Coronary action of endothelin-1 and vasopressin during acute hypertension in anesthetized goats. Role of nitric oxide and prostanoids

Coronary reactivity to endothelin-1 and vasopressin during acute, moderate hypertension, and the role of nitric oxide (NO) and prostanoids in this reactivity was examined in anesthetized goats. Left circumflex coronary flow was electromagnetically measured, and hypertension was induced by constriction of the thoracic aorta in animals nontreated (7 goats) or treated with the inhibitor of NO synthesis Nw-nitro-L-arginine methyl esther (L-NAME, 6 goats) or the cyclooxygenase inhibitor meclofenamate (6 goats). Under normotension (19 animals), basal mean values for mean arterial pressure and coronary vascular conductance (CVC) were 89+/-3 mm Hg and 0.36+/-0.038 ml/min/mm Hg, respectively. Endothelin-1 (0.01-0.3 nmol) and vasopressin (0.03-1 microg) dose-dependently decreased CVC, which, for endothelin-1 ranged from 5+/-1% (0.01 nmol; P<0.01) to 66+/-4% (0.3 nmol; P<0.001) and for vasopressin ranged from 9+/-1% (0.03 microg P<0.01) to 41+/-3% (1 microg; P<0.001). During nontreated and treated hypertension, mean arterial pressure increased to approximately 130 mmHg (P<0.01), and CVC decreased (17%) only during L-NAME-treated hypertension. The effects of endothelin-1 and vasopressin on CVC were decreased by approximately 50% during nontreated hypertension, and this was abolished by L-NAME and was not affected by meclofenamate. Therefore, during acute, moderate hypertension, the coronary vasoconstriction to endothelin-1 and vasopressin is attenuated, which may be related with increased NO release but not with prostanoids.     

Atrasentan treatment of pulmonary vascular disease in piglets with increased pulmonary blood flow

We studied the effect of chronic endothelin A receptor blockade by atrasentan on the pulmonary endothelin-1 system and vascular endothelial growth factor (VEGF) expression in piglets with high pulmonary blood flow. Twenty-five 4-week-old piglets with high pulmonary blood flow were randomized to three groups: sham operated (n = 8), placebo (water) (n = 7), or treatment with atrasentan (2 mg/kg per day) (n = 10). After 3 months, mean pulmonary arterial pressure (PAP) was higher in the placebo group than in the sham group [18 +/- 2 mm Hg versus 14 +/- 1 mm Hg; P < 0.05 (ANOVA)]. Atrasentan treatment was associated with lower cardiac output, PAP (14 +/- 1 mm Hg), and medial wall thickness of pulmonary arteries (diameter: 50-150 microM) compared with placebo [13.6 +/- 3.0% versus 18.1 +/- 4.2%; P < 0.05 (ANOVA)]. Quantitative real-time polymerase chain reaction for endothelin-1, endothelin B receptor, and endothelin-converting enzyme-1 mRNA in lung tissue did not differ. However, immunostaining as well as mRNA for VEGF were lower in atrasentan-treated animals (relative gene expression: atrasentan versus placebo: 0.8 +/- 0.3 versus 1.5 +/- 0.3; P = 0.009). Atrasentan treatment effectively reduces medial hypertrophy in piglets with chronic pulmonary hyperperfusion. Chronic endothelin A receptor blockade by atrasentan may interfere with the expression of VEGF.     

Reversal of hypercapnia induces endothelin-dependent constriction of basilar artery in rabbits with acute metabolic alkalosis

We recently concluded that constriction of basilar artery due to respiration-induced hypocapnia in rabbits with acute metabolic alkalosis and accompanying compensatory hypercapnia was independent of NO and K(ATP) channels. Based on reports that endothelin-1-mediated hypocapnic constriction of the rabbit basilar artery in vitro, we further investigated whether the respiration-induced hypocapnic constriction was endothelin-1 mediated. Metabolic alkalosis was induced acutely following ketamine/xylazine injection. The ET(A) plus ET(B) receptor antagonist, PD145065 (1 microM), and the selective ET(A) receptor antagonist, BQ610 (3 microM), completely relaxed the hypocapnic constriction, as determined in a cranial window. Unexpectedly, the ET(B) receptor antagonists, BQ788 and RES-701-1 (3 microM), relaxed the constriction by 72.1+/-2.8% (4) and 77.2+/-8.7% (5), respectively (means+/-S.E. (n)). To investigate whether the large magnitudes of relaxation to both ET(A) and ET(B) receptor antagonists were due to nonselectivity of the antagonists, the effects of the antagonists on the constriction to exogenous endothelin-1 were evaluated. BQ610, BQ788, and RES-701-1 relaxed the 3-5 nM endothelin-1 constriction by only 64.3+/-7.6% (4), 43.5+/-8.5% (5), and 26.7+/-4.8% (3) (means+/-S.E. (n)), respectively, consistent with the selective blocking action of these antagonists. To investigate whether the greater magnitude of BQ610, BQ788, and RES-701-1 relaxation of hypocapnic constricted versus exogenous endothelin-1-constricted vessels was due to differences between constriction elicited by endogenous versus exogenous endothelin-1, the effects of the endothelin receptor antagonists on constriction to isocapnic alkaline suffusate were evaluated. PD145065 (1 microM) and 0.1 mM phosphoramidon, an endothelin-converting enzyme inhibitor, inhibited the constriction to isocapnic alkaline suffusate by 83.8+/-7.8% (6) and 74.3+/-9.7% (8) (means+/-S.E. (n)), respectively, consistent with the endothelin-1 dependency of the constriction. BQ610, BQ788, and RES-701-1 relaxed the isocapnic alkaline suffusate constriction by 74.9+/-6.7% (5), 65.5+/-6.4% (5), and 78.0+/-6.5% (4) (means+/-S.E. (n)), respectively. Thus, the relaxation profile to the selective endothelin receptor antagonists in isocapnic alkaline constricted vessels more closely approximated the relaxation profile observed in hypocapnic constricted as compared to endothelin-1-constricted vessels. Hypocapnia did not alter the 5 nM endothelin-1 constriction. These results suggest that, under conditions of acute metabolic alkalosis and accompanying compensatory hypercapnia, subsequent hypocapnic constriction is endothelin mediated. Both ET(A) and ET(B) receptor activation may mediate the hypocapnic constriction. The hypocapnic constriction is not due to enhanced endothelin-1 constriction and, thus, is due to the release of endothelin-1 and/or additional endothelins.     

Sympathetic stimulation of renin is independent of direct regulation by renal nitric oxide

Nitric oxide (NO) regulates renin secretion through various pathways. The possibility that renal neuronal nitric synthase (nNOS) may mediate beta-adrenergic control of renin was tested. In six Inactin-anesthetized rats, renin secretion rate (RSR) was measured in response to the beta-agonist isoproterenol with and without selective inhibition of nNOS using 7-nitroindazole (7-NI, 50 mg/kg body weight [BW]). 7-NI had no effect on blood pressure (BP) or renal hemodynamics, while isoproterenol increased RSR by 9 ng AngI/h/min (P<.05) similarly with or without 7-NI. Isoproterenol decreased BP by 20 mm Hg (P<.001), but this depressor response was completely blocked by 7-NI. When acute endogenous stimulation of renal sympathetic nerve activity (RSNA) was induced by bilateral carotid occlusion, BP in 12 rats (105+/-5 mm Hg) rose transiently to peak at 121+/-6 mm Hg (P<.005) within 5 min, returning to baseline within 10 min. RSR rose threefold (2.1+/-0.5 to 7.6+/-3.3 ng AngI/ml/min/g kidney weight [KW]; P<.05). Next, 7-NI had no effect on BP (108+/-5 mm Hg), but subsequent carotid occlusion increased and sustained BP by 27+/-5 mm Hg (P<.001), but RSR did not change (2.46+/-0.94 ng AngI/ml/min/g KW). However, if after 7-NI treatment followed by carotid occlusion, the renal perfusion pressure was not allowed to rise, but held constant at 111+/-3 mm Hg, RSR increased from 3.03+/-0.79 to 12.97+/-3.41 ng AngI/ml/min/g KW (P<.025). Thus, neither beta-adrenergic stimulation of RSR with isoproterenol nor direct stimulation of RSR by activation of RSNA with carotid occlusion was modified by selective nNOS inhibition. These data suggest an important nNOS component in the regulation of BP in response to carotid occlusion, but do not support a direct role of renal nNOS mediating sympathetic regulation of RSR.     

Effects of acute systemic endothelin receptor blockade on cardiac electrophysiology in vivo

BQ-123, a selective endothelin-A receptor antagonist, has been demonstrated to suppress arrhythmias. However, the role of physiologic levels of endogenous endothelin-1 (ET-1) with respect to electrophysiologic properties of the heart is unknown. BQ-123 (0.45, 0.9, 1.8, 3.6, 7.2, and 14.4 microg/kg/min; n = 10) or saline (control, n = 5) was administered IV for 15 minutes of continuous-rate infusion at incremental doses to anesthetized normal pigs. BQ-123 had no effect on PR and QT interval, QRS duration, intraatrial and AV nodal conduction time as well as the atrial, AV nodal, and ventricular effective refractory periods. As compared with baseline, BQ-123 at 7.2 and 14.4 microg/kg/min caused an increase in heart rate (99 +/- 17 versus 110 +/- 14 and 118 +/- 14 bpm, respectively; P < 0.05), shortened sinus node recovery time (818 +/- 165 versus 641 +/- 69 and 609 +/- 74 milliseconds, respectively; P < 0.05) and decreased mean arterial pressure at 14.4 microg/kg/min (95 +/- 18 versus 80 +/- 11 mm Hg; P < 0.05). We conclude that in the normal pig, physiologic levels of ET-1 have no effect on conduction properties of atrial, AV nodal, or Purkinje fibers. However, antagonism of ET-1 by BQ-123 unmasks the effect of ET-1 on maintenance of vasomotor tone, which in turn may affect heart rate and sinus node automaticity in the intact pig.     

The effect of the carotid sinus reflex on large coronary artery diameter in anaesthetized dogs

1. The diameter of, and blood flow in, the left circumflex coronary artery was measured in anaesthetized dogs and the carotid sinus reflex was stimulated by bilateral occlusion of the carotid arteries (BCO) for 2 min. 2. The effect of BCO on coronary artery diameter and late diastolic coronary resistance was examined: (a) after bilateral vagotomy; (b) after vagotomy plus antagonism of beta-adrenoceptors with propranolol (1 mg/kg, i.v.); and (c) after vagotomy, antagonism of beta-adrenoceptors and antagonism of alpha-adrenoceptors with phentolamine (0.5 mg/kg, i.v.). 3. After vagotomy BCO increased mean arterial pressure (delta = 72 +/- 7 mmHg), heart rate (16 +/- 3 beats/min), coronary blood flow (37 +/- 11 ml/min) and coronary artery diameter (0.14 +/- 0.04 mm). Late diastolic coronary resistance initially fell (-0.26 +/- 0.13 mmHg min/ml at 30 s) but at the end of the 2 min occlusion it had returned to the baseline level (delta = 0.04 +/- 0.08 mmHg min/ml). 4. In the presence of propranolol BCO increased arterial pressure (28 +/- 12 mmHg), but did not alter heart rate (0.6 +/- 0.4 beats/min) or coronary blood flow (2 +/- 2 ml/min). There was a significant decrease in large artery diameter (-0.24 +/- 0.07 mm) and an increase in late diastolic coronary resistance (0.46 +/- 0.12 mmHg min/ml). A mechanical increase in afterload did not affect large coronary artery diameter or coronary resistance. 5. Antagonism of alpha-adrenoceptors abolished the reflex-induced constriction of the large coronary artery (delta = -0.02 +/- 0.02 mm) and the coronary resistance vessels (delta LDCR = -0.02 +/- 0.03 mmHg min ml).(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of UK-52,046, an alpha 1-adrenoceptor antagonist, on baroreflex function in man.

1. In a placebo controlled study (six healthy male subjects), the effects of UK-52,046 (0.4 microgram kg-1 i.v.) and prazosin (0.25 mg i.v.) on baroreflex function were compared, at doses which produced antagonism to phenylephrine, but which had no effect on supine blood pressure. 2. Baroreflex function [delta R-R interval ms mm Hg-1 change in SBP] was assessed following increases in systolic blood pressure (SBP) with phenylephrine and during the Valsalva manoeuvre. 3. At these doses neither UK-52,046 nor prazosin had an effect on supine SBP or heart rate; however following prazosin, standing SBPs at 5 s (69.7 +/- 7.6 mm Hg) and at 3 min (65.5 +/- 11.7 mm Hg) were less than the respective pre-treatment (P less than 0.05) values (96.0 +/- 2.9, 110.3 +/- 6.2 mm Hg) and placebo (82.7 +/- 5.6, 98.7 +/- 11.1 mm Hg). UK-52,046 had no significant effects on standing SBP at 5 s or 3 min. At 5 s, pre- and post-treatment R-R intervals (584 +/- 26, 541 +/- 27 ms respectively) were not significantly different with prazosin, but at 3 min the post-treatment R-R interval following prazosin (519 +/- 17 ms) was less (P less than 0.05) than the pre-treatment value (658 +/- 36 ms). 4. UK-52,046 had no effect on baroreflex sensitivity (12.7 +/- 1.3 ms mm Hg-1) compared with placebo (17.9 +/- 2.7 ms mm Hg-1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Renal effects of a new member of adrenomedullin family, adrenomedullin2, in rats

A new member of the adrenomedullin family, adrenomedullin2, was identified in mammals. The effects of adrenomedullin2 on renal hemodynamics and urine formation were examined in rats. Intrarenal arterial infusion of adrenomedullin2 at rates of 30, 100 and 300 pmol/kg/min decreased blood pressure and increased heart rate in a dose-dependent fashion. Adrenomedullin2 infusion at 100 pmol/kg/min significantly increased renal blood flow and urine flow. At the higher infusion rate (300 pmol/kg/min), adrenomedullin2 significantly decreased urine flow. Continuous intrarenal infusion of adrenomedullin2 at 100 pmol/kg/min significantly increased renal blood flow from 6.7+/-0.5 to 8.8+/-0.5 ml/min and decreased renal vascular resistance from 16+/-1 to 11+/-1 mm Hg min/ml. Urine flow was significantly increased from 21.5+/-4.9 to 36.2+/-8.5 microl/min and urinary excretion of sodium was increased from 2.3+/-0.9 to 4.9+/-1.4 microEq/min. Blood pressure, heart rate and glomerular filtration rate did not change. Infusion of a similar dose of adrenomedullin also increased renal blood flow (6.8+/-0.4-8.8+/-0.6 ml/min), urine flow (25.4+/-3.2-42.8+/-9.4 microl/min) and urinary excretion of sodium (2.8+/-0.6-6.5+/-1.2 microEq/min), decreased renal vascular resistance (15+/-1-11+/-1 mm Hg min/ml) and did not alter glomerular filtration rate. Thus, the renal actions induced by adrenomedullin2 were similar to those of adrenomedullin. These data suggest that adrenomedullin2 may play an important role in the regulation of renal hemodynamics and urine formation.     

Regional blood flow responses to acute ANG II infusion: effects of nitric oxide synthase inhibition.

We hypothesized that nitric oxide (NO) opposes regional vasoconstriction caused by acute angiotensin II (ANG II) infusion in conscious rats. Mean arterial pressure (MAP), blood flow, and vascular conductance (regional blood flow/ MAP; ml/min/100 g/mm Hg) were measured and/or calculated before and at 2 min of ANG II infusion (0.05 or 1 microg/kg/min, i.a.) in the absence and presence of NO synthase (NOS) inhibition [N(G)-nitro-L-arginine methyl ester (L-NAME), 0.25 or 1 mg/kg, i.a.]. ANG II reduced stomach and hindlimb conductance only after NOS inhibition. For example, whereas 0.05 microg/kg/min ANG II did not attenuate conductance in the stomach (i.e., 1.04+/-0.08 to 0.93+/-0.12 ml/min/100 g/mm Hg), this variable was reduced (i.e., 0.57+/-0.14 to 0.34-/+0.05 ml/min/100 g/mm Hg; p < 0.05) when ANG II was infused after 0.25 mg/kg L-NAME. In addition, whereas hindlimb conductance was similar before and after administering 1 microg/kg/min ANG II (i.e., 0.13+/-0.01 and 0.09+/-0.02, respectively), this variable was reduced (i.e., 0.07+/-0.01 and 0.02+/-0.00, respectively; p < 0.05) when ANG II was infused after 1 mg/kg L-NAME. These findings indicate that NO opposes ANG II-induced vasoconstriction in the stomach and hindlimb. In contrast, whereas both doses of ANG II decreased (p < 0.05) vascular conductance in the kidneys and small and large intestine regardless of whether NOS inhibition was present, absolute vascular conductance was lower (p < 0.05) after L-NAME. For example, 1 microg/kg ANG II reduced renal conductance from 3.34+/-0.31 to 1.22+/-0.14 (p < 0.05). After 1 mg/kg L-NAME, renal conductance decreased from 1.39+/-0.18 to 0.72+/-0.16 (p < 0.05) during ANG II administration. Therefore the constrictor effects of NOS inhibition and ANG II are additive in these circulations. Taken together, our results indicate that the ability of NO to oppose ANG II-induced constriction is not homogeneous among regional circulations.     

Inhibition of the renin-angiotensin system ameliorates genetically determined hyperinsulinemia

This study was performed in order to assess the potentially different effects of the angiotensin-converting enzyme inhibitor captopril and of the angiotensin II receptor antagonist irbesartan on the metabolic syndrome in an animal model. Male NZO/BL6 F1 mice were treated with captopril, irbesartan, or placebo for 10 months: Control animals treated with placebo developed a metabolic syndrome with obesity (55.5+/-6.3 g), hypertension (146+/-10 mm Hg), hyperinsulinemia (7.2+/-5.7 ng/ml), hypercholesterolemia (5.1+/-0.7 mmol/l), cardiac hypertrophy (269+/-44 mg) and atherosclerotic plaques in the ascending aorta (3.6+/-1.5 microm(2)). Treatment with angiotensin-converting enzyme inhibitor or angiotensin II receptor antagonist significantly (p<0.001) reduces hypertension (73+/-5 and 78+/-11 mm Hg), cardiac hypertrophy (203+/-26 and 202+/-18 mg) and atherosclerosis (2.2+/-0.9 and 1.8+/-0.8 microm(2)). In addition, they prevented the development of obesity (42.2+/-3.5 and 38.3+/-2.8 g) and hyperinsulinemia (3.6+/-1.5 and 1.8+/-0.4 ng/ml). In conclusion, long-term treatment with an angiotensin-converting enzyme inhibitor or an angiotensin II receptor antagonist can ameliorate obesity and hyperinsulinemia in a genetically determined mouse model.     

Preliminary observations of the acute effects of selective serum thromboxane inhibition and angiotensin converting enzyme inhibition on blood pressure and renal hemodynamics in hypertensive humans

CGS 13080, a selective thromboxane synthetase inhibitor, was given intravenously (0.6 mg/kg over 6 hours) to eight hypertensive (diastolic 95-115 mm Hg) euvolemic caucasian females on their customary salt intake (24 hour urine Na: 142.9 +/- 14.8 meq). No change occurred in blood pressure or glomerular filtration rate (GFR): 95.2 +/- 7.2, control versus 95.0 +/- 9.0, CGS 13080 (ml/min); or renal plasma flow (RPF): 363.2 +/- 34.2, control, versus 373.2 +/- 31.2, CGS 13080, (ml/min). Prostaglandin production was altered: platelet generation of thromboxane B2 83.3 +/- 10.9, control, versus 5.4 +/- 1.8, CGS 13080 (ng/hr) (P less than .001); urinary prostaglandin E (PGE) 249.0 +/- 56.3, control, versus 443.9 +/- 79.8, CGS 13080 (ng/6 hr) (P = .06); urinary 6-ketoprostaglandin F1 alpha (6-keto-PGF1 alpha) 188.6 +/- 23.4, control, versus 287.9 +/- 21.8, CGS 13080 (ng/6 hr) (P = .01); urinary thromboxane B2 54.8 +/- 12.9, control, versus 58.6 +/- 20.3 CGS 13080 (ng/6 hr) (P = NS). Serum levels of renin, angiotensin II and aldosterone were not altered by CGS 13080. Captopril when dosed to lower diastolic blood pressure 5-7 mm Hg did not significantly affect GFR, RPF or RVR. Nor did it affect platelet generation of thromboxane B2 or urine concentrations of PGE, 6-keto-PGF1 alpha or thromboxane B2. Captopril did increase renin levels 1.2 +/- 0.2, control, versus 2.9 +/- 1.1, captopril (ng/ml/hr) (P = NS), but did not statistically change angiotensin II, or aldosterone levels.(ABSTRACT TRUNCATED AT 250 WORDS)     

Effect of nisoldipine upon the general and coronary hemodynamics of the anesthetized dog

The effect of nisoldipine (5 micrograms/kg/i.v.) was studied in anesthetized intact dogs. This calcium antagonist increased heart rate by 68%, doubled cardiac output, and increased coronary sinus flow from 62 +/- 10 ml/min to a maximum of 131 +/- 7 ml/min. Mean systemic pressure decreased from 125 +/- 10 mm Hg to a minimum of 115 +/- 2 mm Hg for at least 15 min after the injection. Mean pulmonary artery pressure increased from 12 +/- 2 mm Hg to 18 +/- 4 mm Hg within 2 min of the injection. Left ventricular work (joules/s) doubled and right ventricular work trebled during the first 15 min after injection. Peripheral resistance fell by 57%, total pulmonary resistance by 40%, and coronary vascular resistance by half. Coronary sinus O2 content increased by 50%, and cardiac efficiency (index) increased from 0.2 (control) to a maximum of 0.46, within 2 min after the injection of the drug.     

Renal effects of alacepril in essential hypertension.

Short-term effects of alacepril, an angiotensin-converting enzyme inhibitor (ACEI), on renal function and hemodynamics were investigated in 10 hypertensive subjects (aged 55.7 +/- 9.5 years, mean +/- SD). Renal plasma flow (RPF) and glomerular filtration rate (GFR) were examined before and after 12-week administration of alacepril, by [131I]hippuran and [99mTc]DTPA, respectively. Alacepril (50 mg/day) caused a significant decrease in both systolic and diastolic blood pressure (SBP and DBP, from 161 +/- 8 to 140 +/- 10 mm Hg and from 100 +/- 3 to 90 +/- 5 mm Hg, respectively). Alacepril increased GFR (from 63.4 +/- 22.2 to 69.1 +/- 22.1 ml/min/1.73 m2, p less than 0.05) without changing RPF (from 438 +/- 194 to 432 +/- 148 ml/min/1.73 m2, p greater than 0.05). Serum creatinine and electrolytes were not changed by alacepril administration. These data show that short-term alacepril administration improves renal function, probably owing to relaxation of renal vasoconstriction.     

Role of A2A receptor in the modulation of myocardial reperfusion damage.

Adenosine protects myocardium from ischemia and reperfusion damage; however, the mechanism of action is still under discussion. We investigated whether (a) adenosine protects isolated crystalloid-perfused rabbit heart from ischemia/ reperfusion injury; (b) this action is receptor mediated and what receptor subtypes are involved, and (c) this action is dependent on an enhanced nitric oxide production. Our results showed a cardioprotective effect of adenosine (10(-4) M), of nonselective adenosine-receptor agonist 5'-N-ethyl-carboxamidoadenosine (NECA; 5 x 10(-6) M), and of A2A agonists CGS 21680 (10(-8) and 10(-6) M), 2-hexynylNECA (10(-7) M). On the contrary, A1 agonist CCPA (10(-8) and 10(-6) M) does not provide any protection. The effect has been achieved in terms of significant reduction in contracture development during reperfusion [diastolic pressure was 46.8 +/- 7.1 mm Hg (p < 0.01); 46.1 +/- 7.8 mm Hg (p < 0.01); 46.9 +/- 5.5 mm Hg (p < 0.01); and 59.3 +/- 6.7 mm Hg (p < 0.05) with 10(-4) M adenosine, 5 x 10(-6) M NECA, 10(-6) M CGS 21680, and 10(-7) M 2-hexynylNECA, respectively, versus 77.6 +/- 5.0 mm Hg in control]; reduced creatine phosphokinase release (13.5 +/- 1.6, 22.2 +/- 7.9, 14.2 +/- 3.3, and 14.1 +/- 4.5 U/gww in treated hearts vs. 34.6 +/- 7.2 U/gww in controls; p < 0.05); improved energy metabolism [adenosine triphosphate (ATP) content is 9.9 +/- 0.5, 10.4 +/- 0.6, 9.8 +/- 0.5, and 10.5 +/- 0.5 micromol/gdw in treated hearts vs. 7.6 +/- 0.2 micromol/gdw; p < 0.05]. Moreover, our data indirectly show a functional presence of A2A receptors on cardiomyocytes as the protection is A2A mediated and exerted only during reperfusion, although in the absence of blood and coronary flow changes. These activities appear independent of nitric oxide pathways, as adenosine and 2-hexynylNECA effects are not affected by the presence of a nitric oxide-synthase inhibitor (10(-4) M L-NNA).     

Effect of antiischemic therapy on coronary flow reserve and the pressure-maximal coronary flow relationship in anesthetized swine.

The effect of nifedipine (0.5, 1.0, and 2.0 micrograms/kg/min), metoprolol (0.1, 0.5, and 1.0 mg/kg), the beta 1-selective adrenoceptor partial agonist epanolol (10, 50, and 200 micrograms/kg), or equivalent volumes of isotonic saline (n = 6, in each group), on coronary blood flow capacity were studied in anesthetized swine. Intracoronary bolus injections of adenosine (20 micrograms/kg/0.2 ml) were administered without and during three levels of coronary stenosis, prior to and following each dose of drug, to obtain maximal coronary blood flows at different perfusion pressures in the autoregulatory range. Coronary perfusion pressures were varied by partial inflation of a balloon around the left anterior descending coronary artery. Special care was taken that the stenoses not lead to myocardial ischemia. Three indices of coronary blood flow capacity were used: absolute coronary flow reserve (ACFR, the ratio of maximal to resting coronary blood flow), the slope and the extrapolated pressure at zero flow (Pzf) of the pressure-maximal coronary flow (PMCF) relationship, and relative coronary flow reserve (RCFR, the ratio of maximal coronary blood flow with a stenosis to maximal coronary blood flow without a stenosis) at two of the three levels of stenosis. Nifedipine decreased ACFR from 4.5 +/- 1.9 to 1.9 +/- 0.3 (mean +/- SD; p less than 0.05), reflecting in part the increase in resting coronary blood flow. The nifedipine-induced changes in maximal coronary blood flow were not only due to a drop in perfusion pressure, as the slope of the PMCF relationship decreased from 2.27 +/- 0.49 ml/(min.mm Hg) to 1.54 +/- 0.51 ml/(min.mm Hg) (p less than 0.05), and Pzf decreased from 30 +/- 4 mm Hg to 20 +/- 7 mm Hg (p less than 0.05). Consequently, calculated maximal coronary blood flow was attenuated from 114 +/- 31 ml/min to 93 +/- 37 ml/min at 80 mm Hg, but was enhanced from 23 +/- 13 to 37 +/- 24 ml/min at 40 mm Hg coronary perfusion pressure. In concert with the change in the PMCF relationship, RCFR at equivalent severe stenosis increased from 0.33 +/- 0.06 to 0.47 +/- 0.10 (p less than 0.05). No changes were observed with metoprolol, epanolol, or saline. The effect of nifedipine on the PMCF relationship not only provides a mechanism for the drug's antiischemic action, but should also be considered in the interpretation of coronary flow reserve measurements in patients on nifedipine treatment.     

Nifedipine prevents sympathetic vasoconstriction distal to severe coronary stenoses

Cardiac sympathetic nerve stimulation ( CSNS ) can induce vasoconstriction distal to severe coronary stenoses by activation of vascular alpha 2-adrenoceptors. Whether nifedipine can antagonize this CSNS -induced vasoconstriction was tested in 11 anesthetized, vagotomized dogs. CSNS decreased the end-diastolic resistance of intact coronary arteries from 0.76 +/- 0.07 to 0.56 +/- 0.05 mm Hg x min x 100 g/ml (p less than 0.05). In contrast, the resistance distal to severe stenoses, which were defined by a reduction of the postocclusive reactive hyperemia to almost zero, was increased during CSNS from 0.52 +/- 0.06 to 0.87 +/- 0.14 mm Hg x min x 100 g/ml (p less than 0.05). This increase in resistance was associated with severe ischemia, as indicated by a net lactate production of the circumflex-perfused myocardium and a decrease in systolic segment shortening from 8.4 +/- 0.7 to 7.0 +/- 0.7% (p less than 0.05). Both intracoronary (10 micrograms) and intravenous (10 micrograms/kg) administration of nifedipine did not change the poststenotic resistance at rest, but did prevent the CSNS -induced increase in resistance, the decrease in regional contraction, and the net lactate production. We conclude that nifedipine can prevent the deleterious role of alpha-adrenoceptor-mediated vasoconstriction in the genesis of myocardial ischemia.     

Contribution of the endothelin system to the renal hypoperfusion associated with experimental congestive heart failure.

The objective of this study was to define further the local activation of endothelin-1 (ET-1) and the ETA receptor as well as the functional consequences of activated ET-1 for renal hypoperfusion associated with experimental congestive heart failure (CHF). We studied eight rabbits permanently instrumented with Doppler flow probes around the renal arteries before and after the induction of epinephrine-induced CHF. CHF was characterized by left-ventricular dysfunction (fractional shortening 34+/-2% vs. 46+/-3%; p < or = 0.05) and dilatation (LVEDd 13.6+/-0.3 vs. 11.5+/-0.4 mm; p < or = 0.05), decreased mean arterial pressure (59.4+/-2.9 vs. 74.6+/-3.7 mm Hg; p < or = 0.05), increased heart rate (236+/-11 vs. 216+/-8 beats/min; p < or = 0.05) and renal vasoconstriction (vascular resistance 49.65 +/-8.55 vs. 24.61+/-5.85 U; p < 0.05; blood flow velocity, 1.58+/-0.21 vs. 3.63+/-0.31 kHz; p < 0.05). ET-1 concentrations were significantly increased not only in plasma (7.67+/-0.47 vs. 4.56 +/-0.69 pg/ml; p < 0.05) but also in renal tissue (4.8+/-0.5 vs. 3.5 +/-0.64 pg/mg; p < 0.05). Northern analysis revealed an unchanged expression of ETA receptor messenger RNA (0.79+/-0.05 vs. 0.77+/-0.04 arbitrary units; NS) in renal tissue, whereas expression of prepro-ET-1 was below the range of detection. In CHF, selective ETA-receptor antagonism with BQ-123 (1 mg/ kg bolus, i.v.) significantly increased renal blood flow velocity (3.07+/-0.38 vs. 1.33+/-0.19 kHz; p < 0.05) and reduced renal vascular resistance (29.63+/-6.22 vs. 58.17+/-8.75 U; p < 0.05) without significant effects on mean arterial pressure or heart rate. These studies demonstrate activation of the renal ET system, unaltered gene expression, and functional integrity of the renal ETA receptor in CHF. They indicate a principal functional role for the ETA receptor in renal vasoconstriction and suggest blockade of the renal ETA receptor as an important strategy to attenuate renal hypoperfusion in CHF.     

Terbutaline infusion in cardiogenic shock: acute hemodynamic effects and clinical response

The effect of terbutaline infusion was studied in six patients with cardiogenic shock due to acute myocardial infarction. Terbutaline was initiated at 3 micrograms/kg/min, and the subsequent infusion rate was adjusted according to heart rate and blood pressure. At 3 hours after infusion arterial pressure increased from 62 +/- 13 mm Hg (mean +/- S.D.) to 89 +/- 13 mm Hg (P less than 0.001), cardiac index increased from 1.38 +/- 0.29 liter/min/m2 to 2.68 +/- 0.47 liter/min/m2 (P less than 0.001), and heart rate increased from 92 +/- 32 beats/min to 112 +/- 29 beats/min (P less than 0.005). Pulmonary artery wedge pressure fell from 24 +/- 7 mm Hg to 17 +/- 3 mm Hg (P less than 0.01), right atrial pressure fell from 12 +/- 4 mm Hg to 6 +/- 3 mm Hg (P less than 0.005), and systemic vascular resistance fell from 1880 +/- 641 dyn-sec/cm5 to 1515 +/- 418 dyn-sec/cm5 (P less than 0.05). In addition, urine flow increased from 4 +/- 6 ml/hr to 314 +/- 237 ml/hr (P less than 0.05), and subjective improvement was noted in all subjects. Undesirable effects observed were hypokalemia (all subjects), supraventricular tachycardia (one subject), and ventricular ectopic beats (three subjects), which responded to potassium replacement and other treatments. All patients required prolonged maintenance infusion to maintain adequate hemodynamic and clinical response. Four patients were weaned off from maintenance therapy after a mean duration of 4.8 days and eventually were discharged from the hospital.(ABSTRACT TRUNCATED AT 250 WORDS)     

Vasodilator properties of prostacyclin after coronary artery bypass surgery

The vasodilatory properties of prostacyclin were studied in 12 intubated patients who underwent coronary artery bypass surgery. When infused in doses of 2.5, 5, 10, and 20 ng/kg/min, prostacyclin produced a dose-dependent decrease in systemic vascular resistance from 2,702 +/- 143 to 1,654 +/- 106 dynes/cm5/m2 (p less than 0.05). Heart rate, right atrial pressure, and pulmonary arterial and capillary wedge pressures did not change. Cardiac function was improved, since stroke volume index increased from 29.5 +/- 1.4 to 35.5 +/- 2.0 ml/min/m2 (p less than 0.05) and the rate pressure product decreased from 13.3 +/- 1.3 to 10.9 +/- 0.9 X 10(3) mm Hg/beats/min (p less than 0.05), while stroke work index remained unchanged. These hemodynamic changes were associated with a dose-dependent decrease in arterial oxygen tension which occurred from 278 +/- 25 to 133 +/- 22 mm Hg; however, oxygen transport increased as a result of the prostacyclin-induced increase in cardiac index. This study demonstrates that prostacyclin is a potent arterial vasodilator that may be of interest in the treatment of postoperative vasoconstriction occurring after coronary artery bypass surgery.     

Endothelin-A receptor antagonism promotes decreased vasodilation but has no differential effect on coronary artery compliance in hypertensive patients

The importance of endothelin-1 in the pathophysiology of essential hypertension is unclear. We therefore examined whether there is a differential effect of endothelin-A antagonism on vasodilation and coronary artery compliance in hypertensive compared to normotensive patients. We examined atherosclerotic non-stenotic arteries from 18 non-diabetic, 10 normotensive patients and eight hypertensive patients, before and after intracoronary infusion of BQ-123 (6 mumol), an endothelin-A receptor antagonist. The systolic and diastolic artery lumen area in the proximal segment was measured using an intravascular ultrasound catheter. Systolic blood pressure decreased only in hypertensive patients (F = 5.44, P = 0.03), after BQ-123 administration. The diastolic artery lumen increased from 8.9 +/- 2.9 mm at baseline to 10.8 +/- 3.0 mm after BQ-123 administration (P < 0.05) in normotensive patients and from 10.6 +/- 4.6 mm to 10.8 +/- 4.0 mm (P = NS) in the hypertensive patients (F = 3.98, P = 0.01). The respective values for the systolic artery lumen, in the two groups, before and after BQ-123 were: 10.2 +/- 3.4 mm and 12.7 +/- 3.2 mm (P < 0.01) in the normotensive group and 12.0 +/- 5.5 mm and 12.8 +/- 5.0 mm (P = NS) in the hypertensive group (F = 3.37, P = 0.08). Artery compliance did not have a differential response to BQ-123. In conclusion, endothelin-A antagonism causes decreased vasodilation but does not have a differential effect on coronary artery compliance in hypertensive patients.