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Background: DPP4 (dipeptidyl peptidase-4) inhibitors comprise a class of oral diabetes medication that have the potential for off-target cardiovascular effects. We previously showed that DPP4 inhibition attenuates the hypotensive effect of acute ACE (angiotensin-converting enzyme) inhibition and increases norepinephrine. Here, we investigated the effects of DPP4 during sustained ACE inhibition compared with during therapy with an ARB (angiotensin receptor blocker) or calcium channel blocker (neutral comparator) in a randomized, double-blinded crossover study. Methods: We enrolled 106 adults with type 2 diabetes and hypertension and 100 received intervention. Subjects were randomized to one of 3 blood pressure arms: ramipril, valsartan, or amlodipine for a total of 15 weeks and received 3 one-week crossover therapies in random order: placebo + placebo, sitagliptin + placebo, and sitagliptin + aprepitant separated by 4-week washout. Results: We found that DPP4 inhibition increased norepinephrine during ramipril but did not increase blood pressure. Aprepitant, a NK1 (substance P) receptor blocker, lowered standing heart rate during renin-angiotensin-aldosterone system blockade with ramipril or valsartan. Conclusions: Increased catecholamines during concurrent ACE and DPP4 inhibition may contribute to cardiovascular complications in patients predisposed to heart failure.

Contemporary anticancer drugs have significantly improved cancer survival at the expense of cardiovascular toxicities, including heart disease, thromboembolic disease, and hypertension. One of the most common side effects of these drugs is hypertension, especially in patients treated with vascular endothelial growth factor inhibitors, as well as tyrosine kinase inhibitors and proteasome inhibitors. Adjunctive therapy, including corticosteroids, calcineurin inhibitors, and nonsteroidal anti-inflammatories, as well as anti-androgen hormone therapy for prostate cancer, may further increase blood pressure in these patients. Cancer therapy-induced hypertension is often dose limiting, increases cardiovascular mortality in cancer survivors, and is usually reversible after interruption or discontinuation of treatment. The exact molecular mechanisms underlying hypertension are unclear, but recent discoveries indicate an important role for reduced nitric oxide generation, oxidative stress, endothelin-1, prostaglandins, endothelial dysfunction, increased sympathetic outflow, and microvascular rarefaction. In addition, genetic polymorphisms in vascular endothelial growth factor receptors are implicated in vascular endothelial growth factor inhibitor-induced hypertension. Diagnosis, management, and follow-up of cancer therapy-induced hypertension follow national hypertension guidelines because evidence-based clinical trials specifically addressing patients who develop hypertension as a result of cancer therapy are currently lacking. Rigorous baseline assessment of patients before therapy is started requires particular emphasis on assessing and treating cardiovascular risk factors. Hypertension management follows guidelines for the general population, although special attention should be given to rebound hypotension after termination of cancer therapy. Management of these complex patients requires collaborative care involving oncologists, cardiologists, hypertension specialists, primary care professionals, and pharmacists to ensure the optimal therapeutic effect from cancer treatment while minimizing competing cardiovascular toxicities.

Epoxyeicosatrienoic acids (EETs) reduce blood pressure by acting in the vasculature and kidney, and interventions to increase circulating EETs improve insulin sensitivity and prevent diabetes in animal models. Inhibition of EET hydrolysis with a sEH (soluble epoxide hydrolase) inhibitor is an attractive approach for hypertension and diabetes. We tested the hypothesis that sEH inhibition increases circulating EETs, reduces blood pressure, and improves insulin sensitivity, blood flow, and inflammation in a randomized, double-blind, placebo-controlled crossover study. Sixteen participants with obesity and prediabetes were randomized to GSK2256294 10 mg QD or placebo for 7 days, insulin sensitivity was assessed by hyperinsulinemic-euglycemic clamp, and adipose and muscle tissues biopsies were performed to assess insulin-stimulated Akt phosphorylation. We assessed tissue and plasma EETs and their respective diol concentrations and sEH activity within plasma, muscle, and adipose tissues. GSK2256294 reduced circulating and adipose tissue sEH activity, but blood pressure, circulating EET, and tissue EETs were unchanged. Plasma sEH activity correlated with muscle and adipose tissue sEH activity. Insulin sensitivity assessed during hyperinsulinemic clamps, as well as adipose and muscle phosphorylated-Akt/Akt expression were similar during GSK2256294 and placebo. sEH inhibition with GSK2256294 reduced plasma F2-isoprostanes (50.7±15.8 versus 37.2±17.3 pg/mL; P =0.03) but not IL (interleukin)-6. Resting blood pressure, forearm blood flow, and renal plasma flow were similar during GSK2256294 and placebo. We demonstrate that GSK2256294 administration for 7 days effectively inhibits sEH activity in plasma, muscle, and adipose tissue and reduces F2-isoprostanes—a marker of oxidative stress—but does not improve insulin sensitivity or blood pressure.

Epoxyeicosatrienoic acids (EETs) are lipid signaling molecules formed from arachidonic acid by the action of CYP450s. EETs cause vasodilation, exert anti-inflammatory effects, and enhance insulin secretion and sensitivity in rodents. EETs are metabolized to less active dihydroxyeicosatrienoic acids (DHETs) by sEH (soluble epoxide hydrolase), and 14,15-DHET has been reported to be increased in patients with primary aldosteronism, but the effects of aldosterone on EET concentrations and sEH activity are unknown. We tested the hypothesis that treatment of primary aldosteronism would alter EET concentrations in humans. We studied 9 patients with primary aldosteronism before and at least 3 months after unilateral adrenalectomy (6) or treatment with a mineralocorticoid antagonist (3). Circulating total EET concentrations increased to 18.5±12.6 from 11.9±5.9 nmol/L with treatment of primary aldosteronism ( P =0.027). Among the regioisomers of EETs, 14,15-EET significantly increased after treatment, whereas 11,12-EET and 8,9 EET were unaltered. Total DHET concentrations and specific regioisomers of DHET did not change significantly. Circulating total EETs (ρ=−0.52, P =0.026), 14,15-EET ( ρ =−0.56, P =0.015), and 11,12-EET ( ρ =−0.48, P =0.042) correlated inversely with aldosterone. We also assessed EETs after a 12-hour aldosterone or vehicle infusion in a randomized cross-over study in healthy volunteers. Plasma EETs were similar after 12-hour aldosterone or vehicle infusion. Lastly, 3-day infusion of aldosterone in mice decreased EET concentrations in adipose and muscle and increased sEH expression as determined by molar ratio of DHETs to EETs and soluble epoxide hydrolase ( Ephx2 ) mRNA expression in adipose tissue. These studies suggest that prolonged exposure to increased aldosterone decreases EET concentrations.

See related article, pp 606–613 Incretin-based therapies for type 2 diabetes mellitus increase glucose-dependent insulin secretion, reducing the risk of fasting hypoglycemia, and suppress glucagon secretion. Whereas stable glucagon-like peptide (GLP)-1 analogs require injection, dipeptidyl peptidase 4 (DPP4) inhibitors are orally bioavailable. DPP4 inhibitor use has grown rapidly in the United States because sitagliptin was approved in 2006. In April 2016, however, the Food and Drug Administration (FDA) added warnings to the labels of saxagliptin and alogliptin, indicating that these DPP4 inhibitors may increase the risk of heart failure. The FDA warnings resulted from a review of 3 major randomized, placebo-controlled clinical trials investigating the cardiovascular effects of DPP4 inhibitors that yielded disparate results with respect to the association between DPP4 inhibitor use and risk of heart failure. The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients With Diabetes Mellitus Thrombolysis in Mycoardial Infarction (SAVOR-TIMI) 53 trial enrolled 16 492 patients with a history of cardiovascular disease or risk factors for cardiovascular disease.1 There were no differences between the saxagliptin and placebo groups in the primary combined end point of cardiovascular death, myocardial infarction or ischemic stroke or the major secondary combined end point of cardiovascular death, myocardial infarction, ischemic stroke, hospitalization for unstable angina, coronary revascularization, or heart failure. Unexpectedly, however, saxagliptin was associated with a significantly increased risk of hospitalization for heart failure compared with placebo (hazard ratio, 1.27; 95% confidence interval [CI], 1.07–1.51; P =0.007).1 The Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care (EXAMINE) trial enrolled 5380 patients with type 2 diabetes mellitus and a recent acute coronary event; there was no effect of drug on the primary composite end point of cardiovascular death, myocardial infarction, and …

To test the hypothesis that the bradykinin receptor 2 ( BDKRB2 ) BE1+9/−9 polymorphism affects vascular responses to bradykinin, we measured the effect of intra-arterial bradykinin on forearm blood flow and tissue-type plasminogen activator (t-PA) release in 89 normotensive, nonsmoking, white American subjects in whom degradation of bradykinin was blocked by enalaprilat. BE1 genotype frequencies were +9/+9:+9/−9:−9/−9=19:42:28. BE1 genotype was associated with systolic blood pressure (121.4±2.8, 113.8±1.8, and 110.6±1.8 mm Hg in +9/+9, +9/−9, and −9/−9 groups, respectively; P =0.007). In the absence of enalaprilat, bradykinin-stimulated forearm blood flow, forearm vascular resistance, and net t-PA release were similar among genotype groups. Enalaprilat increased basal forearm blood flow ( P =0.002) and decreased basal forearm vascular resistance ( P =0.01) without affecting blood pressure. Enalaprilat enhanced the effect of bradykinin on forearm blood flow, forearm vascular resistance, and t-PA release (all P P =0.04 for both). t-PA release tended to be decreased in response to bradykinin in the +9/+9 group ( P =0.08). When analyzed separately by gender, BE1 genotype was associated with bradykinin-stimulated t-PA release in angiotensin-converting enzyme inhibitor–treated men but not women ( P =0.02 and P =0.77, respectively), after controlling for body mass index. There was no effect of BE1 genotype on responses to the bradykinin type 2 receptor–independent vasodilator methacholine during enalaprilat. In conclusion, the BDKRB2 BE1 polymorphism influences bradykinin type 2 receptor–mediated vasodilation during angiotensin-converting enzyme inhibition.

This study tested the hypothesis that angiotensin promotes oxidative stress and inflammation in humans via aldosterone and the mineralocorticoid receptor. We measured the effect of intravenous aldosterone (0.7 μg/kg per hour for 10 hours followed by 0.9 μg/kg per hour for 4 hours) and vehicle in a randomized, double-blind crossover study in 11 sodium-restricted normotensive subjects. Aldosterone increased interleukin (IL)-6 (from 4.7±4.9 to 9.4±7.1 pg/mL; F=4.94; P =0.04) but did not affect blood pressure, serum potassium, or high-sensitivity C-reactive protein. We next conducted a randomized, double-blind, placebo-controlled, crossover study to measure the effect of 3-hour infusion of angiotensin II (2 ng/kg per minute) and norepinephrine (30 ng/kg per minute) on separate days after 2 weeks of placebo or spironolactone (50 mg per day) in 14 salt-replete normotensive subjects. Angiotensin II increased blood pressure (increase in systolic pressure: 13.7±7.5 and 15.2±9.4 mm Hg during placebo and spironolactone, respectively; P 2 ; P P =0.002). Angiotensin II transiently increased free plasma F 2 -isoprostanes similarly during placebo and spironolactone. Angiotensin II increased serum IL-6 concentrations during placebo (from 1.8±1.1 to 2.4±1.4 pg/mL; F=4.5; P =0.04) but spironolactone prevented this effect (F=6.4; P =0.03 for spironolactone effect). Norepinephrine increased blood pressure and F 2 -isoprostanes but not aldosterone or IL-6. Aldosterone increases IL-6 in humans. These data suggest that angiotensin II induces IL-6 through a mineralocorticoid receptor–dependent mechanism in humans. In contrast, angiotensin II–induced oxidative stress, as measured by F 2 -isoprostanes, is mineralocorticoid receptor independent and may be pressor dependent.

This study tests the hypothesis that spironolactone influences plasminogen activator inhibitor-1 (PAI-1) concentrations through mineralocorticoid receptor antagonism rather than through changes in potassium. Effects of spironolactone (50 mg per day) and triamterene (50 mg per day) on fibrinolytic balance were compared in 18 normotensive and 20 hypertensive subjects pretreated with hydrochlorothiazide (HCTZ; 12.5 mg per day). Blood pressure and serum potassium were similar in spironolactone and triamterene treatment groups. The effect of the 2 drugs on the renin-angiotensin-aldosterone system was also similar. In contrast, spironolactone and triamterene exerted opposing effects on PAI-1 antigen ( P =0.006 for drug effect). In normotensive subjects, triamterene (from 10.1±7.8 to 16.9±9.9 ng/mL at 9 am , P =0.019; from 7.6±5.4 to 11.5±7.3 ng/mL at 11 am , P =0.027; from 9.3±7.7 to 13.7±8.5 ng/mL for average of all time points, P =0.054) but not spironolactone significantly increased PAI-1 antigen. In hypertensive subjects, spironolactone significantly decreased PAI-1 antigen (from 22.0±23.4 to 16.7±19.0 ng/mL at 10 am , P =0.041; from 17.5±21.7 to 12.7±16.8 ng/mL at 11 am , P =0.043; from 20.3±22.6 to 16.6±19.7 ng/mL for average of all time points, P =0.014), whereas there was no effect of triamterene. Only spironolactone significantly decreased the molar ratio of PAI-1 to tissue-type plasminogen activator (t-PA) in hypertensive subjects. By regression analysis, predictors of mean PAI-1 response were spironolactone versus triamterene ( P =0.014), hypertension ( P =0.002), and PAI-1 response to HCTZ ( P =0.019), with a trend for aldosterone ( P =0.061). Mineralocorticoid receptor antagonism prevents the effect of activation of the renin-angiotensin-aldosterone system on PAI-1 antigen in normotensive subjects and improves fibrinolytic balance in hypertensive subjects through a potassium-independent mechanism.

To test the hypothesis that NO influences aldosterone production in humans, we examined the effect of N G -nitro- l -arginine methyl ester ( l -NAME) on aldosterone concentrations in the presence and absence of the NO precursor l -arginine (3 g TID) and the angiotensin-converting enzyme inhibitor ramipril (10 mg QD). Ten normal subjects were given l -NAME (66 μg/kg per min for 30 minutes) or vehicle in random order on separate days during placebo and after randomized, double-blind treatment with l -arginine, ramipril, or l -arginine plus ramipril. Infusion of l -NAME significantly increased systolic blood pressure (all P P ≤0.02) during all 4 treatment arms. After placebo pretreatment, serum aldosterone was significantly higher during l -NAME infusion than during vehicle (6.6±1.7 versus 3.3±0.5 ng/dL; P =0.045). Combined treatment with l -arginine plus ramipril abolished this effect. There was no effect of l -NAME on plasma renin activity (PRA; P =0.297) or angiotensin II concentrations ( P =0.537). However, there was a significant interactive effect of l -NAME and time on serum potassium ( P =0.039). There was a significant linear relationship between PRA and aldosterone concentration after vehicle infusion ([aldosterone]=3.9·PRA+1.9; r 2 =0.476; P =0.027) and l -NAME infusion ([aldosterone]=7.2·PRA+3.1; r 2 =0.457; P =0.032), and the intercepts of these lines were different ( P =0.029). There was a significant linear relationship between serum potassium and aldosterone during l -NAME ([aldosterone]=8.2 · [potassium]−28.9; r 2 =0.609; P =0.008) but not during vehicle ( P =0.313). These data suggest that endogenous NO modulates aldosterone synthesis in humans.

Abstract —Studies in isolated vessels and rat models of hypertension suggest that angiotensin (Ang)-(1-7) potentiates the vasodilator effect of bradykinin, possibly through ACE inhibition. We therefore tested the hypothesis that Ang-(1-7) potentiates the vasodilator or tissue plasminogen activator (TPA) response to bradykinin in the human forearm vasculature. Graded doses of Ang-(1-7) (10, 100, and 300 pmol/min), bradykinin (47, 94, and 189 pmol/min), and Ang I (1, 10, and 30 pmol/min) were administered through the brachial artery to 8 normotensive subjects in random order. Thirty minutes after initiation of a constant infusion of Ang-(1-7) (100 pmol/min), bradykinin and Ang I infusions were repeated. There were no systemic hemodynamic effects of the agonists. Bradykinin significantly increased forearm blood flow ( P P =0.007, from 1.1±1.0 to 23.6±6.2 ng/min per 100 mL at 189 pmol/min), whereas Ang I caused vasoconstriction ( P =0.003, from 3.3±0.4 to 2.5±0.3 mL/min per 100 mL at 30-pmol/min dose). There was no effect of Ang-(1-7) on either forearm blood flow ( P =0.62, 3.3±0.4 to 3.5±0.4 mL/min per 100 mL at 300 pmol/min) or TPA release ( P =0.52, from 0.7±0.8 to 1.0±0.7 ng/min/100 mL at 300 pmol/min). Moreover, there was no effect of 100 pmol/min Ang-(1-7) on the vasodilator [ P =0.46 for Ang-(1-7) effect] or TPA [ P =0.82 for Ang-(1-7) effect] response to bradykinin or the vasoconstrictor response to Ang I [ P =0.62 for Ang-(1-7) effect]. These data do not support a role of Ang-(1-7), given at supraphysiological doses, in the regulation of human peripheral vascular resistance or fibrinolysis.

Abstract —Bradykinin is a potent endothelium-dependent vasodilator that contributes to the blood pressure lowering effect of angiotensin-converting enzyme inhibition. Angiotensin-converting enzyme inhibitors are widely prescribed for the treatment of hypertension, although the efficacy of this therapy has been reported to vary among different ethnic groups. To determine whether vascular sensitivity to bradykinin is decreased in blacks compared with whites, we measured forearm blood flow with venous plethysmography in response to intraarterially-administered bradykinin (100, 200, and 400 ng/min) under salt-controlled conditions in 28 (14 black, 14 white) normotensive subjects genotyped for the ACE insertion/deletion ( I/D ) polymorphism. Acetylcholine (ACh) (15, 30, and 60 μg/min) and sodium nitroprusside (SNP) (0.8, 1.6, and 3.2 μg/min) were infused as endothelium-dependent and endothelium-independent controls. Compared with whites, blacks exhibited a blunted vasodilator response to bradykinin (maximal blood flow: 20.4±2.5 versus 10.9±1.4 mL · 100 mL −1 · min −1 , P =0.004) and SNP (14.1±1.6 versus 9.9±1.7 mL · 100 mL −1 · min −1 , P =0.05) but not to ACh (10.5±2.8 versus 6.6±1.0 mL · 100 mL −1 · min −1 , P =0.21). White subjects who carried at least 1 ACE D allele demonstrated significantly greater vasodilator responses to bradykinin compared with those homozygous for the I allele ( DD or ID versus II , F=5.6, P ACE D allele had a significantly greater vasodilator response to bradykinin than those who carried the I allele ( DD versus ID or II , F=8.3, P =0.01). The ethnic difference was most pronounced in subjects heterozygous at the ACE I/D locus in which blacks had a markedly attenuated response to bradykinin compared with whites (F=41.0, P ACE I/D genotype on the vasodilator responses to SNP or ACh in either ethnic group. These data confirm that vascular reactivity to bradykinin and the endothelium-independent vasodilator SNP is decreased in normotensive blacks compared with whites, consistent with attenuated vascular smooth muscle reactivity. The data suggest that genetic variation at the ACE gene locus interacts with ethnicity to impact the vascular response to bradykinin.

Abstract —Angiotensin-converting enzyme (ACE) inhibition significantly decreases plasminogen activator inhibitor-1 (PAI-1) without altering tissue plasminogen activator (tPA) during activation of the renin-angiotensin-aldosterone system in humans. Because ACE inhibitors and angiotensin II type 1 (AT 1 ) receptor antagonists differ in their effects on angiotensin II formation and bradykinin degradation, the present study compared the effect of equivalent hypotensive doses of an ACE inhibitor and AT 1 antagonist on fibrinolytic balance. Plasma PAI-1 antigen, tPA antigen, plasma renin activity, and aldosterone were measured in 25 normotensive subjects (19 white, 6 black; 14 men, 11 women; mean age 38.5±1.8 years; mean body mass index 25.3±0.7 kg/m 2 ) during low salt intake alone (10 mmol Na/d), low salt intake + quinapril (40 mg PO bid), and low salt intake + losartan (50 mg PO bid). Compared with low salt alone (systolic blood pressure [BP] 118.8±2.2 mm Hg), both quinapril (106.3±2.5 mm Hg, P P P =0.009), but not quinapril, lowered heart rate. Both drugs significantly lowered aldosterone ( P P P =0.03) and activity ( P =0.018). PAI-1 activity was lower during treatment with quinapril than with losartan ( P =0.015). The average PAI-1 antigen concentration was 13.0±2.0 ng/mL during low salt alone, 10.5±1.6 ng/mL during quinapril treatment, and 12.3±2.1 ng/mL during losartan treatment. In contrast, plasma tPA antigen concentrations were reduced during treatment with losartan ( P =0.03) but not with quinapril. This study provides the first evidence that ACE inhibitors and AT 1 antagonists differ in their effects on fibrinolytic balance under conditions of activation of the renin-angiotensin-aldosterone system. Further studies are needed to address the mechanism for the contrasting effects of these 2 classes of drugs on fibrinolysis and to define the clinical significance of these differences.

Abstract —Increased plasma renin activity (PRA) has been associated with an increased risk of myocardial infarction (MI), whereas angiotensin-converting enzyme (ACE) inhibition appears to reduce the risk of recurrent MI in patients with left ventricular dysfunction. These observations may be partially explained by an interaction between the renin-angiotensin system (RAS) and fibrinolytic system. To test this hypothesis, we examined the effect of salt depletion on tissue-type plasminogen activator (tPA) antigen and plasminogen activator inhibitor-1 (PAI-1) activity and antigen in normotensive subjects in the presence and absence of quinapril (40 mg BID). Under low (10 mmol/d) and high (200 mmol/d) salt conditions there was significant diurnal variation in PAI-1 antigen and activity and tPA antigen. Morning (8 am through 2 pm ) PAI-1 antigen levels were significantly higher during low salt intake compared with high salt intake conditions (ANOVA, F=5.8, P =0.048). PAI-1 antigen correlated with aldosterone ( r =0.56, P −7 ) during low salt intake. ACE inhibition significantly decreased 24-hour (ANOVA for 24 hours, F=6.7, P =0.04) and morning (F=24, P =0.002) PAI-1 antigen and PAI-1 activity (F=6.48, P =0.038) but did not alter tPA antigen. Thus, the mean morning PAI-1 antigen concentration was significantly higher during low salt intake than during either high salt intake or low salt intake and concomitant ACE inhibition (22.7±4.6 versus 16.1±3.3 and 16.3±3.7 ng/mL, respectively; P

Abstract —This study tested the hypothesis that gender affects the pressor and renal vasoconstrictor responses to angiotensin (Ang) I and Ang II in salt-replete normotensive subjects. Ang I and Ang II were infused in graded doses into 9 men and 8 women in a randomized, single-blind, crossover study. There were no differences between genders in baseline blood pressure, heart rate, sodium excretion, renal plasma flow, angiotensin-converting enzyme (ACE) genotype, ACE activity, plasma renin activity, aldosterone, or Ang II levels. Although pressor responses to Ang I and Ang II were similar in men and women, there was a negative relationship between the change in mean arterial pressure and the change in heart rate during Ang I and II infusion in women only. The half-time of the pressor response after discontinuation of Ang I but not Ang II infusion was greater in men than in women (9.5±2.2 versus 4.3±2.1 minutes, P 2 ; Ang II, −233±25 versus −175±18 U/1.73 m 2 ; P

In vitro and animal studies have demonstrated that the effect of angiotensin II (Ang II) on aldosterone is mediated through the Ang II type 1 receptor. However, it has been difficult to demonstrate an effect of Ang II type 1 receptor blockade on aldosterone levels in human studies. One possible explanation is that subjects have not been studied under salt-controlled conditions. Therefore, we examined the effects of losartan on the aldosterone and renal plasma flow responses to Ang II infusion in six normotensive subjects under low and high salt conditions. Ang II was infused in graded doses (0.3 to 10 ng/kg per minute) in the presence and absence of losartan (a single 50-mg oral dose). Renal plasma flow was assessed by measurement of para-aminohippurate clearance. Blood pressure, plasma aldosterone levels (low salt conditions only), and para-aminohippurate clearance were measured before and after each Ang II dose. Losartan had no effect on baseline systolic pressure but attenuated the systolic pressure response to exogenous Ang II during both low salt (0.7±1.9 versus 6.7±1.4 mm Hg, P =.001) and high salt (2.0±1.9 versus 12.3±2.1 mm Hg, P =.006) conditions. Under low salt conditions, losartan reduced the baseline plasma aldosterone level from 1135±204 to 558±102 pmol/L ( P =.015) and blocked the aldosterone response to Ang II (−49±110 versus +436±83 pmol/L, P =.019). During high salt conditions, losartan had no effect on baseline renal plasma flow but attenuated the renal plasma flow response to Ang II (−90.1±15.1 versus −185.1±2.6 mL/min per 1.73 m 2 , P =.013). These data confirm that losartan lowers both basal and exogenous Ang II–stimulated aldosterone levels under low salt conditions. Losartan does not significantly affect baseline renal plasma flow but does attenuate the renal plasma flow response to exogenous Ang II under high salt conditions.