J.D. Swales

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.

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.

DIETARY SALT AND HYPERTENSION

It has been argued that hypertension in developed countries is largely or wholly the result of excessive salt intake. As a result there are substantial pressures to reduce salt ingestion. Although it is likely that extreme salt restriction will lower blood-pressure, this is not a practical possibility. Evidence in favour of a more modest limitation of salt intake is conflicting and the possible harmful effects of salt restriction have not been assessed. Until more conclusive evidence is obtained it would be premature to advocate such massive public-health measures as reducing the sodium content of food.

Assessment of baroreceptor-cardiac reflex sensitivity using time domain analysis in patients with IDDM and the relation to left ventricular mass index

Summary Autonomic dysfunction in insulin-dependent diabetic (IDDM) patients has been associated with abnormalities of left ventricular function and an increased risk of sudden death. A group of 30 patients with IDDM and 30 age, sex and blood pressure matched control subjects underwent traditional tests of autonomic function. In addition, baroreceptor-cardiac reflex sensitivity (BRS) was assessed using time domain (sequence) analysis of systolic blood pressure and pulse interval data recorded non-invasively using the Finapres beat-to-beat blood pressure recording system. ’Up BRS sequences–increases in systolic blood pressure associated with lengthening of R-R interval, and ’down BRS sequences–decreases in systolic blood pressure associated with shortening of R-R interval were identified and BRS calculated from the regression of systolic blood pressure on R-R interval for all sequences. We also assessed heart rate variability using power spectral analysis and, after expressing components of the spectrum in normalised units, assessed sympathovagal balance from the ratio of low to high frequency powers. IDDM subjects underwent 2-D echocardiography to assess left ventricular mass index. Standard tests of autonomic function revealed no differences between IDDM patients and control subjects, but dramatic reductions in baroreceptor-cardiac reflex sensitivity were detected in IDDM patients. ’Up BRS when supine was 11.2 ± 1.5 ms/mmHg (mean ± SEM) compared with 20.4 ± 1.95 in control subjects (p < 0.003) and when standing was 4.1 ± 1.9 vs 7.6 ± 2.7 ms/mmHg (p < 0.001). Down BRS when supine was 11.5 ± 1.2 vs 22 ± 2.6 (p < 0.001) and standing was 4.4 ± 1.9 vs 7.3 ± 2.5 ms/mmHg (p < 0.003). There were significant relations between impairment of the baroreflex and duration of diabetes (p < 0.001) and poor glycaemic control (p < 0.001). From a fast Fourier transformation of supine heart rate data and using a band width of 0.05–0.15 Hz as low-frequency and 0.2–0.35 Hz as high frequency total spectral power of R-R interval variability was significantly reduced in the IDDM group for both low-frequency (473 ± 62.8 vs 746.6 ± 77.6 ms2p = 0.002) and high frequency bands 125.2 ± 12.9 vs 459.3 ± 89.8 ms2p < 0.0001. When the absolute powers were expressed in normalised units the ratio of low frequency to high frequency power (a measure of sympathovagal balance) was significantly increased in the IDDM group (2.9 ± 0.53 vs 4.6 ± 0.55, p < 0.002 supine: 3.8 ± 0.49 vs 6.6 ± 0.55, p < 0.001 standing). Thus, time domain analysis of baroreceptor-cardiac reflex sensitivity detects autonomic dysfunction more frequently in IDDM patients than conventional tests. Impaired BRS is associated with an increased left ventricular mass index and this abnormality may have a role in the increased incidence of sudden death seen in young IDDM patients. [Diabetologia (1996) 39: 1385–1391]

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.

Surgical reversal of two-kidney one clip hypertension during inhibition of the renin-angiotensin system.

Conscious rats with two-kidney one clip Goldblatt hypertension had the constricting clip removed during continuous infusion of either dextrose, saralasin, or captopril. Other dextrose-infused animals underwent removal of the ischemic kidney or a sham procedure. Direct arterial blood pressure (BP) was recorded throughout the 15-hour preoperative and subsequent 24-hour postoperative period. Rats were studied in the early phase (1-3 weeks duration) or chronic phase (greater than 4 months) of hypertension. Animals subjected to a sham procedure returned to preoperative BP values. The BP of animals unclipped or nephrectomized did not return to previous hypertensive levels. Instead, a biphasic response was seen where BP partially recovered from an operative fall and then slowly declined to normal at 24 hours; this effect occurred in both stages of hypertension. At 24 hours, removal of the ischemic kidney was as effective as removal of the constricting clip in the correction of both early and chronic phase hypertension. Rats infused with saralasin or captopril demonstrated an acute (within 2 hours) and sustained fall in BP, but not to normotensive levels. This fall was significant in all animals (p less than 0.01) apart from chronic phase rats infused with saralasin where no significant fall was seen. Although animals infused with saralasin or captopril commenced at a lower preoperative BP, the biphasic pattern of response to unclipping was identical to that of dextrose-infused unclipped rats. Thus, sustained inhibition of the renin-angiotensin system did not modify the correction of hypertension produced by removal of the constricting clip, and the response to surgical correction did not appear to be entirely mediated by changes in the activity of the renin-angiotensin system, particularly in the chronic stage. Equally, the rapidity of correction is not consistent with a role of vascular hypertrophy.

The troublesome search for evidence: three cultures in need of integration.

The history of medical science teaches us that two features are crucial to advanceÐnamely, independence from sponsors and integration of divergent disciplines. I have described elsewhere how, in my three years as Director of Research and Development for the National Health Service (NHS), the Services `dedicated R & D budget became a ®ction: when healthcare ministers had to choose between research and care, research suffered disproportionately 1. As for integration, I was continually troubled by the tension between basic and applied science. Directly or indirectly, the NHS supports not only research programmes that are very applied in nature, addressing the immediate needs of healthcare 2 , but also clinical and biomedical research that needs to be done in the NHS rather than university or commercial laboratories. I quickly learnt the importance of being sure of my audience before describing these programmes. From a laboratory-schooled audience, applied work at best elicited grudging recognition. Was it alìtrials or development stuff?, I was asked in scathing tones. This was not what they understood by real science, red in tooth and claw, exploring the mechanisms of disease. Health ministers and policy-makers took the opposite view: members of the science lobby, they declared, had no right to dictate their own agenda, unrelated to the needs of the NHS; governmental priorities were how to reducètrolley waits in emergency departments or waiting listsÐmatters far removed from molecular genetics. Moreover, a third culture lay in the backgroundÐthat ofèvidence-based medicine. At times, integration seemed a lost cause. The uneasy relationship between laboratory science and clinical medicine goes back a long way. In the nineteenth century, these things were better managed in mainland Europe. Claude Bernard summarized the approach that gave the French and German schools their revolutionary successes 3. Arguing that physiological processes were just as causally determined as any other natural process, he gave the biological sciences the concept of`determinism which has been the implicit assumption behind their stratospheric growth in modern times. The control of disease depended upon an understanding of physiological and chemical mechanisms, since, as Comte had observed, the same natural laws apply to both. This assertion seems almost a cliche  to readers accustomed to the writings of modern reductionist biologists. What had greatest impact was the conclusion Bernard drew from this approachÐthat there was little place in medical progress for clinical observations on individuals or populations. Observation devoid of experimentation was equivalent to …

Changes in leucocyte sodium transport in normotensive relatives of hypertensive subjects. Dissociation from blood pressure.

It has been postulated that depressed membrane sodium transport is a necessary step in blood pressure elevation in essential hypertension. Accordingly, leucocyte sodium efflux-rate constants were estimated in 14 normotensive subjects who had one or more first-degree relatives with essential hypertension, and also in 14 matched control subjects with no such family history, before and after taking bendrofluazide for 7 days. Efflux rates in the controls did not change after the diuretic. However, in the relatives, mean total sodium efflux-rate constant was at first significantly depressed but later rose to normal with the diuretic. This was due almost entirely to an increase in glycoside-sensitive sodium pump activity. Blood pressure remained unchanged in both groups. Thus, assuming that perturbations in leucocytes reflect similar abnormalities in other cell lines, major changes in sodium transport in the normotensive individual without accompanying changes in blood pressure suggest that, while these changes may be a marker for later hypertension, they do not participate directly in blood pressure control.

Leukocyte ionized calcium and sodium content and blood pressure in humans.

The relationship between leukocyte ionized calcium concentration, sodium content, and blood pressure was studied in normotensive subjects with (n = 17) and without (n = 21) a family history of hypertension and in untreated patients with essential hypertension (n = 22). There was a highly significant correlation between intracellular ionized calcium and mean supine blood pressure (measured on the same occasion) in normal subjects with no family history of hypertension (r = +0.73, p less than 0.01). This relationship was lost in normal subjects with a family history of hypertension, and in hypertensive patients there was a nonsignificant negative correlation between intracellular ionized calcium and blood pressure (r = +0.08 and -0.31, respectively). Intracellular ionized calcium was similar in the normotensive groups (both, 126 +/- 7 nmol/L) and slightly but nonsignificantly elevated in hypertensive patients (143 +/- 10 nmol/L; p = 0.09). There was no correlation between intracellular ionized calcium and sodium content in any group (r less than 0.1). These results indicate that while leukocyte ionized calcium in normotensive subjects with no family history of hypertension may reflect smooth muscle contractility resulting in the positive correlation between leukocyte ionized calcium and blood pressure, this relationship is lost in hypertensive patients and subjects predisposed to hypertension. This may be due to an altered relationship between leukocyte and smooth muscle calcium handling in these subjects or to non-calcium-mediated influences on blood pressure.