Hemodynamic effects of infusion versus bolus administration of atrial natriuretic factor.

The cardiovascular responses to intravenous bolus administration of several synthetic atrial natriuretic peptides were examined in conscious spontaneously hypertensive rats and compared with the hemodynamic effects of continuous infusions of the peptides. Rats were instrumented with pulsed Doppler flow probes to allow measurement of regional blood flow in the conscious, unrestrained hypertensive rat. Bolus administration of increasing doses (0.036-18 nmol/kg) of atriopeptin II, alpha-rat atrial natriuretic peptide, Wy-47,663, or alpha-human atrial natriuretic peptide caused short-lived, dose-dependent reductions in mean arterial pressure and renal vascular resistance. A marked but transient (10-40 seconds) increase in renal blood flow was observed after administration of the peptides. Mesenteric and hindquarter vasodilation also were observed after bolus injection of high doses of the atrial peptides. Infusion of alpha-rat atrial natriuretic peptide or Wy-47,663 (0.045-1.44 nmol/kg/min) resulted in sustained reductions in mean arterial pressure. The fall in arterial pressure was accompanied by significant reductions in regional blood flow in the renal, mesenteric, and hindquarter vascular beds. Dose-dependent increases in regional vascular resistances were observed in all three vascular beds during the peptide infusions. These data indicate that the hemodynamic responses to synthetic atrial peptides are greatly dependent on the mode of administration of the peptide in conscious spontaneously hypertensive rats. Stable, sustained responses were observed only during infusion steady state conditions.

Selective antagonism of humoral versus neural vasoconstrictor responses by nisoldipine.

The effects of nisoldipine administration on vascular reactivity to humoral and neural vasoconstrictor stimuli were examined in the intact rat. For these experiments, rats were instrumented with miniaturized pulsed Doppler flow probes to allow continuous measurement of renal, mesenteric, and hindquarters blood flow. In conscious and anesthetized rats, intravenous doses of angiotensin II (75 and 150 ng/kg), norepinephrine (0.6 and 1.2 microgram/kg), and epinephrine (0.6 and 1.2 microgram/kg) caused dose-dependent increases in arterial pressure and renal and mesenteric vascular resistance. Nisoldipine (0.7 microgram/min) administration significantly attenuated (p less than 0.05) the pressor and regional vasoconstrictor actions of all three circulating pressor agents; however, nisoldipine infusion had little effect on neurally mediated regional vasoconstrictor responses elicited by electrical stimulation of the posterior hypothalamus or greater splanchnic nerve. These data indicate that nisoldipine depressed vascular responsiveness to humoral vasoconstrictor agents, while neural vasoconstrictor responses were unaffected. Thus nisoldipine appears to exert preferential antagonistic effects on humoral rather than on neural vasoconstrictor stimuli.

Recombinant human complement C5a receptor antagonist reduces infarct size after surgical revascularization.

OBJECTIVES: This study tested the hypothesis that a recombinant human C5a antagonist, CGS 32359, attenuates neutrophil activation and reduces infarct size in a porcine model of surgical revascularization. METHODS: CGS 32359 (0.16-16 micromol/L) dose-dependently inhibited superoxide production by human C5a-activated porcine neutrophils (18 +/- 3.7 vs 1.6 +/- 0.5 nmol/5 min/5 x 10(6) neutrophils; P <.05) and reduced neutrophil adherence to coronary endothelium from 194 +/- 9 to 43 +/- 6 neutrophils/mm(2) (P <.05). The left anterior descending coronary artery was occluded for 50 minutes, after which saline solution (n = 8), mannitol-buffer vehicle (n = 9, 102 mg/kg bolus, 102 mg. kg(-1). h(-1)), or CGS 32359 (CGS, n = 7, 60 mg/kg bolus, 60 mg. kg(-1). h(-1)) was infused. After ischemia, 1-hour arrest was achieved by means of multidose hypothermic (4 degrees C) blood cardioplegia, followed by 2.5 hours of off-bypass reperfusion. The ligature on the left anterior descending artery was released before the second infusion of cardioplegic solution. RESULTS: Area at risk was similar in all groups (saline solution, 27% +/- 2%; mannitol-buffer vehicle, 26% +/- 2%; CGS, 26% +/- 2% left ventricular mass). Infarct size (area necrosis/area at risk) was significantly reduced by CGS (18% +/- 6%, P <.05) versus saline solution (52% +/- 3%) and mannitol-buffer vehicle (60% +/- 4%). Postischemic systolic shortening (sonomicrometry) in the area at risk was significantly improved with CGS (0.8% +/- 0.9%) compared with saline solution (-3.7% +/- 1.1%) and mannitol-buffer vehicle (-6.4% +/- 1.0%). Myeloperoxidase activity from accumulated neutrophils was less in the ischemic zone of CGS (0.014 +/- 0.002 U/100 mg tissue; P <.05) than mannitol-buffer vehicle (0.133 +/- 0.012 U/100 mg tissue). CONCLUSIONS: We conclude that the recombinant human C5a receptor antagonist CGS 32359 inhibits surgical ischemia-reperfusion injury after coronary occlusion.

Cardiovascular effects of central calcitonin gene-related peptide in conscious rats.

Calcitonin gene-related peptide (CGRP) is a potent peripheral vasodilator. In the present study, the cardiovascular effects of centrally administered CGRP were examined in conscious, normotensive rats. The rats were chronically instrumented with miniaturized pulsed Doppler flow probes to allow measurement of regional blood flow in the conscious animals. Injection of increasing doses of CGRP (0.3 to 3.0 micrograms/kg) in the lateral cerebroventricles transiently increased arterial pressure (maximal change = 13 +/- 3 mm Hg) and markedly increased heart rate (maximal increase = 88 +/- 10 b/min). The heart rate response was sustained over a period of 20 to 30 minutes. Central CGRP decreased hindquarter vascular resistance but had no effect on renal or mesenteric vascular resistances. In contrast, intravenous injections of CGRP reduced arterial pressure and renal, mesenteric, and hindquarter vascular resistances. The tachycardia response to central CGRP was attenuated by pretreatment with propranolol or hexamethonium, indicating that the heart rate response was mediated, in part, through increases in cardiac sympathetic tone. These data indicate that central CGRP may alter cardiovascular function through alterations in sympathetic outflow.

Effects of atrial natriuretic factor in conscious rhesus monkeys with acute volume expansion.

The renal and hemodynamic responses to intravenous anaritide, a human atrial natriuretic factor [102-126] at 0.3 to 20 micrograms/kg in conscious rhesus monkeys with and without acute extracellular hypervolemia were analyzed and compared. Acute isotonic saline loading (intravenous bolus at 10 mL/kg plus continuous infusion at 0.25 mL/kg/min 30 min prior to and maintained throughout experiment) significantly augmented urine output (UV) and urinary Na+ excretion rate (UNaV) by 31% and 91%, respectively. Radial mean arterial pressure (MAP) and heart rate (HR) were not affected by volume expansion. Anaritide at doses higher than 0.3 micrograms/kg reduced MAP in a dose-dependent fashion in euvolemic monkeys. In contrast, reduction in MAP was observed only at the highest dose (20 micrograms/kg) of anaritide in hypervolemic monkeys. The hypotensive responses to anaritide at 20 micrograms/kg in euvolemic and hypervolemic animals were similar (-26 +/- 5 v -24 +/- 5 mm Hg, respective maximum changes in MAP). UV and UNaV were increased by anaritide at 3 to 20 micrograms/kg in both euvolemic and hypervolemic monkeys; however, the increases at each effective dose of anaritide were greater or tended to be greater in hypervolemic rhesus monkeys compared with euvolemic rhesus monkeys. Compared to vehicle responses, HR was not affected by anaritide in either group of animals. In conclusion, acute extracellular hypervolemia potentiates the renal but suppresses the hypotensive responses to anaritide in conscious rhesus monkeys.

Infusion of recombinant human prorenin into rhesus monkeys. Effects on hemodynamics, renin-angiotensin-aldosterone axis and plasma testosterone.

Prorenin, the biosynthetic precursor of active renin, is present in high concentrations in the kidney and reproductive organs. We have proposed that prorenin may be the vehicle of local renin systems, separating the functions of circulating and tissue renin. In the present study, we investigated the effect of increasing plasma prorenin 3- to 4-fold by infusing recombinant prorenin, 400 ng/min for 40 min, into male rhesus monkeys. The prorenin was first warmed to 37 degrees C to reduce the endogenous renin activity to a minimum. The study included a 20 min baseline and a 40 min recovery period. Plasma prorenin increased from 72 +/- 14 ng/mL/h to a maximum of 246 +/- 18 ng/mL/h during the infusion (P less than .001) and fell to 169 +/- 23 ng/mL/h 40 min after the infusion was stopped. Active renin did not change significantly. Plasma aldosterone increased slightly during the prorenin infusion (by 13%) and returned to baseline during the recovery period (P less than .05 compared to the infusion period). Plasma testosterone fell significantly from 1.9 +/- 0.1 ng/mL to 1.6 +/- 0.1 ng/mL during the infusion and further to 1.4 +/- 0.1 ng/mL during the post-infusion period (P less than .05). Blood pressure fell slightly but not significantly. Heart rate, glomerular filtration rate and renal blood flow, as well as urine flow and urine sodium and potassium excretion showed no significant change. These results demonstrate that human recombinant prorenin is not converted to active renin in the circulation of rhesus monkeys.(ABSTRACT TRUNCATED AT 250 WORDS)

Regional vasodilator actions of calcitonin gene-related peptide in conscious SHR.

In the present study the regional hemodynamic effects of CGRP were examined in conscious unrestrained spontaneously hypertensive rats (SHR). The animals were chronically instrumented with miniaturized pulsed Doppler flow probes to allow continuous measurement of renal, mesenteric and hindquarter blood flow. Bolus intravenous injection of CGRP (0.1-5 micrograms/kg) produced a dose-dependent fall in mean arterial pressure (maximal change = -48 +/- 5 mmHg) which was accompanied by a marked tachycardia (maximal change = 143 +/- 16 b/min). Depressor responses to CGRP were sustained for approximately 3-5 min. CGRP markedly reduced regional vascular resistance in all three vascular beds. No regional-selective vasodilator response was observed. These data indicate that CGRP is a potent vasodilator peptide in conscious SHR. The study suggests further that CGRP may contribute to the physiologic regulation of cardiovascular function.

Hemodynamic effects of calcitonin gene-related peptide in conscious rats.

The cardiovascular effects of calcitonin gene-related peptide (CGRP) were examined in conscious, unrestrained rats. Changes in mean arterial pressure, heart rate and cardiac output were continuously monitored before and after i.v. bolus injection of CGRP (0.1-5 micrograms/kg). Injection of the peptide caused dose-dependent reductions in mean arterial pressure (-24 +/- 4 mmHg), which were accompanied by marked tachycardia. Cardiac output was significantly increased after CGRP but little change was observed in stroke volume. CGRP also reduced total peripheral resistance (-46 +/- 6%). These data indicate that the hypotensive actions of CGRP are mediated through peripheral vasodilation rather than through reductions in cardiac output. Pretreatment with propranolol significantly reduced the tachycardia responses to CGRP from 81 +/- 11 beats/min to 36 +/- 4 beats/min, but did not abolish the increase in heart rate. These data suggest that CGRP produces a tachycardia through reflex increases in cardiac sympathetic tone and through possible direct positive chronotropic effects on the heart.

Hypotensive response to atrial natriuretic factor in conscious chronic pulmonary hypertensive rats.

The hypotensive effects of anaritide (Wy-47,663), a 26 amino acid atrial natriuretic factor, were examined in conscious, monocrotaline-induced chronic pulmonary hypertensive rats. Anaritide (0.25-8 micrograms/kg per min i.v.) decreased systemic arterial pressure at 2-8 micrograms/kg per min by as much as -15.6 +/- 0.4 mm Hg. The pulmonary hypotensive response to anaritide was not different from vehicle treatment. We conclude that anaritide is more effective in decreasing systemic than pulmonary arterial pressures in monocrotaline-induced pulmonary hypertensive rats.

In vitro and in vivo interactions of nitrovasodilators and zaprinast, a cGMP-selective phosphodiesterase inhibitor.

We have examined the interaction of zaprinast, a selective inhibitor of cGMP phosphodiesterase, with guanylate cyclase activators on vascular smooth muscle relaxation in vitro and in vivo. Isolated porcine coronary arterial rings precontracted with prostaglandin F2 alpha (PGF2 alpha) were relaxed dose dependently by the guanylate cyclase activators nitroglycerin and nitroprusside, the cGMP phosphodiesterase inhibitor zaprinast and the endothelium-dependent agent bradykinin. A 1 h pretreatment with 0.5 mM nitroglycerin shifted the dose-response curve to nitroglycerin to the right by a factor of 90, reflecting the development of tolerance. The dose-response curve to sodium nitroprusside was also affected, albeit to a much lesser degree (9-fold increase in IC50). Both zaprinast and bradykinin remained unaffected by nitroglycerin pretreatment. A 30 min pretreatment of rings with zaprinast (1 microM) had no effect on nitroglycerin- or nitroprusside-induced relaxation in control rings, but enhanced vasorelaxation to both nitrovasodilators 7- and 2-fold, respectively, in tolerant rings. Similarly, a 30 min pretreatment of rings with 0.1 microM nitroprusside enhanced zaprinast-induced vasorelaxation 4- and 8-fold, respectively, in control and tolerant rings. Similar observations were made in vivo in anesthetized spontaneously hypertensive rats where zaprinast (0.1-3.0 mg/kg i.v.), caused dose-dependent reductions in mean arterial pressure. This effect was enhanced when rats had been pretreated with nitroprusside (1 micrograms/kg per min). In comparison, in zaprinast-pretreated rats the magnitude of depressor responses to nitroprusside (0.5-5.0 micrograms/kg) was not altered, but the duration of hypotensive response to the highest dose of nitroprusside was enhanced by zaprinast. These data demonstrate an enhanced vasodilatory response of nitrocompounds in combination with peak I-selective phosphodiesterase inhibitors.

Rat atriopeptin III alters hypothalamic neuronal activity.

The effect of pressure application of rat atriopeptin III on extracellularly recorded action potentials of 39 hypothalamic neurons was studied in chloral hydrate-anesthetized male rats. Thirteen of these neurons were histologically located within the boundaries of the paraventricular nucleus. Atriopeptin III was a potent inhibitor of the spontaneous activity of 5 (38%) of these neurons and increased the spontaneous activity of one (8%) other neuron (7 paraventricular neurons were unresponsive to atriopeptin III). Neurons not located within the paraventricular nucleus responded similarly to pressure application of atriopeptin III. Twenty-seven percent (n = 7) were inhibited and 12% (n = 3) were excited while the remaining 16 (61%) neurons were unresponsive to atriopeptin III. Similar applications of an inactive fragment of atriopeptin III (amino acid sequence 18-28) did not alter the spontaneous activity of any neuron (n = 6). These results illustrate that atriopeptin III, an atrial peptide which is also present in the brain, can alter the spontaneous activity of hypothalamic neurons. This provides additional evidence for central activity of this peptide.

Systemic administration of an inhibitor of endothelin-converting enzyme for attenuation of cerebral vasospasm following experimental subarachnoid hemorrhage.

The potent vasoconstrictor peptide, endothelin-1 (ET-1), has been implicated in the pathophysiology of cerebral vasospasm that occurs after subarachnoid hemorrhage (SAH). This peptide is synthesized as a large prepropeptide that requires a series of modifying steps for its activation. The last of these steps involves the proteolytic conversion of a relatively inactive propeptide, Big ET-1, to its active, 21-amino acid peptide form. The enzyme responsible for converting Big ET-1 to ET-1 is a metalloprotease called endothelin-converting enzyme (ECE). In the present study the authors examined the effects of a newly developed inhibitor of ECE on responses to ET peptides in the normal basilar artery and on pathophysiological constriction in the spastic basilar artery after SAH. In the first series of experiments the authors examined normal basilar arteries in the rabbit, which were exposed transclivally and measured on-line using videomicroscopy. Intravenous administration or topical application of an active inhibitor of ECE, CGS 26303, blocked vasoconstrictor responses to topically applied Big ET-1 but not to ET-1. In contrast, topical application of a structurally related compound that does not inhibit ECE, CGS 24592, was ineffective in blocking vasoconstriction that was elicited by a topical application of Big ET-1. These findings indicate that CGS 26303 when administered systemically is capable of blocking the conversion of Big ET-1 to ET-1 in the basilar artery without affecting the ability of the vessel to respond to ET-1. In the second series of experiments the authors examined the effects of the ECE inhibitor on cerebral vasospasm after experimental SAH. Intraperitoneal administration of CGS 26303 via osmotic minipumps significantly attenuated the delayed spastic response of the basilar artery to an intracisternal injection of autologous blood. This study provides the first evidence that systemic administration of an inhibitor of ECE is capable of preventing cerebral vasospasm after SAH. The results reinforce a growing body of evidence that ETs play a critical role in the development of spastic constriction after SAH. Moreover, the findings indicate that blocking the conversion of Big ET-1 to its active ET-1 form using CGS 26303 may represent a feasible strategy for ameliorating cerebral vasospasm.

Prevention and reversal of cerebral vasospasm by an endothelin-converting enzyme inhibitor, CGS 26303, in an experimental model of subarachnoid hemorrhage.

Delayed cerebral ischemia due to cerebral vasospasm is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (SAH). Increasing evidence implicates the potent vasoconstrictor peptide endothelin (ET) in the pathophysiology of cerebral vasospasm. In the present study the authors examined the therapeutic value of blocking the production of ET-1 by inhibiting the conversion of its relatively inactive precursor, Big ET-1, to a physiologically active form. An inhibitor of ET-converting enzyme (ECE), CGS 26303, was injected intravenously after inducing SAH in New Zealand white rabbits. Injections of CGS 26303 were initiated either 1 hour after SAH (prevention protocol) or 24 hours after SAH (reversal protocol). One of three concentrations (3, 10, or 30 mg/kg) of CGS 26303 was injected twice daily, and all animals were killed by perfusion fixation 48 hours after SAH occurred. Basilar arteries were removed and sectioned, and their cross-sectional areas were measured in a blind manner by using computer-assisted videomicroscopy. Treatment with CGS 26303 attenuated arterial narrowing after SAH in both the prevention and reversal protocols. The protective effect of CGS 26303 achieved statistical significance at all dosages in the prevention protocol and at 30 mg/kg in the reversal protocol. These findings demonstrate that inhibiting the conversion of Big ET-1 to ET-1 via intravenous administration of an ECE inhibitor can be an effective strategy for limiting angiographic vasospasm after SAH. Moreover, the results demonstrate that treatment with the ECE inhibitor is capable of reducing vasospasm even when initiated after the process of arterial narrowing has begun. Finally, the results provide further support for the role of ET in the establishment of cerebral vasospasm. The ECE inhibitor CGS 26303 thus represents a promising therapeutic agent for the treatment of cerebral vasospasm following aneurysmal SAH.

Lack of renal vasodilation during intrarenal infusion of synthetic atriopeptin II in conscious intact SHR.

Synthetic atriopeptin II (APII) was infused directly into the right renal artery of intact conscious SHR at rates of 0.25-1 microgram/kg/min, while simultaneously measuring blood pressure (MAP) and selected regional blood flows. The latter were measured using chronically implanted miniaturized Doppler flowprobes that were placed on the right and left renal artery, superior mesenteric artery and abdominal aorta. The effects of intrarenally (i.r.) infused APII on these vascular beds were compared to the effects of the same amounts of APII given intravenously (i.v.) in the same SHR. I.r. and i.v. infusions caused similar reductions of MAP and all four blood flows. Also effects on calculated resistances were comparable, implying that resistance increased most in the mesentery and least in the two kidneys. The increase in right renal resistance during i.v. infusions of APII was not different from the effect during i.r. infusions. Also, during i.r. infusions into the right kidney, effects on the left and right kidney were not different. Our observations suggest that synthetic APII has no direct effects on the renal vasculature of intact conscious SHR.

Effects of atrial natriuretic factor on drinking responses to central angiotensin II.

The present study examined the effects of ANF(4-28) [Wy-47,663], a synthetic 25 amino acid human atrial natriuretic factor, on the dipsogenic actions of centrally-administered angiotensin II in conscious rats. Bolus injection (100 ng) or continuous infusion (60 ng/min) of Wy-47,663 or vehicle into the lateral cerebroventricle had no effect on mean arterial pressure or heart rate. No obvious behavioral changes were observed after central administration of Wy-47,663 or vehicle. Central injection of angiotensin II (15 or 30 ng) promptly elicited prolonged drinking responses in vehicle-treated rats. In rats pretreated with Wy-47,663, the onset of the angiotensin II-induced drinking responses was significantly delayed compared to vehicle-treated animals. However, Wy-47,663 had no effect on the total volume consumed over 30 minutes after angiotensin II injection. Intravenous infusion of Wy-47,663 (2 micrograms/kg/min) failed to alter the dipsogenic action of centrally administered angiotensin II. These data indicate that atrial natriuretic factor found within the brain but not the peripheral circulation may participate in the regulation of extracellular fluid volume by modulating the dipsogenic actions of the central renin-angiotensin system.

Pharmacological evidence for rapid destruction of efferent renal nerves in rats by intrarenal infusion of 6-hydroxydopamine.

In a previous study we reported that intrarenal (i.r.) infusion of 1 mg 6-hydroxydopamine (6-OHDA) in rats resulted in selective efferent denervation of the infused kidney. Although the vasoconstrictor response to electrical stimulation of the posterior hypothalamus (PH) was already abolished 24 h after infusion, norepinephrine (NE) content of the kidney was reduced by only approximately 50% at that time. In the present study, the status of renal nerves 45 min after infusion of 6-OHDA by i.r. application of scorpion venom (SV), a NE releasing agent, was investigated. In saline pretreated rats, 10 micrograms SV i.r. caused a rapid increase (+355 +/- 80%) in vascular resistance in the injected kidney, whereas only minor changes were observed in resistances of the non-injected kidney, mesentery and hindquarters. Pretreatment of animals with phentolamine (1 mg/kg i.v.) largely abolished the vasoconstrictor response (+57 +/- 20%), confirming dependence of the effect of SV on release of NE from nerve terminals. Finally, pretreatment with 1 mg 6-OHDA i.r. also resulted in abolition of renal vasoconstriction following SV (+7 +/- 6%). The results indicate that as early as 45 min after i.r. infusion of 1 mg 6-OHDA in rats, efferent renal nerve endings are no longer functional.

Hemodynamic, neural, and humoral mechanisms of aortic coarctation hypertension in the rat.

The present study was designed: (a) to examine the contribution of the renin-angiotensin system (RAS) to elevated regional vascular resistance during the onset of aortic coarctation hypertension, and (b) to determine the role of angiotensin II (Ang II)-neural interactions during the maintenance of high arterial pressure (AP). In the first study, rats were instrumented chronically with miniaturized pulsed Doppler flow probes on the right renal and superior mesenteric arteries 3 days prior to complete aortic ligation. After ligation, AP and renal and mesenteric vascular resistances increased significantly. In sham-ligated rats, small increases in AP and decreases in regional vascular resistances were observed. Captopril, administered 6 h postligation, reduced AP and regional vascular resistance in ligated rats to preligation levels, indicating that the RAS was responsible for these acute increases. In the second study, Ang II-neural interactions were examined by treating 12- to 14-day postligation hypertensive rats with captopril or with hexamethonium, a ganglionic blocker, followed by captopril. Depressor responses to captopril were also examined in aortic-ligated rats pretreated with hydralazine. Captopril alone and captopril after hydralazine caused similar reductions in AP (-26 +/- 2% and -27 +/- 1%, respectively). After ganglionic blockade, the depressor responses to captopril were attenuated (-13 +/- 2%). The marked differences in the efficacy of captopril to lower AP in the ganglionic-blocked group of rats suggested that the pressor actions of Ang II were mediated, in part, through indirect actions on the sympathetic nervous system.

Differential responsiveness of conduit and resistance coronary arteries to endothelin A and B receptor stimulation in anesthetized dogs.

The effects of endothelin-1 (ET-1), an ET(A)/ETB-receptor agonist, and IRL 1620, a potent and selective ETB-receptor agonist, were assessed on left circumflex coronary artery diameter (sonomicrometry) and flow (electromagnetic flow probe) in pentobarbital-anesthetized dogs. Intracoronary (i.c.) bolus injections of ET-1 (80 pmol/dose) caused large, sustained coronary diameter decreases (281 +/- 39 microns) and transient flow increases (5.6 +/- 2.6 ml/min), followed by transient (10.0 +/- 1.9 ml/min) and then sustained flow reductions (6.6 +/- 2.5 ml/min) before terminating in ventricular fibrillation after two to five doses (max delta s; n = 4 dogs). IRL 1620 boluses (5-2,000 pmol/dose i.c.; max delta s; n = 3) also dose-dependently and transiently increased (16.8 +/- 1.4 ml/min; 200 pmol), then transiently decreased (12.8 +/- 1.5 ml/min; 1,600 pmol) flow but had minimal effects on diameter (delta = -23 +/- 4 microns; 2,000 pmol). Doses of IRL 1620 beyond 400 pmol were accompanied by a slowly responding, sustained decrease in baseline flow (-9.2 +/- 2.7 ml/min) and baseline diameter (232 +/- 150 microns). In a separate group of dogs (n = 5), IRL 1620 (400 pmol i.c.) was evaluated before and after sequential inhibition of cyclooxygenase (indomethacin; 10 mg/kg i.v.) and then nitric oxide synthase (N omega-nitro-L-arginine methyl ester, L-NAME; 50 mg/kg i.v.). Indomethacin alone did not affect the flow increase to IRL 1620 (11.0 +/- 2.0 versus 11.8 +/- 1.8 ml/min) but blunted the flow decrease by 30 +/- 6% (10.6 +/- 1.4 versus 7.1 +/- 0.7 ml/min).(ABSTRACT TRUNCATED AT 250 WORDS)