Human ventricular myocytes in vitro exhibit both early and delayed preconditioning responses to simulated ischemia.

Myocardial tissue has been demonstrated to exhibit, in response to brief periods of ischemia, both an immediate period of cytoprotection [i.e. early or "first window" preconditioning response (EPR)], and a later period of cytoprotection [i.e. delayed or "second window" preconditioning response (DPR)], when exposed to a subsequent prolonged hypoxic insult. EPR has been documented in vitro in isolated cardiac myocytes, as well as in situ in intact hearts or trabeculae, for a number of vertebrate species, including humans. However, there are no reports to date of DPR in human cardiac myocytes. To address this question, human ventricular myocytes (HVM) primary isolates were prepared from fetal ventricular muscle, grown to confluency, and studied in primary culture in serum-free medium (> 90%) ventricular myocytes as determined by immunohistochemical analysis with an anti-myosin chain antibody). Using cell viability as determined by trypan blue exclusion, an EPR response could readily be detected following 15, 30, or 60 min of simulated ischemia (SI) in a hypoxic (< 1 tau pO2) buffer containing 11 mmol/l 2-deoxyglucose, followed by a prolonged (c. 17 h) SI challenge. In addition, HVM exposed to 60 min of SI, followed after 24 h by a period of SI, also exhibited a "second window" DPR (80 +/- 10% compared to 71 +/- 11% survival, in preconditioned and non-preconditioned cultures; P < 0.05; n = 18 independent experiments). Thus, in response to short periods of SI, human ventricular myocytes in vitro exhibit both "first window" and "second window" cytoprotective responses to subsequent, prolonged ischemic stress.

Selective adenosine A3 receptor stimulation reduces ischemic myocardial injury in the rabbit heart.

OBJECTIVE: The aim of this study was to determine whether selective activation of the adenosine A3 receptor reduces infarct size in a Langendorff model of myocardial ischemia-reperfusion injury. METHODS: Buffer-perfused rabbit hearts were exposed to 30 min regional ischemia and 120 min of reperfusion. Infarct size was measured by tetrazolium staining and normalized for area-at-risk (IA/AAR). RESULTS: Preconditioning by 5 min global ischemia and 10 min reperfusion reduced infarct size (IA/AAR) to 19 +/- 4% (controls: 67 +/- 5%). Replacing global ischemia with 5 min perfusion of the rabbit A3-selective agonist, IB-MECA (A3 Ki: 2 nM; A1 Ki: 30 nM) elicited a concentration-dependent reduction in infarct size; 50 nM IB-MECA reduced IA/AAR to 24 +/- 4%. The A1-selective agonist, R-PIA (25 nM) reduced IA/AAR to a similar extent (21 +/- 6%). However, while the cardioprotective effect of R-PIA was significantly inhibited (54 +/- 7% IA/AAR) by the rabbit A1-selective antagonist, BWA1433 (50 nM), the IB-MECA-dependent cardioprotection was unaffected (28 +/- 6% IA/AAR). A non-selective (A1 vs. A3) concentration of BWA1433 (5 microM) significantly attenuated the IB-MECA-dependent cardioprotection (61 +/- 7% IA/AAR). CONCLUSIONS: These data clearly demonstrate that selective A3 receptor activation provides cardioprotection from ischemia-reperfusion injury in the rabbit heart. Furthermore, the degree of A3-dependent cardioprotection is similar to that provided by A1 receptor stimulation or ischemic preconditioning.

Cloning, expression and pharmacological characterization of rabbit adenosine A1 and A3 receptors.

The role of adenosine A1 and A3 receptors in mediating cardioprotection has been studied predominantly in rabbits, yet the pharmacological characteristics of rabbit adenosine A1 and A3 receptor subtypes are unknown. Thus, the rabbit adenosine A3 receptor was cloned and expressed, and its pharmacology was compared with that of cloned adenosine A1 receptors. Stable transfection of rabbit A1 or A3 cDNAs in Chinese hamster ovary-K1 cells resulted in high levels of expression of each of the receptors, as demonstrated by high-affinity binding of the A1/A3 adenosine receptor agonist N6-(4-amino-3-[125I]iodobenzyl)adenosine (125I-ABA). For both receptors, binding of 125I-ABA was inhibited by the GTP analog 5'-guanylimidodiphosphate, and forskolin-stimulated cyclic AMP accumulation was inhibited by the adenosine receptor agonist (R)-phenylisopropyladenosine. The rank orders of potency of adenosine receptor agonists for inhibition of 125I-ABA binding were as follows: rabbit A1, N6-cyclopentyladenosine = (R)-phenylisopropyladenosine > N-ethylcarboxamidoadenosine > or = I-ABA > or = N6-2-(4-aminophenyl) ethyladenosine > > N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide > N6-(4-amino-3-benzyl)adenosine; rabbit A3, N6-(3-iodobenzyl)adenosine-5'-N-methyluronamide > or = I-ABA > > N-ethylcarboxamidoadenosine > N6-2-(4-aminophenyl) ethyladenosine = N6-cyclopentyladenosine = (R)-phenylisopropyladenosine > N6-(4-amino-3-benzyl)adenosine. The adenosine receptor antagonist rank orders were as follow: rabbit A1, 8-cyclopentyl-1,3-dipropylxanthine > 1,3- dipropyl-8-(4-acrylate)phenylxanthine > or = xanthine amine congener > > 8-(p-sulfophenyl)theophylline; rabbit A3, xanthine amine congener > 1,3-dipropyl-8-(4-acrylate)phenylxanthine > or = 8-cyclopentyl-1,3-dipropylxanthine > > 8-(p-sulfophenyl)theophylline. These observations confirm the identity of the expressed proteins as A1 and A3 receptors. The results will facilitate further in-depth studies of the roles of A1 and A3 receptors in adenosine-mediated cardioprotection in rabbits, which can now be based on the appropriate recombinant rabbit A1 and A3 receptor pharmacology.

Zaprinast, but not dipyridamole, reverses hemodynamic tolerance to nitroglycerin in vivo.

Hemodynamic tolerance to nitroglycerin was developed in spontaneously hypertensive rats following 2-3 days of pretreatment with 100 mg/kg of nitroglycerin administered s.c. 3 times/day. Tolerance was evaluated both in vivo, by administering ascending bolus doses of nitroglycerin of 1-300 micrograms/kg i.v., and ex vivo in isolated, denuded aortic vascular rings by exposure to ascending concentrations of nitroglycerin of 0.0003-100 microM. Tolerance was observed as a significant blunting of the hypotensive and vasorelaxant effect of nitroglycerin. Co-incubation of tolerant aortic rings and pretreatment of tolerant SHR with 10 microM and 0.1-10 mg/kg zaprinast, respectively, resulted in full restoration of the vasorelaxant and hypotensive effect of nitroglycerin. Zaprinast partially reversed hemodynamic tolerance at 0.01 mg/kg. Conversely, dipyridamole (10 microM) reversed tolerance ex vivo, but was ineffective in reversing tolerance in vivo at pretreatment doses of 30 and 60 mg/kg. Following a 100-micrograms/kg i.v. challenge dose of nitroglycerin, aortic cyclic guanosine monophosphate (cGMP) levels were lower in nitroglycerin tolerant SHR when compared to non-tolerant SHR. Pretreatment of tolerant SHR with 10 mg/kg zaprinast restored the increase in cGMP levels to nitroglycerin to that seen in non-tolerant SHR. Conversely, dipyridamole (30 mg/kg) pretreatment was not effective in restoring cGMP levels. These data therefore suggest that reversal of hemodynamic tolerance in vivo is related to restoration of changes in vascular cGMP levels. Zaprinast, a selective cGMP phosphodiesterase inhibitor, effectively reverses tolerance and dipyridamole, a rather non-selective inhibitor, does not.

Species-dependent pharmacodynamic effects of the selective low Km cyclic AMP phosphodiesterase III inhibitors WIN 58993 and WIN 62005.

We describe the biochemical and pharmacologic effects of two novel fused pyridinones derived from milrinone: WIN 58993 and WIN 62005. Both WIN 58993 and WIN 62005 competitively inhibit cyclic GMP-inhibitable low Km cyclic AMP phosphodiesterase (PDE III) from rat heart and canine aorta with Ki values of 25 +/- 3 and 26 +/- 5 nM, respectively, and are selective (at least 160-fold) for PDE III inhibition relative to other PDE isozymes. WIN 58993 and WIN 62005 were given to conscious, chronically instrumented rats and dogs intravenously (i.v.) or perorally (p.o.). Because the doses of WIN 58993 and WIN 62005 required to decrease mean arterial blood pressure (MAP) by 20% were estimated to be 0.9 and 0.7 mg/kg, respectively, the compounds appear to be equipotent after acute i.v. administration in rats. However, the duration of the depressor responses in rats apparently differs since MAP remained significantly decreased 6 h after i.v. or p.o. administration of WIN 58993, but returned to control levels < or = 4 h after administration of WIN 62005. WIN 58993 may be slightly less potent than WIN 62005 after acute i.v. administration to dogs since significant increases in left ventricular (LV)dP/dtmax first occurred at doses of 0.1 and 0.03 mg/kg, respectively. LVdP/dtmax significantly increased in 30 min and returned to baseline 3 h after p.o. administration of 1 mg/kg WIN 58993. After p.o. administration of 1 mg/kg WIN 62005. LVdP/dtmax was significantly increased in 30 min and remained increased for at least 6 h. These data suggest that WIN 58993 and WIN 62005 are potent, selective, p.o.-active inhibitors of PDE III.(ABSTRACT TRUNCATED AT 250 WORDS)

Cyclic GMP potentiation by WIN 58237, a novel cyclic nucleotide phosphodiesterase inhibitor.

The objectives of this study were to determine the potency and selectivity of the structurally novel cyclic nucleotide phosphodiesterase (PDE) inhibitor, WIN 58237 (1-cyclopentyl-3-methyl-6-(4- pyridyl)pyrazolo[3,4-d]pyrimidin-4-(5H)-one), and to determine if this compound possesses cyclic GMP (cGMP) PDE inhibitory activity in vitro and in vivo. WIN 58237 is a competitive inhibitor of cGMP PDE V from canine aorta, with a Ki value of 170 nM. It is a relatively less potent inhibitor of calmodulin-sensitive PDE I and cGMP-inhibitable cyclic AMP PDE III; but does inhibit cyclic AMP PDE IV with an IC50 value of approximately 300 nM. In vitro, WIN 58237 is a functional cGMP PDE inhibitor at submicromolar concentrations as evident by potentiation of both sodium nitroprusside- and atrial natriuretic factor-mediated vasorelaxation of contracted, endothelial-denuded rat aortic rings. Moreover, WIN 58237 possesses vasorelaxant activity in the presence of an intact endothelium or nitric oxide. Similar results are evident in vivo, as WIN 58237 (0.3-3.0 mg/kg i.v.) decreases mean arterial pressure in conscious spontaneously hypertensive rats with an associated increase in vascular (aortic) cGMP content in vivo. Both the decrease in mean arterial blood pressure and increase in aortic cGMP content are attenuated by the nitric oxide synthase inhibitor, N omega-nitro-l-arginine. However, WIN 58237 may possess an additional depressor mechanism of action. WIN 58237 restores vasorelaxation responsiveness to nitroglycerin in vitro and in vivo in models of vascular tolerance.(ABSTRACT TRUNCATED AT 250 WORDS)

Pharmacologic and pharmacodynamic effects of the selective low Km cyclic AMP phosphodiesterase III inhibitors WIN 63291 and WIN 62582.

We describe the biochemical, pharmacologic, and in vivo pharmacodynamic profiles of two novel inhibitors of the cyclic GMP-inhibitable, low Km cyclic AMP phosphodiesterase (PDE) III; WIN 63291, a 6-quinolinyl analogue of the prototypic PDE III inhibitor milrinone and WIN 62582, an imidazopyridinone. Both WIN 62582 and WIN 63291 competitively inhibit PDE III from rat, dog, and human heart and from rat and canine aorta with IC50 values of 5-37 and 55-80 nM, respectively; the IC50 values for milrinone ranged from 300 to 520 nM. WIN 62582 and WIN 63291 are at least 1,000-fold selective for PDE III relative to inhibition of PDE isozymes I, II, IV, and V. We evaluated WIN 62582 and WIN 63291 in conscious rats and dogs after intravenous (i.v.) and oral (p.o.) administration. The dose of WIN 62582 required to reduce mean arterial blood pressure (MAP) by 20% (ED20) in rats was 1.8 mg/kg, with a pharmacodynamic duration of action of approximately 2 h. In comparison, the estimated i.v. ED20 for WIN 63291 in rats was 0.4 mg/kg, with a pharmacodynamic duration of action > 6 h. In conscious dogs, the i.v. doses of WIN 62582 and 63291 required to increase left ventricular (LV)dP/dtmax significantly were 0.1 and 0.01 mg/kg, respectively. In dogs, WIN 63291 0.1 mg/kg p.o. increased LVdP/dtmax by 86% in 30 min; LVdP/dtmax remained increased by 60% for at least 6 h. In comparison, WIN 62582, 0.3 mg/kg p.o., increased LVdP/dt by 56% in 30 min and remained increased by 40% at 6 h.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasoconstrictor action of angiotensin I-convertase and the synthetic substrate (Pro11,D-Ala12)-angiotensin I.

A chymase (also referred to as angiotensin I-convertase) specific for the conversion of angiotensin (Ang) I to Ang II has been identified in human heart. This serine protease is also present in dog and marmoset vasculature. We examined the vasoconstrictor effects of Ang II putatively generated from an angiotensin-converting enzyme (ACE)-resistant convertase synthetic substrate (SUB) in vivo and in vitro. In marmosets, SUB (7 to 700 micrograms/kg i.v.) or Ang I (0.1 to 30 micrograms/kg) caused similar dose-dependent increases in mean arterial pressure (10 to 100 mm Hg) and decreases in heart rate. Pressor effects of SUB were slightly attenuated at low (but not high) doses by captopril (CAP, 1 mg/kg i.v.) and blocked by losartan (5 mg/kg i.v.); in contrast Ang I pressor effects were substantially blocked by both. In isolated canine superior mesenteric artery, Ang I-induced contraction was eliminated by losartan and reduced but not eliminated by 10 mumol/L CAP. When combined with the serine protease inhibitor chymostatin, CAP eliminated Ang I-induced contraction, but chymostatin alone had no effect. SUB-induced contraction was not blocked by CAP but was equally blocked by chymostatin (25 mumol/L) alone or by the combination of CAP (10 mumol/L) and chymostatin (25 mumol/L); losartan (10 mumol/L) eliminated SUB-induced responses. Previous studies have suggested that Ang I-convertase is important for production of Ang II in the heart. Our results are consistent with a potential role for Ang I-convertase in the production of Ang II in the vasculature, resulting in Ang II-mediated vasoconstriction.

Chronic monitoring of cardiovascular function in the conscious guinea pig using radio-telemetry.

An implantable radio-telemetry device for chronic monitoring of arterial pressure and heart rate in the conscious guinea pig was validated against measurements using an exteriorized, indwelling catheter. There were no significant differences between simultaneous measurements in animals instrumented with both the telemetry system and the conventional catheter (implanted 24 hrs prior to comparisons) in response to a variety of vasoactive agents. The device was shown to be accurate up to 3 weeks after implantation (longest time point tested). Resting pressures and heart rates in the telemetered guinea pig were stable in 100% of the animals tested. In contrast, animals instrumented with only exteriorized catheters showed a significant decline in pressure by 8 days after surgery and a 39% attrition rate due to loss of catheter patency. Performance of the telemetric device was examined in both normal and sodium-deficient animals, since the latter is a useful normotensive model in which blood pressure is rendered highly renin-dependent for evaluating the efficacy of potential antihypertensive agents that target the renin-angiotensin system. The telemetered guinea pig is an appropriate model for assessing responses to chronic exposure of cardiovascular agents.

Zaprinast increases cyclic GMP levels in plasma and in aortic tissue of rats.

The purpose of this study was to determine if significant relationships exist between plasma and aortic cyclic GMP (cGMP) levels and pharmacodynamic effect after the i.v. administration of the cGMP-selective phosphodiesterase inhibitor zaprinast to conscious, spontaneously hypertensive rats. Zaprinast dose-dependently increased plasma and aortic cGMP levels at 10, 18 and 30 mg/kg and decreased mean arterial blood pressure (MAP) at 18 and 30 mg/kg. The concentrations of cGMP in the plasma and in the aorta were significantly correlated (r = 0.765, P < 0.0001). The changes in MAP were significantly correlated to aortic (r = -0.750, P < 0.0001) and plasma (r = -0.762, P < 0.0001) cGMP levels. We conclude that plasma cGMP may be an index of cGMP-selective phosphodiesterase inhibition in vivo.

Lack of cross-tolerance between nitroglycerin and endothelium-derived relaxing factor-mediated vasoactive agents in spontaneously hypertensive rats.

The purpose of this study was to determine whether cross-tolerance develops between nitroglycerin and endothelium-derived relaxing factor (EDRF)-mediated vasoactive agents in vivo. Spontaneously hypertensive rats (SHR) were made tolerant by pretreatment with high doses of nitroglycerin (100 mg/kg s.c., 3 times/day, for 3 consecutive days). The hypotensive effect of challenge doses of nitroglycerin (1, 10, 300, 100 micrograms/kg i.v.) was completely abolished in nitroglycerin-pretreated SHR. To evaluate cross-tolerance, the effects of the following EDRF-dependent vasoactive agents on blood pressure were determined in groups of nitroglycerin-pretreated and vehicle-pretreated SHR: acetylcholine, bradykinin and L-arginine. In addition, the hypotensive effects of zaprinast (M & B 22,928), a cyclic guanosine monophosphate (cGMP) phosphodiesterase inhibitor, and the hypertensive effects of the nitric oxide-synthase inhibitor N omega-nitro-L-arginine were also evaluated. In all cases, there was no difference in the effects of these agents on blood pressure when compared in nitroglycerin-pretreated (tolerant) and vehicle-pretreated (non-tolerant) SHR. The use of a variety of agents which modulate EDRF release or its effects by several different mechanisms suggests that cross-tolerance does not occur between nitroglycerin and EDRF in vivo.

Hemodynamic and renal effects of the protein kinase inhibitor staurosporine in conscious rats.

To evaluate the pattern of hemodynamic responses produced by an inhibitor of protein kinase C (PKC), staurosporine 0.03-0.55 mg/kg was administered intravenously (i.v.) to conscious, normotensive rats chronically instrumented with vascular catheters for direct measurement of blood pressure (BP) and i.v. administration of drugs and either an aortic flow probe for measurement of cardiac output (CO) or miniaturized pulsed Doppler flow probes for measurement of hindquarter, renal, and mesenteric vascular resistances. Staurosporine decreased mean arterial pressure (MAP) and total peripheral resistance (TPR) and increased heart rate (HR) in a dose-dependent manner. Because staurosporine decreased resistance in all three vascular beds monitored (hindquarter, renal, and mesenteric), staurosporine is probably a nonselective vasodilator that decreases MAP by decreasing resistance in a number of peripheral vascular beds. Staurosporine produced biphasic effects on CO, dF/dtmax and peak aortic blood flow; these parameters were significantly increased at doses less than 0.3 mg/kg and decreased to levels equal to or significantly less than control values at doses greater than 0.3 mg/kg. In comparison, the calcium channel blocker nitrendipine decreased MAP and TPR and increased HR, CO, dF/dtmax, and peak aortic flow in a dose-dependent manner over the entire dose range (0.01-1 mg/kg i.v.). Staurosporine (0.3 mg/kg) and nitrendipine (1 mg/kg) produced similar changes in MAP (-44 +/- 3 and -33 +/- 2 mm Hg, respectively), yet staurosporine affected dF/dtmax to a lesser extent than nitrendipine (-5 +/- 36 and 390 +/- 46 ml/s/s, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Differential hemodynamic responses to selective inhibitors of cyclic nucleotide phosphodiesterases in conscious rats.

Selective inhibition of either the low Km cyclic AMP (cAMP) or low Km cyclic GMP (cGMP) phosphodiesterase (PDE) promotes vasorelaxation and, consequently, produces depressor effects. To evaluate the systemic and regional hemodynamic effects of selective inhibitors of these PDE isozymes, CI-930 (0.1-10 mg/kg), an inhibitor of low Km cAMP PDE, or zaprinast (3-30 mg/kg), an inhibitor of low Km cGMP PDE, was given i.v. to conscious, normotensive rats. The rats were chronically instrumented with vascular catheters and either an ultrasonic transit-time flow probe around the ascending aorta or miniaturized pulsed Doppler flow probes around the superior mesenteric and left renal arteries and the abdominal aorta. CI-930 and zaprinast, at cumulative doses of 3 and 30 mg/kg, respectively, produced comparable reductions in mean arterial pressure (-22 +/- 3 and -19 +/- 4 mm Hg, respectively) and total peripheral resistance (-0.41 +/- 0.07 and -0.42 +/- 0.06 mm Hg/ml/min, respectively) but affected other hemodynamic variables differently. CI-930 at 3 mg/kg increased the heart rate (HR), maximal aortic flow acceleration (dF/dt), and peak aortic flow and decreased the stroke volume (SV). Cardiac output (CO) was not affected by CI-930. Zaprinast at 30 mg/kg increased the CO, dF/dt, and peak aortic blood flow. The HR and SV were unaffected by zaprinast. Although both CI-930 and zaprinast increased the dF/dt and peak aortic flow, these parameters were affected more by CI-930 than by zaprinast. CI-930 decreased hindquarter, mesenteric, and renal vascular resistances in a dose-dependent manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Cardiovascular cyclic nucleotide phosphodiesterases and their role in regulating cardiovascular function.

We have described five phosphodiesterase (PDE) isozymes that can be found in cardiac and vascular smooth muscle of animals and humans. Much of the evidence for the role that these isozymes have in the regulation of cellular processes has been generated through, or awaits, the identification of selective and potent PDE inhibitors. While selective inhibitors of the cGMP-inhibitable (cGi)-PDE isozyme have been approved for use in the acute treatment of heart failure, selective inhibitors of the cGMP-PDE have not been extensively explored as potential candidates for the treatment of cardiovascular diseases. More potent selective inhibitors of the cGMP-PDE isozyme are needed to determine whether these pharmacological potentiators of EDRF and ANP will be useful in the therapy of angina, hypertension or heart failure.

Effects of paraventricular nucleus lesions on chronic renal hypertension.

The contribution of the paraventricular nucleus region of the hypothalamus (PVN) to the maintenance of one-kidney, figure-8 renal wrap hypertension was determined in this study. Electrolytic ablation of the PVN was performed 4 wk after the production of hypertension or sham operation. Ablation of the PVN region significantly reduced mean arterial pressure (MAP) from 150 +/- 9 to 110 +/- 3 mmHg in the hypertensive rats. In the sham-hypertensive group, the lesion decreased MAP from 118 +/- 2 to 99 +/- 4 mmHg. In both groups of animals MAP from 118 +/- 2 to 99 +/- 4 mmHg. In both groups of animals MAP returned to prelesion values by day 7 postlesion. When ganglionic blockade was performed on day 7 postlesion, the fall in MAP was greater in hypertensive rats (-44 +/- 5 mmHg) than in normotensive rats (-26 +/- 3 mmHg). In a separate group of rats studied 3 days after PVN ablation, ganglionic blockade produced similar decreases in MAP in the wrapped and sham-operated animals. These studies suggest that the PVN contributes to the increased functional sympathetic nervous system associated with one-kidney, figure-8 renal hypertension. Although ablation of the PVN region decreases MAP, neural mechanisms compensate to return MAP to hypertensive levels.

The effects of iodixanol and iopamidol on hemodynamic and cardiac electrophysiologic parameters in vitro and in vivo.

Iodixanol is a new, nonionic, dimeric contrast medium which, in concentrations appropriate for radiographic use, is hypotonic with respect to plasma. The purpose of these in vivo and in vitro studies was to compare the effects of iopamidol, iodixanol formulated to isotonicity with sodium salts (sodium formulation), and iodixanol formulated to isotonicity with sodium, calcium, and magnesium salts (cationic formulation) on hemodynamic and electrophysiologic parameters. In vitro, the spontaneous rate of contraction by guinea pig right atrial and force development by right ventricular papillary muscles were evaluated in the presence of 1% to 100% (v/v) of the three contrast media. Iopamidol significantly (P less than .05) decreased the rate of atrial contraction to a greater extent than either formulation of iodixanol. Iopamidol decreased papillary muscle force development more than the sodium formulation of iodixanol (P less than .05). The cationic formulation of iodixanol had little effect (less than 30% change) on papillary muscle force development at concentrations up to 100%. The contrast media were also injected into the left coronary arteries of open-chest, anesthetized dogs at 0.8 mL/second for 5 to 30 seconds. All contrast media increased (P less than .05) systolic blood pressure (SBP), mean arterial pressure (MAP), and peak left ventricular pressure (LVP). Iopamidol increased LVP and LV end diastolic pressure to a greater extent (P less than .05) than the cationic formulation of iodixanol. We conclude that iopamidol affected cardiovascular parameters more than iodixanol.

N omega-nitro-L-arginine attenuates the accumulation of aortic cyclic GMP and the hypotension produced by zaprinast.

To determine if N omega-nitro-L-arginine (NNA), an inhibitor of the synthesis and/or release of endothelium-derived relaxing factor (EDRF), alters the response to zaprinast, a selective inhibitor of cyclic GMP (cGMP) phosphodiesterase, zaprinast (3-30 mg/kg) or vehicle (1 ml/kg) was given to conscious, spontaneously hypertensive rats (SHR) in a cumulative i.v. dose-response manner 30 min after pretreatment with NNA (1 or 3 mg/kg) or saline (1 ml/kg). Mean arterial pressure (MAP) was measured 5 min after each dose of zaprinast. Five minutes after the last dose of zaprinast (30 mg/kg), the rats were anesthetized with pentobarbital (25 mg i.v.). A segment of the abdominal aorta was freeze-clamped in situ and removed for the determination of cGMP levels. NNA (3 mg/kg) decreased basal aortic cGMP levels by 54% and increased MAP by 37 +/- 2 mm Hg. Zaprinast (30 mg/kg) increased aortic cGMP by 187% and decreased MAP by 49 +/- 4 mm Hg. NNA (3 mg/kg) reduced the accumulation of cGMP in aortic tissue (from 4.1 +/- 0.4 to 1.3 +/- 0.1 fmol/microgram protein) and attenuated the depressor response (from -49 +/- 4 to -31 +/- 4 mm Hg) produced by zaprinast. These data are consistent with the hypothesis that NNA inhibits the tonic release of EDRF and that the depressor effects of zaprinast are due, at least in part, to the potentiation of the vasodilator effects of EDRF in vivo. Moreover, since the changes in MAP produced by NNA and zaprinast were significantly correlated with cGMP levels in aortic tissue, the concentration of cGMP in vascular tissue may be a determinant of blood pressure in SHR.