The phenotypic patterns of essential hypertension are the key to identifying "high blood pressure" genes.

The genes that cause or increase susceptibility to essential hypertension (EH) and related animal models remain unknown. Their identification is unlikely to be realized with current genetic approaches, because of ambiguities in the genotype-phenotype relationships in these polygenic disorders. In turn, the phenotype is not just an aggregate of traits, but needs to be related to specific components of the circulatory control system at different stages of EH. Hence, clues about important genes must come through the phenotype, reversing the order of current approaches. A recent systems analysis has highlighted major differences in circulatory control in the two main syndromes of EH: (1) stress-and-salt-related EH (SSR-EH)--a constrictor hypertension with low blood volume; (2) hypertensive obesity--SSR-EH plus obesity. Each is initiated through sensitization of central synapses linking the cerebral cortex to the hypothalamic defense area. Several mechanisms are probably involved, including cerebellar effects on baroreflexes. The result is a sustained increase in sympathetic neural activity at stimulus levels that have no effect in normal subjects. Subsequent progression of EH is largely through interactions with non-neural mechanisms, including changes in concentration of vascular autacoids (e.g., nitric oxide) and the amplifying effect of structural changes in large resistance vessels. The rising vasoconstriction increases heterogeneity of blood flow, causing rarefaction (decreased microvascular density) and deterioration of vital organs. SSR-EH also increases food intake in response to stress, but only 40% of these individuals develop hypertensive obesity. Their brain ignores the adiposity signals that normally reduce eating. Hyperinsulinemia masks the sympathetic vasoconstriction through its dilator action, raises blood volume, whilst renal nephropathy and other diabetic complications are common. In each syndrome the neural and non-neural determinants of hypertension provide targets for identifying high BP genes. Reading the genome from the phenotype will require new approaches, such as those used in developmental genetics. In addition, transgenic technology may help verify hypotheses and examine whether an observed effect is through single or multiple mechanisms. To obtain answers will require substantial collaborative efforts between physiologists and geneticists.

Assessment of prevalence of left ventricular hypertrophy in hypertension.

The reported prevalence of left ventricular hypertrophy (LVH) in human hypertension is much lower than that among animals with experimental hypertension. With current methods of determining left ventricular mass by M-mode echocardiography, the standard error of a single estimate is high and consequently so is the SD of the population distribution. This accounts for the large overlap in individual values of left ventricular mass index (LVMI) between hypertensive and normotensive groups. The high SD is due to the use of the cube algorithm for relating measurements made in a single plane to the whole left ventricle, and to the difference between actual and assumed left ventricular geometries. These are not problems with nuclear magnetic resonance imaging, which provides information about the entire left ventricle without assumptions about geometry. M-mode echocardiography is well suited for estimating differences between mean LVMI values for groups of subjects but it underestimates the prevalence of LVH. In most series only about 30% of hypertensives have been reported to have LVH. The estimated prevalence of structural remodelling is increased to 50-60% of the same group of subjects when 'low-SD' measurements such as wall thickness and the wall thickness: internal radius ratio are employed. The estimated prevalence of LVH and remodelling is still greater with multivariate discriminant function analysis, with which it is found in about 70% of hypertensives. Overall, the data suggest that prevalence of LVH in established hypertension is high. The 30% of subjects reported to have LVH on the basis of LVMI measurements that are beyond the limits of the control group probably have the most severe changes. The inability to detect lesser grades of left ventricular remodelling reliably is due to the way LVMI is derived by echocardiography, rather than to intrinsic inaccuracies. It suggests that existing approaches should be supplemented by greater use of 'low-SD' variables and discriminant functions. Detecting the full spectrum of left ventricular structural changes in individuals with hypertension is needed for risk assessment and, increasingly, for management aimed at minimizing irreversible myocardial damage. Nuclear magnetic resonance imaging provides 'global' and more accurate information about left chamber structure than does M-mode echocardiography but its cost at present is much greater. Nevertheless, the information provided by echocardiography may be adequate for the above applications, but the high SD of LVMI is a weakness. Greater use of 'low-SD' variables and multivariate discriminant functions may help overcome this problem.

Circulatory control and the supercontrollers.

NEUROHUMORAL SYSTEMS AS SUPERCONTROLLERS: The brain and closely linked hormone systems play a crucial part in short- and long-term cardiovascular control and have many features of adaptive control systems. The cardiovascular control system is a multivariate system, while changes in environmental conditions often result in alterations in system parameters and other non-linearities, in contrast to the fixed parameters of linear control systems. In blood pressure control these features are exemplified by diurnal circadian fluctuations, alterations in lifestyle and psychosocial stress. Because the neurohumoral controllers are involved in virtually all aspects of homeostasis, they can be regarded as supercontrollers. THE CIRCULATORY SYSTEM AND THE BRAIN: Analysis in conscious animals of the effects of circulatory disturbances suggests that the central nervous system integrates information from multiple sources of afferents. Integration of the information associated with most reflex and behavioural disturbances is mediated by many neuron groups at different levels of the neuraxis, including suprapontine brain regions. The disturbances considered include baroreflexes in intact animals, some central actions of alpha-methyldopa and reflex responses to hypoxia and haemorrhage. The operations involve the brain in comparisons of the relative magnitude of different inputs, while the occurrences of non-linear changes in baroreflex properties signify alterations in the parameters of the controller. NEUROHUMORAL MECHANISMS AND CARDIOVASCULAR DEVELOPMENT: Neurohumoral mechanisms also play a key role in cardiovascular development. Increased sympathetic activity early in life causes hypertension in spontaneously hypertensive rats (SHR) and accounts for the differences in blood pressure and structural variables from corresponding values in Wistar-Kyoto (WKY) rats. In contrast, the renin-angiotensin system affects early cardiovascular development in the same way in each strain, so that it is unlikely to be a cause of hypertension in SHR. However, after drug withdrawal following treatment of young rats with the angiotensin converting enzyme inhibitor enalapril, there were between-strain differences in late cardiovascular development. Late development is relatively small in SHR compared to WKY rats, which contributes to the long-term attenuation of hypertension in SHR and to the normalization of blood pressure in WKY rats.

Cardiovascular development after enalapril in spontaneously hypertensive and Wistar-Kyoto rats.

We studied the long-term effects after withdrawal of enalapril, an angiotensin-converting enzyme inhibitor, on tail systolic pressure and cardiovascular structural properties in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Observations in control rats were from 4 to 35 weeks of age, whereas treated rats received enalapril from 4 to 20 weeks and were studied for a further 15 weeks. We measured blood pressure and the ratio of left ventricle weight to body weight and derived methoxamine log dose-perfusion pressure curves in the isolated hindquarter bed. From the changes in resistance properties we also estimated the changes in structure using a model developed previously. During therapy, blood pressure was depressed to a common value in both strains. After drug withdrawal, by age 35 weeks, previously treated SHR developed only mild hypertension, whereas blood pressure of WKY had recovered to the corresponding control level. At 21 weeks, soon after enalapril was stopped, left ventricular development was depressed in both strains; the depression was slightly greater in SHR, but that of vascular resistance was proportionately similar in each strain. Late cardiovascular development between 21 and 35 weeks was attenuated in the previously treated groups. For the left ventricle, it was similar in each strain, but for the vasculature, late development was relatively smaller in SHR than WKY. In the former, the pattern of development between 21 and 35 weeks was the same as in untreated controls and appeared to be mediated in response to the rise in blood pressure.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular hypertrophy and hypertension: causes and consequences.

In chronic hypertension, vascular resistance is raised and there is concentric left ventricular (LV) hypertrophy, at least in animal models. Together these changes enhance hemodynamic performance ("amplifier" properties) and help maintain elevated blood pressure (BP) and net microcirculatory exchange. Sometimes there is vascular "remodelling", with only luminal narrowing, but no net increase in medial mass. This can be related to non-uniform distribution of wall stress: when the amount of hypertrophy normalizes average wall stress, that on luminal side tends to be undercorrected accounting for preferential growth in that direction, whilst stress on the adventitial side is overcorrected, which results in a tendency to reabsorb material. In Goldblatt hypertension, about 20% of the rise in BP is due to the renal artery stenosis resistance, with the rest differing during the early and late phases: the early contribution is due to angiotensin II (AngII)-mediated systemic constriction and subtle fluid volume changes, whilst later on the cardiovascular amplifiers take over many of the actions of AngII. In SHR, trophic sympathetic nervous system actions are crucial for the rise in BP and development of structural changes and both contribute to the elevation of BP. Neonatal sympathectomy + prazosin treatment prevents hypertension and structural changes in SHR. Angiotensin converting enzyme (ACE) plays a similar role in cardiovascular development in SHR and Wistar Kyoto (WKY) rats. Prolonged administration of ACE inhibitors to SHR produces long term attenuation of hypertension because of an impaired capacity for cardiovascular development in adult animals. In human hypertension, long term treatment with common antihypertensive drugs is required to produce substantial regression of cardiovascular hypertrophy. Since it imposes marked non-uniformity on the distribution of capillary blood flow, with the potential for rarefaction and organ damage, therapy aimed at regression of hypertrophy is a worthwhile target.

Factors influencing the success of withdrawal of antihypertensive drug therapy.

We have reviewed the literature on the effect of withdrawal of antihypertensive therapy on return to hypertension. We also present our data from 83 patients in whom a 12-month follow-up period showed that 28% required re-institution of therapy within 10 weeks of withdrawal of medication, over half by 20 weeks, but a significant proportion (28%) stayed normotensive off therapy for a year. All patients had met the criteria for resumption of antihypertensive medication after 2 years of therapy. We also demonstrated predictive effects of left ventricular hypertrophy and duration of therapy on rate of redevelopment of hypertension. Our study raises the possibility that echocardiography may indicate the likelihood of a rapid return to hypertension when drug therapy is ceased.

Cardiac baroreflex in hypertension: role of the heart and angiotensin II.

Sigmoid logistic function curves provide a powerful means of characterizing the baroreceptor-heart rate reflex. In hypertension the operating range of the reflex is reset in the direction of the elevated resting BP; this can be accounted by rapid resetting of the threshold of the arterial baroreceptors. In addition, there is a deficit in the vagal component of the heart rate (HR) range. Reduction in gain occurs in moderate/severe hypertension, but may be absent in young primary hypertensives. All the changes are reversible, and reversibility of HR range and gain is related to reducing left ventricular hypertrophy or central blood volume rather than to reduction in BP. High plasma angiotensin II can further accentuate the vagal deficit. An input-output model has been developed from comparison of perivascular cuff and drug methods for eliciting the reflex, which place different loads on the heart; the greater load changes simulate many of the alterations in reflex properties observed in hypertension. We conclude that during changes in vasomotor tone in normal animals, about 70% of the drive for the cardiac baroreflex comes from arterial baroreceptors and about 30% from low threshold cardio-pulmonary baroreceptors. In hypertension, the vagal deficit in HR range is due to afferent interactions involving arterial and low and high threshold cardio-pulmonary baroreceptors.

Differential role of brain ascending noradrenergic bundles in the circulatory effects of alpha-methyldopa and clonidine.

We examined the contribution of the ascending noradrenergic (NA) projections to the circulatory effects of intracisternal (i.c.) administration of clonidine and alpha-methyldopa (alpha-MD) in conscious rabbits. We compared the effects of combined dorsal and ventral NA fibre bundle lesions with those of individual bundle lesions. Local microinjection of 6-hydroxydopamine (6-OHDA) bilaterally into both NA fibre bundles in the midbrain produced marked reduction in norepinephrine (NE) after 4 weeks in all forebrain regions examined, but dopamine concentrations generally were not affected. The decreases in mean arterial pressure (MAP) and heart rate (HR) to i.c. injections of clonidine in animals with forebrain NE depletion were similar to those observed in vehicle-injected animals. In contrast, the normal decrease in HR produced by alpha-MD was abolished in rabbits with lesions of both the dorsal and ventral NA bundle (8% of control) and markedly reduced in rabbits with lesions of only the ventral bundle (33% of control). Lesions of the dorsal bundle alone produced a modest attenuation of bradycardia (62% of control). The effects of the lesions were not observed in sinoaortically denervated (SAD) rabbits, suggesting that the main component of the bradycardia affected was baroreflex vagal facilitation. The effects on the hypotension produced by alpha-MD were only slight.(ABSTRACT TRUNCATED AT 250 WORDS)

Afferent control of vasopressin and renin release during haemorrhage in normal and autonomically blocked rabbits.

1. The role of the arterial and cardiac baroreceptors on the arginine vasopressin (AVP) and plasma renin activity (PRA) responses to haemorrhage was studied in conscious rabbits. They were bled at a rate of approximately 3% of their blood volume (BV)/min, both when the autonomic nervous system (ANS) was intact and during ANS blockade, which markedly enhances the AVP response due to the much greater haemodynamic disturbance. Under each condition of ANS function 2 x 2 factorial analysis was performed, each with four groups of rabbits, including animals with both sets of baroreceptors working, one or other set working and neither set working. 2. With intact ANS, haemorrhage had to be terminated at different times in the four groups. This presents problems for factorial analysis due to differences in the relationship between plasma AVP (or PRA) and release rate. A method for overcoming this was developed by extrapolating the BV-log AVP curves to a common time from the start of bleeding. 3. Under both conditions of ANS function the arterial and cardiac baroreceptors together accounted for 90-95% of the rise in AVP during haemorrhage. With normal ANS function, the rise in AVP was about 70% through cardiac (probably ventricular) baroreceptors (P = 0.01) and about 30% through arterial baroreceptors (P = 0.08). This compares with an earlier study at a rate of bleeding of 1.8% BV/min, where the entire drive came from the cardiac receptors. During ANS blockade, plasma AVP was enhanced approximately five-fold, which was mostly mediated through the arterial baroreceptors, but the cardiac baroreceptor component was also greater; arterial/cardiac baroreceptor drive was 2/1. 4. Baroreflexes played no role in renin release during haemorrhage, but the experiments with ANS blockade suggest that a hormonal factor, which was related to the cardiac innervation, may limit the rise in PRA in the latter part of haemorrhage.

Structural determinants of vascular resistance properties in hypertension. Haemodynamic and model analysis.

The average internal radius (ri) of the resistance vessels of the hindquarter (HQ) bed was narrower in renovascular and genetic hypertension than in normotensive controls. The narrowing was approximately uniform over the full range of vasomotor tone, which accounted for the bed's property as an 'amplifier' of vascular resistance (R) (increased slope (S) of the dose-R response curve) and for the elevated R at maximum dilatation (Rmin). In the model we examined the effects on the dose-R curve parameters of altering wall/internal radius (w/ri) ratio, ri and wall 'stiffness' one at a time, whilst the others were held constant: only narrowing of ri led to increases in both S and Rmin; with hypertrophy alone, S increased but Rmin was reduced, whilst increased wall stiffness increased Rmin but lowered S. Thus, for hypertrophy to be associated with rises of both S and Rmin, it must be linked to lumen narrowing, to increased wall stiffness, or to both. Preferential deposition of new material towards the lumen will link hypertrophy to narrowing. It has been suggested that narrowing can occur without hypertrophy ('remodelling'). In the model an increase of only 1-2% WV was required to produce rises in w/ri of congruent to 30-50% when associated with congruent to 10-15% reduction in ri, which is close to the limit of detection. From the literature, the sites of greater narrowing in hypertension extend down to small arteries and large arterioles. The rise in BP upstream from those sites, due to the vascular amplifier, offsets the down-stream effects of vascular narrowing on blood flow and this negative feedback system helps to maintain elevation of BP at a stable level. We also examined developmental rise in R between 4 and 50 weeks, which affected SHR and WKY in the same proportion: structural factors (vascular length of larger arteries, 'rarefaction' of arterioles and capillaries) accounted for only about half the rise in R, and the remainder was probably due to developmental changes in muscle function.

Release of endothelium-derived relaxing factor from resistance arteries in hypertension.

Aortic rings from SHR are reported to have a decreased relaxation response to the endothelium-dependent agent acetylcholine compared with rings from WKY rats. Thus, a reduced EDRF (nitric oxide) response could contribute to hypertension. We found that in mesenteric small resistance arteries (200 microns I.D.) taken from 5- to 50-week old rats and mounted in a Mulvany-Halpern myograph, that the concentration-response curves to acetylcholine were similar in range and sensitivity (EC50) in arteries from SHR and WKY rats at the same age. Similarly, in small resistance arteries from human buttock skin, the relaxation to acetylcholine was not different between vessels from normotensive volunteers (mean BP = 95.2 +/- 1.5 mm Hg) and patients with untreated essential hypertension (mean BP = 116.5 +/- 2.5 mm Hg). In rabbits with chronic renovascular hypertension (cellophane renal wrap), acetylcholine and adenosine infusions into the lower abdominal aorta caused falls in hindquarter resistance that were enhanced in range, but with no change in sensitivity compared with normotensive rabbits. In normotensive rabbits, nitric oxide synthase inhibition with N omega-nitro-L-arginine infusion caused a rise in blood pressure, fall in hindquarter conductance and blockade of the acetylcholine responses. These experiments suggest that at the level of resistance arteries in vivo and in vitro, a defect in the receptor-stimulated response to EDRF associated with hypertension could not be detected. Apparently, basal nitric oxide is important in resting vasodilator tone, but its role in chronic hypertension is still unclear.

Are cardiac and vascular "amplifiers" both necessary for the development of hypertension?

The vascular amplifier leads to enhancement of all resistance responses, from full dilatation to maximum constriction. The mechanism of resistance amplification is narrowing of the resistance vasculature, which is approximately constant at all levels of vasomotor tone. From the literature, the site of narrowing is localized to the small arteries and large arterioles. The narrowing at rest leads during constriction, to patchy reduction in blood flow in the microcirculation. The enhanced resistance responses of the vascular amplifier during constriction, increase blood pressure (BP) upstream, which minimizes the hemodynamic effects on the microcirculation and helps to maintain venous return. Concentric left ventricular (LV) hypertrophy is an amplifier of stroke volume and cardiac output. It reinforces the elevation of BP upstream from the site of vascular narrowing. This appears important for the initiation and maintenance of hypertension, in view of findings in SHR showing: (1) that in the course of normal development of hypertension the vascular amplifier properties develop before the onset of hypertension, which occurs in parallel with an increase in rate of LV hypertrophy; (2) after brief periods of enalapril treatment, hypertension redevelops in parallel with the redevelopment of LV hypertrophy, whilst the vascular amplifier properties remain suppressed; (3) treatment with immuno-sympathectomy plus prazosin prevents the development of both LV hypertrophy and hypertension but only produces gradual suppression of the vascular amplifier properties. The role of the sympathetic nervous system on LV-hypertrophy is mediated through alpha 1-adrenoceptors.

Exercise training reduces the sympathetic component of the blood pressure-heart rate baroreflex in man.

1. Exercise training reduces resting sympathetic activity, but the effects on sympathetic activation or withdrawal during baroreflex responses to blood pressure perturbations are controversial. The purpose of this study was to investigate the effects of training on both the vagal and sympathetic reflex heart rate responses to blood pressure changes. 2. Using 10 healthy males in a randomized cross-over design, we examined the effects of three 30 min cycling sessions at 70% of maximal capacity for 4 weeks on the steady-state reflex heart rate responses to perturbations in mean arterial pressure induced with injections of nitroprusside and phenylephrine. The method provides a sigmoidal relationship between changes in heart rate and blood pressure. The upper plateau (maximum tachycardia in response to blood pressure reduction) and lower plateau (maximum bradycardia in response to blood pressure elevation) are mainly mediated by the cardiac sympathetics and vagus, respectively. The slope of the relationship is a measure of reflex gain. 3. Training, which increased maximal oxygen consumption by 13 +/- 2% (mean +/- standard error of the difference), reduced supine and standing blood pressures by 3 +/- 1/3 +/- 1 mmHg (P less than 0.05) and 4 +/- 1/2 +/- 2 mmHg (P less than 0.05 for systolic), respectively, whereas resting heart rate was lowered by 6 +/- 1 beats/min (P less than 0.05). Reflex sensitivity in the presence of functioning vagus and sympathetics was not altered with training, but the vagal component of sensitivity, as assessed after sympathetic blockade with propranolol, was significantly reduced.(ABSTRACT TRUNCATED AT 250 WORDS)

Amplifier function of resistance vessels and the left ventricle in hypertension.

We have recently modeled the structural factors responsible for the increased slope of the dose-vascular resistance response curves in the hindquarter bed under both in vitro and in vivo conditions. Slope increases when the ratio of wall thickness to internal radius (ri) increases and when ri decreases, but the slope decreases with greater wall stiffness. Enhanced slope is an indicator of the vascular amplifier properties. Resistance at maximum vasodilation in hypertension is also structurally determined converting enzyme inhibitors in spontaneously hypertensive rats (SHR) suggest that the reduction in ri can be reversed, suggesting that it is due to vascular hypertrophy. The concentrically hypertrophied left ventricle is an amplifier of stroke volume. Together, the vascular and left ventricular amplifiers contribute about 70% to the elevated total peripheral resistance in renovascular hypertension. In SHR, the vascular amplifier is present early in postnatal life before the onset of hypertension, which occurs in parallel with left ventricular hypertrophy (LVH). The development of the vascular amplifiers appears to be under the control of the renin-angiotensin system, whilst LVH appears to be under sympathoadrenal control, acting through cardiac alpha-adrenoceptors. Early immunosympathectomy plus prazosin treatment specifically prevents development of LVH in SHR and also prevents hypertension. In human hypertension, cardiac hypertrophy also plays an important role; after a period of prolonged therapy, the rate of redevelopment of hypertension when the drugs are stopped depends on the degree of regression of LVH during treatment. We conclude that the early development of vascular and cardiac amplifiers in primary hypertension appears to be genetically determined and the role of the heart in pathogenesis appears to be greater than previously thought.

Left ventricular blood flow during aortic pressure reduction in hypertensive dogs.

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.

Afferent vascular resistance control during hemorrhage in normal and autonomically blocked rabbits.

We examined the role of the arterial and cardiac baroreceptors on the hindquarter conductance and heart rate responses of conscious rabbits bled at approximately 3% blood volume (BV)/min to 80% BV (i.e., 20% BV removed). We used rabbits with both sets of baroreceptors working and when only one or neither sets was working. Each animal was studied with normal effector function and during autonomic blockade (hormonal + local effectors), where release of arginine vasopressin (AVP) and renin (angiotensin II, ANG II) were enhanced. The local response (LR) to hemorrhage was determined in a separate group of neurohumorally blocked rabbits. The estimated constrictor response (ECR) was the difference between the LR and net conductance response. In normal rabbits, the ECR was 49 units, with the estimated arterial-to-cardiac barorecptor drive ratio approximately 2.8:1 and with the two receptor groups acting by simple addition. Both barorecptors contributed to the rise in heart rate, with the relative arterial-to-cardiac baroreceptor drive ratio approximately 4:1. When hemorrhage was performed during autonomic blockade, ECR was 84 units (compared with normal rabbits, P less than 0.01), but blood pressure was poorly maintained and the constrictor effect was not under baroreceptor control. Although the baroreceptors were critical for AVP release during autonomic blockade, they played no role in renin release (ANG II production); the latter was released in large amounts, producing near-maximum constriction, which was unrelated to the afferent input. Thus neurally mediated regulation during hemorrhage has substantial advantages over that mediated primarily through the pressor hormones.