The opioid peptide nociceptin/orphanin FQ mediates prostaglandin E2-induced allodynia, tactile pain associated with nerve injury.

Pain often outlasts its usefulness as warning and aid in wound healing, and becomes chronic and intractable after tissue damage and nerve injury. Many molecules have been implicated as mediators and modulators in persistent pain such as hyperalgesia and tactile pain (allodynia). We previously showed that prostaglandin (PG) E(2), PGF(2alpha) or the neuropeptide nociceptin, also called orphanin FQ (N/OFQ) administered intrathecally (i.t.) produced allodynia in conscious mice. In the present study, we examined the relationship of pain responses between PGs and N/OFQ using the N/OFQ receptor (NOP) antagonist, N-(4-amino-2-methylquinolin-6-yl)-2-(4-ethylphenoxy-methyl)benzamide monohydrochloride (JTC-801), and in mice lacking the N/OFQ prepropeptide (ppN/OFQ(-/-)) and the NOP receptor (NOP(-/-)). JTC-801 dose-dependently blocked the N/OFQ- and PGE(2)-induced allodynia, but not the PGF(2alpha)-induced one. Neither N/OFQ nor PGE(2) induced allodynia in NOP(-/-) mice. By contrast, the N/OFQ-induced allodynia was not affected by inhibition of PG production by a 60-min pretreatment with the non-steroidal anti-inflammatory drug, indomethacin. Among PGE receptor (EP) subtype-selective agonists, the EP4 agonist, AE1-329, markedly stimulated the release of N/OFQ from spinal slices and induced allodynia. AE1-329 also increased nitric oxide production in spinal slices using fluorescent nitric oxide detection, which was blocked by pretreatment with JTC-801. Conversely, PGE(2)-induced allodynia was not observed in ppN/OFQ(-/-) mice. N/OFQ immunoreactive puncta were colocalized with EP4. Taken together, these results demonstrate that PGE(2) induced allodynia by stimulation of N/OFQ release in the spinal cord via EP4 receptor subtypes.

Role of angiotensin and its inhibition in hypertension, ischemic heart disease, and heart failure.

This is a personal historical account relating the events that led to the first application of angiotensin inhibition (either by ACE inhibitors or by angiotensin receptor blockade) to the investigation of the pathogenesis and treatment of hypertension, ischemic heart disease, and heart failure. Included are animal experiments, clinical observations, and the earliest clinical experimental studies that helped define some of the detrimental effects of angiotensin II and the beneficial hemodynamic results of its inhibition, which have been subsequently corroborated and amplified by large randomized outcome trials.

Central effects of angiotensin II and dopamine in sodium-depleted sheep.

The effects of intracerebroventricular (IVT) infusion of angiotensin II (ANG II), the converting enzyme inhibitor SQ 20881, and dopamine were studied in 15 conscious Na-depleted sheep. IVT ANG II (25 ng/min) significantly increased plasma aldosterone (163 +/- 24%) and vasopressin (ADH) (533 +/- 100%). Plasma renin activity (PRA) was decreased to 64 +/- 10% of basal. IVT SQ (1 microgram/min) decreased aldosterone to 70 +/- 10% and ADH to 55 +/- 9% of basal. PRA increased to 124 +/- 10%. There were no significant changes in plasma Na, K, or cortisol levels nor in mean arterial or intracranial pressure after either infusion. Increasing the dose of SQ to 10 micrograms/min resulted in an increased magnitude of change in the same variables. IVT SQ (1 microgram/min) significantly decreased aldosterone level in five nephrectomized sheep. The responses to IVT dopamine (20 micrograms/min) were qualitatively similar to those elicited by IVT SQ. These data support the existence of an endogenous brain renin-angiotensin system (RAS) independent of the renal RAS. ANG II acts centrally to regulate plasma ADH, aldosterone, and PRA levels. The similarity of the responses to SQ and dopamine suggests that a dopaminergic pathway may be involved in these responses.

Failure of chronic administration of the angiotensin I-converting enzyme inhibitor, Teprotide (SQ 20881), to affect the ultrastructure of the adrenal cortex and the aldosterone secretion in the rat.

Administration of Teprotide (SQ 20881), an angiotensin I-converting enzyme inhibitor for up to 10 weeks at a dose of 3 mg. per kg., subcutaneously, twice a day in the rat, effected no change in the ultrastructure of the adrenal cortex nor in the concentration of serum aldosterone. A significant increase (p less than 0.05) in renin granulation indices which was already apparent after 3 weeks of treatment with Teprotide was even more definitive after 10 weeks (p less than 0.01). Moderate renal hypertrophy was present in rats receiving the drug for 3 weeks. Findings pertaining to aldosterone production differed from those reported following acute administration of Teprotide wherein a decrease in the production of serum aldosterone and an increase in plasma renin activity was observed. It has been suggested that decreased aldosterone production following acute administration of Teprotide is a consequence of decreased stimulus of the zona glomerulosa due to diminished synthesis of angiotensin II. If this is the case, mechanisms other than angiotensin II stimulation of the zona glomerulosa must control aldosterone synthesis, perhaps through hormones of the adrenal cortex. Another possibility could be that angiotensin II synthesis may be obtained, after an interval, through an alternative pathway.

Comparison of intrarenal and extrarenal converting-enzyme inhibition by SQ 20 881 on canine renal blood flow.

1. Successive infusions of SQ 20 881 given intra-arterially (i.a.) to the kidney at 0.4 and 0.8 microgram min-1 kg-1 for 50 min each did not alter renal blood flow and renal vascular resistance in spite of 40--47% blockade of the angiotensin I (ANG I i.a.)-induced vasoconstrictor response. 2. SQ 20 881 administered intravenously (i.v., 0.5 mg/kg) after the higher intra-arterial dose did not further decrease the renal response to ANG I (i.a.), but caused an increase in renal blood flow and a decrease in renal vascular resistance. 3. These results indicate that SQ 20 881 has limited efficacy in blocking the renal response to ANG I (i.a.). Under the conditions of these experiments, the renal vasodilator response to SQ 20 881 appears to be due to inhibition of extrarenal rather than intrarenal converting enzyme.

Angiotensin inhibitors for hypertension.

Inhibition of the angiotensin-converting enzyme emerges as a new promising approach to the treatment of hypertension. The intravenously administered teprotide appears to be suitable as a diagnostic test and for initial treatment of certain hypertensive emergencies. The oral inhibitor captopril is effective for chronic maintenance of blood pressure control in various types of hypertension but has been associated with a number of adverse reactions.

Role of vasoconstrictor mechanisms in the control of left ventricular performance of the normal and damaged heart.

The effect on the left ventricle of changes in the state of the arterial vasculature is best identified by utilizing calculations of pulsatile rather than steady flow phenomena. Impedance is the most satisfactory term to describe this effect. The normal ventricle compensates for changes in impedance largely by changes in preload, but the damaged heart loses this compensatory ability and its stroke volume becomes inversely related to outflow resistance. Patients with heart failure behave in a similar fashion and pharmacologic vasodilation may induce marked improvement in left ventricular pump function. Inappropriate vasoconstriction in heart failure may result from stimulation of the sympathetic or renin-angiotensin system. Early experience with converting enzyme inhibitors suggests that blockade of the formation of angiotensin II may be a useful means of treating some patients with heart failure.

Reactive hyperreninemia in renovascular hypertension after angiotensin blockage with saralasin or converting enzyme inhibitor.

Baseline plasma renin activity and responses to saralasin and converting enzyme inhibitor SQ 20881 (teprotide) in 47 untreated patients with surgically correctable renovascular hypertension were compared to those in 100 patients with high- and normal-renin essential hypertension. All 32 renovascular patients on normal sodium intake had high renin-sodium profiles and renin values greater than or equal to 5 ng angiotensin I/mL.h, as compared to 20 of 64 with essential hypertension. Diagnostic discrimination was greatly enhanced by infusion of saralasin or SQ 20881, which elicited marked reactive hyperreninemia in 31 of 32 renovascular patients but in only two of 64 with essential hypertension. Reactive hyperreninemia appeared to be more a specific test for renovascular hypertension than depressor responses. Prior dietary sodium depletion abolished this specificity. The results suggest that after initial screening with renin measurements, testing with angiotensin blocking agents may be a useful secondary screening procedure for more invasive and definitive procedures.

Angiotensin converting enzyme inhibition in patients with congestive heart failure.

The etiology of afterload elevation in congestive cardiac failure is unclear, but experimental evidence suggests a role for the renin-angiotensin system in maintaining elevated peripheral vascular resistance. The angiotensin converting enzyme inhibitor SQ20,881 was administered to eight patients with congestive cardiac failure (four hypertensives, four normotensives) during or one day after diagnostic cardiac catheterization. Various hemodynamic measurements performed before and during blockade indicate that this agent caused improvement in cardiac function in all patients by decreasing afterload. This improvement correlated with the decrease in total vascular resistance but was independent of the baseline blood pressure and plasma renin activity. These results suggest that inhibition of angiotensin converting enzyme is a worthwhile approach to the treatment of congestive heart failure, although its exact mechanism of action remains unclear.

Accentuated vascular and endocrine response to SQ 20881 in hypertension.

We assessed vascular and hormonal responses to inhibition of peptidyldipeptide hydrolase, which converts angiotensin I to angiotensin II (converting enzyme) and degrades bradykinin (kininase II), in subjects given 10 meq of sodium to activate both systems. In nine normal subjects a threshold dose of 30 MICROgram per kilogram of the inhibitor, SQ 20881, modestly influenced mean blood pressure (-5 +/- 1 mm Hg, P less than 0.05), and renal blood flow (+50+/-8 ml per 100 g per minute), plasma renin activity (+ 2.3 +/- 0.6 ng per milliliter per hour), and angiotensin II (-11 +/- 3 pg per milliliter) more strikingly (P less than 0.01). In six patients with essential hypertension the threshold inhibitor dose was reduced to 10 microgram per kilogram; 30 kilogram per kilogram had an enhanced (P less than 0.01) effect on mean blood pressure (-11 +/- 2 mm Hg), renal blood flow (137 +/- 20 ml per 100 g per minute), and angiotensin II concentration (-29 +/- 12 pg per milliliter). SQ 20881 elevated plasma bradykinin concentration (7.4 +/- 2.6 ng per milliliter, P less than 0.02) only in the hypertensive patients. Because both renin-angiotensin and kallikrein-bradykinin systems are influenced, vascular responses to SQ 20881 must be interpreted cautiously, but this agent has excellent antihypertensive characteristics.

Role of the renin-angiotensin system in the regulation of aldosterone biosynthesis and arterial pressure during sodium deficiency.

The aldosterone and arterial pressure response to long-term infusion of two angiotensin II inhibitory analogues, [Sar1,Ala8]angiotensin II and [Sar1,Ile8]angiotensin II, and the angiotensin I-converting enzyme inhibitor, SQ 20,881, was studied in conscious dogs during sodium deficiency. Plasma aldosterone concentration (PAC), plasma cortisol concentration (PCC), and plasma renin activity (PRA) were determined by radioimmunoassay. In conscious dogs after dietary sodium restriction (5 mEq of Na+/day) for 21 days, PAC averaged 37.5 +/- 8.9 (mean +/- SE) ng/dl, PCC averaged 1.3 +/- 0.5 microng/dl, PRA averaged 3.23 +/- 0.42 ng/ml per hour, and arterial blood pressure (AP) averaged 103 +/- 5 mm Hg. During long-term infusion of [Sar1,Ala8]angiotensin II (5 microng/kg min-1), PAC averaged 34.7 +/- 8.5 ng/dl, PCC averaged 1.5 +/- 0.5 microng/dl, PRA averaged 16.4 +/- 3.1 ng/ml per hour, and AP averaged 88 +/- 5 mm Hg. During long-term infusion of [Sar1,Ile8]angiotensin II (5 microng/kg min-1), PAC averaged 45.8 +/- 12.6 ng/dl, PCC averaged 1.75 +/- 0.5 microng/dl, PRA averaged 13.6 +/- 4.3 ng/ml per hour, and AP averaged 86 +/- 5 mm Hg. During long-term infusion of angiotensin I-converting enzyme inhibitor (5 microng/kg min-1), PAC averaged 14.9 +/- 4.8 ng/dl, PCC averaged 1.75 +/- 0.5 microng/dl, PRA averaged 20.3 +/- 5.3 ng/ml per hour, and AP averaged 76 +/- 5 mm Hg. The intrinsic agonistic properties of the angiotensin II inhibitory analogues on the adrenal cortex negate their use for defining the role of the renin-angiotensin system in the regulation of aldosterone biosynthesis during sodium deficiency. The precipitous fall in aldosterone secretion and arterial blood pressure during long-term infusion of angiotensin I-converting enzyme inhibitor demonstrates the importance of the renin-angiotensin system in mediating aldosterone biosynthesis during sodium deficiency and the essential role of the renin-angiotensin-aldosterone system in the regulation of arterial pressure during sodium deficiency.

Relationship between aldosterone and bradykinin.

To assess relationships between plasma bradykinin and the individual elements of the renin-angiotensin-aldosterone system 11 normal subjects and five subjects with adrenal insufficiency were studied on an intake of 200 mEq sodium/100 mEq potassium. In adrenal insufficiency subjects, plasma bradykinin did not change when angiotensin II levels were increased by an infusion rate of 3 ng/kg per min for 30 minutes; plasma aldosterone remained undetectabel. In normal subjects, angiotensin II at 3 ng/kg per min or potassium at 20 mEq/hour infused intravenously for 2 hours both significantly increased plasma aldosterone levels, yet neither stimulus altered plasma bradykinin. Thus, acute elevations in angiotensin II and plasma aldosterone were not associated with changes in the levels of plasma bradykinin. In five additional normal subjects on an intake of 10 mEq sodium/100 mEq potassium, a threshold dose of converting enzyme inhibitor (SQ 20881) at 30 microng/kg was given intravenously. Five minutes after administration of the drug, blood pressure and plasma angiotensin II levels had significantly declined and plasma bradykinin levels had significantly increased (P is less than 0.02). Within 10-20 minutes, however, all had returned to control accompanied by a sustained increase in plasma renin activity, and a decrement in plasma aldosterone. Plasma renin activity, which had increased by more than 2-fold after the administration of the converting enzyme inhibitor, remained elevated until the completion of the study at 320 minutes. Eighty minutes after beginning the infusion, plasma aldosterone levels returned to control. Thus, the results suggest that plasma bradykinin correlates more closely with acute changes in plasma renin activity (and angiotensin I) than plasma aldosterone or angiotensin II, suggesting a role for converting enzyme in the regulation of both plasma renin activity and plasma bradykinin. Furthermore, the declines in blood pressure observed with converting enzyme inhibition may be attributable to both changes in plasma angiotensin II and plasma bradykinin concentrations. However, it is emphasized that these short-term studies may not reflect the role of bradykinin in the long-term control of blood pressure.

Design of specific inhibitors of angiotensin-converting enzyme: new class of orally active antihypertensive agents.

A hypothetical model of the active site of angiotensin-converting enzyme, based on known chemical and kinetic properties of the enzyme, has enabled us to design a new class of potent and specific inhibitors. These compounds, carboxyalkanoyl and mercaptoalkanoyl derivatives of proline, inhibit the contractile response of guinea pig ileal strip to angiotensin I and augment its response to bradykinin. When administered orally to rats, these agents inhibit the pressor effect of angiotensin I, augment the vasodepressor effect of bradykinin, and lower blood pressure in a model of renovascular hypertension.

Possible role of renin in hypertension as suggested by renin-sodium profiling and inhibition of converting enzyme.

To block renin activity, a nonapeptide converting-enzyme inhibitor was given to 65 seated hypertensive patients. Depressor responses occurred only when control plasma renin activity exceeded 2 ng of angiotensin I per milliliter per hour and correlated directly in amplitude with control plasma renin activity and with induced increments in activity (P less than 0.001 for both). Depressor responses, like renin activity, were characteristic for renin subgroups as defined by renin-sodium profiling. Before and after sodium deprivation, the nonapeptide reduced diastolic pressure in all patients with high renin (by 17.3 and 19.8 per cent) and most patients with normal renin (by 9.1 and 17.7 per cent). Low-renin patients remained unresponsive. This enzyme blockade may cause bradykinin accumulation. But if, as seems likely, depressor responses are due to blockade of angiotensin II formation, the results indicate that, irrespective of sodium balance, measurements of plasma renin activity reflect its contribution to blood-pressure maintenance. The results suggest broad participation of the renin system in common forms of hypertension.

Effect of intrarenal angiotensin II blockade on renal function in conscious dogs.

The effects of intrarenal infusion of 1-sar-8-ala angiotension II (P 113) and a converting enzyme inhibitor, SQ 20881, at doses that did not affect systemic blood pressure (2.0 mug/kg per min) were studied in conscious, uninephrectomized dogs. In dogs receiving approximately equal to 5 mEq/day of sodium, intrarenal infusion of P 113 increased renal blood flow (RBF) from 219.8 +/- 32.3 to 282.7 +/- 20.0 ml/min (P less than 0.004), and with intrarenal SQ 20881 infusion from 215.3 +/- 14.2 to 278.0 +/- 22.2 ml/min (p less than 0.005). In sodium-restricted dogs (approximately equal to 5 mEq/day), glomerular filtration rate (GFR) also increased with intrarenal P 113 infusion from 57.9 +/- 5.7 to 66.3 +/- 6.6 ml/min (P less than 0.05), and with SQ 20881 infusion from 43.1 +/- 2.1 to 55.7 +/- 4.5 ml/min (P less than 0.01). Dogs on approximately equal to 5 mEq/day of sodium showed significant increases in plasma renin activity (PRA) with intrarenal infusion of the peptides, unmasking a negative feedback inhibition of renin release by angiotensin II. No increases in RBF, GFR, or PRA were seen with infusion without inhibitors, or in dogs give P 113 or SQ 20881 while on approximately equal to 80 mEq/day of sodium. In addition, angiotensin II inhibition increased sodium excretion during sodium restriction. These findings suggest that intrarenal angiotensin II is intimately involved in renal responses to sodium restriction which result in conservation of sodium and water.