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Biomedical subjects

N K Hollenberg

Publications and source records attributed to N K Hollenberg.

At least 55 records · Page 3Linked to original sources
PubMed1999

Altered adrenal sensitivity to angiotensin II in low-renin essential hypertension.

Low-renin essential hypertension (LREH) describes a widely recognized classification validated by clinical features, including salt-sensitive blood pressure and diuretic responsiveness. Classic physiological teaching has cited normal plasma aldosterone concentration despite suppressed renin as evidence for adrenal supersensitivity to angiotensin II (Ang II). We studied 94 patients with LREH, 242 normal-renin hypertensives, and 135 normal subjects as controls. Low-renin hypertensives did not differ significantly from the other groups in either basal or Ang II-stimulated aldosterone concentrations on a high-sodium diet. Stimulated with a low-sodium diet, LREH patients demonstrated the smallest rise in basal aldosterone secretion. Ang II responsiveness was also subnormal: the rise in aldosterone after Ang II infusion in LREH (613+/-39 pmol/L), although greater than in nonmodulators (180+/-17 pmol/L; P=0.001), was less than either the patients with intact modulation (940+/-53 pmol/L; P=0.001) or normotensives (804+/-50 pmol/L; P<0.05). Blacks with LREH demonstrated an even lower response than low-renin whites ((388+/-50 versus 610+/-47 pmol/L; P=0.0001). In contrast, the rise in systolic blood pressure with Ang II infusion on a low-salt diet was greatest among LREH patients (P=0. 001). Patients with LREH and nonmodulators were equally salt-sensitive. These results indicate that the adrenal response in LREH is normal on a high-salt diet but becomes progressively more abnormal as sodium control mechanisms are stressed. The factors that mediate enhanced adrenal response to Ang II with sodium restriction may be defective, suggesting the existence of alternative physiological mechanisms for sodium homeostasis in the low-renin state.

Adrenal Glands↗
PubMed1999

Sodium pump inhibition and regional expression of sodium pump alpha-isoforms in lens.

Both hypertension and cataract formation have been associated with reductions in sodium pump activity, possibly as a result of an endogenous inhibitor. The objective of the present study was to answer 4 closely related questions: (1) Is the lens sodium pump effectively inhibited by a labile, digitalis-like factor we have identified in the peritoneal dialysate from hypertensive patients in end-stage renal failure? (2) How does that inhibition compare to that induced by ouabain? (3) Does sodium pump isoform distribution determine the degree of lens sodium pump inhibition? (This question was precipitated by the unanticipated finding that the labile DLF was more effective in inhibiting lens sodium pump than was anticipated.) (4) Is sodium pump activity altered in lens in response to increased salt intake, a maneuver known to increase endogenous digitalis-like factor? We found that whereas ouabain produced equivalent or significantly less inhibition of lens Na(+), K(+)-ATPase from calf or rabbit, respectively, compared with brain, labile digitalis-like factor preferentially inhibited lens compared with brain. Analysis of whole-lens preparations from rabbit, calf, and normal human lens revealed substantial alpha2- and alpha3-isoforms of the sodium pump but little alpha1-isoform. Ouabain inhibition of whole-lens Na(+),K(+)-ATPase from rabbit and calf were comparable: for rabbit lens, K(i)=5.2x10(-7) mol/L; for calf lens, K(i)=1.0x10(-6) mol/L. Limited quantities of labile digitalis-like factor prohibited similar determinations; however, its concentration-activity profile paralleled that of ouabain. Na(+), K(+)-ATPase activity, measured in the 3 major anatomic regions of lens and normalized to nucleus, was greatest in epithelium (56. 9+/-17.9) compared with cortex (5.8+/-1.4) and nucleus (1.0+/-0.0; P=0.01). Immunohistochemistry of rabbit lens found abundant alpha2- and alpha3-isoforms in epithelium and limited alpha3 but undetectable alpha1 in cortex and nucleus. Finally, rats randomized to a high Na diet showed significantly reduced lens Na(+), K(+)-ATPase activity compared with those on a low Na diet, consistent with the effects of a sodium pump inhibitor. In conclusion, the present study suggests that digitalis-like factor may provide a link between hypertension and cataract formation.

Animals↗
PubMed1999

The renal profile of eprosartan.

The angiotensin II (AII) receptor antagonist eprosartan is a highly selective, nonpeptide drug specific for the AT1 receptor subtype that completely inhibits pressor, aldosterone secretory, and renal vasoconstrictive effects produced by AII infusions in healthy humans. It increases effective renal plasma flow in both salt-replete and salt-restricted healthy men, and maintains glomerular filtration rates in patients with essential hypertension and those with renal insufficiency after either single or multiple doses. In healthy salt-restricted men, the drug suppresses and stimulates aldosterone and renin, respectively, in the initial few hours after administration. This feedback inhibition for renin release and suppression of aldosterone is reduced with normal sodium intake. Eprosartan is natriuretic in salt-restricted subjects and does not induce sodium retention even when it reduces blood pressure. These properties, in addition to antagonism of AII effect at the AT1 receptor, no doubt contribute to the agent's antihypertensive effect in patients with essential hypertension. Pharmacodynamic studies predict that doses of up to 400 mg are safe. Additional preliminary studies suggest that doses as high as 1200 mg are safe and well tolerated, while producing meaningful hemodynamic and neurohumoral effects in patients with essential hypertension.

Acrylates↗
PubMed1999

The paradox of the low-renin state in diabetic nephropathy.

Although diabetic nephropathy is often a low renin state, the renin system appears to be implicated in its pathogenesis. In this study, it was hypothesized that the low plasma renin activity (PRA) is misleading, masking and perhaps reflecting an activated intrarenal renin system. PRA and renal vascular responses (inulin and para-aminohippurate clearance) to graded doses of an angiotensin II (AngII) antagonist, irbesartan, were assessed in eight healthy volunteers and 12 patients with type 2 diabetes mellitus and nephropathy on a 10 mmol Na intake, to activate the renin system. Basal PRA was suppressed in type 2 diabetes mellitus compared with the healthy subjects (0.58 +/- 0.14 versus 1.58 +/- 0.28 ng/L per s, mean +/- SEM; P < 0.01). Despite the low PRA, renal perfusion rose more in response to irbesartan in type 2 diabetes mellitus (714 +/- 83 to 931 +/- 116 ml/min; P = 0.002) than normal (624 +/- 29 to 772 +/- 49 ml/min; P = 0.008). The youngest patients were hyperfiltrating and showed the largest rise in renal plasma flow in response to irbesartan, whereas renal plasma flow rose less and GFR fell in patients with low basal GFR. PRA rose in response to irbesartan more gradually in the patients with type 2 diabetes mellitus, but ultimately matched the normal response. To account for the apparent paradox of a heightened renal hemodynamic response to an AngII antagonist in the face of a low PRA in type 2 diabetes mellitus, and the rise in PRA following the AngII antagonist, it is proposed that there is increased intrarenal AngII production in type 2 diabetes mellitus. This increase could account for suppressed circulating renin, the exaggerated renal vasodilator response to irbesartan, and the therapeutic effectiveness of interrupting the renin system in diabetic nephropathy.

Adult↗
PubMed1999

Relationship between insulin resistance and nonmodulating hypertension: linkage of metabolic abnormalities and cardiovascular risk.

Insulin resistance is a feature common to patients with diabetes and to some with hypertension. It is assumed that this feature confers the increased metabolic risk in hypertension. However, the state of the renin-angiotensin system might contribute to cardiovascular risk, although there is no clear mechanistic explanation. Our recent observation that insulin levels are increased in a specific subset of patients with normal/high-renin hypertension, the nonmodulators, provided the background for the current hypothesis: to ascertain whether abnormalities in lipid and carbohydrate metabolism are observed in the same patients in whom alterations in sodium transport, sodium homeostasis, and the renin-aniotensin system response have been identified. Exploration of a family history of cardiovascular risk was a secondary goal. Insulin sensitivity (assessed by a 75-g oral glucose load), lipid levels, and two defects in the renin-angiotensin system were assessed in 62 hypertensive and 14 normotensive subjects placed on a high (210 mmol/l) and a low (10 mmol/l) sodium intake for 2 weeks, to classify them as low-renin, nonmodulator, or modulating hypertensive subjects. Only in nonmodulators were the following cardiovascular risk factors significantly increased: fasting insulin (P < 0.01); increment in post-glucose load insulin (P < 0.01); total, LDL, and VLDL cholesterol and triglyceride levels (P < 0.05); and erythrocyte Na+/Li+ countertransport activity (P < 0.001). Both nonmodulators and low-renin hypertensive subjects had a significantly (P < 0.01) increased frequency of a family history of hypertension by questionnaire compared with subjects with intact modulation. However, only nonmodulators had a significantly (P < 0.02) higher frequency of a family history of myocardial infarction. Thus, there is a clustering of metabolic abnormalities in a discrete subset of the essential hypertensive population with a specific dysregulation of the renin-angiotensin system--nonmodulation. The absence of this cluster in low-renin hypertensive subjects may explain their relatively diminished cardiovascular risk. Its presence in nonmodulators likely contributes to the increased cardiovascular risk observed in normal/high-renin hypertension.

Adult↗
PubMed1999

The state and responsiveness of the renin-angiotensin-aldosterone system in patients with type II diabetes mellitus.

We have recently reported a combination of renal features that suggests independent angiotensin-mediated control of the renal circulation in the majority of hypertensive patients with type II diabetes. To ascertain whether other tissue elements of the renin-angiotensin-aldosterone system (RAAS) also were activated, we examined the adrenal response to angiotensin II (AngII) infusion on a low salt diet. We assessed also the renin response to the upright position in patients on a low salt diet and renin suppression in patients on a high salt diet. We compared responses in 42 hypertensive patients with type II diabetes (53.1 +/- 1.4 years, mean +/- SEM), 25 healthy controls (52.6 +/- 4.4 years); and 137 essential hypertensives without diabetes (43.3 +/- 1.2 years). A low renin state, defined as a plasma renin activity (PRA) <2.5 ng angiotensin I (AI)/mL/h after 5 to 7 days on a 10-mmol Na diet and 2 h of upright posture, was found in 21% of the essential hypertensives, but in only 14% of patients with type II diabetes. On this diet, PRA increased from 2.7 +/- 0.4 supine to 10.1 +/- 1.3 ng AI/mL/h upon standing in healthy subjects. In patients with type II diabetes, PRA was 3.6 +/- 0.4 and increased to 9.1 +/- 1.0 ng AI/mL/h. On a high salt (200 mmol) diet, healthy subjects showed the expected PRA suppression (0.3 +/- 0.1), but in patients with type II diabetes the PRA was less suppressed (1.2 +/- 0.3 ng AI/mL/h; P = .003). Thus, in most hypertensive patients with type II diabetes the RAAS shows normal activation, but is poorly suppressible. AngII infused intravenously to assess adrenal responsiveness in patients on a low salt diet caused an essentially identical increase in aldosterone concentration in patients with type II diabetes (21.1 +/- 1.7 to 44.0 +/- 5.9 ng/dL) and in essential hypertension (20.6 +/- 1.4 to 43.7 +/- 2.8 ng/ dL). The frequency of nonmodulation assessed as a blunted adrenal response to AngII infusion was identical in type II diabetes (47%) and in essential hypertension (46%) after exclusion of the low renin patients. Thus, at the level of one tissue renin system, the adrenal glomerulosa, responses were unaltered in patients with type II diabetes. The relative unresponsiveness of the renal blood supply to infused AngII in type II diabetes in association with an enhanced renal vasodilator response to angiotensin converting enzyme inhibition probably reflects local, intrarenal actions secondary to the diabetic state. The infrequency of a low renin state, and the inappropriately high renin levels on a high salt intake, provide a rational basis for pharmacologic interruption of the renin system to treat patients with type II diabetes.

Adult↗
PubMed1999

One's grandparents as the determinant of effective antihypertensive therapy.

We have known for 70 years that familial factors influence blood pressure level. Modern genetics suggest that 30-40% of blood pressure variation reflects genetic factors. We have known for more than 40 years that patients differ in their response to specific antihypertensive agents, with little insight beyond demographics into the responsible mechanism for the variation in that response. Only recently has interest been evident in attempts to bring these two questions together. Specifically, do familial factors influence the response to specific antihypertensive therapy? One example involves the attempt to use the response to angiotensin- converting enzyme (ACE) inhibitors as an intermediate phenotype. An analogous attempt involves recognition of the fact that ACE inhibition reverses many of the features of non-modulation- which is an expression of an angiotensinogen (AGT) gene polymorphism. The ESPRIT Study was the first to enroll hyper-tensive sibling pairs into a therapeutic trial, designed to assess responses to ACE inhibitor treatment with lisinopril. This pathway of investigation is likely to be very fruitful over the next several decades, to the point that 'pharmacogenetics' will be an element in selecting antihypertensive therapy.

Antihypertensive Agents↗
PubMed1999

Pharmacologic interruption of the renin-angiotensin system and the kidney: differential responses to angiotensin-converting enzyme and renin inhibition.

Pharmacologic interruption of the renin-angiotensin system has played a crucial role in determining its contribution to physiology, pathophysiology, and has made an enormous contribution to therapeutics. Despite this record of success, no pharmacologist would have chosen the angiotensin-converting enzyme (ACE) step for pharmacologic blockade. As renin is rate-limiting in the cascade and has remarkable specificity for its substrate, renin inhibition would have made a far more attractive target. Indeed, evidence reviewed in this article supports this case. A renin inhibitor developed to block rat renin produced a larger reduction in plasma angiotensin II concentration than did two ACE inhibitors at the top of their dose-response relationship. In humans, renin inhibition led to a larger increase in renal plasma flow in healthy human volunteers studied on a low salt diet to activate the renin system than did ACE inhibitors. Again, the studies used doses in each case at the top of the dose-response relationships for renal hemodynamics. Because the response to AT1 receptor blockade was very similar to the response induced by renin inhibitors, the results suggest that both classes of agent acted via their influence on the renin system. Moreover, the data suggest that 30 to 40% of angiotensin II formation influencing the kidney in the healthy human during renin system activation is formed via renin-dependent, but ACE-independent, pathways. These findings have potentially important therapeutic implications, and certainly help to justify the major therapeutic trials now ongoing and planned.

Angiotensin II↗
PubMed1998

Thy-1, a novel marker for angiogenesis upregulated by inflammatory cytokines.

We identified the cell surface glycoprotein Thy-1 on the endothelium of newly formed blood vessels in four models of angiogenesis in adult rats. Anti-Thy-1 staining showed that Thy-1 was upregulated in adventitial blood vessels after balloon injury to the carotid artery. Preabsorption with a rat Thy-1-Ig fusion construct eliminated all immunoreactivity and thus confirmed the specificity of the Thy-1 staining. Thy-1 was also expressed in the endothelium of small blood vessels formed after tumor implantation in the cornea, in periureteral vessels formed after ligation of the renal artery, and in small blood vessels of the uterus formed during pregnancy. In contrast with its expression during adult angiogenesis, Thy-1 was not expressed in the endothelium of blood vessels during embryonic angiogenesis. In vitro, the inflammatory cytokines interleukin-1beta and tumor necrosis factor-alpha upregulated Thy-1 mRNA by 8- and 14-fold, respectively. Vascular endothelial growth factor, basic fibroblast growth factor, transforming growth factor-beta, and platelet-derived growth factor-BB had no effect on Thy-1 mRNA. Thus, Thy-1 appears to be a marker of adult but not embryonic angiogenesis. The upregulation of Thy-1 by cytokines but not growth factors indicates the importance of inflammation in the pathogenesis of adult angiogenesis.

Angioplasty, Balloon↗
PubMed1998

Dissociation of vascular and adrenal responsiveness to angiotensin II following calcium channel blockade.

Calcium channel blockers as a class reduce both vascular resistance and systemic blood pressure. However, it is not known if different classes of calcium channel blockers have similar effects on the renin-angiotensin-aldosterone system. We investigated vascular and adrenal responses to endogenous and exogenous angiotensin II in normotensive subjects before and after receiving isradipine or diltiazem. Subjects achieved low salt balance before study and underwent an angiotensin II infusion and upright posture study. After re-achieving salt balance the subjects received either isradipine (n=10), or diltiazem (n=7) for three days before repeating the study. Both agents lowered blood pressure and significantly shifted the dose response relationship of angiotensin II and mean blood pressure (P<0.01). In contrast, aldosterone secretion in response to upright posture and angiotensin II infusion was significantly reduced (P<0.01) by isradipine but not by diltiazem. The in vitro effects of both agents on aldosterone secretion from bovine adrenal glomerulosa cells paralleled the in vivo observations showing that angiotensin II-stimulated aldosterone secretion was markedly blunted by isradipine and minimally by diltiazem. These results suggest a tissue specificity for the effects of different classes of calcium channel blockers. Dihydropyridine calcium channel blockers may exert their antihypertensive effect by blocking both vascular and adrenal responses to angiotensin II.

Adrenal Glands↗
PubMed1998

Obesity, salt intake, and renal perfusion in healthy humans.

Renal perfusion rises as obesity develops during short-term overfeeding in animal studies. In humans, the assessment is complicated by the need to normalize renal perfusion for body size. We made use of the fact that radioactive xenon washout measures renal perfusion per unit of tissue mass to address this issue by comparing 45 moderately obese and 147 lean healthy potential kidney donors. All were disease free. The rationale for involving kidney donors reflects the fact that the xenon method for measuring renal perfusion demands injection of the xenon directly into the renal artery, which can be accomplished during the arteriogram that is a necessary part of potential kidney donor evaluation. In 21 obese subjects (body mass index [BMI], 29.1+/-0.9) in balance on a 10-mmol sodium intake, renal perfusion (352+/-16 mL x 100 g(-1) x min(-1)) was significantly higher than predicted from findings in the 95 lean control subjects (313+/-3 mL x 100 g(-1) x min(-1); P=0.035) after adjustment for age. With a high sodium intake (200 mmol), however, renal perfusion was not significantly different in 24 obese subjects (BMI, 28.8+/-0.7; 323+/-13 mL x 100 g(-1) x min(-1)) in comparison to 52 lean controls (341+/-10 mL x 100 g(-1) x min(-1) after adjustment for age. Systolic and diastolic blood pressures were similar in obese and age- and gender-matched lean control subjects. Renal vasodilation was seen in association with sustained obesity in humans. While the mechanisms of obesity-related vasodilation are unclear, the dependence on sodium intake in this study is consistent with a role for the renin-angiotensin system. The findings are not in accordance with a reduction in renal perfusion reported in healthy obese humans in whom measured renal perfusion was indexed for body size.

Adolescent↗
PubMed1998

Pathways for angiotensin II generation in intact human tissue: evidence from comparative pharmacological interruption of the renin system.

Multiple lines of evidence have suggested that alternative pathways to the angiotensin-converting enzyme (ACE) exists for angiotensin II (Ang II) generation in the heart, large arteries, and the kidney. In vitro studies in intact tissues, homogenates, or membrane isolates from the heart and large arteries have repeatedly demonstrated such pathways, but the issue remains unresolved because the approaches used have not made it possible to extrapolate from the in vitro to the in vivo situation. For our in vivo model, we studied young and healthy human volunteers, for the most part white and male; when these subjects achieved balance on a low salt diet to activate the renin system, the response of renal perfusion to pharmacological interruption of the renin system was studied. With this approach, we studied the renal vasodilator response to 3 ACE inhibitors, 2 renin inhibitors, and 2 Ang II antagonists at the top of their respective dose-response relationships. When these studies were initiated, our premise was that a kinin-dependent mechanism contributed to the renal hemodynamic response to ACE inhibition; therefore, the renal vasodilator response to ACE inhibition would exceed the alternatives. To our surprise, both renin inhibitors and both Ang II antagonists that were studied induced a renal vasodilator response of 140 to 150 mL/min/1.73 m2, approximately 50% larger than the maximal renal hemodynamic response to ACE inhibition, which was 90 to 100 mL/min/1.73 m2. In light of the data from in vitro systems, our findings indicate that in the intact human kidney, virtually all Ang II generation is renin-dependent but at least 40% of Ang I is converted to Ang II by pathways other than ACE, presumably a chymase, although other enzyme pathways exist. Preliminary data indicate that the non-ACE pathway may be substantially larger in disease states such as diabetes mellitus. One implication of the studies is that at the tissue level, Ang II antagonists have much greater potential for blocking the renin-angiotensin system than does ACE inhibition-with implications for therapeutics.

Angiotensin II↗
PubMed1997

Renal sodium pump regulation in deoxycorticosterone salt hypertension in the rat.

The renal sodium pump participates in sodium homeostasis and has been predicted to have a role in salt dependent forms of hypertension. However, the status of the renal sodium pump in volume-dependent hypertension is unclear. We assessed the renal sodium pump and its activity in the deoxycorticosterone acetate (DOCA)-salt model in rats, a model of volume-dependent hypertension. Sprague-Dawley rats on ad libitum diet were compared with four groups of litter mates receiving high or low salt diets, with or without DOCA administration. The renal sodium pump evaluation included measurement of hydrolytic activity, ouabain binding capacity and affinity, sodium activation, active pump units (determined by phosphoenzyme level), dephosphorylation rate, and isoform specific molecular expression. Intrinsic enzyme properties, including sodium and ouabain affinities, as well as turnover rate per sodium pump, were identical among the five groups. In contrast, the combination of DOCA and high salt intake (DOCA high salt) produced marked, significant increases in hydrolytic activity, ouabain binding capacity, phosphoenzyme level, and alpha1-isoform expression. DOCA low salt animals showed much smaller but significant increases in pump number. We conclude that DOCA and volume expansion may each alter renal sodium pump regulation, but volume expansion is clearly dominant. Increased renal sodium pump activity in DOCA high salt animals would, if unmitigated, favor sodium reabsorption and may contribute to hypertension.

Animals↗
PubMed1997

Tissue-specific regulation of the sodium pump in DOCA-salt hypertension.

Alterations in sodium pump activity have been associated with volume-sensitive hypertension, but little is known regarding the molecular regulation of the catalytically active alpha-subunit of the sodium pump in these models. We examined changes in the mRNA abundance of the alpha-isoforms in tissues that might participate in sodium and volume regulation in the deoxycorticosterone acetate (DOCA)-high salt rat model. These tissues included kidney, heart, aorta, pituitary, and hypothalamus. This study assessed alterations arising from changes in dietary salt intake alone, from DOCA administration alone, and those requiring both DOCA and high salt with their attendant volume expansion and hypertension. Increased sodium intake produced no significant change in any isoform in the five tissues studied. DOCA administered with a low salt diet produced no significant change in any of the alpha-isoforms in any of the tissues studied. The combination of DOCA and high salt (HS), on the other hand, brought about a twofold increase in renal alpha1-mRNA abundance compared with control (alpha1, CTL: 101.1 +/- 9.3, DOCA-HS: 197.3 +/- 22.9, P < .0001). DOCA-HS also induced a marked increase in both alpha1- and alpha2-mRNA in the aorta (alpha1, CTL: 122.5 +/- 33.3 v DOCA-HS: 487.2 +/- 59.9, P = .001; alpha2, CTL: 126.6 +/- 40.0 v DOCA-HS: 559.8 +/- 271.7, P = .01). In contrast DOCA-HS animals showed a significant reduction in the alpha2-, but not alpha1-, mRNA abundance in heart (alpha2, CTL: 118.0 +/- 11.7 v DOCA-HS: 61.1 +/- 9.1, P = .006). No change was observed in pituitary or hypothalamus with DOCA-HS. Of factors known to modulate the mRNA abundance of the sodium pump, only the putative endogenous sodium pump inhibitor might account for the changes in the aorta and kidney. Reductions in aldosterone or hypertension might reduce alpha2 in the heart. Only the renal response would favor sodium reabsorption, which could contribute to the hypertensive process.

Animals↗
PubMed1997

Specificity of the vascular smooth muscle contractile response to a labile digitalis-like factor in peritoneal dialysate: the influence of potassium.

Although multiple lines of evidence have suggested that a circulating endogenous digitalis-like factor (DLF) might contribute to the pathogenesis of sodium-sensitive hypertension, the subject remains controversial. This study was designed to compare the influence of potassium on vascular responses to an endogenous DLF isolated from peritoneal dialysate (PD) in volume-expanded patients with other sodium pump inhibitors, such as ouabain and bufalin, and the influence of serotonin as an index of specificity. An increase in bath potassium (K+) concentration from 2.7 to 10 mmol/L relaxed bovine facial artery precontracted with serotonin, but induced a secondary paradoxical contractile response in vascular-smooth muscle (VSM) precontracted with ouabain, bufalin, or the endogenous DLF from PD. There was a strong correlation between the primary contraction induced by each sodium pump inhibitor, and the magnitude of the paradoxical secondary contractile response. The increase in potassium concentration did not influence ouabain binding in the 20 min required for the experimental protocol, although binding was decreased after 120 min. The findings indicate that the VSM contractile response induced by the agent isolated from PD reflects VSM sodium pump inhibition, supporting its candidacy as a circulating regulator of the sodium pump.

Animals↗
PubMed1997

Autonomy of the renin system in type II diabetes mellitus: dietary sodium and renal hemodynamic responses to ACE inhibition.

Recognition that non-insulin-dependent diabetes mellitus (NIDDM) is a leading cause of end-stage renal disease (ESRD), and a focus of recent therapeutic and genetic studies on the renin system have rekindled interest in mechanisms by which angiotensin converting enzyme (ACE) inhibitors influence the diabetic kidney. We evaluated the renal hemodynamic status of 19 hypertensive patients with NIDDM under controlled sodium balance, low (10 mmol/day for 5 to 7 days) or high (200 mmol/day for 5 to 7 days). The renal plasma flow (RPF) response to ACE inhibition and to angiotensin II (Ang II) infusion was measured as para-aminohippurate (PAH) clearance before and during enalapril administration (10 mg b.i.d. for 3 days). Our premise was that if renal vasodilation induced by ACEI involves kinins, prostaglandins, and/or nitric oxide, vasoconstrictor responses to Ang II would be blunted. Conversely, if the dominant ACE inhibitor action were a reduction in Ang II formation, the consequence would be up-regulation and an enhanced vasoconstrictor response to exogenous Ang II. RPF in NIDDM on a high-salt diet was lower than in age-matched controls (477 +/- 25 vs. 551 +/- 25 ml/min/1.73 m2; P = 0.02). Enalapril increased RPF in NIDDM to 511 +/- 29 ml/min/1.73 m2 (P < 0.05) and enhanced renal vasoconstrictor responses to Ang II infusion, from -68 +/- 9 to -106 +/- 18 ml/min/1.73 m2 (P = 0.03). Baseline plasma renin activity (PRA) and plasma aldosterone significantly exceeded matched normotensive controls (1.1 +/- 0.5 vs. 0.3 +/- 0.1 ng AI/ml/hr and 10 +/- 0.9 vs. 4.1 +/- 0.5 ng/dl, P < 0.01, respectively). Conversely all measures in studies on a low-salt diet were normal. Our findings indicate that: (1) NIDDM with hypertension is associated with reduced RPF when dietary salt intake is high, (2) reduced Ang II formation is the dominant mechanism of ACEI-induced renal vasodilation in hypertensives with NIDDM; and (3) the sustained renal hemodynamic responses to ACE inhibition despite high-salt balance, and the increased PRA suggest an autonomous renin-angiotensin system suppressed subnormally by a high salt diet in patients with NIDDM despite greater volume expansion.

Adult↗