Ace inhibition in renal disease: risks and benefits.

The kidney is one of the principal target organs of hypertension and most diseases of the kidney are associated with blood pressure elevation. Studies in animal models of hypertensive renal disease have provided insights into the complex relationship between systemic and glomerular hypertension. The intrarenal renin-angiotensin system (RAS) appears to play an important role in the pathogenesis of progressive glomerular injury. Thus, angiotensin converting enzyme inhibitors (ACEi) may have a specific therapeutic advantage in the treatment of hypertension associated with progressive renal disease. However, in contrast to their possible renoprotective effect in diabetic nephropathy or in renal hypertension, there are increasing evidence that, in the presence of a reduction in renal perfusion, intrarenal haemodynamic effect of ACEi may lead to compromised renal function. ACEi appear to have dual effects on renal function depending on the setting in which they are administered.

Peripheral adrenoceptors in hypotension of hemodialyzed uremic patients.

Hypotension is a common problem in patients on hemodialysis. To further investigate this problem, the number of platelet alpha 2-adrenoceptors and the activity of lymphomonocyte beta 2-adrenoceptors were measured in 10 hemodialyzed patients with normal blood pressure and in 10 sex- and age-matched persistently hypotensive hemodialyzed patients. Density of alpha 2-adrenoceptors was assessed by the specific binding of 3H-yohimbine to intact platelets, while the function of beta 2-adrenoceptors was estimated by the production of cAMP after the exposure of lymphomonocytes to isoprenaline. The maximal number of alpha 2-adrenoceptors was increased in the hypotensive compared to the normotensive group (262.13 vs. 77.21 fmol/mg protein; p < 0.01). Plasma norepinephrine was higher in the hypotensive than in the normotensive uremic patients (640 +/- 195 vs. 344 +/- 156 pg/ml; p < 0.01). Plasma epinephrine did not differ in the two groups (90 +/- 30 vs. 94 +/- 24 pg/ml). The amount of cAMP, produced by stimulation of lymphomonocytes, was lower in the hypotensive than that in the normotensive uremic patients (7.7 +/- 2.4 vs. 15.6 +/- 5.4 pmol/10(6) cells; p < 0.002). The increased number of alpha 2-adrenoceptors together with a high level of norepinephrine and reduced activity of adenylate cyclase (coupled with beta 2-adrenoceptors) support the hypothesis that hypotension in the hemodialyzed uremic patients may be related to a defect in adrenoceptor coupling mechanisms.

An ultrasonographic method to measure the sensitivity of the baroreflex in clinical practice: application to pharmacological studies.

To determine whether it is possible to assess baroreceptor sensitivity by measuring changes in blood velocity in the carotid artery and changes in the heart rate, we performed a series of 108 experiments in 19 hypertensives aged 20-57 years (mean 46.6 +/- 8.6). In each experiment, we took simultaneous measurements of carotid artery blood flow velocity (Doppler technique), the brachial intra-arterial blood pressure and the heart rate, during a rapid and transient increase in blood pressure induced by injections of phenylephrine. We then calculated the maximum slope of the regression lines correlating blood velocity with the heart period (Trieste method) and blood pressure with the heart period (Oxford method). We obtained good accuracy from the Trieste method compared with the Oxford method, as assessed by the mean of the sum of the squares (difference + 5%, NS). After the administration of 4 mg oral lacidipine to 13 essential hypertensives, aged 37-54 years (47.6 +/- 5.3), baroreflex sensitivity was not changed, as assessed by either method (Oxford method 10.1 +/- 5.5 versus 9.8 +/- 6.2 ms/mmHg; Trieste method - 0.57 +/- 0.32 versus - 0.49 +/- 0.31 ms/Hz). The coefficients of variation for the two methods, calculated for the measurements taken before and after the administration of lacidipine, were not statistically different (Oxford method 25.0 +/- 18.4 versus 36.2 +/- 16.0; Trieste method 36.7 +/- 19.2 versus 39.7 +/- 19.2). The new non-invasive Trieste method thus showed the same accuracy and precision as the invasive Oxford method in measuring baroreflex sensitivity and can be used in pharmacological studies.

Reduction of blood pressure in obese hyperinsulinaemic hypertensive patients during somatostatin infusion.

Hypertension in the obese may be related to hyperinsulinaemia. To investigate this relationship further, we infused somatostatin (250 micrograms/h in 100 ml saline) or saline, single-blind and in a random order, for 10 h in seven obese hyperinsulinaemic hypertensive patients and in seven normo-insulinaemic hypertensive controls. Every 2 h, blood pressure, plasma insulin, glucose, sodium, potassium, renin, cortisol and aldosterone concentrations and the urinary sodium:creatinine ratio were determined. Two hours after the somatostatin infusion was started, mean arterial blood pressure was significantly reduced in the obese hyperinsulinaemic patients (from 128 +/- 11 to 114 +/- 11 mmHg, P less than 0.05) but not in the controls and this reduction persisted throughout the study. The somatostatin infusion reduced plasma insulin and increased plasma glucose similarly in both groups. Plasma sodium, potassium, renin, cortisol and aldosterone concentrations and the urinary sodium:creatinine ratio were unchanged after the somatostatin infusion. These results suggest that hyperinsulinaemia could help sustain the blood pressure rise in obesity.

Regional hemodynamic effects of slow-release nicardipine in elderly patients with hypertension: evaluation by a new ultrasound technique.

Blood flow in superficial vessels was measured by means of combined two-dimensional and continuous-wave Doppler echography. In vitro validation of the technique showed precision to within 10% at flow rates greater than 300 ml/min. Assessment of common carotid artery blood flow was used to calculate vascular resistance in a single-blind, crossover study of 16 elderly patients over the age of 60 years (mean 67.7 +/- 6.5) with essential hypertension. The pulsatility index of the brachial artery was also determined. Before the study patients had previously received either placebo (twice a day) for 2 weeks or slow-release (SR) nicardipine (40 mg twice a day) for 2 months. During the study patients received a single 40 mg dose of nicardipine SR, after which mean arterial blood pressure decreased from 131 +/- 11 to 110 +/- 10 mm Hg (p less than 0.001) and from 122 +/- 13 to 108 +/- 11 mm Hg (p less than 0.001) in patients who had previously received placebo and nicardipine, respectively. Carotid vascular resistance decreased from 14.6 +/- 2.9 to 10.4 +/- 2.8 mm Hg.sec.ml-1 (p less than 0.001) and from 14.6 +/- 4.1 to 11.0 +/- 2.0 mm Hg.sec.ml-1 (p less than 0.01), respectively. The pulsatility index of the brachial artery changed from 9.4 +/- 4.4 to 9.7 +/- 8.3 and from 8.2 +/- 4.3 to 9.4 +/- 4.1, respectively (not significant). These data show that nicardipine SR reduces resistance both in the common carotid artery and in the brachial artery. Furthermore this drug appears to have an additional effect on the distensibility of the large arteries.

Arterial compliance and baroreceptor sensitivity after chronic treatment with indapamide.

Arterial compliance, assessed by the ratio of stroke volume to pulse pressure, and baroreceptor sensitivity (Oxford method), were determined in ten patients with essential hypertension, treated with placebo or indapamide (2.5 mg/day), in a cross-over, single blind study. After three months of therapy, mean arterial pressure was significantly reduced from 127 +/- 10 to 118 +/- 9 mmHg, (P less than 0.001), as was total peripheral vascular resistance (from 3017 +/- 561 to 2457 +/- 614 dyne/sec/cm-5/m2, P less than 0.001). Significant increases occurred in cardiac index (3.47 +/- 0.55 to 4.03 +/- 0.86 l/min/m2, P less than 0.01), baroreceptor sensitivity assessed with phenylephrine (from 11.69 +/- 7.9 to 15.0 +/- 9.1 msec/mmHg, P less than 0.01) or with nitroglycerine (from 4.77 +/- 1.6 to 7.11 +/- 2.7 msec/mmHg, P less than 0.01) and arterial compliance (from 1.27 +/- 0.42 to 1.55 +/- 0.57, P less than 0.01). A significant direct correlation was found between arterial compliance and baroreceptor sensitivity assessed during induced increase and reduction of BP, both during placebo (r = 0.88, P less than 0.001 and r = 0.77, P less than 0.01, respectively) and during active therapy (r = 0.94, P less than 0.001 and r = 0.92, P less than 0.001, respectively). These results support the conclusion that chronic treatment with indapamide enhances arterial compliances and reduces the heart load and blood vessel stress. The same effect could explain the enhancement of baroreceptor sensitivity promoted by the drug.