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Objective: Previous studies testing the hypothesis that symptoms of anxiety and depression increase blood pressure (BP) levels show inconsistent and limited findings. We examined the association between those symptoms across adult life and BP in late middle age., Methods: Using data from 1683 participants from the MRC NSHD, we investigated associations between affective symptoms at ages 36, 43, 53 and 60-64 years and SBP and DBP at age 60-64. Multivariable linear regression was used to examine the effect on BP of affective symptoms at each age separately and as a categorical cumulative score based on the number of times an individual was classified as a 'case'. Models were adjusted for sex, BMI, educational attainment, socio-economic position, heart rate, lifestyle factors and antihypertensive treatment., Results: In fully adjusted models, we observed lower SBP in study members with case-level symptoms at one to two time-points [-1.83 mmHg; 95% confidence interval (CI) -3.74 to 0.01] and at three to four time-points (-3.93 mmHg; 95% CI -7.19 to -0.68) compared with those never meeting case criteria suggesting a cumulative inverse impact of affective symptoms on SBP across adulthood (P value for trend 0.022). Sex and BMI had a large impact on the estimates while not other confounders. Potential mediators such as heart rate and lifestyle behaviours had a little impact on the association. SBP at age 36 and behavioural changes across adulthood, as additional covariates, had a little impact on the association. A similar but weaker trend was observed for DBP., Conclusion: A cumulative effect of symptoms of anxiety and depression across adulthood results in lower SBP in late middle age that is not explained by lifestyle factors and antihypertensive treatment. Mechanisms by which mood may impact BP should be investigated.

Although it has been extensively scrutinized, the factor(s) involved in the initiation and development of hypertension in spontaneously hypertensive rats (SHRs) remains unresolved. The objective of the present study was to determine whether, early in development, the causal mechanism(s) for the development of hypertension in young SHRs involves an integration of 2 processes, specifically an upregulation of structurally based vascular resistance properties and a rightward shift in the hemodynamic component of pressure-natriuresis. Mean arterial pressure was determined in conscious 4-week-old SHRs and Wistar-Kyoto rats via previously implanted aortic catheters. Structurally based hindlimb vascular resistance properties were assessed in 2- and 4-week-old SHRs and Wistar-Kyoto rats. Renal interstitial hydrostatic pressure was measured after short-term manipulations of renal arterial pressure (RAP) in 4-week-old, anesthetized rats. Although mean arterial pressure in conscious SHRs (113±5 mm Hg) and Wistar-Kyoto rats (110±6 mm Hg) was not significantly different at 4 weeks of age, SHRs at 2 and 4 weeks of age already had increases in structurally based vascular resistance properties of ≈30% above age- and weight-matched Wistar-Kyoto rats. Furthermore, the acute RAP-renal interstitial hydrostatic pressure relationship was found to be linear in both strains, and the temporal coupling of the stimulus to response was rapid; that is, renal interstitial hydrostatic pressure responses to changes in RAP were <2 s. Although the slope of the RAP-renal interstitial hydrostatic pressure relationship was not significantly different between strains, the relationship was significantly shifted (18%) to higher RAPs in SHRs. These results suggest that alterations in both vascular structure and renal function in young SHRs occur before elevations in mean arterial pressure.

Background: The "nondipping" pattern (NDP) of blood pressure, characterized by the absence of the reduction in blood pressure (BP) that typically takes place during the night time, has been associated with elevated cardiovascular morbidity, including stroke, myocardial infarction, and sudden cardiac-related death. In various cardiovascular diseases, reduced vagal control of cardiac function and elevated lability of cardiac repolarization have been associated with increased risk for ventricular arrhythmia and sudden death. The aim of this study was to assess temporal QT variability, arterial baroreflex sensitivity (BRS), and baroreflex effectiveness index (BEI) in two groups of otherwise healthy subjects, one group consisting of those with a normal BP pattern and the other with a nondipping BP pattern., Methods: Ninety-five healthy subjects underwent 24-h ambulatory BP (AMBP) monitoring. A minimum of 10% reduction in BP during the night relative to daytime levels is considered normal (as found in "dippers"). These individuals were classified as "dippers" (n = 59) and individuals without 10% reduction in BP during night were classified as "nondippers" (n = 36). Electrocardiogram (ECG) readings and beat-to-beat BP were recorded at 1,000 Hz with the subjects at rest in the supine posture for 20 min. BRS, BEI, and QT variability index (QTVI) were calculated., Results: There were no differences between the study groups with respect to age, gender, and average BP. Nondippers showed an increase in QTVI (-1.28 +/- 0.48 in nondippers vs. -1.52 +/- 0.29 in dippers, P < 0.05) and a decrease in BEI (0.34 +/- 0.17 in nondippers vs. 0.43 +/- 0.17 in dippers, P < 0.05), whereas BRS did not differ between the groups., Conclusion: A nondipping BP pattern in healthy subjects is associated with elevated myocardial repolarization lability and impaired baroreflex function, suggesting dysfunction of the autonomic nervous system.

Background: We have used a novel ultra high-frequency (55MHz) ultrasound technique to non-invasively measure the radial arterial vessel wall and separate the intima-media (IMT) complex into measurements of intima and media thickness (IT and MT). Since no previous study has measured IT and MT separately in individuals with prehypertension and hypertension, the aim of the current study was to measure IT and MT thickness of the radial arteries among individuals with prehypertension, hypertension and healthy subjects., Methods and Results: Individuals with prehypertension (n=32), hypertension (n=34) and healthy subjects (n=29) underwent ultra high-resolution ultrasound of the radial artery. Individuals with prehypertension showed a 14% increase in IT compared to healthy subjects (0.083+/-0.020mm versus 0.073+/-0.015mm; p<0.05), whereas no difference was seen in MT. Individuals with hypertension showed a 12% increase of in IT compared to healthy subjects (0.082+/-0.018mm versus 0.073+/-0.015mm, p<0.05), whereas no differences were seen regarding MT. Prehypertensive and hypertensive individuals did not differ regarding IT and MT., Conclusion: Both prehypertension and hypertension are associated with thickening of the intimal layer of the radial artery. The present data indicates that intima thickening appears early during the development of hypertension even when blood pressure is only slightly elevated.

Objectives: Impaired arterial baroreflex sensitivity (BRS) has been associated with cardiac mortality and non-fatal cardiac arrests after a myocardial infarction. Patients with chronic renal failure (CRF) have a poor prognosis because of cardiovascular diseases, and sudden death is common. The aim of this study was to assess whether BRS or the baroreflex effectiveness index (BEI), a novel index reflecting the number of times the baroreflex is active in controlling the heart rate in response to blood pressure fluctuations, is associated with prognosis in CRF., Methods: Hypertensive patients with CRF who were treated conservatively, by haemodialysis or peritoneal dialysis were studied. Electrocardiogram and beat-to-beat blood pressures were recorded continuously and BRS and BEI were calculated. Patients were then followed prospectively for 41 +/- 15 months (range 1-64)., Results: During follow-up 69 patients died. Cardiovascular diseases and uraemia accounted for the majority of deaths (60 and 20%, respectively), whereas sudden death occurred in 15 patients. In adjunct with established risk factors such as age, diabetes, congestive heart failure and diastolic blood pressure, reduced BEI was an independent predictor of all-cause mortality among CRF patients [relative risk (RR) 0.50, 95% confidence interval (CI) 0.33-0.71 for an increase of one standard deviation in BEI, P < 0.001]. Diabetes and reduced BRS were independent predictors of sudden death (RR 0.29, 95% CI 0.09-0.86 for an increase of one standard deviation in BRS, P=0.022)., Conclusions: Both BEI and BRS convey prognostic information that may have clinical implications for patients with cardiovascular diseases in general.

Background: Recent guidelines for the management of arterial hypertension have proposed that, to prevent cardiovascular disease, lifestyle modifications are required even in the case of high-normal blood pressure (HNBP)., Objective: To assess myocardial repolarization and spontaneous cardiac baroreflex sensitivity (BRS) in newly diagnosed and never-treated individuals., Design and Participants: We studied healthy individuals with HNBP according to the 2003 European Society of Hypertension-ESC guidelines and, for comparison, patients with renovascular hypertension (RVH) and healthy individuals with normal blood pressure (NBP)., Main Outcome Measures: Electrocardiogram and beat-to-beat blood pressure were recorded and spontaneous cardiac baroreflex sensitivity and the temporal QT interval variability index (QTVI) were calculated., Results: Individuals with HNBP had increased QTVI values compared with those with NBP (-1.23 +/- 0.37 compared with -1.52 +/- 0.26; P < 0.05), whereas patients with RVH had additionally increased QTVI values that were greater than those in healthy individuals with NBP or HNBP (-0.81 +/- 0.75; P < 0.05 compared with both groups). BRS was reduced in both groups of individuals with increased blood pressures compared with NBP (8.2 +/- 4.1 ms/mmHg for individuals with HNBP, 6.1 +/- 4.3 ms/mmHg for patients with RVH and 10.8 +/- 3.5 ms/mmHg for NBP; P < 0.05 for both)., Conclusion: In otherwise healthy individuals, even a moderate blood pressure increase is associated with increased myocardial repolarization lability and reduced baroreflex sensitivity (BRS). Patients with RVH have an additionally increased QTVI, with values similar to those reported in congestive heart failure. Future studies are needed to establish the value of QTVI and BRS measurements among individuals with HNBP in predicting the risk of progression to hypertension and end-organ damage.

Background: Impaired arterial baroreflex function has been associated with an increased risk of ventricular arrhythmia and sudden death. This has also been suggested for patients with chronic renal failure (CRF) who are at high risk for cardiovascular morbidity. The aim of this study was to investigate the arterial baroreflex function in CRF patients with emphasis on analyzing the time during which the arterial baroreflex is active, the baroreflex effectiveness index (BEI)., Methods: Beat-to-beat blood pressure (measured with Portapres) and electrocardiography were continuously registered during 30 min rest in 216 hypertensive CRF patients on hemodialysis (n=95), continuous ambulatory peritoneal dialysis (n=59), or conservative treatment (n=59). The spontaneous sequence method was used to calculate BRS and BEI. Age-matched healthy subjects (n=43) were examined for comparison., Results: The BRS was reduced by 51% and the BEI by 49% in CRF patients compared with healthy subjects (P<.001 for both). In addition, CRF patients with diabetes showed further reductions compared with patients without diabetes (15% reduction of BRS and 44% of BEI, P<.01 for both). The treatment modality for renal failure had no effect on BRS or BEI. In a multivariate linear regression analysis, age, body mass index, and systolic blood pressure were independent predictors of BRS, whereas age and diabetes were independent predictors of BEI in patients with CRF., Conclusions: We conclude that BEI, which is markedly reduced in hypertensive patients with CRF, may convey information on arterial baroreflex function that is complementary to BRS.

This randomized, double-blind, placebo-controlled crossover study evaluated the effects of the angiotensin II type 1 (AT1)-receptor blocker candesartan cilexetil on renal blood perfusion and glomerular filtration in patients with primary hypertension with diastolic blood pressure of 100 to 114 mm Hg. After a 4-week placebo run-in period, patients were randomized to receive either 16 mg candesartan cilexetil or placebo once daily for 6 weeks, after which they were switched to the alternative treatment. At the end of each period, 24 h after the last dose, renal assessments were made and the plasma renin activity, plasma concentrations of angiotensin II, aldosterone, and catecholamines were measured. Compared with placebo, candesartan cilexetil significantly reduced mean arterial pressure, by 8 mm Hg (95% confidence interval [CI], 3;12). Renal vascular resistance was significantly reduced by 0.03 mm Hg/mL min(-1) (95% CI, 0.01; 0.06). There was a small nonsignificant increase in renal plasma flow. The filtration fraction fell slightly from 0.24 to 0.22 (95% CI, -0.00, 0.04). As expected, angiotensin II concentrations and plasma renin activity were increased and the aldosterone concentrations were reduced. Catecholamine concentrations were unaffected. In conclusion, 6 weeks' treatment with 16 mg candesartan cilexetil once daily induced a reduction of renal vascular resistance and a trend toward increased renal plasma flow despite a reduction in mean arterial pressure. Because the glomerular filtration rate was maintained the filtration fraction was reduced, indicating a decreased glomerular capillary pressure.

It has been suggested, mainly by in vitro findings, that cardiovascular tissue in the spontaneously hypertensive rat (SHR) should be more prone to proliferate/hypertrophy than that of the Wistar-Kyoto rat (WKY). The present study tests the hypothesis that the tissue of the low-pressure compartment in SHR, being structurally similar to that of the WKY, shows an increased growth response due to activation of the GH-IGF-I system. An aortocaval fistula (ACF) was induced in 64 SHR and WKY male rats and 44 rats served as controls. They were all followed for 1, 2, 4 and 7 days after surgery. In separate groups of SHR (n=4) and WKY (n=3), central venous pressure was measured by telemetry recordings prior to opening of the fistula and for up to 16 h post-surgery. Systolic blood pressure was measured during the week post-surgery. The right ventricular (RV) and the caval vein IGF-I mRNA and RV IGF-I receptor and GH receptor mRNAs were quantitated by means of solution hybridisation assay. In rats with ACF the systolic blood pressure decreased, approximately 29% in SHR and 16% in WKY between 1 and 7 days post-surgery (P<0.05, n=5-6 in each group). SHR with ACF showed a transient elevation in central venous pressure vs WKY. Within the week following fistula induction both strains showed a similar, pronounced increase in RV hypertrophy. SHR with ACF showed a smaller, or even blunted, overall response with respect to activation of the GH-IGF-I system compared with WKY, the latter showing clear-cut elevation of gene expressions. Two days after shunt opening in SHR, RV and caval vein IGF-I mRNA increased by 57% and 108% (P<0.05 for both, n=5-6 in each group) respectively, and these expressions were then turned off, whereas RV GH receptor and IGF-I receptor mRNA expression remained unaffected compared with WKY rats. WKY rats showed on average a later and a greater response of GH-IGF-I system mRNA expression vs SHR. The present in vivo study suggests that the SHR requires less activation of the GH-IGF-I system for creating a given adaptive structural growth response.

The effects of the angiotensin II receptor blocker candesartan cilexetil on systemic and forearm haemodynamics and baroreceptor sensitivity were evaluated in this randomized, placebo-controlled, double-blind, crossover study. After a 4-week placebo run-in period, 22 patients with essential hypertension (diastolic blood pressure 100-114 mmHg) were randomized to receive either candesartan cilexetil 16 mg or placebo once daily for 6 weeks. At the end of each period, 24 h after the last dose, invasive haemodynamic assessments were performed. Simultaneously, the plasma renin activity and plasma concentrations of angiotensin II, aldosterone and catecholamines were measured. Compared to placebo, candesartan cilexetil significantly reduced mean arterial pressure by 8 mmHg (95% CI: 2.6; 12.3), while cardiac output, stroke volume and heart rate were unchanged. Forearm vascular resistance was reduced by 1 mmHg x ml(-1) x L x min (CI: 0.3; 2.3). The baroreceptor sensitivity was not influenced, but a change in the set-point was noted. Plasma renin activity and angiotensin II concentrations were increased, while the aldosterone concentration was significantly reduced. Plasma catecholamine concentrations were unaffected. In conclusion, 6 weeks' treatment with candesartan cilexetil 16 mg o.d. induced systemic and forearm vasodilatation and a reduction in blood pressure without compromising cardiac performance. The plasma concentration of aldosterone was reduced.

Objectives: This study was performed to assess the acute effects of the new angiotensin II antagonist, candesartan cilexetil, on systemic and renal haemodynamics in patients with sustained essential hypertension [diastolic blood pressure (DBP) 95-114 mmHg]., Methods: After 4 weeks of placebo treatment, systemic and renal haemodynamics were investigated in 17 patients with a mean age of 62 years and a mean systolic and diastolic blood pressure of 170/98 mmHg, just before (baseline) and for 4 h after administration of a single oral dose of candesartan cilexetil, 16 mg. Plasma concentrations of candesartan (the active compound formed from the pro-drug candesartan cilexetil), angiotensin II (Ang II), as well as plasma renin activity (PRA), were measured before and after dosing., Results: At 2, 3 h and 4 h after dosing with candesartan cilexetil, systolic blood pressure (SBP) and DBP, as well as mean arterial pressure (MAP), were significantly lower than at baseline. The mean reduction in MAP 4 h after dosing was 8.8 mmHg (-6.5%). This effect was due to a fall in total peripheral resistance (TPR), while heart rate (HR), stroke volume (SV) and cardiac output (CO) were virtually unchanged. After 4 h there was a marked reduction in renal vascular resistance (RVR) of 0.0273 mmHg x ml(-1) x min (-16%), resulting in an increased renal plasma flow of 64.9 ml x min(-1) (14%). The glomerular filtration rate was increased by 7.75 ml x min(-1) (8%), and the filtration fraction (FF) was not significantly changed. There was no apparent relationship between the changes observed in systemic and renal haemodynamic variables and plasma concentrations of candesartan. Plasma renin activity increased over the study period, but in general the patients had low PRA. Changes in plasma concentrations of angiotensin II were inconsistent between patients., Conclusion: A single oral tablet of candesartan cilexetil, 16 mg, induced systemic and renal arterial vasodilatation and blood pressure reduction, without compromising renal perfusion or filtration or affecting cardiac performance. Plasma renin activity which was low in general, increased over the study period, but changes in plasma concentrations of angiotensin II were inconsistent.

Spillover of norepinephrine (NE) into plasma is used frequently as an index of NE release and therefore of sympathetic nerve activity. An important limitation of NE spillover is that it reflects not only release but also uptake processes that intervene before the transmitter reaches the circulation. To overcome this limitation, we developed a method for estimating NE release based on measurements of the specific activities of [3H]NE in plasma and interstitial fluid during intravenous infusion of [3H]NE. We applied this method to examine relationships among NE release, tissue uptake, and spillover in the human heart, kidneys, and forearm. The sum of uptake and spillover of released NE provided an estimate of NE release into the interstitial fluid. In the kidneys, NE release averaged three times NE spillover, in skeletal muscle, 12 times NE spillover, and in the heart, >20 times NE spillover. Thus NE release greatly and variably exceeds NE spillover from these organs, so that assessing regional sympathetic function requires an understanding of the relationship of NE spillover to NE release.

We investigated the effect of a 4-day oral salt load (150 mmol NaCl extra per day) on blood pressure, erythrocyte sodium transport and the activity in the renin-angiotensin system in six males with primary hypertension, who had attained normotension on chronic enalapril treatment for 4 years. The design was a placebo-controlled, randomized, two-way cross over, double-blind study, i.e. each patient served as his own control. Intracellular erythrocyte sodium and potassium content were measured by flame photomometry. The increase in the intracellular sodium concentration during 1 h in 37 degrees C incubation of whole-blood with ouabain (compared with no-ouabain) was measured to determine the rate of active sodium efflux. 24-h blood pressure registration was performed with Space-lab equipment (SL 90202) before and at the end of the salt load. Left ventricular morphology was evaluated with echocardiography and the minimal vascular resistance of the hand vascular bed with water plethysmography at baseline and after 4 years on enalapril. Four years' enalapril treatment caused a significant decrease in blood pressure, left ventricular mass and minimal vascular resistance. During the 4-day salt load average 24-h blood pressure was significantly elevated, 129+/-3/85+/-2 mmHg as compared to 124+/-2/82+/-2 mmHg during placebo treatment (p=0.025). The change (delta) in MAP during high salt intake showed a negative relationship to delta-sodium efflux rate constant (r=-0.65, p=0.047). No significant relationship was found between the blood pressure response to the salt load and structural cardiovascular changes. In conclusion, a short-term oral salt load in hypertensive patients on chronic enalapril treatment caused a blood pressure rise, which was related to cellular sodium transport but not to structural cardiovascular changes.

There are experimental data suggesting that epinephrine (Epi) may act as a cotransmitter in sympathetic nerves, stimulating presynaptic beta 2-receptors and enhancing norepinephrine (NE) release. To examine neuronal Epi release, patients with congestive heart failure and hypertension and healthy subjects were examined with the isotope-dilution method. At baseline, small cardiac and renal Epi spillovers were found in patients. During intense supine exercise, cardiac NE and Epi spillovers increased concomitantly with similar magnitude, whereas no renal Epi spillover could be detected. Blockade of neuronal uptake 1 caused a consistent decrease in both cardiac and renal fractional extractions of NE and Epi. The present study demonstrates baseline cardiorenal Epi release in patients with congestive heart failure and renal Epi release in hypertensive patients. Furthermore, Epi is removed by neuronal uptake in both the heart and kidney, and cardiac Epi spillover increases during exercise. This study, in contrast to other results, provides evidence for cardiac neuronal Epi release.

Objective: To compare, using data from published studies, the efficacy of chronic inhibition of the renin-angiotensin system in inducing persistent downregulation of hemodynamic and cardiovascular structural changes in an adult rat with established genetic hypertension with the widely accepted known downregulation in young genetically hypertensive rats., Study Selection: We report on 36 studies that satisfied our inclusion criteria (angiotensin converting enzyme inhibitor or angiotensin II receptor antagonist treatment that lowered arterial pressure levels for at least 3 weeks). Of the 24 studies concerning developing hypertensive rats, a significant number (n = 17) also examined the persistence of any hemodynamic or cardiovascular effects after withdrawal of treatment. Conversely, of 15 studies using adult rats only seven and three reported on post-treatment hemodynamic and cardiovascular structural indices respectively., Results: During treatment the hemodynamic and cardiovascular structural changes produced were qualitatively and quantitatively similar in the young and adult treated rats. Critical assessment of the persistence of these effects after withdrawal of treatment again found qualitatively similar responses. However, the strength of this finding is limited by the paucity of studies concerning adult rats in which equivalent treatment durations and equipressor doses of treatments were compared between these two age groups., Conclusions: Blockade of the renin-angiotensin system appears to have an efficacy in reversing established hypertension and hypertrophy similar to that with which it prevents the development of hypertension and hypertrophy. This partial 'cure' of hypertension after withdrawal of treatment is clearly evident when treatment is initiated during the development of hypertension and appears to be similar even when treatment is initiated in established hypertension.

Induction of two-kidney, one clip hypertension (renal hypertension) is characterized by a slow increase in left ventricular tension and aortic wall stress, as opposed to aortocaval fistula or shunt volume overload, which induces a marked and rapid onset of wall stress in the caval vein and right ventricle. In the present study, we applied hemodynamic challenge to study the growth response involving gene expression of insulin-like growth factor-I (IGF-I) and growth hormone receptor (GH-R) mRNA in aorta and caval vein. Volume overload and pressure overload were induced in Wistar rats by means of shunt and renal hypertension, respectively. Systolic pressure was measured before excision of the great vessels, which was performed between 2 and 12 days postoperatively. Aortic and caval vein IGF-I and GH-R mRNA expressions were measured by means of a solution hybridization assay, and the caval vein was analyzed for IGF-I protein by immunohistochemistry. In the volume-distended but not pressurized caval vein in shunt rats, verified by telemetry recordings, there was an eightfold increase in IGF-I and 3.5-fold increase in GH-R mRNA at day 4 versus control. The IGF-I protein appeared to be localized in smooth muscle cells. In the aorta of the renal hypertension group, changes were of a slower onset. At day 7, there was a fourfold increase in IGF-I and five-fold increase of GH-R mRNA expressions versus sham-operated rats. Both the shunt caval vein and renal hypertension aorta showed evidence of a structural adaptation of the growth response. The present study suggests that acute elevation in vascular wall stress is an important triggering factor for overexpression of IGF-I and GH-R mRNA in great vessels. The growth hormone/insulin-like growth factor axis may be an important link in mediating structurally adaptive growth responses in the blood vessel wall.

Therapy with angiotensin II-converting enzyme (ACE) inhibitors has been suggested to prevent cardiovascular hypertrophy in hypertension even in doses that are subantihypertensive. We investigated the effects of two different ACE inhibitors on blood pressure and cardiovascular changes during as well as after discontinuation of treatment in spontaneously hypertensive rats (SHR). SHR were treated with either enalapril (ENA) or ramipril (RAM) from age 12 to age 20 weeks. Each drug was given in either an antihypertensive (ENA 15 mg center dot kg-1, RAM 3 mg center dot kg-1) or a subantihypertensive (ENA 50 mu g center dot kg-1, RAM 10 mu g center dot kg-1) dose. Mean arterial pressure (MAP) was reduced with antihypertensive doses of ENA (26%) as well as RAM (21%). Regression of cardiovascular changes occurred as reduction in left ventricular (LV) weight/body weight ratio (25 and 21% for ENA and RAM, respectively), reduction in perfusion pressure at maximal vasodilation of the perfused hindquarter (PPdil, 17 and 17%), and reduction in maximal developed pressure (PPmax, 13 and 17%). These effects partly persisted 10 weeks after treatment was discontinued. However, treatment with subantihypertensive doses of ENA and RAM had no effect on MAP, LV/body weight ratio, PPdil, or PPmax. Overall, regression of cardiovascular parameters correlated closely to the decrease in MAP. Similarly, no changes in MAP, LV weight/body weight ratio, PPdil, or PPmax were noted when young SHR were treated with subantihypertensive doses of RAM from age 6 to age 12 weeks, during which time hypertension becomes established. At doses having equal effects on blood pressure, plasma concentrations of RAM were considerably lower than those of ENA. Skeletal muscle concentrations were very low or undetectable in comparison to plasma concentrations for both drugs. Therefore, both RAM and ENA caused regression of cardiovascular changes that could be explained by a concomitant reduction in blood pressure. This regression persisted for a considerable time after discontinuation of treatment. On the other hand, no specific antitrophic effects in the absence of blood pressure reduction was evident with either drug. Furthermore, despite substantial differences in plasma concentrations, RAM, and ENA administered chronically appeared to affect cardiovascular parameters equally in the adult SHR.

Greater smooth muscle growth is an important feature of the changes in blood vessel morphology in hypertension. The increase in vessel wall thickness: lumen ratio resulting from vascular hypertrophy impacts directly on total peripheral vascular resistance thereby influencing the severity of hypertension. The roles played by mechanical forces, vasoactive substances, growth factors and endocrine hormones in mediating hypertrophic vascular growth responses in vivo are currently under investigation. Here we review our current research aimed at: (a) defining the roles in vivo, of the renin-angiotensin system (RAS) and sympathetic nervous system (SNS), in the development of cardiovascular hypertrophy; (b) defining the importance of endogenous vasodilator systems, in particular, the ability of nitric oxide to inhibit trophic responses induced by the RAS and SNS and (c) examining whether trophic stimulation via the two neurohumoral systems as well as the antitrophic activity of the vasodilator systems is in part dependent on changes in blood pressure. In these studies the obligatory enzyme ornithine decarboxylase has proved to be a useful marker of ongoing hypertrophic cardiovascular growth.

To evaluate the effect of metformin on insulin sensitivity and to further examine the relationship between insulin resistance, sympathetic nerve activity and blood pressure, 6 obese insulin resistant, normoglycemic hypertensive men were investigated (age 49 +/- 2 years, BMI 27.6 +/- 1.2, mean +/- SEM). The study had a placebo controlled, double blind, cross over design with 6 weeks' metformin treatment (850 mg b.i.d) vs placebo. Blood pressure was measured weekly. At the end of each treatment period, glucose infusion rate (GIR), muscle sympathetic nerve activity (MSA) and renal and total body norepinephrine (NE) kinetics (radioisotope dilution) were examined during euglycemic hyperinsulinemic clamp. Fasting insulin was 13 +/- 3 and 10 +/- 2 mU/l and fasting glucose 5.3 +/- 0.2 and 5.1 +/- 0.1 mmol/l after placebo and metformin treatment, respectively (ns). GIR during the last hour of the insulin clamp was 3.7 +/- 0.6 vs 3.6 +/- 0.6 mg/kg x min (ns). Resting MSA, total body and right renal NE spillover did not differ significantly after placebo and metformin treatment. Systolic and diastolic blood pressures were 151 +/- 10/95 +/- 5 mmHg after placebo and 146 +/- 5/94 +/- 5 mmHg after metformin treatment (ns). Thus metformin treatment did not have any significant effect on insulin sensitivity, blood pressure or sympathetic activity in this small group of patients. Renal plasma flow and MSA increased significantly during the insulin clamp, whereas renal NE and total body NE spillover remained unchanged, suggesting nonuniform regional sympathetic nerve responses to acute hyperinsulinemia.

In spontaneously hypertensive rats (SHR) and Wistar-Kyoto (WKY) rats, we examined tissue and adrenal norepinephrine concentrations, left ventricular (LV) weight, LV weight/body weight ratio (LV/BW), hindquarter resistance properties, ie, perfusion pressures at maximum dilatation and constriction (PPmax, PPmin), and the slope of the methoxamine log dose-PP curve. In series 1, we studied 4-week-old controls (SHRc, WKYc), sympathectomized rats (SX; SHRsx, WKYsx), and SX rats also given prazosin (SXP; SHRsxp, WKYsxp). With SX and SXP, adrenal norepinephrine concentrations increased in both strains, but tissue (LV, muscle, kidney) norepinephrine was depleted. At 4 weeks, LV/BW, PPmin, and PPmax were all greater in SHRc than in WKYc. With SX, these differences between strains remained unchanged, but SXP abolished them completely, indicating the importance of blockade of alpha-adrenergic receptor stimuli of adrenal origin. In SHRc (but not in WKYc), there was evidence of reinnervation after 4 weeks of SX. Hence, in series 2, the SXP period was extended to 8 weeks, and we studied SHRc, WKYc, SHRsxp, and WKYsxp. Systolic blood pressure was already elevated at 4 weeks in SHRc, and by 35 weeks it was 64 mm Hg greater than in WKYc. At 21 and 35 weeks, LV/BW, PPmax, PPmin, and slopes were all greater in SHRc than in WKYc, and the findings suggested greater LV and vascular hypertrophy than at 4 weeks. In SHRsxp hypertension, LV hypertrophy and the vascular changes were completely prevented over the entire 35-week observation period. SXP mainly affected SHR and had few effects on WKY rats. The sympathetic nerves and adrenals are probably the sources of alpha-adrenergic receptor stimulation in young SHR. They account for the development of hypertension and for most of the cardiovascular structural differences between SHR and WKY rats.

The present study was designed to explore to what extent pressure reduction by antihypertensive therapy and pressure elevation by renal hypertension are able to affect structural vascular and cardiac changes in young spontaneously hypertensive rats (SHR). Pressure elevation in SHR was induced by means of superimposing 2 kidney, 1 clip renal hypertension (2K1C). Pressure reduction was achieved by means of the vasoselective calcium antagonist felodipine from 6 to 13 weeks of age in both clipped and unclipped SHR. Vascular structure of the skeletal muscle was assessed hemodynamically by perfusing a hindlimb preparation and left ventricular dimensions were calculated from pressure-volume relationships of isolated hearts arrested in diastole. Induction of renal hypertension in SHR resulted, besides augmentation of arterial pressure in a marked concentric left ventricular hypertrophy, i.e. elevations of wall thickness to internal radius ratio. Likewise, in renal hypertensive SHR, a structural adaptation of the skeletal muscle vascular bed occurred, reflected as elevations of minimal vascular resistance and maximal generated perfusion pressure. Antihypertensive treatment for 8 weeks with felodipine reduced and also prevented mean arterial pressure from increasing further in SHR, and in SHR with superimposed renal hypertension by approximately 15% (p < 0.001 for both). In renal hypertensive SHR, felodipine partly prevented the development of exaggerated structural changes, both in the heart and in the skeletal muscle vascular bed, as reflected by reduced wall thickness to internal radius ratio and reduced minimal vascular resistance by 22% and maximal pressure response by 10% respectively (p < 0.01 for both parameters).(ABSTRACT TRUNCATED AT 250 WORDS)

Myocardial capillary exchange capacity was investigated by stereologic and functional techniques in parallel during pressure-overload cardiac hypertrophy and after long-term antihypertensive therapy with the vasodilator felodipine. In 26-week-old female spontaneously hypertensive rats (SHR) blood pressure increased by 25% and left ventricular weight (LVW/BW) increased by 18% compared to Wistar-Kyoto rats (WKY). Myocardial capillary surface and volume densities normalized for organ weight were similar in both ventricles for both strains. Moreover, capillary surface density was higher sub-epicardially (EPI) than in the subendocardium (ENDO) in the left ventricle of SHR. Thirteen weeks of felodipine-therapy (SHR-Felo) normalized blood pressure without affecting LVW/BW although a transition from concentric to eccentric hypertrophy is known to occur. Myocardial capillary surface and volume densities and the left ventricular ENDO-EPI-gradient in surface density were similar to untreated SHR. However, felodipine-treatment increased right ventricular weight and capillary volume density. Functional capillary exchange was estimated in terms of permeability surface area products (PS) for Cr-EDTA and vitamin B12 and normalized for organ weight. PSCr-EDTA, PSB12 and the ratio PSCr-EDTA/PSB12 (an index of capillary permeability) were similar in SHR and WKY. Furthermore, the relation between functional and stereological indices of exchange capacity was investigated in a multiple linear regression analysis. However, no significant correlation between PS and neither capillary surface nor volume density was found. In conclusion, myocardial capillary exchange capacity was well adapted to the pressure overload cardiac hypertrophy present in female SHR. Despite induction of right ventricular hypertrophy, felodipine-treatment did not affect capillary exchange capacity. Furthermore, when functional and stereologic estimates were performed in parallel, the importance of dynamic factors for myocardial capillary exchange capacity (e.g. heterogeneity) was illustrated.

We measured left ventricular blood flow with radioactive microspheres during aortic pressure reduction in 10 open-chest, anesthetized dogs with left ventricular hypertrophy due to chronic hypertension and in 10 matched normotensive dogs. Heart rate and left atrial pressure were held constant, and autonomic reflexes were abolished with ganglionic blockade. Aortic diastolic pressure was lowered from baseline to 90, 75, and 60 mm Hg with an arteriovenous fistula. During aortic pressure reduction, a stepwise decline in the endocardial-to-epicardial flow ratio in hypertrophied hearts from 1.23 +/- 0.04 at baseline to 0.96 +/- 0.09 at a diastolic pressure of 75 mm Hg parallelled that in normal hearts and was not associated with any deterioration in left ventricular performance. However, a further fall in the endocardial-to-epicardial flow ratio to 0.76 +/- 0.10 at a diastolic pressure of 60 mm Hg in hypertrophied hearts exceeded that in normal hearts (0.92 +/- 0.05, p less than 0.05) and was accompanied by evidence of left ventricular isovolumic and end-systolic dysfunction. We conclude that in hearts with pressure-overload left ventricular hypertrophy, aortic pressure reduction causes a transmural blood flow redistribution from subendocardial to subepicardial muscle layers. At moderately low aortic pressures, this redistribution is more pronounced than in normal hearts and is associated with functional evidence of myocardial ischemia.

Various colonies of the spontaneously hypertensive rat (SHR) of the same age demonstrate different forms of the left ventricle (LV) in end-diastole. SHR from breeders in Australia and Switzerland exhibit concentrically hypertrophied LV, evident from an increased wall thickness to internal radius ratio (w/ri), while SHR from a Danish colony show an unchanged w/ri ratio, indicating eccentrically hypertrophied LV. These differences may be related to changes in arterial blood pressure and/or altered cardiac filling patterns. A more favourable situation seems to prevail for the eccentrically hypertrophied SHR heart compared with the concentrically hypertrophied heart, the former demonstrating enhanced cardiac function. Thus, an LV with increased diastolic diameter, as in the eccentrically hypertrophied SHR heart, can produce an elevated stroke volume for a given degree of myocardial shortening. In renal hypertension, however, LV function was depressed, probably due to a factor, possibly released upon clipping of the renal artery, that has inherent negative inotropic properties. Here, the reduction of LV performance could be explained neither by the changed LV geometrical design nor by the altered myocardial myosin isoenzyme pattern. At low aortic pressures and hence limited coronary perfusion, LV performance is attenuated in SHR and renal hypertensive rats, most likely due to the vascular structural changes within the coronary vascular bed.

Five current lines of cardiovascular studies in rats are outlined, mainly dealing with some functional and structural relationships of particular relevance for hypertension and ordinary aging: 1. Characteristics of the smooth muscles and their neurogenic control in 'Windkessel' arteries, conduit arteries, precapillary resistance vessels and venous capacitance vessels from normotensive rats (WKY) with comparisons to rats with primary hypertension (SHR). 2. Different types of structural renovascular adaptation, comparing aging with advancing SHR hypertension, with 'high-pressure' and 'low-pressure' kidneys in one-clip, two-kidney renal hypertension, and with hypertrophied kidneys in uni-nephrectomized normotensive rats. 3. Relationships between 'structural autoregulation', wall distensibility, vascular reactivity and smooth muscle sensitivity in SHR and WKY hindquarter resistance vessels along with aging. 4. Relationships between wall thickness, luminal dimension and contractility in left ventricles from SHR and WKY during aging, and when one-clip, two-kidney hypertension is superimposed. 5. Interference with the capacity of the neurohormonal mechanisms counteracting blood loss in rats when on chronic low-salt diet.

In hypertension the small arteries undergo structural changes that increase vascular resistance, both in vivo and in vitro. The hallmark of a physiological vascular amplifier is that enhanced resistance responses must occur about the resting value. For this to happen, the average radius of the resistance vessels must be narrower than normal; increased wall thickness without narrowing does not result in this type of amplification. In primary hypertension in spontaneously hypertensive rats (SHR), the structural changes in the resistance vessels precede the elevation in blood pressure. This is consistent with the hypothesis that these changes cause hypertension. The role of the sympathetic nervous system in early vascular development is unclear, in view of the absence of regression of amplifier properties in the hindlimb vessels after extensive immunosympathectomy. However, short periods of enalapril treatment in young animals attenuate the development of hypertension and normalize hindlimb resistance properties, suggesting that the renin-angiotensin system may have a role in early vascular growth. Studies in tissue culture suggest that both systems could play a role in smooth muscle growth, in conjunction with growth factors such as platelet-derived growth factor (PDGF)-like peptides and endothelin. The early structural change that occurs in hypertension is probably a variant of normal development of the resistance vasculature, with greater secretion of 'normal' growth factors and/or enhanced responsiveness of the vascular smooth muscle.

Cardiac function was studied in spontaneously breathing, adult spontaneously hypertensive rats (SHR) and Wistar-Kyoto normotensive rats (WKY). By rapid intravenous blood infusion, the relation between left ventricular end-diastolic pressure (LVEDP) and stroke infusion, the relation between left ventricular end-diastolic pressure (LVEDP) and stroke volume (SV) was determined while the cardiac nervous control was pharmacologically blocked. Since SV is greatly influenced by the level of afterload (mean arterial pressure, MAP), SV was also determined at increased MAP (constriction of abdominal aorta) and at decreased MAP (vasodilation by hydralazine). At low LVEDP levels, a rightward shift of the Frank-Starling relationship was observed in SHR. This rightward shift seems mainly to depend on the increased MAP present in SHR since it was less prominent if MAP was lowered to normotensive levels in SHR. Maximal SV during volume infusion was similar in SHR and WKY, despite a much higher MAP in SHR. When peak SV was instead compared at similar MAP levels for both (either at normotensive' or 'hypertensive' levels) it was always significantly greater in SHR, and was increased largely in proportion to their increased left ventricular weight. This indicates that the left ventricular hypertrophy present in SHR is, at least at this stage, a physiological adaptation of the heart to increase its performance, in order to maintain a normal SV and hence cardiac output, despite an increased arterial pressure.

It has been much discussed whether left ventricular hypertrophy (LVH) in hypertension implies improved or impaired cardiac performance, mainly because experiments in various hypertensive models have given controversial results. It has, for example, been suggested that increased collagen content may depress LV function both in renal and spontaneous hypertension (SHR) in rats. For such reasons cardiac performance was studied both in SHR and in normotensive control rats (NCR) before and during superimposed two-kidney, one clip Goldblatt hypertension, and also 1 week after reversal of hypertension by unclipping. The LV function of the isolated hearts was determined in an antegrade working heart perfusion system. Further, myocardial morphology, with regard to fibrous tissue infiltration and energy metabolic status, were evaluated in the renal hypertensive rats before and after unclipping. Compared with NCR, maximal cardiac performance was elevated in the hypertrophied SHR hearts, but depressed when renal hypertension was superimposed, even though this led to further LVH. However, one week after reversal of renal hypertension, when LVH was still considerable, cardiac function was increased well above the control level, even though the stores of high energy compounds and the content of myocardial fibrous tissue was almost the same as during renal hypertension. It is concluded that LVH generally enhances cardiac performance, but that concomitant renal hypertension exerts a cardio-depressive influence which can neither be ascribed to an increased fibrous tissue content nor to a reduced energy charge potential. It is therefore suggested that some negative inotropic agent of renal or extrarenal origin is released during two-kidney, one clip renal hypertension, which offsets the enhanced performance induced by the left ventricular hypertrophy.

The relationships between cardiac performance, coronary flow, coronary vascular resistance at maximal vasodilatation and myocardial oxygen consumption were determined in isolated hearts from spontaneously hypertensive rats (SHR), normotensive Wistar-Kyoto rats (WKY) and from SHR given metoprolol (beta 1-selective blocker) and felodipine (selective calcium antagonist) for 35 weeks. A working heart perfusion system was used. An oxygen electrode allowed continuous measurement of oxygen tension in the venous coronary effluent. Blood pressure was reduced close to normal levels in treated SHR. Treatment also caused a substantial reduction of left ventricular weight. In both treated and untreated SHR, maximal cardiac performance, expressed as peak stroke volume, was enhanced above that of WKY at high perfusion pressures, while performance at low perfusion pressures was clearly reduced in the former groups. At a given workload, myocardial oxygen consumption (mmol O2/min per g) was reduced in both groups of SHR. This suggests a physiological structural adaptation to an elevated cardiac load in hypertension, where more myofibrils contribute to produce a given amount of work and therefore less oxygen is consumed per unit muscle mass. Coronary flow was reduced at any given perfusion pressure and oxygen extraction was increased in untreated SHR versus WKY. By causing regression of hypertensive structural vascular changes, treatment markedly increased coronary flow and correspondingly decreased oxygen extraction. Thus, by enhancing the myocardial nutritional supply with antihypertensive treatment, the reduced cardiac function at low perfusion pressure in untreated SHR was almost normalized.

Left ventricular (LV) function and end-diastolic dimensions were determined during antegrade and retrograde perfusions, respectively. Isolated hearts from spontaneously hypertensive rats (SHRs) and renal hypertensive rats and SHRs to which either feldopine, nifedipine, alpha-methyldopa, or a combination of felodipine and metoprolol was administered were used. Maximal cardiac function [cardiac output x (aortic pressure - left atrial pressure)] was elevated in SHRs, but depressed in those with renal hypertension. The diastolic pressure-volume relationships revealed eccentric rather than concentric LV hypertrophy in the SHRs. Renal hypertension in SHRs caused concentric LV hypertrophy. Antihypertensive therapy with calcium antagonists (but not with alpha-methyldopa) caused reduction of LV wall thickness, but increased LV end-diastolic volume (EDV). In SHRs, coronary flow was reduced at any given level of aortic pressure. At low aortic pressures (and hence, limited coronary perfusion), cardiac function was attenuated in SHRs. This reduction could be reversed by administration of antihypertensive therapy. These results suggest an improvement in maximal stroke work in SHRs as a result of eccentric hypertrophy which allows increased stroke volume for a given degree of myocardial shortening. Structural coronary vascular changes, which can be reversed by antihypertensive therapy, can limit coronary perfusion--and hence, cardiac performance--at low aortic pressures in SHRs. Maintenance of maximal cardiac function in treated SHRs, despite a reduction in LV wall thickness, may be due to an increase in LV end-diastolic volume.

1. Central blood volume and total blood volume were determined in spontaneously hypertensive rats and Wistar-Kyoto rats at two ages (6 and 12 weeks), representing 'borderline' hypertension and early 'established' hypertension. 2. A technique was used where plasma and erythrocyte indicators were injected into conscious rats. Blood volume in the cardiopulmonary compartment, present in the 'resting' awake steady state, could then be estimated by sudden freezing of the entire rat. 3. Twelve week-old spontaneously hypertensive rats showed a decreased total blood volume, and the fraction of blood contained in the cardiopulmonary area was significantly increased compared with that of normotensive Wistar-Kyoto rats. 4. In 6 week-old spontaneously hypertensive rats, total blood volume was only marginally decreased but here also a tendency towards centralization of the blood was seen. 5. Thus, along with the development of spontaneously hypertensive rat hypertension, a decreasing blood volume tends to become increasingly centralized to the cardiopulmonary area. Both neuro-hormonal influences and structural wall changes in the low-pressure capacitance side may contribute to this.

1. The influence of different arterial pressures on the relationship between diastolic filling pressure and stroke volume was studied during pharmacological cardiac nerve blockade in adult, anaesthetized spontaneously hypertensive rats in comparison with matched normotensive Wistar--Kyoto rats. 2. Peak stroke volumes, obtained by rapid blood volume expansion were similar in both types of rat, despite a more than 40% higher mean arterial pressure in the spontaneously hypertensive rats. 3. When peak stroke volumes were compared in the two groups at equal 'normotensive' or 'hypertensive' arterial pressures, they were always greater in the spontaneously hypertensive rats. 4. Calculation of diastolic wall/lumen ratios indicated that the increase of maximal stroke work in the spontaneously hypertensive rats closely matched the hypertrophic increase in wall/lumen ratio of the left ventricle. 5. These results indicate that left ventricular hypertrophy in established primary hypertension is a physiological adaptation to match left ventricular performance to the raised afterload.

The present study examined changes in left ventricular design and function in spontaneously hypertensive rats (SHR) and normotensive Wistar Kyoto rats (WKY), and in SHR exposed to voluntary physical exercise in running wheels (R-SHR) and their respective sedentary controls (C-SHR). End-diastolic volumes were obtained in vitro by determining the pressure-volume relationships of isolated hearts arrested in diastole. Cardiac function and myocardial oxygen consumption were also assessed in vitro by means of an antegrade working heart perfusion technique. Compared with WKY and C-SHR respectively, ordinary SHR and R-SHR had increased end-diastolic volumes, whereas the ratios between wall thickness and internal radius were relatively unchanged. Maximal cardiac performance was elevated in the structurally enlarged SHR heart compared with WKY, whereas it remained unchanged after chronic physical exercise. Long-term voluntary running in SHR caused an elevation of cardiac output due to an increased stroke volume, while arterial pressure was unaltered. The stimulus for the cardiac redesign to a structurally enlarged heart can probably best be explained by a chronic elevation in cardiac filling. Hence, enlarged left ventricles can then produce higher stroke volumes for given degrees of myocardial fibre shortenings. Thus, despite structurally enlarged left ventricles in SHR and in R-SHR and also increased arterial pressure in SHR compared with WKY (thereby elevating systolic wall stress), cardiac function was maintained and even augmented, which was not associated with an increase in total myocardial oxygen consumption.

The aim of the study reported was to explore differences in neuro-effector characteristics of the resistance vessels from normotensive and hypertensive rats (WKY and SHR), which from five to twelve weeks of age had been exposed to either low-sodium (0.5 mM/100 g food), control-sodium (5 mM/100 g) or high-sodium (50 mM/100 g) diet. Isolated small mesenteric arteries (diameter 150-200 microM) were mounted in a two-vessel Mulvany-Halpern myograph. Noradrenaline sensitivity was similar in all arteries. Frequency-response curves of SHR arteries were steeper than in WKY. In both strains low-sodium curves were displaced to higher frequencies with little difference between control and high-sodium curves. Inhibition of the Na-K-ATPase with ouabain enhanced neurogenic responses more than noradrenaline responses, but to similar extents in all sodium groups. The results suggest that chronic low-sodium diet substantially reduces the total adrenergic transmitter release per impulse.

The relative influence of sympathetic and parasympathetic nervous control of heart rate and heart rate variability, of mean arterial pressure (MAP) and MAP variability was investigated in young spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). An on-line computerized system was used for continuous intra-arterial measurements of MAP and heart rate every 2.5 min in freely moving rats with indwelling arterial catheters. Variability was expressed as the standard deviation in each rat. Heart rate and MAP showed clear diurnal rhythms, both in WKY and SHR. Blood pressure variability was clearly higher in SHR than in WKY, both during dark active hours and during light hours of relative sleep, and it did not change in response to either beta-adrenoceptor or vagal blockade. Structural vascular changes with the consequent increase in vascular reactivity may be one explanation for the elevated blood pressure variability in SHR. Heart rate variability was clearly reduced in SHR compared with WKY. This may be due to a reduced tonic vagal discharge in SHR, whereby a vagally mediated tachycardia is eliminated. The vagal withdrawal is part of the defence reaction, which is more easily elicited in SHR than in WKY.

Spontaneously hypertensive rats (SHR) were given either 'low' (LNa; 0.5 mmol Na 100 g-1 food), 'control' (CNa; 12 mmol) or 'very high' (vHNa; 120 mmol) sodium diets from 5 to 13-14 weeks of age, to explore how these 240-fold variations in Na intake affected body weight, cardiac, renal and adrenal weights, overall water-electrolyte equilibrium and haemodynamic balance during rest, mental stress and blood loss. Body growth was retarded both in vHNa and LNa SHR presumably reflecting disturbed appetite due to the greatly altered dietary Na contents. Compared with CNa SHR, both cardiac and renal weights 100 g-1 body wt were slightly increased in vHNa and decreased in LNa SHR, with opposite changes of adrenal weights. Total body water, haematocrit and plasma Na-K levels were largely equal in the three groups. Furthermore, cardiac output (CO), stroke volume (SV) and central blood volume (CBV) did not differ significantly between groups; if anything, CO and SV were higher and CBV lower in vHNa and LNa SHR than in CNa SHR. However, while mean arterial pressure (MAP) was only marginally elevated in vHNa compared with CNa SHR, both MAP and total peripheral resistance (TPR) were lowered about 15% in LNa SHR with signs of increased sympathetic activity to the heart also during rest. Despite an apparently normal volume and cardiac output balance in LNa SHR, the latter changes suggest a disturbed neuro-hormonal cardiovascular control.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study examined changes in left ventricular design in spontaneously hypertensive (SHR) and normotensive Wistar-Kyoto (WKY) rats in response to different types of antihypertensive therapy. Blood pressure was reduced for 12 weeks by either peripheral vasodilators [hydralazine or felodipine (calcium antagonist)] or by sympatholytic drugs (alpha-methyldopa or metoprolol). End diastolic volumes (EDV) were obtained in vitro by determining the diastolic pressure-volume relationships of isolated perfused hearts, arrested in diastole by excluding calcium from the perfusate. Wall thickness (w) and internal radius (ri) were calculated from a ventricle considered as a spherical model. Compared with WKY, untreated SHR had elevated EDV and w. Vasodilator therapy, particularly felodipine, increased EDV but reduced w, while sympatholytic therapy with alpha-methyldopa reduced EDV in SHR. It is suggested that cardiac design is affected not only by the prevailing arterial pressure level which will affect w, but also by the haemodynamic situation. Vasodilators turn such a situation into one characterized by increased cardiac output and hence increased cardiac filling, whereas sympatholytic drugs by venodilatation will turn the haemodynamic situation towards a state characterized by reduced cardiac filling. Left ventricular EDV (ri) therefore seems to adapt to long-term filling conditions, while w adapts to bring w:ri ratio in balance with the pressure load.

The relationships between cardiac performance, coronary flow, minimal coronary vascular resistance and myocardial oxygen consumption (MVO2) were explored in isolated hearts from spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto rats (WKY) and in hearts from SHR given a combination of metoprolol and felodipine (selective calcium antagonist) for 35 weeks. Antihypertensive therapy markedly reduced arterial pressure and caused a substantial regression of left ventricular hypertrophy. An antegrade working-heart perfusion system was used, allowing measurements of stroke volume, coronary flow and MVO2 at varying pre- and afterloads. In untreated SHR cardiac function was reduced at low and enhanced at high perfusion pressure compared with WKY. Minimal coronary vascular resistance, which was greatly increased in SHR, was significantly reduced by treatment, allowing higher coronary flow for any given perfusion pressure and consequently a lower degree of oxygen extraction. In addition, at a given workload, MVO2 was reduced in both untreated and treated SHR. These results stress the importance of having adequate coronary perfusion within a hypertensive structurally redesigned coronary vascular bed in order to maintain cardiac performance. With antihypertensive therapy in SHR, an improved coronary flow capacity was created due to regression of the hypertensive vascular changes.

Pheochromocytomas are rare chromaffin cell tumors that nevertheless must be excluded in large numbers of patients who develop sustained or episodic hypertension as well as in many others with suggestive symptoms or with a familial history of pheochromocytoma. Diagnosis of pheochromocytoma depends importantly on biochemical evidence of excess catecholamine production by a tumor. Imperfect sensitivity and specificity of commonly available biochemical tests and the low incidence of the tumor among the tested population mean that considerable time and effort can be expended in confirming or ruling out pheochromocytoma in patients where the tumor is suspected. Measurements of plasma free metanephrines provide a superior test compared to other available tests for diagnosis of pheochromocytoma. In particular, the high sensitivity of plasma free metanephrines means that a normal test result reliably excludes all but the smallest of pheochromocytomas so that no other tests are necessary. Measurements of plasma free metanephrines, when systematically combined with other diagnostic procedures outlined in this review, provide a more efficient, reliable and cost-effective approach for diagnosis of pheochromocytoma than offered by previously available approaches.

Summary: Method: In this prospective intervention study, 33 obese patients with obstructive sleep apnoea syndrome (OSAS) (24 men, 9 women) were consecutively enrolled for a weight reduction program at the Obesity Unit, Karolinska University Hospital. 23 of 33 patients used OSAS-device, 19 with Continuous Positive Airway Pressure and 4 with Mandibular Retaining Device. The patients were investigated with questionnaires, blood tests and ambulant nocturnal polysomnography before and after a 6-month program. Patients with OSAS-device slept without it during the sleep studies. The intervention consisted of 8 weeks low calorie diet and group meetings, followed by a day-care program of behaviour change support. Results: 27 of 33 patients (82%, 21 men and 6 women) completed the study. After the intervention there were highly significant decreases (p <0.001) in Body Mass Index from mean(S.D.) 40(5) to 34(3), apnoea–hypopnoea index from 43(24) to 26(20) and Epworth Sleepiness Scale (ESS)-score from 9(4) to 6(4). Sleep quality (arousal index, sleep efficiency, percentage deep sleep) and metabolic status (blood pressure, blood glucose levels, lipidemia) were also significantly improved. There was a significant correlation between increased percentage deep sleep and reduced ESS-score. There were no differences due to gender or use/no use of OSAS-device. Conclusion: The results suggest that weight loss, induced by low calorie diet and behaviour change support, significantly improves nocturnal respiratory parameters, sleep quality, daytime sleepiness and metabolic status in obese OSAS patients after 6 months. [Copyright &y& Elsevier]