Herbert Thurston

Pulse Pressure and Resistance Artery Structure in the Elderly

There has been recent interest in the possibility that resistance vessel structural adaptation in hypertension may be more closely related to pulse pressure than to other blood pressure parameters. We investigated the relation between blood pressure and resistance vessel structure in a group of subjects from an age group (older than 60 years) in which a widening of pulse pressure is a typical finding and characterized blood pressure parameters using 24-hour ambulatory blood pressure monitoring. We studied resistance vessels retrieved from biopsies of skin and subcutaneous fat taken from the gluteal region of 32 subjects under local anesthesia (age, 70 +/- 1 years [mean +/- SEM], 21 of whom were hypertensive and 11 normotensive. Media-lumen ratio was higher in the hypertensive than the normotensive subjects (18.6 +/- 1.6% versus 12.8 +/- 1.2%, P < .01) and correlated with age (r = .44, P < .05), clinic systolic pressure (r = .35, P < .05), 24-hour systolic pressure (r = .40, P < .05), and 24-hour pulse pressure (r = .56, P < .001). Stepwise multivariate regression analysis identified clinic and 24-hour pulse pressure as the only significant predictors of media-lumen ratio independent of age, other parameters of clinic blood pressure, and blood pressure variability (R2 = 41%, P < .05). These findings confirm those from animal models of hypertension in demonstrating the importance of pulse pressure in relation to cardiovascular structural adaptation and have important implications for the goals of treatment of hypertension in the elderly.

Arterial wall uptake of renal renin and blood pressure control.

We have studied the contribution of circulating renin of renal origin to renin-like activity within the arterial wall and to blood pressure. Bolus injections of renin sufficient to elevate blood pressure by 44.7 mm Hg caused aortic renin to rise from 0.13 to 1.48 ng angiotensin I/100 mg/hr in nephrectomized rats. Elevation of aortic renin was still present at 6 hours, and this was associated with significant blood pressure elevation (p less than 0.05) which could be reversed by infusion of sarcosine, alanine, angiotensin II (saralasin). Prevention of the pressor effect by pretreatment with the converting enzyme inhibitor captopril did not reduce renin uptake. When kidneys were left in situ, although significant uptake of renin could be demonstrated 1 hour after injection, the increase at 3 hours was no longer significant (p greater than 0.05) and blood pressure returned to normal by 1 1/2 hours. This change in blood pressure may be related to the much more rapid clearance of circulating renin in the presence of normal kidneys or to other renal factors influencing the blood pressure response. The present studies demonstrate therefore that most of the renin-like activity within the aortic wall is derived from plasma renin and it seems probable that this component of the renin-angiotensin system plays an important role in blood pressure maintenance in the nephrectomized rats injected with renin. The relationship is less obvious in the presence of normal kidneys where additional influences may come into play.

Impaired endothelium-dependent relaxation in isolated resistance arteries of spontaneously diabetic rats

1 Previous studies have shown that endothelium‐dependent relaxation in the aorta of spontaneously diabetic bio bred rats (BB) is impaired. 2 We have investigated noradrenaline (NA) contractility, endothelium‐dependent acetylcholine (ACh) and bradykinin (BK) relaxation, and endothelium‐independent sodium nitroprusside (SNP) relaxation in mesenteric resistance arteries of recent onset BB rats and established insulin treated BB rats, compared to their age‐matched non diabetic controls. 3 There was no significant difference in the maximum contractile response or sensitivity to noradrenaline in either of the diabetic groups compared to their age‐matched controls. 4 Incubation with the nitric oxide synthetase inhibitor NG‐nitro‐L‐arginine (L‐NOARG) resulted in a significant increase in maximum contractile response to noradrenaline in the recent onset age‐matched control group (P<0.05). Analysis of the whole dose‐response curve (using ANOVA for repeated measures with paired t test) showed a significant left‐ward shift following the addition of l‐NOARG (P<0.001). A similar but less marked shift (P<0.01) was evident in vessels from recent onset diabetics. An overall shift in both sensitivity and maximum response was also evident in the age‐matched non diabetic controls of the insulin‐treated group (P<0.05). However, by contrast, there was no significant change in sensitivity in the insulin‐treated diabetic rats. 5 ACh‐induced endothelium‐dependent relaxation was significantly impaired in the recent onset diabetic rats compared to their age‐matched controls (47 ± 11% versus 92 ± 2%, P<0.05, n = 6), and in the insulin treated diabetic rats (34 ± 5% versus 75 ± 6%, P<0.05, n = 6). The relaxation responses to BK also were significantly impaired in the diabetic rats compared to their age‐matched controls (recent onset: 20 ± 3% versus 72 ± 7%, P<0.05, n = 6; insulin treated: 12 ± 9% versus 68 ± 7%, P<0.05, n = 7). 6 Incubation with either the nitric oxide synthetase substrate, L‐arginine, or the free radical scavenging enzyme superoxide dismutase (150 μml−1) failed to improve the attenuated response of acetylcholine‐induced relaxation in the diabetic vessels. 7 Endothelium‐dependent relaxation mediated by ACh and BK was significantly attenuated in both the diabetic and control vessels after incubation with L‐NOARG. 8 Pretreatment with a cyclo‐oxygenase inhibitor, indomethacin, significantly enhanced the relaxation to ACh in both the recent onset and insulin treated diabetic rats (42 ± 10%, n = 7 versus 64 ± 7%, n = 7, P<0.05, and 40 ± 5%, n = 7 versus 65 ± 9%, n = 6, P<0.05). 9 Following endothelium removal, there was a marked impairment in endothelium‐dependent relaxation responses to ACh and BK in both the diabetic and control vessels. 10 Incubation with the thromboxane A2 receptor antagonist SQ29548, did not significantly improve the ACh endothelium‐dependent relaxation response in the diabetic vessels. 11 Endothelium‐independent relaxation to sodium nitroprusside was significantly impaired in the first group of diabetic vessels studied; however, subsequent studies showed no impairment of the sodium nitroprusside response in the diabetic vessels. 12 In conclusion, the ability of the endothelium to regulate vascular contractility is reduced in recent onset diabetic vessels, and significantly impaired in established insulin treated diabetics. Relaxation to the endothelium‐dependent vasodilators ACh and BK was impaired in both the recent onset and the established insulin treated diabetics, and the ACh response was significantly improved following pretreatment with indomethacin, suggesting a role for a cyclo‐oxygenase‐derived vasoconstrictor. Preliminary studies with a thromboxane A2 receptor antagonist, SQ29548 did not significantly improve the impaired relaxation to ACh, indicating that the vasoconstrictor prostanoid is not thromboxane A2.

Impact of Statin Therapy on Central Aortic Pressures and Hemodynamics: Principal Results of the Conduit Artery Function Evaluation-Lipid-Lowering Arm (CAFE-LLA) Study

Background— Statins reduce the risk of cardiovascular events in people with hypertension. This benefit could arise from a beneficial effect of statins on central aortic pressures and hemodynamics. The Conduit Artery Function Evaluation–Lipid-Lowering Arm (CAFE-LLA) study, an Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT) substudy, investigated this hypothesis in a prospective placebo-controlled study of treated patients with hypertension. Methods and Results— CAFE-LLA recruited 891 patients randomized to atorvastatin 10 mg/d or placebo from 5 centers in the United Kingdom and Ireland. Radial artery applanation tonometry and pulse-wave analysis were used to derive central aortic pressures and hemodynamic indices at repeated visits over 3.5 years of follow-up. Atorvastatin lowered low-density lipoprotein cholesterol by 32.4 mg/dL (95% confidence interval [CI], 28.6 to 36.3) and total cholesterol by 35.1 mg/dL (95% confidence interval, 30.9 to 39.4) relative to placebo. Time-averaged brachial blood pressure was similar in CAFE-LLA patients randomized to atorvastatin or placebo (change in brachial systolic blood pressure, −0.1 mm Hg [95% CI, −1.8 to 1.6], P=0.9; change in brachial pulse pressure, −0.02 mm Hg [95% CI, −1.6 to 1.6], P=0.9). Atorvastatin did not influence central aortic pressures (change in aortic systolic blood pressure, −0.5 mm Hg [95% CI, −2.3 to 1.2], P=0.5; change in aortic pulse pressure, −0.4 mm Hg [95% CI, −1.9 to 1.0], P=0.6) and had no influence on augmentation index (change in augmentation index, −0.4%; 95% CI, −1.7 to 0.8; P=0.5) or heart rate (change in heart rate, 0.25 bpm; 95% CI, −1.3 to 1.8; P=0.7) compared with placebo. The effect of statin or placebo therapy was not modified by the blood pressure–lowering treatment strategy in the factorial design. Conclusions— Statin therapy sufficient to significantly reduce cardiovascular events in treated hypertensive patients in ASCOT did not influence central aortic blood pressure or hemodynamics in a large representative cohort of ASCOT patients in CAFE-LLA.

Vascular renin-like activity and blood pressure maintenance in the rat. Studies of the effect of changes in sodium balance, hypertension and nephrectomy.

SUMMARY Aortic renin-like activity and plasma renin concentration were measured in rats subjected to dietary salt loading or depletion. Homogenates prepared from rat aortic tissue generated angtotensin I from plasma substrate at both pH S3 and pH 6.5. Aortic renin-like activity measured at incubation pH 6.5 and plasma renin concentration changed in parallel, rising with salt restriction and falling with salt loading. However, the capacity of aortic bomogenate to generate angiotensin I at an incubation pH of 53 did not snow any signiflcant change with alteration of sodium balance. In addition, administration of the converting enzyme inhibitor (CEI) SQ20,881 produced a greater fall of blood pressure in salt-depleted than salt-loaded animals.

Endothelium-dependent relaxation in resistance vessels from the spontaneously hypertensive rats.

The endothelium-dependent vasodilator acetylcholine was used to observe relaxation responses of noradrenaline-contracted mesenteric resistance vessels from 3-, 6-, 12- and 18-week-old spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Relaxation responses were greater than normal in the 3-week-old SHR but the pattern of response was different in the 6-18-week-old SHR compared with the WKY. In these older animals, low concentrations of acetylcholine relaxed SHR and WKY vessels to a similar extent, but high concentrations (greater than 10(-7) mol/l) caused the partially relaxed vessels to contract again. Indomethacin enhanced relaxation in the 12-week-old SHR and reduced the difference between the SHR and WKY. The reduction in acetylcholine-induced, endothelium-dependent relaxation in SHR suggested that a functional change occurred, causing the vessels to release a vasoconstrictor factor that opposes the action of endothelium-derived relaxing factor.

Evidence against potassium as an endothelium‐derived hyperpolarizing factor in rat mesenteric small arteries

Endothelium‐derived hyperpolarizing factor (EDHF) has recently been identified as potassium released from endothelial cells into the myo‐endothelial space. The present study was designed to test this hypothesis. In rat small mesenteric arteries, mounted in a wire myograph, relaxation to acetylcholine or potassium was not significantly changed following incubation with oxadiazolo‐quinoxalin‐1‐one (ODQ, 4 μM) and indomethacin (10 μM, n=9). Maximal relaxations to acetylcholine occurred in all arteries, were maintained and were significantly greater (P<0.01, n=9) than the transient relaxations to potassium, which only occurred in 30–40% of vessels. Removal of the vascular endothelium abolished relaxant responses both to potassium and acetylcholine (P<0.005, n=9). Compared with responses in 5.5 mM potassium PSS, relaxation responses to added potassium in arteries maintained in 1.5 mM potassium PSS were more marked and were not dependent on the presence of an intact endothelium (n=8). Incubation with BaCl2 (50 μM) significantly inhibited the maximal relaxant response to potassium in the presence of an intact endothelium in 5.5 mM potassium PSS (P<0.05, n=4), but had no effect on relaxation of de‐endothelialized preparations in 1.5 mM potassium PSS (n=5). Treatment with ouabain (0.1 mM) abolished the relaxant response to potassium in 1.5 mM potassium PSS (P<0.001, n=9), but only partly inhibited the maximal relaxant response to acetylcholine in 5.5 mM potassium PSS (P<0.01, n=5). These data show that at physiological concentrations of potassium an intact endothelium is necessary for potassium‐induced relaxation in rat mesenteric arteries. Furthermore, the response to potassium is clearly different to that from acetylcholine, indicating that potassium does not mimic EDHF released by acetylcholine in these arteries.

Endothelium-dependent relaxation in resistance arteries from spontaneously hypertensive rats: effect of long-term treatment with perindopril, quinapril, hydralazine or amlodipine

Objective To examine the effects of different types of anti hypertensive treatment on endothelium-dependent relaxation in resistance arteries from spontaneously hypertensive rats (SHRs). Design and methods Three-week-old SHRs were treated with the angiotensin converting enzyme (ACE) inhibitor perindopril (1 mg/kg/day) or quinapril (3 mg/kg/day) or the vasodilator hydralazine (50 mg/kg/day) or the calcium antagonist amlodipine (10mg/kg/day). Control SHRs and Wistar-Kyoto (WKY) rats were treated with water. After 21 weeks rats were culled and mesenteric resistance arteries were mounted in a myograph. Relaxation responses to the endothelium-dependent vasodilators acetylcholine (ACh) and bradykinin were recorded before and after incubation with the nitric oxide synthase inhibitor A/G-nitro-L-arginine (L-NOARG), as was the relaxation response to the nitric oxide donor sodium nitroprusside (SNP). Results All drugs prevented the rise in blood pressure found in the untreated SHRs. ACh-induced relaxation was significantly impaired in the untreated SHRs compared with the WKY rats. Treatment with either ACE inhibitor prevented the development of this impaired response. ACE inhibitor treatment significantly increased the relaxation response to bradykinin. Despite lowering blood pressure, hydralazine or amlodipine had no effect on ACh- or bradykinin-induced relaxation. Responses to SNP were not different between untreated SHRs and WKY rats and were not affected by drug treatment. Conclusion Specific properties of certain antihypertensive drugs may play an important role in restoring endothelium-dependent relaxation in the small arteries that regulate peripheral resistance in the SHR.

Reversal of two-kidney one clip renovascular hypertension in the rat.

SUMMARY Attempted correction of two-kidney, one clip Goldblatt hypertension in the rat was carried out by three techniques: removal of the constricting dip, removal of the Iscberaic kidney, and converting enzyme blockade by oral captopril. Since duration of hypertension is said to be a critical factor, groups of rats were studied after short term (< 6 weeks from clipping) and chronic (> 4 months) hypertension. Blood pressure, sodium balance, and plasma renin concentration (PRC) were followed before and after these correcting procedures. In a control group of animals, removal of a loose renal artery clip did not Influence blood pressure and only caused trivial postoperative retention of sodium. Undipptng, however, normalized blood pressure in both short-term and chronic hypertension. After a major postoperative fall, blood pressure returned to somewhat elevated levels after nephrectomy in animals with chronic (but not short-term) hypertension. Sodium balance became markedly positive with the fall in blood pressure of operated hypertensive anlmpu and was significantly correlated with the fall in blood pressure in these four groups at 7 days (r = 0.43). Captopril also produced a fall in blood pressure at 24 hours, with a positive sodium balance, although the relationship between blood pressure fall and sodium balance did not reach statistical significance (r = 0 JO). The PRC was elevated in all hypertensive groups, although individual values overlapped with values from normal rats and nonhypertensive rats with a loose renal artery dip. The PRC fell to normal or subnormal values after either operative procedure and stabilized for at least 2 months Independently of whether blood pressure fell or not. It is concluded that neither sodium retention nor renin hypersecretion maintains blood pressure In this model. Also, the rapidity of the blood pressure fall is not consistent with a role for vascular hypertrophy. Tbe greater efficacy of unclipping suggests that the revascularized kidney after this procedure exerts a vasodepressor function independent of sodium excretion or the renin-angiotensin system.

Contraction and relaxation of human internal mammary artery after intraluminal administration of papaverine

The internal mammary artery has become the conduit of choice for coronary artery bypass grafting. Intraluminal papaverine treatment during operation reduces vasospasm and facilitates anastomosis. However, it has been suggested that papaverine may cause intimal damage, and accordingly we have investigated endothelial damage by comparing the responsiveness of internal mammary arteries before and after intraluminal exposure to papaverine (15 mg/mL). Control and papaverine-treated segments of internal mammary artery were obtained from 13 patients undergoing coronary artery bypass grafting and mounted as ring preparations in an organ bath. Cumulative dose contractions to noradrenaline were performed, and the dose producing a half maximal response was determined. Relaxation studies of submaximally contracted arteries were performed using the endothelium-dependent vasodilators acetylcholine and bradykinin and the endothelium-independent vasodilator sodium nitroprusside. In the human internal mammary artery the use of intraluminal papaverine increased the lumen size by 20% (p less than 0.05), and the contractions elicited by noradrenaline were significantly less in the papaverine group than in the control group (p less than 0.05). Endothelium-dependent relaxation to acetylcholine or bradykinin was not affected by papaverine treatment. Endothelium-independent relaxation was the same in both groups, with almost 100% relaxation achieved by sodium nitroprusside. These results indicate that intraluminal papaverine treatment during coronary artery bypass grafting causes a reduction of smooth muscle contraction and does not impair endothelium-dependent relaxation.