H L Mizelle

Abnormal pressure natriuresis : a cause or a consequence of hypertension ?

In all forms of chronic hypertension, the renal-pressure natriuresis mechanism is abnormal because sodium excretion is the same as in normotension despite the increased blood pressure. However, the importance of this resetting of pressure natriuresis as a cause of hypertension is controversial. Theoretically, a resetting of pressure natriuresis could necessitate increased blood pressure to maintain sodium balance or it could occur secondarily to hypertension. Recent studies indicate that, in several models of experimental hypertension (including angiotensin II, aldosterone, adrenocorticotrophic hormone, and norepinephrine hypertension), a primary shift of renal-pressure natriuresis necessitates increased arterial pressure to maintain sodium and water balance. In genetic animal models of hypertension, there also appears to be a resetting of pressure natriuresis before the development of hypertension. Likewise, essential hypertensive patients exhibit abnormal pressure natriuresis, although the precise cause of this defect is not clear. It is likely that multiple renal defects contribute to resetting of pressure natriuresis in essential hypertensive patients. With long-standing hypertension, pathological changes that occur secondary to hypertension must also be considered. By analyzing the characteristics of pressure natriuresis in hypertensive patients and by comparing these curves to those observed in various forms of experimental hypertension of known origin, it is possible to gain insight into the etiology of this disease.

Chronic hyperinsulinemia and blood pressure. Interaction with catecholamines

Although hyperinsulinemia and increased adrenergic activity have been postulated to be important factors in obesity-associated hypertension, a cause and effect relation between insulin, catecholamines, and hypertension has not been established. The aim of this study was to determine whether chronic hyperinsulinemia, comparable with that found in obese hypertensive patients, causes hypertension in normal dogs, increases plasma catecholamines, or potentiates the blood pressure effects of norepinephrine. In six normal dogs, insulin infusion (1.0 milliunits/kg/min) for 7 days, with euglycemia maintained, increased fasting insulin fourfold to sixfold. However, mean arterial pressure did not increase, averaging 99 +/- 2 mm Hg during the control period and 91 +/- 3 mm Hg during the 7 days of insulin infusion. Insulin did not alter plasma norepinephrine or epinephrine, which averaged 171 +/- 27 and 71 +/- 14 pg/ml, respectively, during the control period and 188 +/- 29 and 45 +/- 12 pg/ml during the 7 days of insulin infusion. In six dogs, norepinephrine was infused (0.2 microgram/kg/min) for 7 days to raise plasma norepinephrine to 2,940 +/- 103 pg/ml. Insulin infusion (1.0 milliunits/kg/min) for 7 days during simultaneous infusion of norepinephrine did not further increase mean arterial pressure, which averaged 101 +/- 3 during norepinephrine and 98 +/- 2 mm Hg during insulin plus norepinephrine infusion. Thus, chronic hyperinsulinemia did not increase mean arterial pressure or plasma catecholamines and did not potentiate the blood pressure actions of norepinephrine. These observations provide no evidence that chronic hyperinsulinemia or interactions between insulin and plasma catecholamines cause hypertension in normal dogs.

Cardiovascular responses to long-term blockade of nitric oxide synthesis.

The goal of this study was to determine if there is a basal release of nitric oxide that affects long-term arterial pressure regulation in dogs. Studies were conducted over a 23-day period in eight conscious dogs with indwelling catheters. Nitric oxide synthesis was blocked by continuous intravenous infusion of nitro-L-arginine-methyl ester at 37.1 nmol/kg per minute for 11 days. Arterial pressure increased to 120 +/- 4% of control on the first day, decreased for a few days, and then increased to a maximum value of 122 +/- 6% of control on day 7. Bradycardia was sustained throughout the entire nitro-arginine period. Blockade of nitric oxide synthesis was evidenced by attenuated pressure and flow responses to systemic acetylcholine infusion. The pressor response to phenylephrine was increased for only 1 day, and the hypotensive effects of nitroprusside were enhanced. Also, the variability of arterial pressure was significantly increased during nitro-arginine. Sodium and water balances were positive the first day of nitro-arginine infusion but were unchanged for the entire nitro-arginine period. In conclusion, the data suggest that blockade of the basal release of nitric oxide in dogs causes an increase in the long-term level of arterial pressure without any sustained sodium or water retention.

Role of pressure natriuresis in long-term control of renal electrolyte excretion.

If pressure natriuresis is to play an important role in arterial pressure control, renal perfusion pressure must have a long-term effect on urinary sodium excretion. The aim of this study was to quantitate the importance of renal perfusion pressure per se in controlling renal hemodynamics and electrolyte excretion chronically. Female mongrel dogs (n = 6) were instrumented with bilateral renal artery catheters for measurement of renal perfusion pressure and occluders on both renal arteries for servo-control of renal perfusion pressure at different levels; the urinary bladder was split for determination of renal clearances and electrolyte excretion from each kidney separately. Because both kidneys were exposed to the same neurohumoral influences, any changes in renal function could be attributed to differences in renal perfusion pressure between the two kidneys. After 5 days of control, renal perfusion pressure to one kidney was reduced from 86.7 +/- 0.2 to 74.2 +/- 0.6 mm Hg for 12 days, and pressure in the contralateral kidney increased to 91.5 +/- 0.4 mm Hg. Sodium excretion decreased from 41 +/- 2 to 25 +/- 1 mmol/d in the servo-controlled kidney and increased from 41 +/- 1 to 55 +/- 1 mmol/d in the contralateral kidney during 12 days of servo-control. Urine volume, chloride excretion, and potassium excretion exhibited similar patterns during servo-control. In addition, autoregulation of effective renal plasma flow and glomerular filtration rate was relatively well maintained; however, in the low-pressure kidney, glomerular filtration rate was slightly but significantly lower (approximately 8%) than in the contralateral kidney.(ABSTRACT TRUNCATED AT 250 WORDS)

Temporal Influence of the Renal Nerves on Renal Excretory Function During Chronic Inhibition of Nitric Oxide Synthesis

To determine whether the sympathetic nervous system contributes to the hypertension induced by long-term suppression of nitric oxide synthesis, we determined the neurally induced changes in renal excretory function during chronic administration of NG-nitro-L-arginine methyl ester (L-NAME). Studies were carried out in six conscious chronically instrumented dogs subjected to unilateral renal denervation and surgical division of the urinary bladder into two hemibladders to allow separate 24-hour urine collection from denervated and innervated kidneys. Animals were studied during acute (100 minutes) and chronic (5 days) intravenous infusion of L-NAME at 37.1 nmol/kg per minute (10 micrograms/kg per minute). During the first 100 minutes of L-NAME, there were no significant changes in mean arterial pressure (control: 96 +/- 3 mm Hg), but heart rate fell from 66 +/- 6 to 55 +/- 7 beats per minute. Changes in glomerular filtration rate were not significant, but renal plasma flow and urinary sodium excretion decreased to approximately 75% and 50% of control values, respectively; however, these changes were comparable in both kidneys. In association with these responses, plasma concentrations of norepinephrine (control: 887 +/- 130 pmol/L or 150 +/- 22 pg/mL) and epinephrine (control: 691 +/- 192 pmol/L or 108 +/- 30 pg/mL) tended to decrease. In contrast to the acute responses, mean arterial pressure increased from 92 +/- 3 to 106 +/- 3 mm Hg and heart rate decreased from 72 +/- 4 to 57 +/- 5 beats per minute by day 5 of L-NAME infusion, while renal plasma flow and glomerular filtration rate were not significantly different from control values. Most importantly, there were no significant differences in urinary sodium excretion between innervated (control: 31 +/- 2 mmol/d) and denervated (control 33 +/- 2 mmol/d) kidneys during chronic L-NAME infusion or during the recovery period. These results indicate that the renal sympathetic nerves do not play an important role in promoting sodium retention during either acute or chronic inhibition of nitric oxide synthesis in conscious dogs. Thus, increased renal sympathetic nerve activity does not contribute significantly to L-NAME-induced hypertension.

Role of nitric oxide in long-term angiotensin II-induced renal vasoconstriction.

In vitro studies have indicated that nitric oxide may play an important role in modulating the renal vascular actions of angiotensin II (Ang II). However, the physiological importance of this interaction in the long-term regulation of renal hemodynamics is unknown. Therefore, the goal of this study was to determine if long-term Ang II-induced renal vasoconstriction was potentiated by nitric oxide synthesis inhibition. The intrarenal effects of Ang II were examined in eight unilaterally nephrectomized, conscious dogs before and after systemic inhibition of nitric oxide synthesis. Ang II infusion into the renal artery at 0.5 ng/kg per minute resulted in decreases in renal plasma flow of 15% and 9% after 3 and 5 days, respectively. During this time, glomerular filtration rate decreased 12% after 3 days of angiotensin but was not significantly changed after 5 days. After 4 days of recovery from Ang II, nitric oxide synthesis was inhibited with intravenous NG-nitro-L-arginine-methyl ester (L-NAME) at 10 micrograms/kg per minute for 5 days, and this caused a significant decrease in renal plasma flow but no change in glomerular filtration rate. Infusion of Ang II into L-NAME-pretreated dogs for an additional 5 days further decreased renal plasma flow and glomerular filtration 14% and 11%, respectively. However, the effects of Ang II and L-NAME on renal plasma flow were only additive on days 3 and 5 of this period, and the effects on glomerular filtration were additive on day 3 but were potentiated on day 5.(ABSTRACT TRUNCATED AT 250 WORDS)

Blunted natriuretic response to a high-sodium meal in obese dogs : role of renal nerves

Although the relation between body weight and arterial pressure is well established, the mechanisms involved in the pathogenesis of obesity-related hypertension are unclear. However, recent studies suggest that abnormalities in renal function may be involved. The purpose of this study was to test the hypothesis that obese animals have a reduced ability to excrete a sodium load as a result of abnormal renal nerve function. To quantify the role of renal nerves, we examined changes in renal hemodynamics and sodium excretion in response to a high-sodium meal (200 mmol Na) in separate innervated and denervated kidneys simultaneously within the same conscious dog. Two surgically designed hemibladders with indwelling catheters were used to collect urine from innervated and denervated kidneys of the same dog. Body weight averaged 19.9 +/- 1.0 kg in the control lean dogs and 25.1 +/- 1.1 kg in the obese dogs. Arterial pressure averaged 101 +/- 4 mm Hg in the obese dogs and 90 +/- 4 mm Hg in the lean dogs. In response to the high-sodium meal in lean dogs, urinary sodium excretion increased from 20.8 +/- 4.2 to 189.7 +/- 21.2 mumol/min in the innervated kidneys and from 25.3 +/- 5.9 to 194.8 +/- 26.9 mumol/min in the denervated kidneys. In contrast, urinary sodium excretion in obese dogs increased from 9.6 +/- 1.4 to 129.9 +/- 34.3 mumol/min in the innervated kidneys and from 18.4 +/- 3.7 to 125.2 +/- 30.5 mumol/min in the denervated kidneys.(ABSTRACT TRUNCATED AT 250 WORDS)