Glomerular hyperfiltration predicts the development of microalbuminuria in stage 1 hypertension: the HARVEST

Factors related to the development of microalbuminuria in hypertension are not well known. We did a prospective study to investigate whether glomerular hyperfiltration precedes the development of microalbuminuria in hypertension. We assessed 502 never-treated subjects screened for stage 1 hypertension without microalbuminuria at baseline and followed up for 7.8 years. Creatinine clearance was measured at entry. Urinary albumin and ambulatory blood pressure were measured at entry and during the follow-up until subjects developed sustained hypertension needing antihypertensive treatment. Subjects with hyperfiltration (creatinine clearance >150 ml/min/1.73 m2, top quintile of the distribution) were younger and heavier than the rest of the group and had a greater follow-up increase in urinary albumin than subjects with normal filtration (P<0.001). In multivariable linear regression, creatinine clearance adjusted for confounders was a strong independent predictor of final urinary albumin (P<0.001). In multivariable Cox regression, patients with hyperfiltration had an adjusted hazard ratio for the development of microalbuminuria based on at least one positive measurement of 4.0 (95% confidence interval (CI), 2.1-7.4, P<0.001) and an adjusted hazard ratio for the development of microalbuminuria based on two consecutive positive measurements of 4.4 (95% CI, 2.1-9.2, P<0.001), as compared with patients with normal filtration. Age, female gender, and 24 h systolic blood pressure were other significant predictors of microalbuminuria. In conclusion, stage 1 hypertensive subjects with glomerular hyperfiltration are at increased risk of developing microalbuminuria. Early intervention with medical therapy may be beneficial in these subjects even if their blood pressure falls below normal limits during follow-up.     

ORTHOSTATIC HYPOTENSION AFTER THE FIRST ADMINISTRATION OF PRAZOSIN IN HYPERTENSIVE PATIENTS: ROLE OF THE PLASMA VOLUME

1. Prazosin (2 mg, p.o.) was administered to nine patients with essential hypertension while intra-arterial pressure was recorded by an Oxford portable apparatus. In all patients, 30 min-3 h after the administration, systolic and diastolic pressure fell on assuming the upright posture and four patients fainted. No correlation was found between the degree of fall in pressure and the plasma concentration of the drug. Acute expansion of the plasma volume by means of 6% Dextran infusion reduced the orthostatic blood pressure fall in all cases and a significant inverse correlation was found between plasma volume and orthostatic fall of pressure. 2. After ten days of continuous treatment with prazosin, 2 mg daily, a significant decrease in blood pressure was observed while orthostatic hypotension disappeared, probably due to the plasma volume expansion induced by the drug.     

Nephrotoxic effect of Atractyloside in rats

1. In male albino rats Atractyloside (50 mg/kg i.p.), well-known as inhibitor of oxidative phosphorylation, produces a tubular nephrosis 180 min after its administration. The nephrosis is characterized by a deep lesion in the cells of distal portion of proximal convoluted tubule and is accompanied by an increase of water excrection and by proteinuria, glicosuria, ketonuria, and kaliuria. The glomerulus appears intact; this is confirmed by the creatiniue and urea tests. The renal alteration subsides after 2 days of its onset. Similar effects are observed in mice but not in guinea pigs and rabbits.
2. Carboxyatractyloside (2 mg/kg i.p.), an analogue of atractyloside with a second carboxylic group in position 4, more active inhibitor of oxidative phosphorylation and more toxic, is devoid of any effect on rat kidney.
3. No functional or morphological alterations are observed in liver and heart of rats injected with these drugs.
4. The oxidative phosphorylation in homogenates of kidney and liver of rats pretreated with these compounds is inhibited to different extents.

The possible relationship between nephrotoxic effect of atractyloside and the inhibition of oxidative phosphorylation is discussed.     

Heart rate as a cardiovascular risk factor: do women differ from men?

Considerable progress has been made in our understanding of the role of high heart rate in determining cardiovascular morbidity and mortality. However, whether the association between fast heart rate and cardiovascular disease is equally strong in males and females is still a matter for debate. In most studies, the predictive value of tachycardia for all-cause mortality has been found to be weaker in women than in men, and in some studies no association between heart rate and cardiovascular mortality was observed. In particular, high heart rate appeared to be a weak predictor of death from coronary heart disease in the female gender. Multiple mechanisms by which sympathetic overactivity could cause hypertension and the metabolic syndrome of insulin resistance have been documented. Recent results obtained at the Ann Arbor laboratory from the analysis of four populations indicate that these mechanisms are operative mostly in males in whom tachycardia reflects a heightened sympathetic tone. In women, fast heart rate would merely represent the extreme of a normal distribution. However, tachycardia can also have a direct impact on the arterial wall, as demonstrated in laboratory studies, and can favour the occurrence of cardiac arrhythmias. The impact of these mechanisms may be similar in men and women and could explain why a high heart rate has been found to have a detrimental effect also in the female gender. Pharmacological reduction of high heart rate is an additional desirable goal of therapy in several clinical conditions such as hypertension, myocardial infarction and congestive heart failure. Although a greater effect is expected in men, cardiac slowing could counteract the detrimental haemodynamic effect of tachycardia also in women.     

Sympathetic overactivity in hypertension: a risk factor for cardiovascular disease

Numerous prospective studies have shown that high heart rate is related to the development of hypertension, atherosclerosis, and incidence of cardiovascular events. Experimental studies in monkeys have shown that high heart rate has direct atherogenic effects on the arteries as a result of increased wall stress. However, clustering of several risk factors for coronary artery disease in persons with high heart rate suggests that sympathetic overactivity also accounts for part of the increased cardiovascular morbidity that is observed in persons with tachycardia. Indeed, experimental studies have shown that heightened sympathetic tone can cause obesity, hyperinsulinemia, and insulin resistance, which in the long term can promote the development of atherosclerosis. Through its interaction with plasma insulin, sympathetic overactivity can promote the development of left ventricular hypertrophy. Sympathetic activation can also increase hematocrit and precipitate a procoagulant state. Angiotensin II has an effect both on the central nervous system, enhancing sympathetic outflow, and on the peripheral sympathetic nerves. Among the angiotensin II receptor antagonists, eprosartan showed a particular ability to block presynaptic angiotensin II receptor 1 (AT(1)) receptors at neuro-effector junctions in the sympathetic nervous system, as well as AT(1) receptors in blood vessels. This dual action may represent an important advance in treatment of elevated blood pressure.     

Intra-arterial blood pressure monitoring in the evaluation of the hypertensive athlete

To compare the blood pressure (BP) changes during a long-distance run with those during bicycle ergometry, nine normotensive and 18 hypertensive joggers were studied by means of ambulatory intra-arterial monitoring. In all subjects the ergometric test caused a progressive increase in systolic and little change in diastolic BP. Exertional BP levels were closely related to pre-exercise baseline values (P less than 0.001). A different BP pattern was observed during track running, as a sharp rise in systolic BP reaching maximum values 2-4 min after the start was recorded. Subsequently, systolic BP progressively declined throughout the run, only to increase again during the final sprint. Diastolic BP fell markedly at the onset of the run and then remained substantially stable throughout. A poor relationship was observed between the BP values at peak exercise and baseline levels (P less than 0.05) as the normotensives showed a significantly higher BP response than the hypertensives. On the contrary, during the ergometric test a parallel increase in BP was recorded in the normotensive and the hypertensive joggers. No correlation was found between the BP response to track running and to bicycle ergometry. These results indicate that the BP response to a standard stress test is not predictive of the BP changes determined by a long-distance run. The BP increase with strenuous effort seems to be reduced in hypertensive individuals, probably because of latent impairment of cardiac performance.