in the SHR and 34 +/- 4 mmHg in F344 rats, while the response was only 23 +/- 3 mmHg in WKY rats. Pulse pressure (PP) was increased following noise in all groups. The delay for the BP response for all groups combined was 1.6 +/- 0.1 s. 4. Most animals had minimal HR variations, except F344 rats, responding with a 42 +/- 13 b.p.m. decrease 3.0 s after the stimulus (i.e. 1.3 s after the maximal 34 +/- 4 mmHg SBP rise). 5. The highest SBP (160 +/- 3 mmHg) and diastolic BP (104 +/- 3 mmHg) were observed in inbred SHR. Other groups were normotensive. Resting PP was elevated for SHR (56 +/- 2 mmHg) compared with the other groups (40 +/- 2 mmHg). The highest HR was found in F344 and WF rats, with 389 +/- 11 and 372 +/- 7 b.p.m., respectively. The lowest HR was observed in SHR and Lewis rats, with 335 +/- 7 and 323 +/- 7 b.p.m., respectively. The least sensitive baroreflex function was observed in SHR (0.8 +/- 0.1 b.p.m./mmHg) compared with the other strains (1.4 +/- 0.2 b.p.m./mmHg). 6. The present study confirms the importance of genetic factors on the cardiovascular responses of rats to a noise startle stimulus. Two inbred normotensive rat strains, namely F344 and WKY rats, which exhibit a substantial difference in pressor response to noise, may be used to unravel the mechanisms of sympathetic activation.     

ORTHOSTATIC AND POSTPRANDIAL BLOOD PRESSURE REDUCTION IN PATIENTS WITH ESSENTIAL HYPERTENSION

1. The role of the sympathetic nervous system in orthostatic and postprandial blood pressure reduction in patients with essential hypertension was studied in 13 hypertensive patients and 10 age-matched normotensive subjects. 2. The blood pressure (BP), pulse rate, and plasma norepinephrine (NE) were measured: (i) every minute for 20 min in the upright position after overnight recumbency (ii) every 30 min after food intake for 3 h in the supine position. 3. Orthostatic BP reduction (greater than 13 mmHg in mean BP) was observed in eight hypertensive patients with a maximum after 4 min. Seven of these patients showed postprandial hypotension (greater than 13 mmHg) with a maximum 90 min after eating, while none of the normotensives exhibited such BP reductions. Before and during the tests the plasma NE levels were higher in hypertensive patients than in the normotensives. The plasma NE level was increased from 370 +/- 80 to 790 +/- 110 pg/mL 4 min after standing (P less than 0.01) in hypertensive patients and from 220 +/- 40 to 530 +/- 90 pg/mL (P less than 0.01) in normotensive subjects. The plasma NE level was decreased 90 min after food intake from 390 +/- 90 to 260 +/- 80 pg/mL in hypertensives. Changes in plasma NE correlated with those in mean BP after standing for 4 min (r = 0.379, P less than 0.05) and also with those 90 min after food intake (r = 0.457, P less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)     

Dissociation of blood pressure and sympathetic activation of renin release in sinoaortic-denervated rats

1. Blood pressure (BP) and heart rate (HR) increase 6 and 24 h after sinoaortic baroreceptor denervation (SAD), whereas plasma renin activity (PRA) and renal renin mRNA levels remain unchanged. We postulated that a simultaneous rise in BP could offset the expected activation of renin associated with an increased renal sympathetic discharge secondary to SAD. 2. To test this hypothesis, the increase in BP associated with the onset of SAD was prevented by a continuous infusion of sodium nitroprusside (SNP; 30 microg/kg per h). Changes were measured in five groups of conscious adult male Wistar rats: (i) sham; (ii) SAD; (iii) SAD rats in which the BP was prevented from increasing by infusion of SNP; (iv) sham rats in which the BP was increased by 30% by infusion of phenylephrine (PE; 1.5-2.0 mL/h); and (v) SNP + PE for 3 h by infusion as above. 3. As expected, BP and heart rate (HR) increased significantly following SAD compared with sham rats (152 +/- 4 vs 116 +/- 3 mmHg, respectively, for BP and 503 +/- 6 vs 345 +/- 13 b.p.m., respectively for HR; n = 5; P < 0.05) but remained unchanged when SNP was infused for 3 h (106 +/- 1 mmHg and 455 +/- 9 b.p.m., respectively; n = 5; P < 0.05). 4. Similarly, BP and HR increased with PE infusion compared with PE + SNP (138 +/- 9.9 vs 113 +/- 2.3 mmHg for BP, respectively, and 325 +/- 9 vs 423 +/- 18 b.p.m. for HR, respectively; n = 5; P < 0.05). 5. Plasma renin activity remained unchanged in SAD compared with sham rats (1.67 +/- 0.35 vs 1.05 +/- 0.17 ng angiotensin (Ang) I/mL per h), but increased significantly when hypertension was prevented (5.86 +/- 0.77 ng AngI/mL per h; n = 5; P < 0.05). Renin mRNA levels in the kidneys were unchanged in all groups. 6. These results show that an elevation in BP appears to offset increased renal sympathetic discharge with no change in PRA.     

Comparison of angiotensin II-induced blood pressure and structural changes in Fischer 344 and Wistar Kyoto rats

1. The purpose of the present study was to evaluate the blood pressure (BP) response, the BP and heart rate (HR) components of the startle reaction and the structure of the carotid artery and the aorta during chronic infusion of angiotensin (Ang) II in Fischer 344 (F344) compared with Wistar Kyoto (WKY) rats, two in-bred normotensive contrasted strains. 2. Osmotic mini-pumps filled with saline vehicle or AngII (120 ng/kg per min) were implanted subcutaneously in 8-week-old normotensive rats and infused for 4 weeks in F344 rats (saline, n = 10; AngII, n = 10) and WKY rats (saline, n = 10; AngII, n = 9). Basal BP, HR and the responses to an acoustic startle stimulus (duration 0.7 s, 115 dB) were recorded in conscious rats. The structure of the carotid artery and aorta was determined in 4% formaldehyde-fixed arteries. 3. Compared with WKY rats, vehicle-treated F344 rats had lower bodyweight (BW; 266 +/- 7 vs 299 +/- 9 g; P < 0.05) and heart weight (0.80 +/- 0.02 vs 0.98 +/- 0.04 g; P < 0.05) and higher aortic systolic BP (SBP; 131 +/- 1 vs 123 +/- 5 mmHg; P < 0.001) and diastolic BP (98 +/- 3 vs 89 +/- 2 mmHg; P < 0.001). In F344 rats, compared with the WKY rats, the wall thickness/BW ratio was increased in the carotid artery (156 +/- 9 vs 131 +/- 6 nm/g; P < 0.05) and abdominal aorta (264 +/- 13 vs 217 +/- 12 nm/g; P < 0.05) and decreased in the thoracic aorta (246 +/- 13 vs 275 +/- 8 nm/g; P < 0.05). There was no difference in elastin and collagen density. Angiotensin II differentially enhanced BP in both strains: (SBP: 163 +/- 5 and 132 +/- 4 mmHg in F344 and WKY rats, respectively; P(strain x treatment) < 0.05). Circumferential wall stress was increased in the aorta of F344 rats compared with WKY rats (1176 +/- 39 vs 956 +/- 12 kPa (P < 0.001) and 1107 +/- 42 vs 813 +/- 12 kPa (P < 0.001) in thoracic and abdominal aortas, respectively). The startle response was amplified in F344 rats, with enhanced increases in SBP and pulse pressure (PP) and bradycardia compared with responses of WKY rats (+44 +/- 9 mmHg, +10 +/- 2 mmHg and -40 +/- 17 b.p.m., respectively, in F344 rats vs+28 +/- 4 mmHg, + 4 +/- 2 mmHg and -19 +/- 10 b.p.m. in WKY rats, respectively; P(strain) < 0.05 for BP and PP). The startle response was not affected by AngII. 4. These results indicate a higher BP producing an increase in wall thickness in F344 rats compared with WKY rats. We propose that an increase in sympathetic nervous activity causes these haemodynamic differences, as suggested by the excessive increase in BP during an acoustic startle stimulus. Angiotensin II increased BP in F344 rats, but did not exaggerate the increase in BP during the startle reaction.     

Modulation of stress induced by isometric handgrip test in hypertensive patients following yogic relaxation training

13 essential hypertensive patients aged 41 to 60 years were given yoga training for 60 min daily, Monday through Saturday, for a total duration of 4 weeks. Blood pressure and heart rate (HR) were measured with non-invasive semi-automatic blood pressure monitor. Measurements were recorded before the training and at weekly intervals during the 4 week training period. Results of our study show a significant (P<0.001) reduction in resting HR and rate-pressure-product (RPP) after 2 weeks of yoga training. Systolic pressure (SP), diastolic pressure (DP) (P<0.001) and mean pressure (MP) (P<0.05) showed a significant reduction at 3 weeks of training period. After 4 weeks of training, there was further fall in SP, DP, pulse pressure (PP) (P<0.05), MP (P<0.001), HR and RPP. Isometric handgrip test before yoga training produced a significant rise in SP and MP and insignificant rise in DP, HR and RPP. After yoga training, there was a significant rise in all these parameters. Our results show that yoga training optimises the sympathetic response to stressful stimuli like isometric handgrip test and restores the autonomic regulatory reflex mechanisms in hypertensive patients.     

Centrally produced neuronal nitric oxide in the control of baroreceptor reflex sensitivity and blood pressure in normotensive and spontaneously hypertensive rats

We studied the effect of chronic nitric oxide synthase (NOS) blockade in the brain on mean arterial pressure [MAP (mmHg)], heart rate [HR (bpm)] and baroreceptor reflex sensitivity [BRS (mean slope: bpm/mmHg)] in Wistar-Kyoto (WKY) and spontaneously hypertensive rats (SHR). Intracerebroventricular (i.c.v.) infusion of the nonselective NOS inhibitor N-Nitro-L-arginine-methylester (L-NAME) (50 microg/kg per day, 11-12 days) increased MAP in WKY and SHR (125+/-2.1 vs 118+/-1.1 controls, P<0.01 and 179+/-3.59 vs 156+/-4.0 controls, P<0.001, respectively) without affecting HR. In L-NAME-treated WKY, BRS to bradycardia was suppressed (-0.79+/-0.09 vs -1.76+/-0.17 controls, P=0.001), whereas in SHR, L-NAME did not affect BRS to bradycardia. BRS to tachycardia remained unaffected in either strain. In WKY, 7-nitroindazole (7-NI x Na+) (34 microg i.c.v./kg per day, 11-12 days), a selective nNOS inhibitor, did not affect MAP or HR, but BRS to bradycardia and tachycardia was decreased (-0.37+/-0.20 vs -0.97+/-0.41 controls, P<0.01 and -1.78+/-0.20 vs -2.52+/-0.40 controls, P=0.05, respectively). In SHR, the same dose of 7-NI x Na+ increased resting MAP (171+/-5.00 vs 150+/-7.00 controls, P<0.05) without affecting HR or BRS to bradycardia or tachycardia. Thus in WKY, BRS to acute changes in systemic blood pressure (BP) is regulated by NO produced by nNOS in the brain, serving as a neurotransmitter in sympathetic and parasympathetic efferent pathways. In SHR, systemic BP is regulated in part by NO released by the type I NOS isoenzyme in the brain.     

Contribution of the renin-angiotensin system to short-term blood pressure variability during blockade of nitric oxide synthesis in the rat.

1. The aim of this study was to investigate, by use of spectral analysis, (1) the blood pressure (BP) variability changes in the conscious rat during blockade of nitric oxide (NO) synthesis by the L-arginine analogue NG-nitro-L-arginine methyl ester (L-NAME); (2) the involvement of the renin-angiotensin system in these modifications, by use of the angiotensin II AT1-receptor antagonist losartan. 2. Blockade of NO synthesis was achieved by infusion for 1 h of a low-dose (10 micrograms kg-1 min-1, i.v., n = 10) and high-dose (100 micrograms kg-1 min-1, i.v., n = 10) of L-NAME. The same treatment was applied in two further groups (2 x n = 10) after a bolus dose of losartan (10 mg kg-1, i.v.). 3. Thirty minutes after the start of the infusion of low-dose L-NAME, systolic BP (SBP) increased (+10 +/- 3 mmHg, P < 0.01), with the effect being more pronounced 5 min after the end of L-NAME administration (+20 +/- 4 mmHg, P < 0.001). With high-dose L-NAME, SBP increased immediately (5 min: +8 +/- 2 mmHg, P < 0.05) and reached a maximum after 40 min (+53 +/- 4 mmHg, P < 0.001); a bradycardia was observed (60 min: -44 +/- 13 beats min-1, P < 0.01). 4. Low-dose L-NAME increased the low-frequency component (LF: 0.02-0.2 Hz) of SBP variability (50 min: 6.7 +/- 1.7 mmHg2 vs 3.4 +/- 0.5 mmHg2, P < 0.05), whereas the high dose of L-NAME not only increased the LF component (40 min: 11.7 +/- 2 mmHg2 vs 2.7 +/- 0.5 mmHg2, P < 0.001) but also decreased the mind frequency (MF: 0.2-0.6 Hz) component (60 min: 1.14 +/- 0.3 mmHg2 vs 1.7 +/- 0.1 mmHg2, P < 0.05) of SBP. 5. Losartan did not modify BP levels but had a tachycardic effect (+45 beats min-1). Moreover, losartan increased MF oscillations of SBP (4.26 +/- 0.49 mmHg2 vs 2.43 +/- 0.25 mmHg2, P < 0.001), prevented the BP rise provoked by the low-dose of L-NAME and delayed the BP rise provoked by the high-dose of L-NAME. Losartan also prevented the amplification of the LF oscillations of SBP induced by L-NAME; the decrease of the MF oscillations of SBP induced by L-NAME was reinforced after losartan. 6. We conclude that the renin-angiotensin system is involved in the increase in variability of SBP in the LF range which resulted from the withdrawal of the vasodilating influence of NO. We propose that NO may counterbalance LF oscillations provoked by the activity of the renin-angiotensin system.     

The effects of rilmenidine and atenolol on mental stress, dynamic exercise and autonomic function in mild to moderate hypertension.

1. The effects of 4 week treatment with rilmenidine or atenolol on tests of mental stress, dynamic exercise, autonomic function and psychometric tests were evaluated in a randomized, double-blind, placebo-controlled, cross-over study. 2. After a 4 week placebo run-in, 12 patients with essential hypertension (blood pressure [BP] 160/95 +/- 15/7 mmHg) received rilmenidine 1-2 mg day-1, and atenolol 50-100 mg day-1, each for 4 weeks, with a 4 week placebo wash-out between drug treatments. 3. Both agents produced a comparable reduction in supine and erect BP. During the mental arithmetic test, BP and heart rate (HR) responses were similar for rilmenidine and atenolol. 4. During bicycle exercise, the increase in HR was significantly greater after rilmenidine (+50 vs 41 beats min-1, P = 0.04). During recovery, the areas under the curve for diastolic BP (46,450 vs 51,400 mmHg s, P = 0.02) and HR (49,445 vs 63,597 beats min-1 s, P = 0.001) were significantly less with atenolol than rilmenidine. 5. Neither rilmenidine nor atenolol affected mental performance as judged by arithmetic and psychomotor tests. Physiological responses to autonomic function tests (deep breathing, facial immersion, isometric handgrip and cold pressor) were preserved with both drugs. The standing to lying ratio was higher on atenolol (P = 0.01) and Valsalva ratio was higher on rilmenidine (P = 0.03). 6. In conclusion, rilmenidine and atenolol exerted comparable antihypertensive effects both at rest and during mental and dynamic stress. Atenolol attenuated HR responses to dynamic exercise and the Valsalva manoeuvre; rilmenidine did not interfere with the physiological responses of BP and HR during autonomic function tests.     

Sex-differences in circadian blood pressure variations in response to chronic angiotensin II infusion in rats

1. The aim of this study was to investigate the effect of chronic angiotensin II (AngII) infusion on the circadian rhythms of arterial blood pressure, heart rate (HR) and locomotor activity (ACT) in male and female rats. 2. Radiotelemetry probes were implanted into the aorta in male and female rats and allowed 10 days for recovery. Control levels for mean arterial pressure (MAP), HR and ACT were recorded for 3 days, then AngII (400 ng/kg per min s.c. via osmotic minipump) or vehicle (saline) was infused for 10 days (n = 6 per group). Further recordings of MAP, HR and ACT were made during days 8, 9 and 10 of the infusion period. 3. In response to AngII infusion, night and day-time MAP increased significantly in female (18 +/- 2 mmHg; 28 +/- 7 mmHg) and male (27 +/- 4 mmHg; 30 +/- 3 mmHg) rats, respectively. The degree of elevation in MAP in response to AngII was attenuated in the females during the night period (P(sex) < 0.05) but not the day (P(sex) = 0.2). Control night-day differences in MAP, HR and ACT averaged 7 +/- 1 mmHg, 58 +/- 5 b.p.m. and 30 +/- 4 units in the female and 6 +/- 1 mmHg, 43 +/- 3 b.p.m. (P(sex) < 0.05) and 14 +/- 2 units (P(sex) < 0.05) in male rats, respectively. AngII infusion disrupted MAP circadian rhythm in female (-4 +/- 2 mmHg) and male rats (1 +/- 2 mmHg; P(treat) < 0.01), but did not affect heart rate or locomotor activity. 4. In conclusion, sex differences in the circadian rhythm of heart rate and locomotor activity, but not arterial pressure exist under basal conditions. Circulating AngII modulated the circadian rhythm of MAP in female and male rats but not heart rate or locomotor activity. These findings have important implications for our understanding of circadian blood pressure rhythms in states of activation of the renin angiotensin system.     

Correlation between body mass index and blood pressure indices, handgrip strength and handgrip endurance in underweight, normal weight and overweight adolescents

In the present study, we investigated the correlation between body mass index (BMI), blood pressure (BP) indices and indices of physical fitness in apparently healthy subjects aged 14-18 years. We obtained data from 145 (105 males and 40 females) and assessed the correlation between BMI, and heart rate, systolic pressure (SP), diastolic pressure (DP), pulse pressure (PP), mean arterial pressure (MP), rate-pressure product, endurance in the 40 mm Hg test, handgrip strength (HGS), and handgrip endurance. Subjects with BMI <18.5 kg/m2, 18.5-25 kg/m2 and >25 kg/m2 were classed as underweight (65 males and 9 females), normal weight (27 males and 20 females), and overweight (13 males and 11 females) respectively. In view of gender differences in autonomic regulation, data of male and female subjects were analyzed separately. We used analysis of variance to compare differences between the three groups. Correlation between BMI and other indices was tested using Pearson's correlation coefficient. A P value <0.05 was considered statistically significant Both SP and DP were highest in overweight and least in underweight male subjects (P<0.05 for both), whereas in females, differences in DP alone were statistically significant (P<0.05). In underweight male subjects, there was a positive correlation between BMI and SP, DP, PP, MP and HGS (P<0.05 for all). There was a positive correlation between BMI and SP in overweight male subjects (r = 0.5 P = 0.07, n = 13). A positive correlation was observed between BMI and rate-pressure product (r = 0.5, P = 0.45, n = 11) and BMI and HGS (r = 0.6, P = 0.05, n = 11) in overweight females. Our observations indicate that there are gender differences in the correlation between BMI and BP indices especially in underweight and overweight subjects. The observed differences between the three groups and gender differences in correlation between BMI and BP indices may be due to differences in autonomic function and or energy metabolism.     

Post-resistance exercise hypotension in spontaneously hypertensive rats is mediated by nitric oxide

1. Postexercise hypotension (PEH) plays an important role in the non-pharmacological treatment of hypertension. It is characterized by a decrease in blood pressure (BP) after a single bout of exercise in relation to pre-exercise levels. 2. The present study investigated the effect of a single session of resistance exercise, as well as the effect of nitric oxide (NO) and the autonomic nervous system (ANS), in PEH in spontaneously hypertensive rats (SHR). 3. Catheters were inserted into the left carotid artery and left jugular vein of male SHR (n = 37) for the purpose of measuring BP or heart rate (HR) and drug or vehicle administration, respectively. Haemodynamic measurements were made before and after acute resistance exercise. The roles of NO and the ANS were investigated by using N(G)-nitro-L-arginine methyl ester (L-NAME; 15 mg/kg, i.v.) and hexamethonium (20 mg/kg, i.v.) after a session of acute resistance exercise. 4. Acute resistance exercise promoted a pronounced reduction in systolic and diastolic BP (-37 +/- 1 and -8 +/- 1 mmHg, respectively; P < 0.05), which was suppressed after treatment with L-NAME. The reduction in systolic BP caused by exercise (-37 +/- 1 mmHg) was not altered by the administration of hexamethonium (-38 +/- 2 mmHg; P > 0.05). After exercise, the decrease in diastolic BP was greater with hexamethonium (-26 +/- 1 mmHg; P < 0.05) compared with the decrease caused by exercise alone. 5. The results suggest that acute resistance exercise has an important hypotensive effect on SHR and that NO plays a crucial role in this response.     

EFFECTS ON SHEEP BLOOD PRESSURE OF TREATMENT WITH ANGIOTENSIN, STEROIDS AND SALT

1. Angiotensin II (AII, 0.22 microgram/min) infused for 7-14 days, into adult unanaesthetized wethers, caused a rise in blood pressure of 7 +/- 3/7 +/- 3 mmHg (mean +/- s.e.m.) from control values of 90 +/- 5/54 +/- 3 mmHg (P less than 0.05, n = 11). Cardiac output and pulse interval were not affected. A high salt intake had no effect on blood pressure, cardiac output and pulse interval, nor did it potentiate the action of AII. 2. Ethinyl oestradiol (EE, 20 mg/week) caused a small fall in systolic and diastolic pressure of 6 +/- 3/6 +/- 5 mmHg (n = 7, P less than 0.1, P less than 0.05). When AII (0.22 microgram/min) was given with EE, it still caused a significant rise in blood pressure (P less than 0.01). The synthetic progestin (1 mg of norethisterone [NE] for 8-18 days) plus a high salt diet had no effect on arterial pressure and cardiac output but pulse interval rose significantly (P less than 0.05). 3. Therefore the reduction in vascular reactivity to angiotensin seen in human pregnancy is probably not related to high levels of oestrogen. Further, NE combined with a high salt diet does not cause hypertension in sheep.     

Cardiovascular autonomic regulation in subjects with normal blood pressure, high-normal blood pressure and recent-onset hypertension

1. In the present study, we tested the hypothesis that heart rate variability (HRV) is reduced in recent-onset hypertension and that pressor responses to standard autonomic reflex tests are not any different in hypertensives compared with normotensives. We also hypothesized that subjects with high-normal blood pressure (BP) would be distinguishable from normotensives on the basis of short-term HRV indices. 2. Three groups of subjects, each consisting of 15 men and 10 women, were examined. The first group consisted of subjects with recent-onset hypertension who were not taking antihypertensive medication (mean (+/-SD) age 50 +/- 12 years; BP >/= 140/90 mmHg), the second group consisted of subjects with high-normal BP (mean age 46 +/- 13 years; BP 130-139/85-89 mmHg) and the third group consisted of subjects with normal BP (mean age 48 +/- 12 years; BP < 120/80 mmHg). The aim was to characterize the autonomic state in each group. 3. Blood pressure, heart rate (HR), indices of short-term HRV during supine rest and quiet standing, HR variation during timed deep breathing (HRVdb) and pressor responses to the cold pressor test and sustained isometric handgrip were compared between the groups. 4. Although the three groups were comparable (P > 0.1) in terms of mean HR and low-frequency (LF) power expressed in normalized units at rest and during quiet standing, the standard deviation of normal-to-normal RR intervals (SDNN) during supine rest, LF and high-frequency spectral powers during supine rest and HRVdb were lowest in hypertensives (P 相似文献   

Genetic polymorphisms of the urea transporter gene are associated with antihypertensive response to nifedipine GITS

Nifedipine GITS has diuretic and natriuretic properties, which may enhance its antihypertensive efficacy. We assessed contributions of polymorphisms in the urea transporter-A gene (SLC14A2) to interindividual variations in blood pressure (BP) response to nifedipine treatment. 405 subjects from a single Chinese county received a single oral dose of 30 mg nifedipine GITS (gastrointestinal therapeutic system) daily for 16 days. We genotyped two SNPs in SLC14A2 and found significant associations for the Val227Ile (rs1123617) and Ala357Thr (rs3745009) polymorphisms with BP response to nifedipine treatment. After treatment, subjects with either Ala357/Thr357 or Thr357/Thr357 genotypes had significantly smaller mean changes in systolic BP (SBP) (beta +/- SE = -2.87 +/- 1.24 mmHg, p = 0.020) and diastolic BP (DBP) (beta +/- SE = -1.69 +/- 0.62 mmHg, p = 0.006) compared to those with the Ala357/Ala357 genotype. Subjects with either Val227/Ile227 or Ile227/Ile227 genotypes had significantly larger mean changes in SBP (beta +/- SE = 3.13 +/- 1.19, p = 0.009) and DBP (beta +/- SE = 1.50 +/- 0.60 mmHg, p = 0.013) compared with those with the Val227/Val227 genotype after treatment. Subjects carrying both the Ala357/Ala357 genotype in the Ala357Thr polymorphism and either Val227/Ile227 or Ile227/Ile227 genotypes in the Val227Ile polymorphism had the highest mean change in SBP and DBP. Our study supports the conclusion that polymorphisms in the SLC14A2 gene can predict the antihypertensive efficacy of nifedipine GITS.     

Altered baroreflex control of heart rate in bradykinin B2-receptor knockout mice

Recently, we have shown that a knockout mouse strain lacking the bradykinin B2-receptor gene exhibits an accelerated heart rate (HR) under basal conditions, this alteration being associated with mildly elevated blood pressure (BP) levels and ultimately with the development of cardiomyopathy. The goal of the present study was to determine whether genetic disruption of the B2-receptor alters autonomic cardiovascular reflexes to acute or chronic changes in BP. The direct mean BP and HR levels of unrestrained B2 knockout mice (B2-/-) were higher than those of wild type (B2+/+) controls (131 +/- 2 vs. 105 +/- 2 mm Hg and 480 +/- 5 vs. 414 +/- 8 beats/min, P < 0.01 for both comparisons). The difference in HR observed between groups under basal conditions was nullified by the acute administration of propranolol and atropine as well as by hexamethonium; it was attenuated by long-term blockade of angiotensin AT1 receptors. In B2-/- mice, the presence of an alteration in baroreceptor regulation of HR was supported by a reduced gain in the HR responses to acute nitroprusside-induced hypotension or phenylephrine-induced hypertension (slope of the regression line: 0.82 +/- 0.07 vs. 5.58 +/- 0.08 beats/min per mmHg in B2+/+, P < 0.01), as well as by an exaggerated tachycardic response to chronic hypertension induced by clipping of the left renal artery (60 +/- 3 vs. 15 +/- 3 beats/min in B2+/+, P < 0.01). Our findings indicate that disruption of the bradykinin B2-receptor gene is associated with an impaired baroreflex control of HR. The combination of chronically elevated resting HR and impaired baroreflex control could contribute to the development of cardiomyopathy in these animals.     

Spironolactone reduces brachial pulse wave velocity and PIIINP levels in hypertensive diabetic patients

AIMS: To assess whether spironolactone has beneficial effects on blood pressure (BP), N-terminal propeptide of type III procollagen (PIIINP) and pulse wave velocity (PWV) in hypertensive, type II diabetics. METHODS: Ten patients with type II diabetes and hypertension were enrolled in a randomized, double-blind crossover study comparing 4 months' treatment with spironolactone and placebo with a 4-week washout phase. BP, PIIINP and carotid-radial PWV were measured at the end of each treatment phase. RESULTS: Compared with placebo, spironolactone reduced systolic BP by 15.6 +/- 46.1 mmHg (P = 0.005, 95% CI 2.7-28.5 mmHg), PIIINP by 0.6 +/- 0.3 microg l(-1) (P = 0.04, 95% CI 0.02-1.1 microg l(-1)) and PWV by 0.6 +/- 0.2 m s(-1) (P = 0.008, 95% CI 0.18-1.02 m s(-1)). CONCLUSIONS: Spironolactone is effective at reducing systolic BP and brachial artery stiffness as indicated by PWV. It also reduces PIIINP in type II diabetic patients with hypertension.     

The bradykinin B1 receptor and the central regulation of blood pressure in spontaneously hypertensive rats.

1. We evaluated if the brain bradykinin (BK) B1 receptor is involved in the regulation of blood pressure (BP) in conscious rats. 2. Basal mean BP and HR were 115 +/- 2 and 165 +/- 3 mmHg and 345 +/- 10 and 410 +/- 14 beats min in Wistar Kyoto (WKY) and spontaneously hypertensive rats (SHR), respectively. Intracerebroventricular (i.c.v.) injection of 1 nmol B1 receptor agonist Lys-desArg9-BK significantly increased the BP of WKY and SHR by 7+/-1 and 19+/-2 mmHg, respectively. One nmol Sar[D-Phe8]-desArg9-BK, a kininase-resistant B1 agonist, increased the BP of WKY and SHR by 19+/-2 and 17+/-2 mmHg, respectively and reduced HR in both strains. 3. I.c.v. injection of 0.01 nmol B1 antagonists, LysLeu8-desArg9-BK or AcLys[D-betaNal7,Ile8]-desArg9-BK (R715), significantly decreased mean BP in SHR (by 9+/-2 mmHg the former and 14+/-3 mmHg the latter compound), but not in WKY. In SHR, the BP response to R715 was associated to tachycardia. 4. I.c.v. Captopril, a kininase inhibitor, increased the BP of SHR, this response being partially prevented by i.c.v. R715 and reversed into a vasodepressor effect by R715 in combination with the B2 antagonist Icatibant. 5. I.c.v. antisense oligodeoxynucleotides (ODNs) targeted to the B1 receptor mRNA decreased BP in SHR, but not in WKY. HR was not altered in either strain. Distribution of fluorescein-conjugated ODNs was detected in brain areas surrounding cerebral ventricles. 6. Our results indicate that the brain B1 receptor participates in the regulation of BP. Activation of the B1 receptor by kinin metabolites could participate in the pathogenesis of hypertension in SHR.     

Plasma endothelin-1 in hemodialysis treatment - the influence of hypertension

In patients on chronic hemodialysis hypotensive episodes are frequently encountered during the course of treatment and the prevalence of atherosclerosis is increased. Endothelin-1 (ET-1), an endothelium-derived peptide with vasoconstrictive and mitogenic effects on smooth muscles, is involved in vascular tone regulation and in the pathogenesis of atherosclerosis. The aim of the present study was to investigate plasma ET-1 during hemodialysis treatment and to explore the probable influence of pre-existing hypertension. Forty-seven hemodialysis patients (21 females, mean age 62 +/- 12 years) were evaluated and hypertensive patients (n = 33) were compared to normotensive patients (n = 14). Relative blood volume changes (hemoglobinometry) and blood pressure were measured. Samples were taken before, every hour during and after hemodialysis. Plasma ET-1 was measured by enzyme-linked immunosorbent assay and results were corrected according to hemoconcentration. Hemodialysis with an ultrafiltration rate of 2224 +/- 933 mL was performed. Total blood volume at the end of hemodialysis was 89.4 +/- 8.2% of the pretreatment volume. The fall in blood pressure (137/74 +/- 22/11 mmHg vs 127/73 +/- 30/14 mmHg) correlated with the decrease in blood volume (mean blood pressure: r = 0.33). Plasma ET-1 increased from 1.29 +/- 0.47 pg/mL before to 1.46 +/- 0.56 pg/mL (reference range 0.3-0.9) at the end of hemodialysis (P < 0.05). This rise was more pronounced in patients with hypertension than in normotensive individuals (P < 0.05). The change in blood volume (r = 0.41) and blood pressure (mean blood pressure: r = 0.34) correlated with plasma ET-1 at the end of hemodialysis (P < 0.05). Plasma ET-1 was enhanced in hemodialysis patients compared to normal subjects. During the hemodialysis session an increase in ET-1 was encountered, which was more pronounced in hypertensive than in normotensive patients and paralleled the hemodynamic changes. Apart from pre-existing hypertension, further factors potentially influencing ET-1 include local endothelial injury (arteriovenous fistula) and generalized bioincompatibility reactions (e.g. foreign surface contact) occurring during hemodialysis.     

The haemodynamic effect of the 5HT1 agonist BMS-180048: a class effect of triptans?

AIMS: To investigate the effects of an intravenous infusion of BMS-180048, a novel 5HT1-like agonist, on the systemic, pulmonary and coronary circulations in patients undergoing diagnostic cardiac catheterisation. METHODS: Ten patients (mean age 55 years (range 41-65)) were studied during diagnostic cardiac catheterisation. The haemodynamic response to an intravenous (i.v.) infusion for 30 min of BMS-180048 (0.56 mg kg(-1) h(-1) for 10 min and 0.39 mg kg(-1) h(-1) for 20 min) was assessed via a 7F Swan Ganz catheter and thermodilution cardiac output system. Quantitative coronary angiography was performed at 10 min intervals. RESULTS: BMS-180048 caused a significant increase in systemic arterial systolic blood pressure (rise of 32.5 mmHg, 95% CI 24,44.5) P=0.009), pulmonary artery systolic (12.2 mmHg, 95% CI 6.8,18.5; P=0.009) and diastolic pressures (8.5 mmHg, 95% CI 5.0,13.8; P=0.009), right atrial pressure (4 mmHg, 95% CI 1.5,5.2; P=0.013) and pulmonary capillary wedge pressure (9.5 mmHg 95% CI 5.2,14.0; P=0.09). There was no significant change in cardiac output (0.1 l min(-1), 95% CI -0.17,0.57, P>0.05). Mean coronary artery diameter in the proximal coronary segments decreased by 0.73 mm (95% CI -1.22,-0.15; P=0.03) at 35 min. The corresponding reduction in middle segments was 0.26 mm (95% CI -0.395,-0.08; P=0.02). There was a non-significant trend to constriction in the most distal segments of 0.28 mm (95% CI -0.68,0.015); P=0.06). One patient experienced chest pain with ECG changes suggestive of ischaemia. CONCLUSIONS: BMS-180048 displayed a cardiovascular profile similar to that previously reported for sumatriptan. These changes appear to reflect a class effect of these agents.     

Effect of head-up tilt on cardiovascular responses in normal young volunteers

Since the cardiovascular effects of tilting are influenced by degree as well as duration of the tilt, we planned to study the time course of blood pressure and heart rate (HR) responses during 30 degrees, 60 degrees, 80 degrees head up tilt (HUT). The study was conducted on 20 volunteers aged 18-20 y who were tilted on a tilting table. Blood pressure was determined by sphygmomanometer and HR was calculated from R-R interval of ECG. 30 degrees HUT produced an insignificant decrease in systolic pressure (SP) and pulse pressure (PP) while diastolic pressure (DP), mean pressure (MP) and rate-pressure-product (RPP) registered an insignificant rise. The changes produced by 60 degrees and 80 degrees HUT were more marked than those produced by 30 degrees HUT. While SP and PP decreased significantly, HR and RPP increased significantly. In conclusion, 30 degrees HUT produces insignificant changes while 60 degrees and 80 degrees HUT produce significant changes in SP, PP and RPP.