Kent L. Christensen

Location of Resistance Arteries

Thickening and narrowing of resistance arteries must, by definition, be key elements in the control of the cardiovascular system. However, the precise location of resistance arteries is difficult to establish. This is due to technical problems related to the small size of the vessels, to the measurement conditions disturbing the hemodynamics, and to the status of the animals while the measurements are being made. Furthermore, due to large data heterogeneity, previous studies do not give unequivocal information concerning the pressure profile in the vascular system, or the level of arterial diameter responsible for blood flow. Finally, and importantly, there is little evidence regarding the conscious state, which is thus a major limitation to understanding the mechanisms of blood distribution and the pathogenesis for disease processes such as genetic hypertension. This review first summarizes briefly the techniques which are available for identifying resistance arteries and the inherent technical limitations which are involved. The review then provides a critical assessment of the available data, both as regards measurement of local blood pressures and as regards control of peripheral resistance. The evidence suggests that, at least as regards rats and other small animals, feed arteries as well as more distal microvessels contribute to the maintenance and regulation of blood flow and resistance. Evidence from larger animals is however lacking, and it is thus unclear if resistance function should be based on arterial diameter or anatomic location. Furthermore, evidence concerning man is not available. We therefore conclude the review with suggestions for future research in this area.

Dose-dependent effects of perindopril on blood pressure and small-artery structure.

Long-term treatment of young spontaneously hypertensive rats (SHR) with angiotensin-converting enzyme (ACE) inhibitors has a persistent effect on blood pressure when treatment is withdrawn. The aim of the present study was to determine whether this effect could be mediated by the effect of treatment on resistance-artery structure. We determined the dose dependence of ACE-inhibitor therapy on blood pressure and small-artery structure during treatment and on the recovery of blood pressure when treatment was withdrawn. SHR (40 per group) were treated from age 4 to 24 weeks with one of three doses of perindopril (0.4, 0.8, or 1.5 mg/kg per day). Control groups were untreated SHR and Wistar-Kyoto rats. At 24 weeks, treatment was stopped and small arteries were taken from half of the rats from the mesenteric, femoral, cerebral, and coronary vascular beds for morphological and functional measurements. The blood pressure of the other half of the rats was followed until 36 weeks of age. During treatment, perindopril caused a dose-dependent reduction in blood pressure and in the media-lumen ratio and media area of the small arteries, whereas there was a dose-dependent increase in lumen diameter. The effect of treatment on the structure of arteries from the different vascular beds was homogeneous. Compared with values from Wistar-Kyoto rats, blood pressure normalization in SHR was not associated with full normalization of structure. After withdrawal of treatment, there was an inverse relation between perindopril dose and the persistent effect.(ABSTRACT TRUNCATED AT 250 WORDS)

Early narrowed afferent arteriole is a contributor to the development of hypertension.

The kidney is probably critically involved in the development of essential hypertension, as in many genetic models of hypertension. We have investigated whether a narrowed renal afferent arteriole is involved in the pathogenesis of hypertension in spontaneously hypertensive rats. Systolic blood pressure of 37 F2 generation spontaneously hypertensive rats/Wistar-Kyoto rats was measured at age 7 weeks. The right kidney was removed, and lumen diameter and media cross-sectional area of the afferent arterioles were measured after having been fixed while relaxed and under a transmural pressure of 100 mm Hg. The uninephrectomized rats continued until age 23 weeks, when mean blood pressure was measured. Mean blood pressure at 23 weeks was negatively correlated with lumen diameter at 7 weeks. Quartile analysis based on lumen diameter at 7 weeks showed that compared with rats in the top lumen diameter quartile, rats in the bottom lumen diameter quartile had a reduced media cross-sectional area at 7 weeks (17%), the same systolic blood pressure at 7 weeks, and an increased (16%) mean blood pressure at 23 weeks. We conclude that in spontaneously hypertensive rats a narrowed lumen of distal afferent arterioles at 7 weeks contributes to later development of increased blood pressure. This reduced lumen could be caused by inhibited renal afferent arteriole growth.

Reducing Pulse Pressure in Hypertension May Normalize Small Artery Structure

To investigate the relation between the small artery structure and different blood pressure parameters, spontaneously hypertensive rats were treated from 4 to 24 weeks of age (20 weeks in total) with five different antihypertensive therapies: two angiotensin converting enzyme inhibitors (perindopril and captopril), a calcium antagonist )isradipine(, a β-blocker )metoprolol(, and a vasodilator )hydralazine(. At 24 weeks of age, 24-hour blood pressure was measured, and two mesenteric resistance vessels were taken from each animal. Blood pressure was 227/135 mm Hg )systolic/diastolic( and 161/106 mm Hg in untreated hypertensive and normotensive control rats, respectively. Heart rates were 376 min− and 295 min−1 for the two strains. All treatments reduced all blood pressure parameters except for metoprolol, which did not reduce pulse pressure. In the small arteries, the media cross-sectional area was unaffected by the treatments. When a simple correlation analysis was made, pulse pressure was found to correlate more closely )r = 0.64, p < 0.001( to the resistance vessel media/lumen ratio than any of the other pressure parameters studied: systolic )r=0.5l, p=0.011(, mean )r=0.41, p=0.05(, or diastolic )r=0.28, p=0.l9(. When an analysis of covariance was performed that included pulse pressure, mean blood pressure, and heart rate, which also correlated significantly to the media/lumen ratio, 81% of the variation in the media/lumen ratio could be accounted for by the variation in the three covariates )p<10−5(, pulse pressure being the major factor. In conclusion, it is indicated that a reduction in pulse pressure and heart rate during antihypertensive treatment may be important in preventing the development of abnormal small artery structure in hypertension.

Perindopril changes the mesenteric pressure profile of conscious hypertensive and normotensive rats.

Information about how antihypertensive therapy affects the arterial blood pressure profile in conscious animals is at present not available. Here we report measurements of part of the pressure profile in conscious spontaneously hypertensive rats (SHR, n = 7) and Wistar-Kyoto (WKY, n = 7) rats before and after treatment with the angiotensin-converting enzyme inhibitor perindopril. The previously developed technique that we used, provided simultaneous measurements of the undisturbed arterial blood pressure at the base of mesenteric arcades (P(arc); diameter, approximately 100 microns) and systemic mean blood pressure (MBP). The ratio P(arc)/MBP was 63 +/- 2% (mean +/- SEM) in SHR and 64 +/- 3% in WKY rats. When a bolus of perindopril (0.8 mg/kg) was injected into the aorta, P(arc)/MBP fell within 2 minutes to 51 +/- 2% (P < .05) for SHR and 56 +/- 2% (P < .05) for WKY rats, and these levels were maintained for the next hour. In contrast, MBP did not change for approximately 5 minutes in either strain, whereas after 1 hour MBP still had not changed significantly in WKY rats, but MBP had fallen by 16 +/- 2% (P < .05) in SHR.(ABSTRACT TRUNCATED AT 250 WORDS)

Dissociation of blood pressure and resistance artery structure: potential clinical implications.

Essential hypertension (EH) is associated with structural changes in small arteries (SMASCH) in terms of wall thickening and lumen narrowing throughout the entire resistance circulation. This remodelling process occurs early in EH development and is an important contributor to the elevation of vascular resistance. SMASCH also decreases the vasodilatory capability leading to demand-related organ dysfunction (e.g. microvascular angina) and later contributes to organ failure as seen in hypertensive heart and renal failure. In large groups of patients, office blood pressure (BP) precisely predicts strokes and myocardial infarctions, but it is difficult to apply risk prediction equations based on studies of large numbers of patients in individual patients. Office BP may be a rather poor predictor of future cardiovascular events. Adding other risk factors unrelated to BP (SCORE factors) improves risk prediction, and in subgroups with intermediate risk, there may be added value of considering BP-related parameters such as albuminuria or left ventricular hypertrophy. Being directly related to the process of hyper-resistance and dissociated from BP itself, measurements of SMASCH may contribute to risk over and above office BP and other traditional risk parameters. Furthermore, as only antihypertensive treatment regimens resulting in vasodilatation seem to improve SMASCH, this parameter has the potential to guide and improve the management of EH. SMASCH can be assessed, for example, by plethysmography in the forearm or by echocardiography in the heart. These techniques are accurate and reproducible and could constitute part of the diagnostic apparatus for EH patients. This review focuses on methodological issues of SMASCH, haemodynamic consequences, implementation in the clinical setting and suggestions for future research.

Antitrophic properties of antihypertensive drugs may depend solely on their blood pressure-lowering capability: A comparative study of isradipine, hydralazine, and metoprolol

The objective of this study was to examine the effect of antihypertensive treatment on the structure of intramyocardial resistance vessels in spontaneously hypertensive rats. The rats were divided into four groups: one was used as control and the other three were treated from the age of four to 24 weeks with isradipine, hydralazine, and metoprolol, respectively. Half of the animals in each group were examined at the end of active treatment and the rest were examined three weeks later. The rats were anesthetized and killed during constant flow perfusion with 1 percent glutaraldehyde. The media index was determined by point counting. The media indices of rats treated with isradipine and hydralazine were significantly smaller than those of age-matched spontaneously hypertensive rat controls, whereas the media indices of rats in the metoprolol group did not differ significantly. Three weeks after treatment withdrawal, the media index tended to increase in all three groups, but the values for the isradipine and hydralazine groups were still significantly reduced. Non-invasive blood pressure measurements taken at the same time demonstrated a significant blood pressure reduction in all groups, although differences within each treatment group were evident. All pressures had stabilized on the level of spontaneously hypertensive rats three weeks after withdrawal. Thus, it is evident that both isradipine and hydralazine were able to prevent hypertrophy of intramyocardial vascular structure and continue to do so even after treatment withdrawal. This finding is consistent with previous findings, suggesting a close relationship between the extent of blood pressure reduction and the degree of prevention of vascular hypertrophy.

[PP.27.14] VALUE OF ROUTINE BLOOD PRESSURE MEASUREMENTS, PERFORMED IN AN OUTPATIENT HOSPITAL CLINIC

Objective: Treating hypertension is an important issue in most patients in cardiology, nephrology, endocrinology and geriatrics. Many patients with hypertension are not properly regulated but some patients are being overdosed. There is a relation between antihypertensive therapy and risk of falls and fractures. Routinely, BP is measured in all patients in hospital outpatient clinics. Usually, this is done by and during presence of a nurse or a physician just before or after taking an ECG. Clinical decisions are usually based on such measurements. 7 different Danish departments confirmed that this was their procedure in most outpatients. Design and method: We did an audit of consecutive patients referred from our own cardiology outpatient clinic over a period of 18 months for ambulatory monitoring of blood pressure (AMBP). Nineteen were within the age group from 30–45 yr and fourtyfive were older than 75 yr. Results: In the young age group, BP was 156/99u200ammHg in the outpatient clinic but 141/89u200ammHg during AMBP in the daytime. SBP measured by these two techniques showed poor aggrement (Lin concordance correlation coefficient 0,38). Mean difference was 15u200ammHg. In the old age group, clinic BP was average 171/87u200ammHg but only 132/73u200ammHg during AMBP in the daytime. In 7 patients, the antihypertensive medication was intensified before the AMBP, but 5 were reduced after AMBP due to low BP. SBP measured by these two techniques showed no agreement (evt. Lin concordance correlation coefficient 0.04). Mean difference was 38 mmHg. Using daytime ambulatory BP as reference, we found these values for clinic BP: sensitivity 92%, specificity 13%, positive pred value 30% and neg. predictive value 80%. Conclusions: Clinic BP is not a useful tool in older patients. Average error in our database was 39u200ammHg systolic, and clinical decisions made were often wrong. Older patients who had high BP measured, mostly had normal or low BP in the home. In our outpatient clinic, 60% of clinic BP were above 140/90u200ammHg. Clinic BP in outpatient clinics should be abandoned and replaced by better methods in order to improve management of hypertension.

EFFECT OF ACE-INHIBITION AND BETA-BLOCKADE ON THE HAEMODYNAMIC RESPONSE TO SUPINE AND SITTING REST IN PATIENTS WITH ESSENTIAL HYPERTENSION: PP.14.36

Objective: Blood pressure (BP) measured in the office is the primary tool for diagnosing hypertension and for evaluating the effect of treatment. It is well known that BP decreases when the patient rests, but almost unknown how antihypertensive medication modulates the haemodynamic response to rest. We therefore studied the BP changes in the supine and in the sitting position after 5, 20 and 35 minutes of rest during treatment with ACE-inhibitors (ACE-I) or β-blockers (BB) in patients with essential hypertension. Design and Methods: Thirty previously untreated essentially hypertensive patients were studied in the supine position before and after 1 year of randomized double-blind treatment with either perindopril or atenolol and compared to 15 normotensive controls. BP measurements and echocardiographic assessment of cardiac output were performed after 5, 20 and 35 min of supine rest. Additionally, 28 essentially hypertensive patients, treated with either ACE-I/angiotensin-II-receptor blockers (ARB) or BB, were studied in the sitting position with BP measurements as above. These patients also had daytime ambulatory BP measurements performed. Results: In ACE-I/ARB-treated patients both systolic BP (SBP) and diastolic BP (DBP) decreased progressively during the 30-min observation period, while in BB-treated patients, BP did not change at all. When we compared the resting patterns between the groups, we found these to be significantly different for DBP and heart rate both in the supine and sitting position and for SBP in the supine position. There were no significant differences neither in BP measured in the sitting position after 5 minutes of rest as currently recommended nor in the daytime BP measurements between the groups. Conclusions: ACE-inhibitor and especially beta-blocker treatment alters the haemodynamic response to rest in patients with essential hypertension and this is an additional limitation for office BP measurements. The results of the present study does not allow for a recommendation of changing the guidelines for BP measurements, but certainly urges caution when considering study results based on office BP.