Pulmonary and urinary clearance of atrial natriuretic factor in acute congestive heart failure in dogs.

Atrial natriuretic factor (ANF) is a peptide hormone of cardiac origin elevated in acute congestive heart failure (CHF), which is degraded by the enzyme neutral endopeptidase 24.11 (NEP). This study was designed to investigate the pulmonary and urinary clearance of ANF before and after the initiation of acute experimental CHF in dogs, and to assess the contribution of enzymatic degradation to these clearances in CHF. This study demonstrated a significant clearance of plasma ANF across the pulmonary circulation at baseline, and a tendency for pulmonary clearance to decrease in CHF (1115 +/- 268 to 498 +/- 173 ml/min, NS). The pulmonary extraction of ANF present at baseline was not altered with acute CHF (36.0 +/- 7.8 to 34.9 +/- 12.1%, NS). NEP inhibition (NEPI) abolished both the clearance and extraction of plasma ANF across the lung in CHF. Similarly, significant urinary clearance of ANF was present at baseline, and in acute CHF the urinary clearance of ANF decreased (0.14 +/- 0.02 to 0.02 +/- 0.01 ml/min, P less than 0.05). NEPI prevented the decrease in the urinary clearance of ANF, and enhanced the renal response to endogenous ANF, independent of further increases in plasma ANF during CHF. This study supports an important role for NEP in the pulmonary and urinary metabolism of endogenous ANF during acute CHF.

Angiotensin converting enzyme inhibition modulates endogenous endothelin in chronic canine thoracic inferior vena caval constriction.

Endothelin (ET) is a potent vasoconstrictor peptide which is elevated in plasma in congestive heart failure. Recent studies suggest an important role for angiotensin II (AII) in the activation of ET in cultured cardiomyocytes. Chronic thoracic inferior vena caval constriction (TIVCC) is a model of reduced cardiac output that mimics the neurohumoral activation observed in congestive heart failure. We hypothesized that activation of the renin-angiotensin system in TIVCC plays a role in the activation of ET and that the elevation of endogenous ET contributes to the systemic and renal vasoconstriction that characterizes this model of venous congestion. We studied conscious dogs after 7 d of TIVCC in the presence or absence of chronic angiotensin converting enzyme inhibition with enalapril. TIVCC resulted in marked activation of plasma AII and ET in plasma, right atrium, lung, and renal medulla which was further localized to cardiomyocytes, pulmonary, and renal epithelial cells. Chronic angiotensin converting enzyme inhibition abolished the increases in plasma AII and ET during TIVCC. Acute endothelin A receptor blockade with FR-139317 resulted in significant decreases in mean arterial pressure and systemic vascular resistance in TIVCC. We conclude that activation of the renin-angiotensin system contributes to the activation of circulating and local ET in TIVCC and that this activation plays an important role in the regulation of arterial pressure and systemic vascular resistance in this model of congestive failure.

C-type natriuretic peptide-mediated coronary vasodilation: role of the coronary nitric oxide and particulate guanylate cyclase systems.

OBJECTIVES: We tested the hypothesis that C-type natriuretic peptide (CNP) mediates coronary vasodilation through activation of cyclic guanosine monophosphate (cGMP) by way of particulate guanylate cyclase. BACKGROUND: CNP has known peripheral vasodilator properties, and preliminary data have suggested that it can function as a coronary vasodilator. METHODS: The actions of CNP were studied in instrumented dogs and in organ chamber rings in the presence and absence of a known antagonist to particulate guanylate cyclase, HS-142-1. Additionally, the actions of HS-142-1 were tested on acetylcholine-mediated coronary vasodilation, and immunohistochemical staining was utilized to localize the presence of CNP in the coronary endothelium. RESULTS: CNP relaxed isolated coronary arteries with (mean +/- SEM 45.9 +/- 7%*) and without (72.0 +/- 7%*) an endothelium (*p < 0.05 for CNP effect alone, p < 0.05 for endothelium vs. no endothelium with CNP). Intracoronary infusions increased coronary blood flow (baseline, 64.6 +/- 5.1 ml/min; CNP-5, 79.9 +/- 6.1*; CNP-20, 103.3 +/- 13.6* [*p < 0.05 vs. baseline value]) and reduced coronary vascular resistance (baseline, 1.6 +/- 0.3 mm Hg/ml per min; CNP-5, 1.4 +/- 0.3*; CNP-20, 1.2 +/- 0.3*). Intracoronary injections increased coronary blood flow (delta baseline coronary flow, 30 +/- 9* ml/min [*p < 0.05]). HS-142-1 significantly attenuated these increases (delta coronary flow, 30 +/- 9* ml/min [CNP] to 14 +/- 6 [CNP + HS-142-1] [p < 0.05 CNP vs. CNP + HS-142-1]) and the relaxation of organ chamber rings (56 +/- 7% [CNP] to 18 +/- 6% [HS-142-1 + CNP]). Finally, CNP was localized to the coronary endothelium and smooth muscle by immunohistochemical staining. CONCLUSIONS: CNP functions as a coronary vasodilator through activation of cGMP by way of particulate guanylate cyclase. CNP-mediated coronary vasodilation is attenuated by intracoronary HS-142-1. Intracoronary HS-142-1 does not affect acetylcholine-mediated coronary vasodilation. These observations support a role for exogenous CNP as a potent coronary vasodilator.

Biological role for the endothelin-A receptor in aortic cross-clamping.

The current study was undertaken to define a biological role for the endothelin-A receptor in a clinically relevant model of altered systemic and renal function produced by suprarenal aortic cross-clamping. This model is associated with profound systemic and renal vasoconstriction, acute renal failure, and a significant increase in circulating endothelin. Studies were performed in three groups of anesthetized mongrel dogs. Group 1 (n = 5) underwent aortic cross-clamping for 1 hour; group 2 (n = 5) underwent aortic cross-clamping for 1 hour in the presence of BQ-123, a specific antagonist of the endothelin-A receptor; group 3 (n = 4) received BQ-123 alone. The marked systemic and renal vasoconstriction associated with aortic cross-clamping in group 1 was markedly attenuated in group 2 in the presence of BQ-123. Unlike the vasoconstrictor response, BQ-123 did not attenuate the decrease in glomerular filtration rate associated with this model. Under unstimulated conditions in group 3, BQ-123 had no actions on systemic or renal hemodynamics. In conclusion, the current study demonstrates that the systemic and renal vasoconstriction associated with aortic cross-clamping are in part mediated through the interaction of endothelin and the endothelin-A receptor. This study demonstrates the functional importance of increased endogenous endothelin in the regulation of vascular tone in this pathophysiological state.

Dietary omega 3 polyunsaturated fatty acids augment endothelium-dependent relaxation to bradykinin in coronary microvessels of the pig.

1. The effects of chronic dietary supplementation with omega 3 polyunsaturated fatty acids on endothelium-dependent relaxations were examined in isolated coronary microvessels of the pig. 2. Animals were maintained for four weeks with or without dietary supplementation of purified eicosapentaenoic acid (3.5 g daily) and docosahexaenoic acid (1.5 g daily). Fatty acid profiles of plasma lipids showed that only the fraction of eicosapentaenoic acid increased by the treatment, together with a decrease of that of arachidonic acid. 3. In the treated group, endothelium-dependent relaxations to bradykinin were significantly augmented, while contractions to acetylcholine or relaxations to nitroprusside were unaltered. 4. These results indicate that dietary omega 3 polyunsaturated fatty acids (mainly eicosapentaenoic acid) augment endothelium-dependent relaxations in coronary microvessels of the pig, without changing the ability of vascular smooth muscle to contract or relax.

Indomethacin improves the impaired endothelium-dependent relaxations in small mesenteric arteries of the spontaneously hypertensive rat.

Impairment of endothelium-dependent relaxations may be of primary importance in hypertension, if this impairment were to occur in resistance arteries. Therefore, endothelium-dependent relaxations to acetylcholine were studied in the mesenteric resistance vessels of spontaneously hypertensive and Wistar-Kyoto rats. Rings with and without endothelium were suspended in a myograph filled with physiological salt solution at 37 degrees C and aerated with 95% O2/5% CO2; the isometric tension was recorded. Acetylcholine caused relaxations only in rings with endothelium. In the spontaneously hypertensive rat, relaxations were impaired and markedly biphasic with an early rapid relaxation followed by a secondary contraction. Indomethacin inhibited the secondary response and augmented the duration of the relaxations induced by acetylcholine in the arteries from spontaneously hypertensive rats. These findings suggest that the decreased endothelium-dependent relaxation to acetylcholine in mesenteric resistance vessels of the spontaneously hypertensive rat is due to the release of a constrictor prostanoid which partly offsets the response of the vascular smooth muscle to endothelium-derived relaxing factor(s).

Endothelin-mediated cardiorenal hemodynamic and neuroendocrine effects are attenuated by nitroglycerin in vivo.

Endothelin-1 may function pathophysiologically as a counterregulatory vasoconstrictor peptide that is modified in its activity by the opposing action of endothelium-derived relaxing factor(s) (EDRF). The present study determined in part the integrated cardiorenal and endocrine actions of pathophysiologic plasma concentrations of endothelin in the anesthetized dog. In addition, nitroglycerin, which inhibits vascular smooth muscle contraction by increasing cGMP in a mechanism similar to EDRF, acts like an endogenous nitrovasodilator. Therefore, we tested the hypothesis that nitroglycerin would effectively antagonize the cardiac and renal actions of exogenous endothelin. The results confirm that endothelin-1-mediated vasoconstriction in vivo is heterogenous with a greater renal than coronary action. Further, nitroglycerin effectively blocked endothelin-1-mediated coronary flow reductions, but only partially antagonized reductions in renal blood flow. Endothelin-1-induced reduction in cardiac output also was not antagonized by nitroglycerin despite its effects to preserve coronary blood flow. Nitroglycerin did, however, antagonize endothelin-induced elevations in plasma epinephrine, norepinephrine, and aldosterone. These results would suggest that in pathophysiologic states where endothelin-1 is elevated, such as hypertension or congestive heart failure, there is a major compromising of renal function, and also the production of cardiac ischemia. Since exogenous nitroglycerin is relatively ineffective in antagonizing the renal vasoconstrictive effects of endothelin, it may be that the endogenous vasodilating systems, such as ERDF and prostacyclin, are inadequate in such pathologic states to counter the vasoconstrictor effects of endothelin.

Renal-specific actions of angiotensin II receptor antagonism in the anesthetized dog.

The role of angiotensin II (AII) in the regulation of systemic hemodynamic and renal function and sodium excretion, although important in states characterized by the activation of the renin-angiotensin system, remains unclear under basal conditions. The current studies were designed to define the role of AII in the basal regulation of cardiovascular and renal function using a specific AII receptor antagonist, DuP 753, in the normal anesthetized dog. No changes in mean arterial pressure, cardiac output, or systemic vascular resistance were observed during the infusion of DuP 753. In contrast, a significant increase in glomerular filtration rate (19.7 +/- 0.9 to 26.1 +/- 2.0 mL/min) and renal blood flow (151 +/- 20 to 188 +/- 26 mL/min), with a decrease in renal vascular resistance (0.85 +/- 0.10 to 0.66 +/- 0.06 mm Hg/mL/min) was observed. Associated with the renal hemodynamic changes, a diuretic (0.16 +/- 0.05 to 0.57 +/- 0.21 mL/min) and natriuretic (31.2 +/- 7.0 to 100.5 +/- 22.2 microEq/min) response was also demonstrated. Renal hemodynamic changes were also associated with a decrease in tubular sodium reabsorption characterized by an increase in the fractional excretion of sodium (1.10 +/- 0.3 to 2.61 +/- 0.62%), with an associated decrease in whole-kidney proximal tubular reabsorption indicated by an increase in fractional excretion of lithium (31.2 +/- 2.2 to 40.8 +/- 3.9%). In addition, a kaliuretic (17.9 +/- 2.1 to 27.1 +/- 2.4 microEq/min) response was observed despite a concurrent decrease in plasma aldosterone (10.8 +/- 1.5 to 8.1 +/- 1.0 ng/dL).(ABSTRACT TRUNCATED AT 250 WORDS)

Respiratory epithelium inhibits bronchial smooth muscle tone.

The aim of the present study was to determine whether or not the respiratory epithelium can modulate the responsiveness of bronchial smooth muscle. Paired rings of canine bronchi (4-6 mm OD), in some of which the epithelium had been removed mechanically (by rubbing the luminal surface), were mounted in physiological saline solution, gassed with 95% O2-5% CO2, and maintained at 37 degrees C. The presence or absence of the epithelium was confirmed by histological examination. Removal of the epithelium increased the contractile responses evoked by acetylcholine, histamine, and 5-hydroxytryptamine. Transmural nerve stimulation evoked similar peak responses in the presence and absence of epithelium. In unrubbed preparations, the peak response was followed by a gradual decrease when the stimulation was continued. This decrease, which persisted in the presence of propranolol, was not observed in epithelium-denuded preparations. In bronchial rings contracted with acetylcholine, isoproterenol produced concentration-dependent relaxations which were significantly greater in rings with epithelium compared with denuded rings. These results suggest that respiratory epithelial cells may generate an inhibitory signal to decrease the responsiveness of bronchial smooth muscle to contractile agonists and augment the effectiveness of inhibitory stimuli.

Serotonin reduces coronary flow in the isolated heart of the spontaneously hypertensive rat.

Serotonin may cause vasodilatation or vasoconstriction. In hypertension the vasoconstrictor effects of serotonin predominate. Experiments were designed to study the effects of serotonin on coronary flow in isolated hearts of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats. The hearts were paced at constant rate and perfused by the Langendorff technique at constant pressure (75 cmH2O). In WKY rats serotonin (10-9 to 10-5 mol/l) caused concentration-dependent increases in coronary flow and a decrease in cardiac performance. In SHR, the monoamine caused concentration-dependent, partially reversible decreases in coronary flow, and a marked decrease in cardiac performance. The inhibitor of cyclo-oxygenase indomethacin prevented the decrease in coronary flow and cardiac performance caused by serotonin in SHR, but did not affect the increase in coronary flow in WKY rats. These experiments suggest that in the coronary circulation of SHR the response to serotonin is shifted from vasodilatation to vasoconstriction. The mediator of this vasoconstriction is probably a product of cyclo-oxygenase.

Similarity of blood flows using indocyanine prepared in saline or distilled water.

Directly measured blood flow pumped through a mixer circuit was compared to estimates of flow from indicator dilution curves derived from bolus injections of indocyanine green dye prepared in 0.9% saline (saline dye) and in triple-distilled water (3 D dye). At flows whose mean appearance time was 1.6 s, the mean error of estimate +/-SD of 2.3 +/- 5.1% using 3 D dye was significantly different (P less than 0.05) from that of 5.6 +/- 7.0% using saline dye. Essentially, there was no difference in estimates of blood flow with each dye solution when mean appearance time was increased to 3.8 s. Thus, the error, which was perhaps due to electrolyte in the concentrated indocyanine green dye (saline dye) and subsequent slowed rate of optical stabilization after dilution in plasma, is small and does not explain the overestimation by indocyanine dilution curves of blood flow in intact dogs.

Modulation of endothelium-dependent responses by chronic alterations of blood flow.

To determine whether the blood flow and O2 tension to which a blood vessel is chronically exposed could modulate endothelium-dependent responses, these parameters were altered in the dog either by causing partial occlusion of the femoral artery or by creating a fistula between the femoral artery and vein. Blood flow was reduced by 75% in the clamped artery; mean arterial pressure was unchanged. In the vessels proximal to the fistula, blood flow was elevated and O2 tensions were similar in the vein and artery. After 6 wk the femoral arteries and veins were excised, and their endothelium-dependent responses were studied in vitro. The endothelium-dependent relaxations to acetylcholine, adenosine diphosphate, and alpha 2-adrenergic stimulation were augmented in fistula-operated compared with sham-operated arteries. The responses to these agents in the clamp-operated vessels were not different from those of the sham-operated ones. Relaxation to arachidonic acid in the arteries showed an inverse relationship to blood flow. In the veins proximal to the fistula, the endothelium-dependent relaxations to acetylcholine were augmented and an endothelium-dependent relaxation to alpha 2-adrenergic stimulation was present; only a contractile response was observed in veins from the sham-operated limb in response to the latter. These studies suggest a pattern of increased endothelium-dependent relaxation in vessels exposed to chronically elevated blood flow.

Porcine coronary arteries with regenerated endothelium have a reduced endothelium-dependent responsiveness to aggregating platelets and serotonin.

To test the ability of regenerated endothelium to evoke endothelium-dependent relaxations, male Yorkshire pigs underwent balloon endothelial denudation of the proximal left anterior descending coronary artery. Endothelium-dependent responses were examined in vitro, in rings of coronary segments taken from the denuded area or from the proximal left circumflex coronary artery. The experiments were performed 8 days or 4 weeks after the denudation. Endothelial regrowth was confirmed by histologic examination 8 days after the denudation and by demonstrating the presence of endothelium-dependent relaxations to bradykinin; at that time aggregating platelets evoked normal endothelium-dependent responses. However, 4 weeks after the denudation, the relaxations to aggregating platelets were markedly depressed although continuous endothelial lining was present, and the endothelium-dependent responses to bradykinin, adenosine diphosphate, the Ca2+-ionophore A23187, platelet activating factor, and thrombin were unaltered. Four weeks after denudation, endothelium-dependent relaxations to serotonin were depressed. Higher concentration of serotonin induced endothelium-dependent contractions in quiescent rings with regenerated endothelium, suggesting that regenerated endothelial cells may produce endothelium-derived constricting factor(s) and release less endothelium-derived relaxing factor(s) when exposed to the monoamine. The endothelium-dependent relaxation to serotonin was not reduced by the S2-serotonergic antagonist ketanserin but prevented by the combined S1- and S2-serotonergic blocker methiothepin. The platelet-induced relaxation was due to released serotonin and adenine nucleotides in control left circumflex coronary arteries, but in left anterior descending coronary artery with regenerated endothelium, it was due solely to the latter. The platelet-induced contractions were due to activation of receptors on the smooth muscle cells. Four weeks after denudation, regenerated endothelial cells were morphologically different from native cells; they were elongated and cuboidal, and the number of the cells had increased twofold. At this state, eccentric myointimal thickening was present in the previously denuded portion. These experiments indicate that the protective role of endothelial cells against the vasoconstriction induced by aggregating platelets is depressed in the chronic regenerated state. A lack of responsiveness to serotonin appears to be the cause for the endothelial dysfunction.

Cardiovascular and renal actions of C-type natriuretic peptide.

Studies were performed in two groups of anesthetized dogs (n = 5 per group) to determine the cardiovascular and renal actions of synthetic C-type natriuretic peptide (CNP). Systemic infusion of CNP (group 1; 10 and 50 ng.kg-1.min-1 iv) resulted in marked cardiovascular hemodynamic effects characterized by a decrease in mean arterial pressure, cardiac output, and atrial pressures in association with a decrease in sodium excretion. Bolus administration of CNP (group 2; 5 micrograms/kg iv) to minimize cardiovascular hemodynamic changes resulted in only a transient decrease in arterial pressure. Sodium excretion decreased despite a return of arterial pressure to baseline. These biological responses were associated with increases in plasma guanosine 3',5'-cyclic monophosphate (cGMP) in both groups but with no change in urinary cGMP. With both systemic infusion or bolus administration of CNP, significant increases in plasma aldosterone were observed in association with increases in distal nephron sodium reabsorption. This study demonstrates that CNP exhibits profound systemic hemodynamic actions and is indirectly, or perhaps directly, antinatriuretic.

The effect of cold on adrenergic neurotransmission in canine saphenous arteries and veins.

The effect of severe cold (5 to 10 degrees C) on adrenergic neurotransmission was compared in the isolated cutaneous (saphenous) artery and vein of the dog. The vein contracted to sympathetic nerve stimulation at temperatures as low as 10 degrees C; higher temperatures were needed for the artery to contract. Both blood vessels contracted to exogenous norepinephrine at temperatures as low as 5 degrees C. However, the contractile response to exogenous norepinephrine was less in the saphenous artery, and contractions to high K+ solution were depressed by cooling more in the artery than in the vein. During electrical stimulation of the sympathetic nerves in saphenous arteries and veins previously incubated with labeled norepinephrine, progressive cooling from 37 to 5 degrees C caused a sharp decline in overflow of [3H]norepinephrine and its metabolites. However, overflow of labeled norepinephrine in both blood vessels continued at very cold temperatures. Thus the inability of the saphenous artery to contract to sympathetic nerve stimulation at 10 degrees C can be explained by a greater sensitivity of the arterial smooth muscle to the direct depressant effect of cold, rather than to a differential release or metabolism or norepinephrine in the arterial wall or a loss of responsiveness to norepinephrine at very cold temperatures.

Biological actions of brain natriuretic peptide in thoracic inferior vena caval constriction.

Brain natriuretic peptide (BNP) shares structural and functional similarities to atrial natriuretic peptide (ANP). Although BNP and ANP interact with the same biologically active guanylate cyclase-coupled receptor, recent reports conflict with regard to the biological actions of exogenous BNP in sodium-retaining and edematous states. We studied the biological actions of BNP in normal dogs (n = 5) and sodium-avid dogs with chronic thoracic inferior vena caval constriction (TIVCC) (n = 6). In normal dogs BNP increased glomerular filtration rate, renal blood flow, and urinary sodium excretion and decreased proximal and distal fractional reabsorption of sodium with activation of urinary guanosine 3',5'-cyclic monophosphate (cGMP). These renal actions occurred in association with marked hypotensive actions and activation of systemic cGMP. In TIVCC, a state characterized by chronic reductions of cardiac output, avid sodium retention, edema, and activation of the renin-angiotensin-aldosterone system (RAAS), the renal actions of BNP were absent in association with marked attenuation of the urinary cGMP response. In contrast, an enhanced hypotensive response with preserved activation of systemic cGMP was observed. In neither normal dogs nor TIVCC dogs did BNP inhibit the RAAS. These studies report that BNP is a potent vasoactive and natriuretic peptide with potent proximal and distal tubular actions in normal dogs. These studies also demonstrate that in TIVCC, a model of low cardiac output and congestive failure that results in marked sodium retention with edema in which there is activation of the RAAS, the renal actions of BNP are attenuated while the vasoactive actions are enhanced.

Acute hypoxia and endogenous renal endothelin.

Endothelin (ET) is a potent vasoconstrictor peptide of endothelial cell origin. Recent studies have suggested a nonvascular paracrine and/or autocrine role for endothelin in the kidney. This study was designed to elucidate the renal ET response to acute moderate hypoxia, as reflected by urinary ET excretory rate and renal tissue ET immunoreactivity, and to correlate these responses to the hemodynamic and excretory changes during hypoxia. Experiments were conducted in two groups of anesthetized dogs: hypoxic group (10% O2 ventilation: PO2, 44 mm Hg; N = 7) and time control group (room air ventilation: PO2, 111 mm Hg; N = 6). After 60 min of hypoxia or room air ventilation, kidneys were harvested and stained immunohistochemically for ET. Acute moderate hypoxia was associated with significant increases in urinary ET excretion, urine flow, urinary sodium excretion, and fractional excretion of sodium (P < 0.05). There was no significant change in GFR, RBF, renal vascular resistance, or mean arterial pressure. Renal immunohistochemistry for ET revealed increased staining in the proximal and distal tubules in the hypoxic group as compared with controls. This study demonstrates that acute moderate hypoxia results in increased urinary ET excretion and renal tubular ET immunoreactivity, in association with diuresis and natriuresis, and suggests a nonvascular role of endogenously produced renal ET in the regulation of sodium homeostasis during hypoxia.

Denervation augments alpha-2 but not alpha-1 adrenergic responses in canine saphenous veins.

Experiments were performed in order to determine the influence of sympathetic denervation on alpha-1 and alpha-2 adrenergic responses in canine saphenous veins. In female dogs anesthetized with sodium pentobarbital, the left lumbar sympathetic chain was excised from L1 to L7. After a 3- to 5-week period, the left (denervated) and right (innervated) saphenous veins were removed, cut into rings and suspended for isometric tension recording in organ chambers filled with modified Krebs-Ringer bicarbonate solution. Denervation reduced significantly the norepinephrine content of the venous rings and the contractile responses evoked by the indirect sympathomimetic amine, tyramine. The contractile responses evoked by exogenous norepinephrine were augmented by denervation under control conditions (16.7-fold shift in concentration-effect curve) and also after inhibition of neuronal and extraneuronal uptake and beta adrenoceptors (3.8-fold shift in curve). Denervation increased the contractile responses evoked by the alpha-2 adrenergic agonist, UK 14,304 (5-fold shift in concentration-effect curve), but not those produced by the alpha-1 adrenergic agonist, phenylephrine. The selective augmentation of alpha-2 adrenergic responses by denervation may reflect the preferential innervation of alpha-2 adrenoceptors in the canine saphenous vein.

Pharmacology of pentoxifylline in isolated canine arteries and veins.

Pentoxifylline possesses vasodilator properties, but little information is available on the mechanism of action explaining this vasodilator effect. The present experiments were designed to determine the effects of the compound on vascular smooth muscle, endothelium, and adrenergic nerves in rings of isolated canine blood vessels. Pentoxifylline did not affect basal tension in coronary and femoral arteries or in saphenous and mesenteric veins; it did not alter the rhythmic activity of the latter, but did cause endothelium-independent relaxations of unstimulated basilar arteries. In coronary arteries and saphenous veins, but not femoral arteries contracted with prostaglandin F2 alpha, the compound caused relaxations which were not affected by propranolol or by removal of the endothelium. Pentoxifylline inhibited the endothelium-dependent contractions to the Ca2(+)-ionophore A23187 in the basilar artery. In saphenous veins (with endothelium), pentoxifylline did not inhibit responses to high K+, electrical stimulation of the adrenergic nerves, or exogenous norepinephrine (NE); it reduced contractions evoked by xylazine and hypoxia. In the basilar artery and the saphenous vein, the inhibitory effect of pentoxifylline was prevented by inhibitors of cyclooxygenase and thromboxane synthetase. These experiments suggest that the dilator properties of pentoxifylline in isolated canine blood vessels are primarily at the level of the vascular smooth muscle and may involve decreased production of, or reduced responsiveness to, endogenous thromboxanes.

Endothelin has biological actions at pathophysiological concentrations.

BACKGROUND: Endothelin is an endothelium-derived peptide that produces sustained contraction of arterial and venous smooth muscle in vitro. Several studies have established endothelin as a systemic, renal, and coronary vasoconstrictor in vivo at pharmacological concentrations. Such concentrations of endothelin were antinatriuretic in association with activation of the renin-angiotensin-aldosterone system. Recent studies have demonstrated that endothelin is present in the plasma and that its plasma concentrations are increased in various pathological states associated with systemic and renal vasoconstriction. To date, it remains unclear if such increases in circulating endothelin are associated with biological activity. Thus, the objective of this study was to determine the biological action of endothelin on cardiorenal and endocrine function through administration of exogenous endothelin, which achieves plasma concentrations that have been reported in various pathophysiological conditions. METHODS AND RESULTS: Experiments were conducted in two groups of anesthetized dogs. In group 1, endothelin-1 was infused intravenously at 2.5 ng/kg/ml (n = 6), which produced a doubling of circulating concentrations. Group 2 (n = 8) received saline vehicle to serve as a time control. The current studies demonstrate that a twofold increase in plasma endothelin concentrations did not affect mean blood pressure or coronary blood flow. Heart rate and cardiac output decreased in association with increased renal and systemic vascular resistances and antinatriuresis. CONCLUSIONS: The present studies demonstrate that endothelin at pathophysiological plasma concentrations produced by exogenous endothelin has biological action. These studies support a functional role for endogenous endothelin as a potentially pathophysiological vasoconstrictor peptide hormone in the regulation of cardiovascular, renal, and endocrine function.