Effects of calcium entry blockers on renin-angiotensin-aldosterone system, renal function and hemodynamics, salt and water excretion and body fluid composition

The renal effects of the calcium entry-blocking drugs diltiazem, nifedipine, verapamil and nitrendipine are reviewed. Although nifedipine stimulates plasma renin activity on a short-term basis, none of the calcium entry blockers produces a clinically significant sustained effect on any of the components of the renin-angiotensin-aldosterone system. Although all of the calcium entry blockers effectively lower blood pressure, none adversely affects renal function; glomerular filtration rate and effective renal plasma flow are maintained. Diltiazem may increase glomerular filtration rate via attenuation of the intrarenal effects of angiotensin II or norepinephrine. Although diltiazem and nifedipine increase salt and water excretion on a short-term basis, none of the calcium entry blockers produces a clinically significant sustained effect on salt and water excretion; serum electrolytes, urinary sodium and potassium excretion, body fluid composition and body weight are unchanged. Thus, calcium entry blockers can be expected to assume a prominent role in the treatment of hypertension because of their ability to lower blood pressure while preserving renal perfusion and function.     

Nervous kidney. Interaction between renal sympathetic nerves and the renin-angiotensin system in the control of renal function

Increases in renal sympathetic nerve activity regulate the functions of the nephron, the vasculature, and the renin-containing juxtaglomerular granular cells. Because increased activity of the renin-angiotensin system can also influence nephron and vascular function, it is important to understand the interactions between the renal sympathetic nerves and the renin-angiotensin system in the control of renal function. These interactions can be intrarenal, for example, the direct (by specific innervation) and indirect (by angiotensin II) contributions of increased renal sympathetic nerve activity to the regulation of renal function. The effects of increased renal sympathetic nerve activity on renal function are attenuated when the activity of the renin-angiotensin system is suppressed or antagonized with ACE inhibitors or angiotensin II-type AT(1)-receptor antagonists. The effects of intrarenal administration of angiotensin II are attenuated after renal denervation. These interactions can also be extrarenal, for example, in the central nervous system, wherein renal sympathetic nerve activity and its arterial baroreflex control are modulated by changes in activity of the renin-angiotensin system. In addition to the circumventricular organs, whose permeable blood-brain barrier permits interactions with circulating angiotensin II, there are interactions at sites behind the blood-brain barrier that depend on the influence of local angiotensin II. The responses to central administration of angiotensin II-type AT(1)-receptor antagonists into the ventricular system or microinjected into the rostral ventrolateral medulla are modulated by changes in activity of the renin-angiotensin system produced by physiological changes in dietary sodium intake. Similar modulation is observed in pathophysiological models wherein activity of both the renin-angiotensin and sympathetic nervous systems is increased (eg, congestive heart failure). Thus, both renal and extrarenal sites of interaction between the renin-angiotensin system and renal sympathetic nerve activity are involved in influencing the neural control of renal function.     

Effect of short-term administration of cromakalim on renal hemodynamics and eicosanoid excretion in essential hypertension.

Cromakalim, a novel potassium channel-activating drug, was administered for a 3-day period in eight untreated hospitalized patients with established hypertension. The fixed and single dose of 1.5 mg/day produced a significant reduction in systolic and diastolic blood pressure with a small increase in heart rate. Glomerular filtration rate was unchanged and effective renal plasma flow was slightly increased with a concomitant small decrease in filtration fraction and in renal vascular resistance. No significant change was observed in urinary prostaglandin (PG)E2, PGF2 alpha, and thromboxane B2, while 6-keto-PGF1 alpha (the stable metabolite of prostacyclin) rose from 189 +/- 6 to 368 +/- 115 ng/day. The renal excretion of 6-keto-PGF1 alpha correlates with the modification observed in renal plasma flow, suggesting a compensatory role for prostacylin in preserving renal hemodynamics during antihypertensive therapy with cromakalim.     

Infections of the central nervous system.

Infections of the central nervous system are common, serious medical conditions. One hundred consecutive adult cases with purulent meningitis of known etiology encountered by the Medical Service at Parkland Memorial Hospital were reviewed. Streptococcus pneumoniae was the most common pathogen (56 cases), followed by Neisseria meningitidis (16 cases) and Listeria monocytogenes (seven cases). Hemophilus influenzae, Staphylococcus aureus, and streptococci each accounted for five cases. An additional 15 patients had purulent meningitis with a pathogen being isolated. Twenty five purulent meningitis cases of known etiology after trauma or neurosurgery were reviewed. Staphylococcus aureus (five cases), Staphylococcus epidermidis (four cases), and gram negative bacilli (14 cases) were the most common pathogens. Review of intracranial suppurative infections demonstrated advances in microbiology, antibiotic therapy, and imaging, leading to improvements in therapy. Subdural empyema continues to be a difficult diagnosis to make and apparently is related to the anatomic pathology of the infectious process. To illustrate salient features about granulomatous meningitis and encephalitis, cases of tuberculous meningitis, herpes simplex encephalitis, St. Louis encephalitis, and encephalitis of undetermined etiology are presented and discussed.     

Effect of intrarenal furosemide on renal function and intrarenal hemodynamics in acute renal failure

The ability of short-term furosemide administration to alter intrarenal hemodynamics and to modify the clinical course of acute renal failure was assessed in six patients 2 to 9 days after the onset of acute renal failure. Following renal arterial catheterization, the intraarterial administration of furosemide at a dose of 9.6 mg/min for 30 minutes failed to improve renal function as assessed either by an increase in urine output or a decrease in serum creatinine during the 4 days after administration in the five oliguric patients. In a sixth patient with nonoliguric acute renal failure, urine volume increased with a gradual decrease in blood urea nitrogen and creatinine during the week after study. Furosemide failed to alter either mean renal blood flow or its intrarenal distribution as determined at intervals of 3 to 40 minutes after its infusion. These studies demonstrate that the short-term administration of furosemide in large doses does not improve renal hemodynamics or alter the clinical course of patients with established acute oliguric renal failure.     

The effect of hypophysectomy on the function of the insulin-sensitive central nervous system glucoregulator receptor.

Hypophysectomized and healthy control rats were studied to investigate the mechanism of action of the insulin-sensitive glucoregulator receptor of the central nervous system (CNS). Glucagon-free insulin (500 muU) was injected into the carotid artery, and the peripheral blood glucose was monitored. An immediate significant fall in the blood sugar was observed in intact as well as in hypophysectomized rats. To control these experiments buffer was injected into the carotid artery, or 500 muU insulin was given through the jugular vein of intact and hypophysectomized animals. The systemic blood sugar level remained unchanged for 10-15 min in the control experiments. The results indicate that the function of this insulin-sensitive glucoregulator CNS receptor is not impaired in the hypophysectomized state. The initial phase of its effect, the sudden decrease of the blood sugar level, appears to be independent of pituitary hormone secretion.