Jahn Ha

Dose-Related Cardiovascular Effects of Spironolactone

The aim of this study was to assess the short-term hemodynamic effects of increasing doses of spironolactone (25, 50, and 75 mg/day) on oliguric patients (5 men, mean age 47 +/- 12 years) undergoing hemodialysis for chronic renal impairment. Parameters of interest included heart rate (HR), cardiac output, systemic vascular resistance (SVR), arterial pressure, right atrial pressure, and pulmonary capillary wedge pressure (PCWP). The study also evaluated how spironolactone modified the effects on arterial and right atrial pressures and PCWP of infusion of increasing doses of norepinephrine (20, 40, and 100 ng/kg/min) and angiotensin II (2, 4, and 10 ng/kg/min). Compared with placebo, the lowest dose of spironolactone (25 mg/day) produced statistically significant (p < 0.05) modifications in systemic arterial pressures without a compensatory increase in cardiac output. The modifications were more pronounced at 50 and 75 mg/day, and the latter had a significant dose-dependent effect. Moreover, doses of 50 and 75 mg/day produced significant (p < 0.05) decreases in right atrial pressure and PCWP. Spironolactone administration caused the curve expressing the relation between an infused norepinephrine or angiotensin II dose and the blood pressure response to shift significantly (p < 0.05 to < 0.01) to the right, and the pressor doses of norepinephrine or angiotensin II showed a significant (p < 0.05 to < 0.01) dose-related increase, suggesting that treatment with spironolactone inhibited cardiovascular reactivity. This effect was observed on both the capacitance (i.e., low-pressure) and resistance (i.e., high pressure) vessels.(ABSTRACT TRUNCATED AT 250 WORDS)

Mitogenic activity on human arterial smooth muscle cells is increased in the plasma of patients undergoing hemodialysis with cuprophane membranes.

During hemodialysis on cuprophane membranes, platelets are activated and release in plasma alpha-granule-specific substances such as PF4 or platelet-derived growth factor (PDGF). PDGF is the main source of mitogenic activity found in serum. In vitro, it induces the proliferation of smooth muscle cells (SMC) which is known to be involved in the development of atherosclerotic lesions. Atherosclerosis is one of the major complications of uremic patients undergoing chronic hemodialysis. To investigate whether this complication could be due to the dialysis itself, we measured the mitogenic activity in plasma of 10 patients undergoing hemodialysis on cuprophane membrane, using human arterial SMC in culture. Mitogenic activity in plasma increased about 3-fold during dialysis. These results may provide an argument in favor of a contribution of platelet activation and release of mitogenic activity to atherosclerosis in patients dialysed with cuprophane membranes.

Effects of a potassium-sparing/thiazide diuretic combination on cardiovascular reactivity to vasopressor agents

The vascular effects of a diuretic combination (spironolactone/altizide) were studied in 5 anuric patients undergoing dialysis by measuring changes in cardiovascular reactivity to norepinephrine (NE) and angiotensin II (AII) after infusion of incremental doses of these 2 vasopressor agents. There was a marked dose-response relation between NE and AII administration and mean (NE) or diastolic (AII) blood pressure (BP). Diuretic treatment moderated the increase in mean or diastolic BP induced by NE or AII. In addition, the pressor doses of NE and AII, which are also parameters of vascular reactivity, were significantly increased after diuretic treatment (NE, +101%; AII, +163%). Right atrial and pulmonary capillary wedge pressures increased along with BP in response to NE. Diuretic treatment also moderated the increase in right atrial and pulmonary capillary wedge pressures induced by NE. These results suggest that the antihypertensive action of spironolactone and altizide in combination is mainly due to a direct effect on resistance and capacitance vessels. The mechanisms by which diuretics modify the cardioreactivity remain poorly understood; however, they may modify electrolyte transport (sodium and calcium) across vascular smooth muscle cell membranes or stimulate prostaglandin release.

Long term effects of sustained release verapamil on the renal and systemic haemodynamic parameters in hypertensive patients with mild to severe chronic renal failure.

SummaryCalcium antagonists such as verapamil are among the antihypertensive agents categorised as first line treatments for essential hypertension. They have also shown efficacy in secondary forms of hypertension, including hypertension associated with chronic renal failure, irrespective of the degree of renal impairment. Systemic and renal haemodynamic parameters, and renal function were analysed in 15 hypertensive patients with mild to severe chronic renal failure after a 2-week placebo period and after 4 weeks of administration of verapamil sustained release (SR) 240 mg/ day. After 4 weeks of treatment with verapamil SR, blood pressure was normalised in all patients. Arterial pressure decreased as a result of the decrease in systemic vascular resistance, while cardiac output and heart rate remained unchanged. Verapamil therapy did not significantly affect left cardiac function curves.The normalisation of arterial pressure did not result in changes in the glomerular filtration rate; however, renal vascular resistance decreased significantly, although the filtration fraction remained unchanged. Renal blood flow increased significantly and there was a significant increase in uricosuria and a subsequent decrease in plasma uric acid levels.In conclusion, verapamil SR is an effective and well tolerated treatment for hypertension associated with chronic renal failure.