Mary Ann Johnson

How is the NaCl signal transmitted in NaCl-induced hypertension?

Is the NaCl signal perceived as a small increase in the concentration of NaCl in extracellular fluid? We used 8 g NaCl/100 g soluble nutrients and fed only a hypertonic (1.4% NaCl) or a hypotonic (0.45% NaCl) drink to Dahl salt-sensitive (DS) rats. After 12 weeks, 11 rats receiving the hypertonic drink had a mean blood pressure of 195 mm Hg versus 195 mm Hg in 12 rats receiving the hypotonic drink. Thus, the high-NaCl signal seems unrelated to a higher NaCl concentration in extracellular fluid, thereby suggesting volume signals. Most volume controls are near the third brain ventricle (3V). As a working hypothesis, high dietary NaCl may swell the tissues surrounding 3V, which is slitlike. Such swelling would partially close the upper part of the slit and cause ependymal cells and nerve fibers on opposite walls to touch, possibly leading to hypertension in susceptible humans or rats. To test this, we stereotaxically blocked the aqueduct with inert silicone to produce hydrocephalus of 3V in DS rats and thus prevent ependymal cells and nerve fibers from touching. After blocking or sham-blocking the aqueduct, either a 6% NaCl diet or a 0.23% NaCl diet was started. Intra-arterial blood pressure was taken after 6 weeks. A group of 28 sham-blocked rats and a group of 29 blocked rats, all fed a 0.23% low NaCl diet, had equal blood pressures averaging 130 mm Hg. Forty-six sham-blocked rats fed the 6% NaCl diet averaged 175±3.0 mm Hg blood pressure, whereas 52 blocked rats fed the 6% NaCl diet averaged 149±3.2 mm Hg blood pressure. Thus, with 6% NaCl, blood pressure rose 45 mm Hg in sham-blocked rats and only 19 mm Hg in blocked rats, a 58% reduction (p < 0.001). After 12 weeks on the 6% NaCl diet, 43% of the sham-blocked rats had died compared with an 8% mortality in the blocked rats, an 82% reduction in mortality (p < 0.001). Twenty-seven other DS rats fed a 6% NaCl diet for 6 weeks underwent thermal lesions of periaqueductal fibers. Their blood pressures were 8 mm Hg higher than 17 rats with sham lesions (p = NS). Thus, the aqueductal block lowered blood pressure apparently not through local injury. The key finding in this study is that an aqueduct block sufficient to produce hydrocephalus will markedly lower blood pressure and mortality rate in NaCI-fed DS rats. The mechanism involved is uncertain and may or may not be explained by our working hypothesis. From the University of Minnesota Hospital and School of Medicine (J.Y.L., L.T., S.H., R.H., M.A.J.), Minneapolis, Minnesota, and the Brookhaven National Laboratory (J.I.), Upton, New York.

Prostaglandin E2 (PGE2) in renal papilla in NaCl hypertension

Human essential hypertension is clearly dependent on sodium intake and excretion.1 This “sodium connection” stimulated us to investigate prostaglandin E2 (PGE2) in the renal papillae of two strains of rats, the Dahl S strain, which is highly susceptible to salt-induced hypertension, and the Dahl R strain, which is highly resistant to salt hypertension.2 As seen in Fig. 1, when both strains are on a low-salt diet with 0.3% NaC1, neither strain has blood pressures (BPs) out of the normal range; however, when the two strains begin eating a high salt intake of 4% NaC1, the R strain has no rise of BP at all, while the S strain becomes mildly hypertensive at 4 weeks and solidly hypertensive by 11 weeks.

THE INFLUENCE OF RENAL PROSTAGLANDINS, CENTRAL NERVOUS SYSTEM AND NaCl ON HYPERTENSION OF DAHL S RATS

1.Kidney factors and central nervous system (CNS) factors appear to have powerful influences on NaCl‐induced hypertension. In quick‐frozen kidneys the prostaglandin E2 (PGE2) concentration in the renal papilla is 60% lower in Dahl S rats than in Dahl R rats (17 ng/100 mg vs 42 ng/100 mg; P<0.01) when both S and R rats are on a 0.3% low NaCl diet. When S and R rats eat a 4% high NaCl diet for 4 weeks or 11 weeks, the PGE2 concentration doubles in both strains (P<0.05) but the papillary PGE2 concentration in the S rats is always about half that in the R rats (P<0.01).

CHOLESTEROL ESTER DEPOSITION IS REDUCED IN RATS WITH HYPERCHOLESTEROLEMIA AND HYPERTENSION

High K diets prevent hypertensive endothelial injury and intimal thickening. Cholesterol esters often deposit during hypercholesterolemia. We investigated whether a high K diet would influence cholesterol ester deposits in stroke prone SHR rats. Stroke prone SHR rats were fed for 3 months a basic diet containing 4% cholesterol, 14% coconut oil and 7% NaCl. One group of 13 rats had normal (.5%) K in the diet. Another group of 10 rats ate high (2.1%) K. Mean intra-arterial BPs averaged 165 mmHg in the normal K group and 161 mmHg in the high K group (NS). The serum cholesterol averaged 229 mg/dl in the normal K group and 214 in the high K group (NS). Total aortic cholesterol esters per rat averaged 187 micrograms in normal K vs 68 micrograms in high K, measured by gas chromatography. Thus high K reduced cholesterol ester deposits by 64% (p less than .0003), even though BPs and cholesterol levels were quite similar in the two groups. Both high cholesterol and high BP injure endothelial cells and increase invasion of monocytes and vascular smooth muscle cells into the intima and increase endothelial permeability to proteins. With high plasma cholesterol, these processes lead to atherosclerosis with cholesterol ester deposition. The high K diet, by protecting endothelial cells, can greatly decrease this cholesterol ester deposition. This effect could possibly be useful for preventing heart attacks in human hypertension.

Atherosclerotic cholesterol ester deposition is markedly reduced with a high-potassium diet

In a normal rat on a normal diet, no cholesterol esters are detected in the aorta by gas chromatography. Stroke-prone spontaneously hypertensive rats (SHR) were fed for 3 months a basic diet containing 4% cholesterol, 14% coconut oil and 7% NaCl. One group of 13 rats ingested a normal (0.5%) level of potassium in the diet. Another group of 10 rats ingested a high (2.1%) potassium level. Mean intra-arterial blood pressures averaged 165 mmHg in the normal-potassium group and 161 mmHg in the high-potassium group (NS). Serum cholesterol levels averaged 229 mg/dl in the normal-potassium group and 214 mg/dl in the high-potassium group (NS). Total aortic cholesterol esters per rat involving 16- and 18-carbon chain fatty acids averaged 187 micrograms in normal-potassium rats versus 68 micrograms in high-potassium rats. These were the main esters; other esters were negligible. Thus, the high-potassium diet reduced cholesterol ester deposits by 64% (P less than 0.0003), even though blood pressures and cholesterol levels were quite similar in the two groups. Both high cholesterol and high blood pressure injure endothelial cells and increase the invasion of macrophages and vascular smooth muscle cells into the intima; they also increase endothelial permeability to proteins. With high plasma cholesterol levels, these processes lead to atherosclerosis with cholesterol ester deposition. The high-potassium diet, by protecting endothelial cells, can greatly decrease this cholesterol ester deposition. This effect could be useful for preventing heart attacks and sudden coronary death in human hypertension.

Acute prostaglandin reduction with indomethacin and chronic prostaglandin reduction with an essential fatty acid deficient diet both decrease plasma flow to the renal papilla in the rat

Renal distribution of prostaglandin synthetase is mainly medullary, whereas the major degrading enzyme, prostaglandin dehydrogenase is primarily cortical. This suggests that prostaglandins (PG) released from the renal medulla could affect the medullary blood vessels. In two different experiments we studied the role of PG in the regulation of renal papillary plasma flow in the rat. First study: PG synthesis were stimulated in 34 adult Sprague-Dawley rats by bleeding from the femoral artery 1% of the body weight over a period of 10 minutes. Following this, indomethacin (a PG inhibitor, 10 mg/kg i.v.) was given slowly and then renal papillary plasma flow was measured 25 minutes after the end of infusion. In 17 indomethacin rats the renal papillary plasma flow averaged 18.8 ml/100 g/minute, whereas it averaged 23.0 in 17 non-indomethacin rats given diluent, an 18% reduction (p less than .025). Second study: Male Sprague-Dawley rats were made prostaglandin deficient by fasting rats for one week, followed by 10% dextrose fluid for one week and subsequent institution of an essential fatty acid (EFA) deficient diet for two weeks. With urinary PG excretion in prostaglandin deficient rats 28 ng/24 hours compared to 149 ng in control rats, they could be considered as prostaglandin deficient. When renal papillary plasma flow was measured, the 16 prostaglandin deficient rats had a 16% lower papillary plasma flow than 16 control rats, 21.6 vs 25.6 (p less than .005). These results clearly demonstrate that PG inhibition in rats decreases plasma flow to the papilla, strongly suggesting that PG are vasodilators for the vessels supplying the renal papilla.