Key Points Question What is the association between prescribed dosages of nonsteroidal anti-inflammatory drugs and later incident kidney disease among active young and middle-aged adults? Findings In this cohort study of 764 228 US Army soldiers, prescriptions of more than 7 daily defined doses of nonsteroidal anti-inflammatory drugs per month were associated with modest but significant increases in the adjusted hazard ratios of acute and chronic kidney disease diagnoses. Meaning Prescribers should be cognizant of potential kidney disease risks associated with higher doses of nonsteroidal anti-inflammatory drugs among active young and middle-aged adults; dosage reduction represents an approach that may decrease associated kidney disease outcome rates.

Neuropeptide Y (NPY) is contained in and coreleased with norepinephrine (NE) from sympathetic nerves innervating vascular and cardiac tissues. The effects of NPY infusion on systemic hemodynamics and cardiac performance were compared with those of NE in conscious and pentobarbital sodium-anesthetized rats. A 10-min infusion of NPY (2 nmol.kg-1.min-1) decreased cardiac index (CI) 20% and stroke volume index (SVI) 9% with increases of 20% in mean arterial pressure (MAP) and 48% in total peripheral resistance (TPR). Conversely, NE (1.0 microgram.kg-1.min-1) increased SVI 14%, MAP 29%, and TRP 26%, with no change in CI. Heart rates decreased similarly (approximately 60 beats/min) but only NE-induced bradycardia was reversible by methylatropine nitrate. In anesthetized rats NPY (0.1 nmol.kg-1.min-1) increased left ventricular end-diastolic pressure (LVEDP) 20 +/- 10 mmHg (means +/- SD, n = 7) and decreased dP/dt by 8 +/- 6%. NE (0.07 microgram.kg-1.min-1) produced an equivalent pressor response, however, dP/dt rose 22 +/- 10% whereas LVEDP increased significantly less than with NPY. Thus NPY is a potent vasoconstrictor exerting similar effects to NE on MAP and TPR but, unlike NE, possesses negative inotropic and chronotropic activity.

1. The peptide converting enzyme inhibitor captopril was given (1.25 mg/kg intravenously) to normal and nephrectomized rats and rats with renovascular and deoxycorticosterone hypertension. 2. Captopril lowered blood pressure to a small extent in normal and nephrectomized rats. Bradykinin infusion in nephrectomized animals, however, potentiated the vasodepressor action of captopril. 3. Captopril produced a major blood pressure fall in the early stages of Goldblatt two-kidney one-clip hypertension: even when hypertension had been present for more than 4 months, a substantial vasodepressor action was seen. Rats with deoxycorticosterone-induced hypertension also showed a significant blood pressure fall. 4. Captopril was given to salt-loaded and salt-depleted rats in which the renin-angiotensin system had been blocked by infusion of the competitive angiotensin II antagonist saralasin. Captopril still lowered blood pressure in the salt-depleted group. 5. Captopril lowers blood pressure in situations where the renin-angiotensin system is not responsible for blood pressure maintenance. Further, the fall in blood pressure produced in Goldblatt two-kidney one-clip hypertension is greater than would be predicted on the basis of renin-angiotensin blockade. It is likely therefore that captopril lowers blood pressure by an action additional to angiotensin blockade. Bradykinin potentiation is one possible mechanism by which this may take place.

SUMMARY Aortic renin-like activity and plasma renin concentration were measured in rats subjected to dietary salt loading or depletion. Homogenates prepared from rat aortic tissue generated angtotensin I from plasma substrate at both pH S3 and pH 6.5. Aortic renin-like activity measured at incubation pH 6.5 and plasma renin concentration changed in parallel, rising with salt restriction and falling with salt loading. However, the capacity of aortic bomogenate to generate angiotensin I at an incubation pH of 53 did not snow any signiflcant change with alteration of sodium balance. In addition, administration of the converting enzyme inhibitor (CEI) SQ20,881 produced a greater fall of blood pressure in salt-depleted than salt-loaded animals.In order to determine whether arterial or plasma renin was the important variable in blood pressure regulation, the depressor response to CEI was studied in GoMMatt two-kidney, one dip hypertensive rats before and 1, 2, 6 and 24 hours after bilateral nephrectomy. Aortic and plasma renin concentration were measured in a second series of hypertensive rats at the same times after bilateral nephrectomy. Although plasma renin concentration showed tbe expected fall to basal levels within 1 hour, a signiflcant depressor response to CEI was observed at 1 and 2 hours after bilateral nephrectomy, with a smaller fall at 6 hours. When a competitive antagonist of angiotensin II (saralasin) was infused, a significant fall in Mood pressure occurred 1 hour after bilateral nephrectomy, and no further fall was induced by injection of CEI. Thus, the fall of blood pressure induced by CEI was due to renin-angiotensin blockade and not an additional hypotensive effect Aortic renin-like activity measured at an incubation pH of 6.5 fell slowly after bilateral nephrectomy and was significantly lower only at 6 and 24 hours. This closely parallels the reduction of depressor response observed with converting enzyme inhibitor. However aortic renln-Uke activity measured at pH 5 J showed no significant change at anytime after bilateral nephrectomy except for activity after 1 hour, which was significantly elevated. This evidence supports more indirect studies which have suggested that arterial renin-like activity derived from the kidney is important in blood pressure maintenance by tbe local generation of angiotensin II, and that this activity has a longer half-life than plasma renin. Enzymic activity detected at a low incubation pH probably represents a tissue enzyme that is not important in blood pressure maintenance. . 4 ' 6 The components of the renin-angioelevated plasma renin levels are associated with a tensin system are present in the circulation, where depressor response to pharmacological antagonism of generation of the effector hormone of the system, the renin-angiotensin system. 15 The extent of this role angiotensin II takes place. However, renin-like enis controversial as there are differences in the zymes are also present in many other tissues 6 and angiotensin II could therefore be generated lo...

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