Increase of free arachidonic acid by furosemide in man as the cause of prostaglandin and renin release

Arachidonic acid (C20 : 4), plasma renin activity (PRA), PGF_2α, and sodium excretion were determined before and after furosemide in men. C20 : 4 and PRA increased (p < 0.005) within 10 min after furosemide. PRA then decreased again whereas C20 : 4 levels remained elevated. Maximal excretion of PGF_2α and sodium occurred 30–60 min after furosemide. Indomethacin prevented the rise of C20 : 4, PRA and PGF_2α after furosemide, leaving sodium excretion unaltered. The release of C20 : 4 is assumed to be the primary mechanism of furosemide to increase PG biosynthesis and renin release.     

Sequential changes in plasma renin activity and plasma catecholamines in mildly hypertensive patients during acute,furosemide-induced body-fluid loss

Summary To evaluate the role of adrenergic mechanisms in the acute response of renin to furosemide, plasma renin activity (PRA) and plasma catecholamine concentrations were measured for 3 h after i.v. administration of furosemide 1 mg/kg to 8 patients with mild essential hypertension. Furosemide induced a prompt and long-lasting increase in renin, with PRA more than doubled at all times. The increase in PRA within the first 30 min paralleled the peak increases in urinary water and sodium flow rates, and significant decreases in plasma volume and central venous pressure. There was no change in plasma catecholamine concentrations. Plasma noradrenaline was increased significantly at 60 min and adrenaline at 90 min, once furosemide had induced a marked loss of body-fluid and 65% decrease in central venous pressure. Both catecholamines remained elevated until the end of the study, whereas urinary water and sodium flow rates had returned to their pre-treatment values by 150 min. Mean blood pressure was essentially unchanged throughout the study, whereas heart rate increased significantly after 90 min. The findings suggest that in mildly hypertensive patients adrenergic mechanisms are not involved in the initial renin response to furosemide, but they come into play later, probably as a result of reflex sympathetic activation triggered by marked volume depletion.     

Effect of propranolol on urinary prostaglandin E2 excretion and renal interlobar arterial blood flow after furosemide administration in patients with hepatic cirrhosis

Summary The effect of propranolol on furosemide-stimulated urinary prostaglandin E₂ (PGE₂) excretion and renal blood flow was evaluated in 12 patients with alcoholic liver cirrhosis. Plasma and urine were collected before and 60 min after furosemide 20 mgI with or without propranolol pretreatment, and plasma renin activity (PRA), plasma aldosterone concentration (PAC), urinary excretion of PGE₂ and sodium were determined. The renal interlobar arterial Pulsatility Index (PI), as an index of resistance to blood flow, was also determined before and 60 min after furosemide administration with and without propranolol pretreatment, by using a duplex Doppler ultrasound (Hitachi EUB 565).Urine volume and sodium excretion after furosemide administration were not influenced by the propranolol pretreatment. Furosemide administration significantly increased urinary PGE₂ excretion, PRA and PAC, and these effects were significantly reduced by propranolol. Furosemide administration with or without propranolol significantly reduced renal interlobar arterial PI, the average reduction in PI being significantly lower after furosemide administration with propranolol pretreatment.The results demonstrate that propranolol pretreatment significantly influenced the furosemide-induced increase in urinary PGE₂ excretion and renal interlobar arterial blood flow in cirrhotic patients.     

Influence of captopril on urinary excretion of furosemide in hypertensive subjects

Influence of captopril on urinary excretion of furosemide was examined in a placebo-controlled, crossover design. Furosemide (20 mg) was injected intravenously in eight hypertensive subjects with pretreatment with captopril (25 mg) or matching placebo. Urine samples for furosemide and sodium were collected during the following intervals: -60-0, 0-60, 60-120, and 120-180 minutes after furosemide. Blood samples for plasma renin activity (PRA) and angiotensin II (AII) were obtained, and blood pressure was measured at -60, 0, 60, 120, and 180 minutes after furosemide. No significant difference was observed in urinary excretion of furosemide, volume or sodium between these trials. Although PRA increased following furosemide with captopril, as predicted plasma AII did not increase. Blood pressure significantly decreased following the combined therapy, but not furosemide alone. These data indicate that the urinary excretion of furosemide and its subsequent diuretic effects are not influenced by captopril.     

In vivo inhibition of prostaglandin synthesis in rabbit kidney by non-steroidal anti-inflammatory drugs

To define dose- and time-response properties for in vivo inhibition of renal prostaglandin (PG) synthesis, aspirin, diclofenac sodium, indomethacin and d-naproxen were injected intravenously in different doses to unanaesthetized rabbits. After 30 min. the animals were killed and the post mortem accumulation of PGE2 and PGF2alpha in the renal medulla was determined by mass fragmentography. In control animals, the accumulated levels of PGE2 and PGF2alpha in the medulla were 9.2+/-2.2 (S.D.) and 1.5+/-0.6 microgram/g, respectively. Dose-dependent inhibition was demonstrated with all the drugs. The ED95 was for aspirin 15 mg/kg, for diclofenac sodium 1.5 mg/kg, for indomethacin 1.5 mg/kg and for d-naproxen 5 mg/kg. The duration of inhibition was studied by radioimmunoassay in anaesthetized rabbits by following the urinary excretion of PGF2alpha and PGE2 after an intravenous injection of solvent or test drug in doses twice the ED95. For three hours following aspirin, diclofenac sodium, indomethacin and d-naproxen, the decreases in urinary excretion of PGF2alpha ranged from 64 to 88, 87 to 95, 64 to 90 and from 40 to 77 per cent of the control, respectively, and the decreases in PGE2 excretion were of similar magnitude. Together these results indicate that diclofenac sodium might be used as a long-lasting and potent alternative to indomethacin and aspirin in experimental studies on the renal PG system in vivo.     

Effects of low-dose aspirin on responses to furosemide

We assessed the effects of low-dose aspirin (0.5 and 15 mg/kg/d) on renal prostaglandin synthesis and action in healthy volunteers using intravenous furosemide as a stimulus. Inhibition of platelet cyclo-oxygenase was assessed by changes in serum thromboxane B2 (TXB2) level. After one week of treatment, ten healthy subjects did not show any change in weight, blood pressure, or diuretic and natriuretic responses to furosemide with either dose of aspirin. Serum TXB2 level was reduced to 3% of control by aspirin 0.5 mg/kg/d and to 0.1% by the higher dose. In contrast, urine excretion of TXB2 was only reduced to 68% and 51% of the placebo value, whereas 6-keto-prostaglandin F1 alpha (6kPGF1 alpha) excretion was not decreased by either dose. Furosemide produced a transient increase in excretion rates of TXB2 and 6kPGF1 alpha that was of lesser duration than the diuretic response. These transient increases were slightly reduced by aspirin. Baseline plasma renin activity was not affected by either dose of aspirin. The brisk increment in plasma renin activity seen ten minutes after furosemide, as well as later values (30 and 240 min) were not changed by aspirin. We conclude that chronic low-dose aspirin can profoundly affect platelet PG production without affecting stimulated renal PGI2 production or plasma renin activity. There is a modest reduction in urine TXB2 excretion that is consistent with a primarily renal source of this metabolite.     

Furosemide dynamics: influence of dietary sodium and of saralasin.

The influence of dietary sodium and saralasin on the natriuretic and diuretic response to furosemide (5 mg/kg i.v.) was studied in three groups of conscious rabbits maintained for 4 weeks on either a normal sodium diet (NSD), or a low sodium diet (LSD) or a high sodium diet (HSD). Neither the sodium content in the diet nor saralasin affected glomerular filtration rate or renal plasma flow. Compared to the NSD, an LSD did not affect the furosemide-induced increment in urinary excretion of sodium (dUNaV) but increased the increment in urinary excretion (dUV) (p less than 0.05). An HSD reduced the furosemide-induced dUNaV and dUV (p less than 0.05). Plasma renin activity (PRA) increased following furosemide administration in animals on an NSD and an LSD, but not in those on an HSD. Independent of diet, a positive correlation occurred between the increment in PRA and the dUNaV (p less than 0.001). Saralasin increased PRA and decreased baseline urinary excretion of sodium (UNaV). In addition, in rabbits on an LSD, saralasin reduced the furosemide-induced dUNaV and dUV by 34 and 27% (p less than 0.05), respectively. It is concluded that furosemide-induced diuresis is increased in rabbits on an LSD and decreased in rabbits on an HSD. In animals on an LSD, the increase in furosemide response appears to be associated with changes in the activity of the renin-angiotensin system and in rabbits on an HSD, the decrease in furosemide effect is probably the net result of several factors.     

Blood pressure response to enalaprilic acid in essential hypertension: Dose-response and effect of pre-treatment with furosemide

Summary Enalaprilic acid (MK 422), the active metabolite of enalapril, has recently become available for intravenous administration. In order to establish the proper dose for rapid blood pressure reduction, 9 patients with moderate to severe essential hypertension on a constant sodium intake of 100 mmol/24 h were studied. They received four single doses of MK 422 according to an up-and-down titration schedule. Doses between 5 and 80 mg resulted in effective blood pressure reduction with an onset of action of about 10 minutes. Within this dose range the response was flat. No symptomatic hypotension was observed. The fall in blood pressure was less pronounced in patients with low initial plasma renin activity (PRA). Accordingly, a study was done to show whether the blood pressure response could be augmented by preceding stimulation of PRA by injection of 40 mg furosemide 15 minutes before the administration of MK 422. PRA increased after furosemide, but the blood pressure response to MK 422 was not augmented.     

Frusemide releases renin in the rat kidney when prostacyclin synthesis is suppressed.

The effect of inhibiting prostaglandin (PG) synthesis on basal and frusemide-stimulated renin secretion was examined in the rat isolated perfused kidney. The stable PGI2 derivative, 6-keto PGF1 alpha, was measured by radioimmunoassay in urine collected from the kidney. Treatment of rats with indomethacin (3.0 mg kg-1) reduced 6-keto PGF1 alpha excretion from 121.3 +/- 39.1 (n = 9) to 15.5 +/- 6.6 (n = 9) pg min-1 (P less than 0.02) but had no effect on basal renin secretion. Renal perfusion pressure, flow rate and vascular resistance were similar in treated and control rats. Mean urine flow was lower after treatment. Infusion of frusemide (250 micrograms min-1) did not alter 6-keto PGF1 alpha excretion in control or indomethacin-treated (P greater than 0.05) rats. Although renin secretion was increased during frusemide infusion, there was no significant difference between control (1,806 +/- 384 ng angiotensin I (AI) min-1) and treated (2,310 +/- 554 ng AI min-1) rats (P greater than 0.05). Propranolol, at a dose (8 micrograms min-1) which suppressed renin secretion after isoprenaline stimulation, had no effect on the response to frusemide in indomethacin-treated rats. These results demonstrate that frusemide-stimulated renin secretion in the rat kidney does not require intact renal PGI2 synthesis and is independent of beta-adrenergic mechanisms.     

Analysis of prostaglandins in aqueous solutions by supercritical fluid extraction and chromatography

Trace amounts of prostaglandins (PGs) were selectively analysed without derivatization using supercritical fluid extraction (SFE) and open tubular column supercritical fluid chromatography (SFC). The specific compounds studied were prostaglandin F2 alpha (PGF2 alpha), esters of PGF2 alpha, prostaglandin F1 alpha) and prostaglandin E2 (PGE2). An open tubular column was used with carbon dioxide as the mobile phase and with universal flame ionization detection. Samples were introduced into the column by direct injection using a 1-microliter sample loop or by SFE with solute focusing. The 11 standard compounds were effectively separated within 35 min using a density program at constant temperature. The minimum detectable quantity (signal-to-noise ratio = 3) using the direct injection method was 9 ng for 15-propionate PGF2 alpha isopropyl ester. Using the extraction method, the sample size in the extraction cell was increased to 100 microliters, which made it possible to analyse compounds that were present in low concentrations. Aqueous PG samples were extracted from adsorbents onto which the samples had been loaded.     

Bradykinin-stimulated prostaglandin synthesis in conscious rabbits.

1 Bradykinin was infused intravenously into conscious rabbits to determine its effect on the concentration of prostaglandins in plasma. 6-Oxo-prostaglandin (PG) F1 alpha, the stable hydrolysis product of prostacyclin, and 13,14-dihydro-15-oxo-PGF2 alpha, a metabolite derived from PGE2 and PGF2 alpha, were measured by gas chromatography-electron capture mass spectrometry. 2 Incremental infusions of bradykinin (0.4-3.2 micrograms kg-1 min-1) increased plasma concentrations of both 6-oxo-PGF1 alpha and 13,14-dihydro-15-oxo-PGF2 alpha. 3 Aspirin (10 mg kg-1, i.v.) inhibited bradykinin-stimulated 6-oxo-PGF1 alpha and 13,14-dihydro-15-oxo-PGF2 alpha synthesis at 30 min and 6 h. At 24 h, the mean bradykinin-stimulated 13,14-dihydro-15-oxo-PGF2 alpha concentration was 66% of its original value, whilst 6-oxo-PGF1 alpha remained substantially inhibited. 4 The different rates of recovery of bradykinin-stimulated production of the two prostaglandins after inhibition by aspirin suggests that intravenous bradykinin stimulates prostacyclin and PGE2/PGF2 alpha production in distinct cell populations which synthesize cyclo-oxygenase at different rates.     

Plasma renin activity and renal sodium and water excretion following infusion of arachidonic acid in rats

Plasma renin activity (PRA) and urinary sodium and water excretion were measured following infusion of the prostaglandin (PG) precursor arachiodonic acid (C20 : 4) in normal hydrated rats (saline i.v.: 0.5 ml/hr/100 g body weight) and in rats with moderate volume expansion (saline i.v.: 1.5 ml/hr/100 g body weight). Nonhypotensive doses of C20 : 4 (40–70 μg/min/100 g b.w.) increased PRA in both normal and volume-expanded rats (p < 0.05, and p < 0.025, respectively). In volume-expanded rats, C20 : 4 was followed by reduced urine volume (p < 0.01) and sodium excretion (p < 0.001) in comparison to volume-expanded control rats, whereas in normal hydrated rats these parameters remained unchanged after C20 : 4. The present results indicate that the C20 : 4-stimulated PG-synthetase system can increase PRA independently of the extracellular fluid volume. Futhermore, these results suggest a complex interrelationship between PG-synthetase action, activation of the renal renin—angiotensin system and urinary water and sodium excretion.     

Atropine, sodium cromoglycate, and thymoxamine in PGF2 alpha-induced bronchoconstriction in extrinsic asthma.

In six patients with extrinsic bronchial asthma the inhalation of prostaglandin (PG) F2 alpha in a small dosage produced significant bronchoconstriction, whereas PGE2 produced bronchodilatation. In these patients cholinergic blockade with atropine partially inhibited the PGF2 alpha-induced bronchoconstriction, but the alpha-receptor-blocking drug thymoxamine and sodium cromoglycate did not. These results suggest that the effect of PGF2 alpha is mediated through cholinergic receptors in the airways, and this effect is grossly exaggerated in asthma. The failure to inhibit PGF2 alpha-induced bronchoconstriction with sodium cromoglycate and the observation of an inhibitory effect of sodium cromoglycate in both allergic and exercise asthma suggest that locally formed PGF2 alpha may not be the main factor in the pathogenesis of bronchial asthma.     

Influence of prostaglandin inhibition on dihydralazine induced acute effects in patients with essential hypertension

In order to determine whether vasodilator prostaglandins (PG) contribute to the acute vascular and endocrine responses to intravenously administered dihydralazine, we examined its effects on systolic and diastolic blood pressure (BP), heart rate (HR), plasma renin activity (PRA) and the plasma catecholamines (CA) noradrenaline (NA), adrenaline (A) and dopamine (DA) as well as on sodium, potassium and creatinine clearance (CNa, CK and CCr respectively), urinary flow rate, urinary catecholamines (NA, A, DA) and iPGE2 and i6-keto-PGF1 alpha excretion rate in six patients (three females, three males) with essential hypertension before and after PG synthesis inhibition by the nonsteroidal, anti-inflammatory agent diclofenac. Diclofenac, which reduced urinary iPGE2 and i6-keto-PGF1 alpha excretion by 62% (P = 0.026) and 45% (P = 0.037), respectively, antagonized dihydralazine induced diastolic BP reduction (P = 0.0009), HR increase (P = 0.01), noradrenaline and adrenaline increase in plasma (P = 0.02 and P = 0.05, respectively), increase in urine flow rate (P = 0.03), sodium clearance (P = 0.01) and tended to reduce PRA. We conclude that dihydralazine-mediated changes can be reduced by cyclo-oxygenase inhibition, most likely on the basis of a reduction of its effect on peripheral resistance, thereby leading to less reflex activation of the sympathetic nervous and renin-angiotensin systems.     

Mediation of renin release in essential hypertension by alpha-adrenoreceptors

We studied the role of alpha-adrenoceptors in controlling renin release by infusing increasing doses of phentolamine into six patients with essential hypertension. Furthermore, in order to evaluate the relative importance of alpha 1- and alpha 2-adrenoceptors, phentolamine infusion was repeated in the same patients after pretreatment with prazosin, a selective alpha 1-blocking agent, and oxprenolol, a nonselective beta-blocker. After placebo, phentolamine infusion did not change mean blood pressure or heart rate and increased plasma renin activity (PRA) in a dose-dependent fashion. This finding suggests that the drug acts directly on the intrarenal renin producing apparatus and seems to confirm the inhibitory role of alpha-adrenoceptors in the control of renin release. After prazosin and oxprenolol pretreatment, PRA was respectively increased and decreased but it was unmodified by phentolamine infusion. This latter finding may indicate that both alpha 1- and alpha 2-adrenoceptors are involved in renin release or that alpha-adrenoceptors cannot be clearly differentiated into alpha 1- and alpha 2-subtypes.     

The vasoconstrictor effect of 8-epi prostaglandin F2alpha in the hypoxic rat heart

1. 8-epi prostaglandin (PG) F2alpha, a vasoconstrictor isoprostane, is synthesized under conditions of oxidative stress. This study was undertaken to investigate the vasoconstrictor effect of 8-epi PGF2alpha in the coronary circulation before and after a period of oxidative stress. 2. The effects of the isoprostane 8-epi PGF2alpha and the thromboxane mimetic U46619 were compared in the isolated rat heart perfused in the Langendorff mode at a constant pressure of 80 mmHg. 3. In normal hearts U46619 caused a dose-related reduction in coronary flow (ED50 4.7+/-2.2 nmol). In contrast, 8-epi PGF2alpha had no effect. 4. After reducing perfusion pressure to 20 mmHg for 30 min and reperfusing at 80 mmHg, the dose-response curve to U46619 was unaffected. In contrast, 8-epi PGF2alpha caused a dose-dependent drop in coronary flow (ED50 52.6+/-12.7 nmol), producing a similar maximal reduction to U46619. 5. Similarly, after perfusion with xanthine and xanthine oxidase for either 15 or 30 min there was little change in the response to U46619 in comparison to control hearts. In contrast, 8-epi PGF2alpha caused a reduction in coronary flow similar to that produced by U46619, the magnitude of the response being related to the length of xanthine/xanthine oxidase perfusion. 6. Responses to both U46619 and 8-epi PGF2alpha after xanthine/xanthine oxidase perfusion were blocked by the selective thromboxane receptor antagonist SQ29548 10(-7) M. 7. These results show that oxidative stress in the isolated perfused rat heart reveals a potent vasoconstrictor effect of the isoprostane 8-epi PGF2alpha by an action on the thromboxane receptor. 8. The data also suggest that, since 8-epi PGF2alpha is a partial agonist at the thromboxane receptor, thromboxane receptor reserve is increased by oxidative stress.     

Do alterations of endogenous angiotensin II levels regulate erythropoietin production in humans?

AIMS: Recent evidence suggests a potential role of angiotensin II in the physiological regulation of erythropoietin (Epo) production. While the administration of exogenous angiotensin II (AII) has been used so far to study its effects, the role of endogenous AII has remained unclear. METHODS: To alter endogenous AII in humans experimentally we used furosemide bolus injection as a short-term (study 1) and dietary salt as a long-term modulator (study 2). In an open crossover design, 12 healthy male volunteers received furosemide (F) 0.5 mg kg(-1) intravenously or placebo (P) in random order (study 1). With the same design, 12 volunteers received high-salt (HS), normal-salt (NS) and low-salt (LS) diet (study 2). Plasma renin activity (PRA) was analysed along with AII. Inulin and paraaminohippurate (PAH) clearances were used to indicate glomerular filtration rate (GFR) and renal plasma flow (RPF), respectively. RESULTS: While F stimulated AII and PRA and decreased GFR and RPF significantly, no concomitant alteration of Epo was observed [AUCEpo: placebo 5709 +/- 243 (% of baseline x h), furosemide: 5833 +/- 255 (% of baseline x h); 95% confidence interval (CI) -608.4, 856.0; P = 0.73]. F decreased GFR (from 103.6 +/- 4.0 to 90.6 +/- 4.8 ml min(-1) 1(-1) 73 m-2; 95% CI 1.1, 24.9; P < 0.05), but not RPF (study 1). Correspondingly, LS stimulated and HS decreased AII and PRA significantly. HS increased GFR and RPF. Again, Epo concentrations were not affected (AUCEpo: normal sodium 44 +/- 6.7 mIU x day ml(-1), low sodium 39 +/- 2.4 mIU x day ml(-1), high sodium 48.5 +/- 6.1 mIU x day ml(-1); normal salt/low salt 95% CI -11.9, 21.9, P = 0.54; normal salt/high salt 95% CI -14.4, 23.3, P = 0.63; study 2). CONCLUSIONS: We conclude that, at least in the physiological setting in healthy volunteers, increased concentrations of endogenous AII may not be a major factor of Epo regulation.     

Renin release induced by a nonvasoconstrictor dose of phenylephrine is independent of the renal prostaglandin system in anesthetized dogs

We examined the relationship between prostaglandin (PG) production and renin release induced by a nonvasoconstrictor dose of an alpha-agonist, phenylephrine, in anesthetized dogs. Intrarenal infusion of phenylephrine (1 microgram/min) did not affect systemic blood pressure or renal blood flow, but increased the renin secretion rate about twofold. The effect of phenylephrine on renin release was abolished by the intrarenal infusion of the alpha-antagonist phentolamine (50 micrograms/min), but was not affected by the intravenous administration of the PG synthetase inhibitor indomethacin (5 mg/kg). Urine flow and urinary sodium excretion rate were not altered by phenylephrine. These results suggest that a nonvascular and nontubular alpha-adrenoceptor mechanism, which is independent of the renal PG system, may be involved in renin release.     

Alpha- and beta-adrenoceptors in hypertension. II. Platelet alpha 2- and lymphocyte beta 2-adrenoceptors in children of parents with essential hypertension. A model for the pathogenesis of the genetically determined hypertension

To study whether changes in alpha- and beta-adrenoceptors in human essential hypertension (EHT) might be genetically determined, we assessed platelet alpha 2- and lymphocyte beta 2-adrenoceptor density in 48 normotensive children of normotensive parents (NT) and in 41 normotensive children with one EHT-parent. Both groups did not differ in age, body weight and height, blood pressure, heart rate, plasma catecholamine levels, plasma renin activity (PRA), and lymphocyte beta 2-adrenoceptor density. Platelet alpha 2-adrenoceptor density, however, was in EHT-children significantly higher than in NT-children. In NT-children, platelet alpha 2-adrenoceptors were significantly, inversely correlated with PRA, indicating that they might mirror renal alpha 2-adrenoceptors which inhibitorily regulate renin release. In contrast, in EHT-children PRA was not at all related to platelet alpha 2-adrenoceptors, suggesting an early (even in the normotensive stage) disturbance of the alpha 2-adrenoceptor-mediated regulation in renin release. From these results and those obtained in the experimental rat models of acquired hypertension, a model for the pathogenesis of the genetically determined hypertension is proposed in which a very early step in the development of hypertension is a genetically determined increase in renal alpha-adrenoceptors that causes enhanced sodium retention. This initiates a chain of events that finally results in increased peripheral vascular resistance and, hence, blood pressure. On the other hand, beta-adrenoceptor changes seem to be secondary phenomena due to the elevation in blood pressure.     

INTRACORONARY PGE2 AND VERATRINE INHIBITS RENIN RELEASE IN CONSCIOUS DOGS VIA CHEMOSENSITIVE VENTRICULAR AFFERENTS

1. Prostaglandins (PG) and veratrum alkaloids stimulate ventricular sensory receptors with non-myelinated vagal afferents and mediate inhibitory circulatory responses. 2. The present study in conscious instrumented dogs was carried out to determine the effects of intracoronary artery infusions of veratrine (Ver-IC) and PGE2 (PGE2-IC) on plasma renin activity (PRA). 3. A 15-20 mmHg decrease in arterial pressure was produced during Ver-IC (0.2-0.8 micrograms/kg per min) and PGE2-IC (10-50 ng/kg per min), but there was no change in PRA or heart rate. 4. In contrast, significant increases in PRA (+3.51 +/- 0.37 ng angiotensin I/mL per h; P less than 0.01) and heart rate (+38.5 +/- 6.2 beats/min; P less than 0.001) were elicited in response to a 15-20 mmHg decrease in arterial pressure produced by intravenous infusions of nitroprusside. 5. Pharmacological blockade of afferent fibres in the pericoronary region of the left main coronary artery during Ver-IC resulted in significant hypotension-induced increases in PRA (P less than 0.001) and heart rate (P less than 0.001), thus removing the inhibitory influence of chemosensitive ventricular afferents. 6. Therefore, intracoronary veratrum alkaloids and prostaglandins inhibit hypotension-induced increases in PRA and heart rate in the conscious dog. This is mediated by chemosensitive receptors located in the left ventricular myocardium along with afferent nerves in the pericoronary region and cervical vagi.