Decrease in peripheral sympathetic nervous system activity following renal denervation or unclipping in the one-kidney one-clip Goldblatt hypertensive rat.

Increased sympathetic nervous system activity has been demonstrated in established one-kidney one-clip hypertension in the rat. We have found that renal denervation in this model results in an attenuation of hypertension, unassociated with alterations in sodium or water balance or renin activity. To determine whether the depressor effect of renal denervation is associated with changes in peripheral sympathetic nervous system activity, sham operation (n = 12), renal denervation (n = 13), or unclipping (n = 13) was carried out 2 wk after the onset of one-kidney one-clip hypertension. Normotensive unine-phrectomized age- and sex-matched rats were used as controls (n = 14). Renal denervation resulted in a significant decrease in systolic blood pressure (201+/-7 to 151+/-6 mm Hg), while unclipping lowered systolic blood pressure to normotensive levels (130+/-6 mm Hg). 8 d after operation plasma norepinephrine and mean arterial pressure before and after ganglionic blockade with 30 mg/kg hexamethonium bromide were measured in conscious, unrestrained, resting animals, as indices of peripheral sympathetic nervous system activity. Plasma norepinephrine was significantly higher in hypertensive sham-operated rats (422+/-42 pg/ml) compared with normotensive controls (282+/-25 pg/ml) (P < 0.01). Both renal denervation and unclipping restored plasma norepinephrine to normal levels (273+/-22 and 294+/-24 pg/ml, respectively). Ganglionic blockade in hypertensive sham-operated animals resulted in a significantly greater decrease in mean arterial pressure than occurred in renal denervated, unclipped, or control rats. The data suggest that the depressor effect of renal denervation or unclipping in the one-kidney one-clip hypertensive rat is associated with a decrease in peripheral sympathetic nervous system activity.

Role of the renal sympathetic nerves in the development and maintenance of hypertension in the spontaneously hypertensive rat.

Neurogenic factors and, in particular, enhanced renal sympathetic tone, have been implicated in the pathogenesis of hypertension in the spontaneously hypertensive rat of the Okamoto strain. To examine the hypothesis that the renal sympathetic nerves contribute to the development and maintenance of hypertension by causing urinary sodium retention, 7-wk-old (early hypertensive) and 18-wk-old (established hypertensive) male spontaneously hypertensive rats were subjected to bilateral renal denervation and compared with sham-operated controls. In 7-wk-old animals renal denervation delayed the onset and slowed the rate of development of hypertension. These alterations were associated with a significantly greater fractional excretion of sodium (percentage of sodium intake excreted) during the first 3 wk after denervation. Blood pressure 2 wk after surgery was 169+/-3.5 (sham) vs. 150+/-2.4 mm Hg (denervated) (P < 0.001), corresponding to fractional sodium excretions of 65+/-1.3% (sham) vs. 80+/-2.3% (denervated) (P < 0.001). By the 5th wk after surgery, at which time an increase in renal norepinephrine content of denervated animals suggested reinnervation, blood pressures in the two groups converged (sham, 199+/-6.5 mm Hg vs. denervated 180+/-3.5 mm Hg, NS) and there was no difference in sodium excretion (sham, 77+/-2.5% vs. denervated 79+/-2.3%). Plasma and kidney renin activity of denervated animals did not differ significantly from that of sham-operated controls. In 18-wk-old rats renal denervation did not alter blood pressure or urinary sodium excretion. These data indicate that the renal sympathetic nerves contribute to the development of hypertension in the spontaneously hypertensive rat in part by causing enhanced sodium retention. Once hypertension is established the renal nerves do not play a significant role in the maintenance of increased blood pressure.

Mechanism of postarrhythmic renal vasoconstriction in the anesthetized dog.

The mechanism of postarrhythmic renal vasoconstriction was studied in 28 dogs anesthetized with pentobarbital sodium (30 mg/kg i.v.). Rapid atrial or ventricular pacing or induction of atrial fibrilation were used to produce at least 20% prompt decrease in cardiac output and mean arterial blood pressure. Return to control cardiac output and blood pressure occurred within 3 minutes after cessation of the arrhythmia, but renal blood flow remained significantly decreased (26%) with gradual recovery by 17.7 +/- 6.6 min. Infusion of phentolamine (0.25 mg/min) into the renal artery, intravenous hexamethonium (l mg/kg), adrenal demedullation, or cooling the cervical vagi prevented postarrhythmic renal vasoconstriction. In contrast, renal denervation, intravenous bretylium (10 mg/kg), intravenous atropine (0.5 mg/kg) or intrarenal SQ 20881 (0.20 mg/min) has no effect on postarrhythmic renal vasoconstriction. Intravenous propranolol (0.5 mg/kg) intensified postarrhythmic renal vasoconstriction. These data suggested that the postarrhythmic renal vasoconstrictive response required intact vagi and was due to alpha adrenergic stimulation by adrenal catecholamines. However, femoral arterial catecholamine levels were not elevated above control during postarrhythmic renal vasoconstriction. We therefore sought local vascular pathways by which catecholamines might reach the kidneys. An adrenorenal vascular network was found in each dog. Collection of catecholamines from these vessels during postarrhythmic renal vasoconstriction in six dogs revealed catecholamine concentrations threefold higher than simultaneously collected femoral arterial catecholamines levels. Because ligation of these vessels abolished postarrhythmic renal vasoconstriction in each dog, we conclude that postarrhythmic renal vasconstriction is due to adrenal catecholamines reaching the kidneys through an adreno-renal vascular network and that the response requires intact vagi.

Acquired functional asplenia. Association with spontaneous rupture of the spleen and fatal spontaneous rupture of the liver in amyloidosis.

A 45-year-old woman who had lower extremity ecchymoses and vague abdominal and back complaints was found to have acquired functional asplenia manifested by Howell-Jolly bodies and poikilocytosis on peripheral blood smear. On spleen scan there was inability to take up radioactive colloid. Shortly thereafter, she was found to have a spontaneous rupture of the spleen. At operation, the spleen, liver, and periaortic lymph nodes were found to be diffusely involved with amyloidosis. Five months later, an acute, serious, intra-abdominal condition developed secondary to spontaneous rupture of the liver, and the patient died. To our knowledge, neither acquired functional asplenia nor spontaneous rupture of the liver has been reported previously in association with amyloidosis.

Role of the renal nerves in the pathogenesis of one-kidney renal hypertension in the rat.

Increased sympathetic nervous system activity has been demonstrated in established one-kidney one clip hypertension in the rat. To determine the importance of the renal nerves in this model of hypertension, renal denervation or sham operation was carried out 2 weeks after clipping. Systolic blood pressure (BP) after clipping the renal artery in 27 uninephrectomized male Charles River rats increased significantly from 125 +/- 3 mm Hg to a stable level of 185 +/-7 mm Hg by 2 weeks, in association with a positive sodium balance. Renal denervation in 13 animals resulted in a significant decrease in BP to 137 +/- 7 mm Hg, while no change in BP was seen after sham operation in 14 animals. There was no difference in mean daily water intake, mean daily sodium intake, mean daily urine volume, or mean fractional urinary sodium excretion between sham-operation and renal-denervated animals during the 2 weeks after operation. Plasma renin activity (PRA) and creatinine clearance were not significantly different at sacrifice 2 weeks after operation. Six of the renal-denervated rats were followed for 11 weeks after surgery. The BP rose again to hypertensive levels (187 +/- 8 mm Hg) by 5 weeks after renal denervation. Repeat renal denervation resulted in a significant decrease to 142 +/- 8 mm Hg. Renal denervation in eight rats with established one-kidney Grollman hypertension (185 +/- 8 mm Hg) also resulted ina significant decrease in systolic BP (143 +/- 8 mm Hg). The data demonstrate the importance of intact renal nerves in the maintenance of hypertension in the one-kidney renal hypertensive rat. The depressor effect of renal denervation is not mediated by alterations in sodium intake or excretion, water intake or excretion, creatinine clearance or PRA.

Importance of renal sympathetic tone in the development of DOCA-salt hypertension in the rat.

In many experimental models, acute increases in sympathetic nervous system activity produce disproportionately greater vasoconstriction in the renal vascular bed than occurs in most other vascular beds. Since increased sympathetic nervous system activity has been implicated in the pathogenesis of DOCA-salt hypertension in the rat, we hypothesized that an attenuation of renal sympathetic tone would delay the development of this form of hypertension. Renal denervation was carried out in 5-week-old uninephrectomized male Sprague-Dawley rats 1 week before beginning DOCA-salt treatment. Systolic blood pressures using the tailcuff method in 32 sham-operated rats were significantly (p less than 0.05) elevated above control by Day five (115 +/- 3 vs 128 +/- 3 mm Hg) of DOCA-salt administration and continued to rise, reaching a plateau by Day 21 (192 +/- 5 mm Hg). In contrast, DOCA-salt administration in 32 renal denervated rats did not result in a significant elevation of blood pressure above control until Day 17 (121 +/- 3 vs 135 +/- 3 mm Hg, p less than 0.05). During the first 2 weeks of DOCA-salt treatment, fractional urinary sodium excretion was significantly greater (p less than 0.05) in renal denervated rats than in sham animals. During the third week of DOCA-salt administration, renal denervated rats had a rapid rise in blood pressure and a fall in fractional urinary sodium excretion to the level of the sham-operated animals. Coincident with the development of hypertension was a threefold increase in renal norepinephrine content (5.3 +/- 0.4 ng/g on Day 14 vs 17.7 +/- 3.0 ng/g on Day 24, p less than 0.01), suggesting reinnervation. These data suggest that increased renal sympathetic tone in the DOCA-salt rat facilitates sodium retention and is necessary for the development of the hypertension.

Role of the renal nerves in the maintenance of DOCA-salt hypertension in the rat. Influence on the renal vasculature and sodium excretion.

We previously observed that the renal nerves facilitate sodium retention and contribute to the development of DOCA-salt hypertension in the rat. To determine whether the renal nerves also participate in the maintenance of DOCA-salt hypertension, we studied the effects of renal denervation after 3 or 10 weeks of DOCA-salt treatment on systolic blood pressure, urinary sodium excretion, creatinine clearance, and precapillary arteriolar wall/lumen ratios of renal, hindlimb muscle, and cremaster muscle vascular beds. Systolic blood pressures of animals given DOCA-salt reached a plateau by 3 weeks of treatment at which time a sham operation or renal denervation was performed. Sham operation in hypertensive animals resulted in no change in systolic blood pressure and no change in percent sodium intake excreted. Wall/lumen ratio of the renal precapillary arteriole in sham-operated hypertensive animals was increased compared to similar sized vessels in hindlimb and cremaster muscle. In contrast, renal denervation resulted in a natriuresis and an attenuation of the hypertension (208 +/- 7 mmHg; p less than 0.01). Wall/lumen ratio of the renal capillary arterioles in renal denervated animals was no different than similar sized vessels in hindlimb and cremaster muscle and significantly less than that seen in sham-operated animals (0.85 +/- 0.05 vs 1.03 +/- 0.06; p less than 0.05). In another group of animals, sham operation or renal denervation was performed after 10 weeks of DOCA-salt treatment. At this time neither operation altered systolic blood pressure or sodium balance. In contrast to 3-week DOCA-salt-treated hypertensive sham-operated animals, renal precapillary arteriolar wall/lumen ratio of 10-week animals was no different than similar sized vessels in hindlimb and cremaster muscle. In addition, renal precapillary arteriolar wall/lumen ratio of 10-week DOCA-salt-treated renal-denervated animals was no different than that seen in 10-week DOCA-salt-treated sham-operated hypertensive animals. Creatinine clearance of the 10-week DOCA-salt-treated sham-operated or renal-denervated animals was significantly (p less than 0.01) lower than that of the 3-week DOCA-salt-treated groups (0.25 +/- 0.14 vs 1.03 +/- 0.10 ml/min). These data suggest that the renal nerves contribute to the early established phase of DOCA-salt hypertension by shifting the arterial pressure-renal sodium excretion curve to the right. With time, the renal nerves play a diminishing role in the maintenance of established DOCA-salt hypertension in the rat, while other renal factors, including decreased glomerular filtration rate and probable fixed renal vascular changes, play an increasingly important role.

Intrarenal adenosine produces hypertension via renal nerves in the one-kidney, one clip rat.

The afferent renal nerves enhance sympathetic activity in the one-kidney, one-clip hypertensive rat. We have also found adenosine-sensitive nerve endings in the renal pelvis that, when stimulated, increase sympathetic activity producing hypertension. To determine whether adenosine, which is excreted when renal blood flow is reduced, activates the afferent renal nerves in one-kidney, one-clip hypertension, urinary adenosine concentration was lowered by infusing adenosine deaminase into the renal artery. Urinary adenosine concentration was threefold greater in one-kidney, one-clip hypertensive animals compared with normotensive controls. Intrarenal infusion of adenosine deaminase in one-kidney, one-clip rats lowered urinary adenosine to an undetectable level and attenuated the hypertension. Both plasma norepinephrine levels and the fall in mean arterial pressure after ganglionic blockade decreased during intrarenal adenosine deaminase infusion in one-kidney, one-clip animals. Renal denervation in one-kidney, one-clip animals prevented the changes in mean arterial pressure and plasma norepinephrine levels during intrarenal adenosine deaminase infusion. In contrast to findings in hypertensive animals, intrarenal infusion of adenosine deaminase produced no change in arterial pressure in normotensive controls. These data indicate that urinary adenosine concentration is enhanced in one-kidney, one-clip hypertension and suggest that when urinary adenosine concentration is lowered, sympathetic activity and hypertension became attenuated in this model if the renal nerves are intact.

Endogenous intrarenal adenosine preserves renal blood flow in one-kidney, one clip rats.

Intrarenal adenosine concentration is threefold greater in the one-kidney, one clip hypertensive rat compared with normotensive animals. Since exogenously administered adenosine may increase renal blood flow by direct vasodilation, inhibition of renin release, or prejunctional interruption of adrenergic neurotransmission, these studies examined whether endogenous intrarenal adenosine maintains renal blood flow distal to renal arterial stenosis. Administration of theophylline, which blocks the direct vasodilating effect of adenosine and antagonizes the inhibitory effect of adenosine on renin release and sympathetic neurotransmission, resulted in marked renal vasoconstriction in one-kidney, one clip hypertensive animals. This theophylline-induced renal vasoconstriction was markedly attenuated by angiotensin II blockade with saralasin and was unchanged by renal denervation or beta 1-adrenergic blockade with atenolol. These findings indicate that the marked renal vasoconstriction in one-kidney, one clip hypertension during theophylline administration is mainly mediated by angiotensin II, is to a lesser degree due to inhibition of adenosine-induced vasodilation, and is independent of sympathetic influences. These data suggest that endogenous interstitial adenosine preserves renal blood flow in one-kidney, one clip hypertension mainly by inhibiting renin release.

Acute and chronic intrarenal alpha- and beta- adrenergic receptor stimulation of renin release in the conscious dog.

The effect of continuous intrarenal infusion of norepinephrine, isoproterenol, and methoxamine on renin release was studied in the uninephrectomized conscious dog. Chronic intrarenal infusion of norepinephrine produced a biphasic curve of plasma renin activity (PRA) and a sustained 25 mm Hg increase in mean arterial pressure (MAP). The initial increase in PRA peaked at 3 hours, after which PRA returned to control levels. Alpha- or beta-adrenergic antagonists did not attenuate the initial rise in PRA. The PRA increased again after 48 hours of chronic intrarenal norepinephrine infusion and remained elevated thereafter. The second rise in PRA was increased by 30% with alpha-adrenergic blockade. Chronic intrarenal isoproterenol administration produced a similar increase in PRA, which peaked at 3-5 hours and then returned to control levels. In contrast to norepinephrine, chronic isoproterenol administration did not result in a second increase in PRA. At the end of the chronic isoproterenol infusion period, beta-adrenergic receptor refractoriness was demonstrated, as PRA did not increase significantly in response to a fourfold increase in the dose of isoproterenol. An increase in PRA was produced by acute intrarenal infusion of methoxamine. This increase in PRA was blocked by phentolamine, suggesting a vascular alpha-adrenergic receptor-mediated release of renin.

Intrarenal adenosine produces hypertension by activating the sympathetic nervous system via the renal nerves in the dog.

Studies from our laboratory suggest that the afferent renal nerves from the clipped kidney enhance sympathetic nervous system activity in established one-kidney, one clip and two-kidney, one clip Goldblatt hypertension. Because adenosine is released during renal ischaemia and adenosine has been shown to increase the frequency of afferent renal nerve signals, we proposed the hypothesis that intrarenal adenosine might produce hypertension by activating the sympathetic nervous system via the afferent renal nerves. To examine this hypothesis, changes in arterial pressure and activity of the sympathetic nervous system were measured during renal artery infusion of adenosine before and after renal denervation in uninephrectomized sodium replete conscious dogs. Intrarenal adenosine infusion produced a 21 +/- 3 mmHg mean arterial pressure rise in association with an increase in plasma norepinephrine. Ganglionic blockade during intrarenal adenosine infusion resulted in a significantly greater decrease in arterial pressure compared to control responses. After renal denervation, intrarenal adenosine infusion resulted in no change in arterial pressure, plasma norepinephrine or arterial pressure response to ganglionic blockade. To further assess sympathetic activity changes, right renal norepinephrine secretion and multifibre efferent neural traffic were measured during left renal artery adenosine infusion in alpha-chloralose-anaesthetized dogs. Left renal artery adenosine infusion resulted in increased right renal vascular resistance in association with increased renal norepinephrine secretion and increased efferent neural activity. The data indicate that in the dog with intact renal nerves, intrarenal adenosine produces hypertension by activating the sympathetic nervous system.

Determinants of hospital charges for coronary artery bypass surgery: the economic consequences of postoperative complications.

This is a prospective study of 500 consecutive patients having coronary artery bypass surgery; mean hospital charge from time of surgery to discharge was +11,900 +/- 12,700. Multiple regression analysis was performed using preoperative variables and postoperative complications. No preoperative clinical feature was a significant predictor of higher average charge. Sternal wound infection (p = 0.0001), respiratory failure (p = 0.0001) and left ventricular failure (p = 0.017) were associated with higher average hospital charge. The absence of any complication predicted a lower average charge, and postoperative death (4.4 +/- 4.5 days after surgery) was also associated with lower average charge. A cost equation was developed: hospital charge equalled $11,217 + $41,559 of sternal wound infection, + $28,756 for respiratory failure, + $5,186 for left ventricular failure, - $1,798 for no complication and - $6,019 for death. Recognition of the influence of complications on charges suggests that low average charges can only be achieved by surgical programs with a low complication rate.

Six-year survival after coronary thrombolysis and early revascularization for acute myocardial infarction.

Six-year follow-up was conducted in a consecutive series of 192 patients receiving thrombolytic therapy for acute myocardial infarction (AMI) with ST-segment elevation. Cardiac catheterization was performed within a day, and patients with an open infarct artery routinely had early revascularization: 99 (67%) underwent coronary bypass surgery and 18 (12%) coronary angioplasty. With this treatment strategy, 6-year cardiac mortality was 14.5%, 6% (12 patients) in hospital and 9% (16 patients) for survivors of hospitalization. Multivariate analysis showed that predictors of cardiac death among survivors of hospitalization were a closed infarct artery at catheterization (p less than 0.01), diabetes (p less than 0.01) and anterior myocardial infarction (p = 0.01). A subset of 146 patients underwent radionuclide angiography before hospital discharge; for them, predictors of mortality were a closed infarct artery at catheterization (p less than 0.01), anterior wall AMI (p = 0.02), and Killip class III to IV on admission (p less than 0.06). Left ventricular ejection fraction was not a significant predictor of mortality for this subset of patients.

A difference between front-loaded streptokinase and standard-dose recombinant tissue-type plasminogen activator in preserving left ventricular function after acute myocardial infarction (the Central Illinois Thrombolytic Therapy Study).

A blinded, randomized trial compared the effects of front-loaded streptokinase with those of the conventional dose of intravenous recombinant tissue-type plasminogen activator (rt-PA) on left ventricular (LV) function after acute myocardial infarction (AMI). Thrombolytic therapy was administered in the emergency departments of 30 community hospitals in central Illinois, and subsequent studies were performed at 1 tertiary referral center. Patients aged < or = 75 years with a first AMI who could be treated within 4 hours of the onset of chest pain were randomly assigned to receive either streptokinase (375,000 IU bolus, followed by 1,125,000 IU over 1 hour) or rt-PA (10 mg bolus, followed by 50 mg in the first hour, and 20 mg/hour for the next 2 hours). All patients were treated with aspirin (325 mg) and intravenous heparin. Patients were transferred for angiography within 24 hours. During the 30-month study, 253 patients were treated with intravenous thrombolytic therapy 2.4 +/- 1.0 hour after the onset of AMI. In patients with anterior wall AMI (n = 90), global LV ejection fraction measured by angiography within 24 hours was 45 +/- 12% with rt-PA, and 39 +/- 13% with streptokinase (p < 0.03). Convalescent radionuclide angiography documented a persistent beneficial effect of rt-PA on LV regional wall contractility, but not global ejection fraction. There were no differences between rt-PA and streptokinase in preserving global or regional LV function in patients with inferior wall AMI.

Safety of intravenous gadolinium (Gd-BOPTA) infusion in patients with renal insufficiency.

The safety of gadolinium (Gd-benzyloxypropionictetra-acetate [BOPTA] dimeglumine) infusion was evaluated in 32 patients with severe or moderate chronic renal failure in a prospective, randomized, double-blind, placebo-controlled study. Renal failure was defined as severe if creatinine clearance was between 10 and 29 mL/min, and as moderate if creatinine clearance was between 30 and 60 mL/min. Serum creatinine level and 24-hour urine samples for creatinine clearance were followed up serially for 7 days after the administration of either gadolinium (Gd-BOPTA dimeglumine), 0.2 mmol/kg, or a saline infusion. No patient experienced a significant change in renal function, defined as an increase in serum creatinine level greater than 0.5 mg/dL more than baseline, and no patient required hospitalization or dialysis during the study period. Gadolinium (Gd-BOPTA dimeglumine) appears to be well tolerated in patients with moderate to severe renal failure.

Oxygen free radicals and contrast nephropathy.

Ionic, high-osmolality contrast medium causes nephrotoxicity associated with increased intrarenal adenosine production. To test the hypothesis that oxygen free radicals (produced during intrarenal adenosine catabolism to xanthine) should be implicated in the pathogenesis of ionic, high-osmolality contrast medium nephrotoxicity in humans and to determine whether magnesium protects the kidney from oxygen free radical injury following contrast, 39 patients with mild renal dysfunction were divided into low (LoMg++) and normal (NlMg++) magnesium states and randomized to precoronary angiography oral allopurinol (a xanthine oxidase inhibitor) or placebo. Creatinine clearance and urinary xanthine excretion were measured before and after angiography. Forty-eight hours after contrast medium exposure, placebo-treated LoMg++ and NlMg++ patients had 61%+/-5% and 67%+/-6% increases in urinary xanthine excretion, respectively; however, placebo-treated LoMg++ patients had a greater (79%+/-9% v 35%+/-6%; P < 0.01) decrease in creatinine clearance than placebo-treated NlMg++ patients. Allopurinol-treated LoMg++ and NlMg++ patients had no significant change in urinary xanthine excretion, but did have 40%+/-7% and 33%+/-5% decreases, respectively, in creatinine clearance 48 hours after contrast medium exposure. There was no difference in renal dysfunctional response among placebo-treated NlMg++ patients or allopurinol-treated LoMg++ or NlMg++ patients. These data suggest (1) that oxygen free radicals contribute to ionic, high-osmolality contrast medium nephrotoxicity in hypomagnesemic patients with mild renal disease and (2) that magnesium attenuates the nephrotoxicity mediated by oxygen free radicals.

Transient paradoxical renal vasoconstriction following cardiac operation. Treatment with volume depletion.

Following cardiac operation complicated by inferior myocardial injury, a patient developed normal cardiac output congestive heart failure associated with severe renal vasoconstriction, oliguria and azotemia. The patient's renal dysfunction responded to volume depletion with hemofiltration. These paradoxical renal responses to volume changes may be caused by transiently altered cardiac volume receptor thresholds or afferent signals resulting in cardiorenal dysfunction.

Hypertensive heart disease syndrome in women in a cardiology practice.

The authors hypothesized that a population of female patients exist whose historical and clinical findings are typical regarding hypertensive heart disease syndrome, so they can be readily identified in a clinical practice and benefit from specific therapy.