Biomedical subjects

H R Weiss

Publications and source records attributed to H R Weiss.

At least 55 records · Page 3Linked to original sources

PubMed1998

Relationship between decreased function and O2 consumption caused by cyclic GMP in cardiac myocytes and L-type calcium channels.

We tested the hypothesis that part of the decreased function and metabolism caused by cyclic guanosine monophosphate (GMP) in beating cardiac myocytes is related to inhibition of L-type calcium channels. The steady state oxygen consumption (VO2) of a suspension of ventricular myocytes isolated from hearts of New Zealand white rabbits was measured using oxygen electrodes. Cellular cyclic GMP levels were determined by radioimmunoassay. Cell shortening was measured with a video edge detector. The VO2 was obtained after: (1) adding sodium nitroprusside (NP 10(-8),(-6),(-4) M), (2) pretreatment by BAY K8644 10(-5) M (BAY, L-type calcium channel activator), nifedipine 10(-4) M (NF, L-type calcium channel blocker) or forskolin 10(-7) M (FK, adenylate cyclase activator), then adding NP 10(-8),(-6),(-4) M, (3) pretreatment with both FK 10(-7) M and NF 10(-4) M and subsequently adding NP 10(-8),(-6),(-4) M. NP 10(-4) M decreased VO2 from 707 +/- 34 to 410 +/- 13 (nl O2/min per 10(5) myocytes), decreased the percentage of shortening (Pcs) from 5.7 +/- 0.6 to 3.7 +/- 0.5 and the rate of shortening (Rs) from 65.5 +/- 4.5 (microns/s) to 46.2 +/- 5.5. NP 10(-4) M also increased cyclic GMP from 264 +/- 70 (fmol/10(5) myocytes) to 760 +/- 283. Both BAY and FK increased VO2, Pcs and Rs without changing cyclic GMP. NF decreased Pcs, Rs and VO2. Similar metabolic and functional effects of NP were observed with pretreatment with these agents separately, compared to NP alone, and the elevation of cyclic GMP level was not different from the control group. With FK alone, NP 10(-4) M decreased VO2 by 51%, Pcs by 44% and Rs by 39%. In the presence of both FK and NF, the negative effects of NP were diminished significantly. NP 10(-4) M decreased VO2 by 37%, Pcs by 25% and Rs 20%. Thus, in beating cardiac myocytes, the negative metabolic and functional effects of cyclic GMP were related to inhibition on L-type calcium channels only when adenylate cyclase was stimulated.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗

PubMed1998

Negative metabolic effects of cyclic GMP in quiescent cardiomyocytes are not related to L-type calcium channel activity.

We tested the hypothesis that the negative metabolic effects of elevating cyclic GMP act through inhibition of L-type calcium channels in quiescent cardiac myocytes. The steady state O2 consumption (VO2) of ventricular myocytes, isolated from hearts of New Zealand white rabbits, was measured in a glass chamber using Clark-type oxygen electrodes. The cellular cyclic GMP levels were determined by radioimmunoassay at baseline with either 0.5 mM or 2.0 mM of Ca2+, sodium nitroprusside at increasing concentration (10(-8),(-6),(-4) M) with and without pretreatment by BAY K8644 10(-5) M (L-type Ca2+ channel activator) in 0.5 mM Ca2+, or nitroprusside with and without pretreatment with nifedipine 10(-4) M (L-type Ca2+ channel blocker) in 2.0 mM Ca2+. In the 0.5 mM Ca2+ medium, basal VO2 was 459 +/- 104 (nl O2/min per 10(5) myocytes) with a corresponding cyclic GMP level of 112 +/- 23 (fmol/10(5) myocytes). With nitroprusside 10(-4) M, VO2 was decreased to 285 +/- 39 and cyclic GMP level was significantly elevated to 425 +/- 128. In the same medium, VO2 was slightly increased by BAY K8644 10(-5) M while the cyclic GMP level did not change. With BAY K8644 10(-5) M, nitroprusside 10(-4) M decreased VO2 and increased cyclic GMP to a level which was similar to cells treated with nitroprusside alone. In the 2.0 mM Ca2+ medium, the basal VO2 and cyclic GMP were 518 +/- 121 and 137 +/- 24. In the presence of nitroprusside 10(-4) M, VO2 was decreased to 295 +/- 49 and cyclic GMP was increased to 454 +/- 116. In the same medium, nifedipine 10(-4) M significantly decreased VO2, while the cyclic GMP level was comparable to the baseline. After nifedipine 10(-4) M, nitroprusside 10(-4) M decreased VO2 and increased cyclic GMP to levels which were similar to control. Therefore, in quiescent cardiac myocytes, the negative metabolic effects associated with cyclic GMP were not primarily mediated through inhibition of L-type Ca2+ channels.

Analysis of Variance↗

PubMed1998

Guanylyl cyclase inhibition reduces contractility and decreases cGMP and cAMP in isolated rat hearts.

OBJECTIVE: Several studies have shown that increasing cGMP in the heart reduces contractility, however, decreasing basal cGMP levels have also been shown in some studies to reduce contractility. This study was designed to evaluate the hypothesis that decreasing basal levels of cGMP decreases ventricular contractility, and that this depressed function is associated with a decrease in cAMP. METHODS: Using paced, constant flow, buffer-perfused rat hearts, we determined the effects of intracoronary infusions of the guanylyl cyclase inhibitor, LY83583 (10(-5) M), on ventricular function, oxygen consumption, and ventricular content of cGMP and cAMP. These experiments were conducted in the absence and presence of isoproterenol (ISO) to increase baseline left ventricular developed pressure (LVDP) and cAMP. RESULTS: LY83583, infused for 25 min, decreased LVDP by 44 +/- 3 (SE), 77 +/- 20 and 120 +/- 38 mmHg, in control, 10(-9) M, and 10(-8) M ISO-stimulated hearts, respectively. Regardless of the level of ISO stimulation, LY83583 reduced LVDP to the same sub-basal level. Oxygen consumption also decreased, but proportionately less than LVDP. ISO increased cAMP without changing cGMP. LY83583 decreased cGMP by about 25% at all levels of ISO, and decreased cAMP by 22% in the 10(-8) M ISO-stimulated group. CONCLUSION: Guanylyl cyclase inhibition by LY83583 decreased cGMP, cAMP and ventricular contractility. However, LY83583 depression of contractility was not always associated with a reduction in cAMP, suggesting that LY83583 can depress contractility by both cAMP-dependent and independent mechanisms.

Aminoquinolines↗

PubMed1998

Effect of N-methyl-D-aspartate receptor blockade on the control of cerebral O2 supply/consumption balance during hypoxia in newborn pigs.

Using dizocilpine (MK-801), we tested the hypothesis that N-methyl-D-aspartate (NMDA) receptors are important controllers of cerebral O2 supply/consumption balance in newborn piglets both during normoxia and hypoxia. Twenty-five 2 to 7-day-old piglets were anesthetized and divided into four groups: (1) Normoxia (n = 6), (2) Normoxia + MK-801 (n = 6), (3) Hypoxia (n = 6), and (4) Hypoxia + MK-801 (n = 7). Regional cerebral blood flow (rCBF) in ml/min/100 g was measured using 14C-iodoantipyrine, and we determined arterial and venous O2 saturations by microspectrophotometry, calculating cerebral O2 consumption (VO2) in ml O2/min/100 g in the cortex, hypothalamus and pons. MK-801 did not significantly affect regional VO2 or rCBF in normoxic piglets. Hypoxia resulted in an increase in local rCBF compared to controls: from 41 +/- 6 to 103 +/- 18 in the cortex; 34 +/- 7 to 101 +/- 20 in the hypothalamus; and 45 +/- 10 to 95 +/- 11 in the pons. Pretreatment with MK-801 abolished this hypoxic flow effect in the cortex (51 +/- 2) and hypothalamus (49 +/- 5), but not in the pons (91 +/- 17). Similar results were observed for VO2 with control values of 1.9 +/- 0.3, 1.6 +/- 0.2 and 2.1 +/- 0.3 for the cortex, hypothalamus and pons respectively. Hypoxia resulted in an increase in the VO2 to 3.9 +/- 0.4 (cortex), 3.8 +/- 0.6 (hypothalamus) and 3.9 +/- 0.8 (pons). Pretreatment with MK-801 prior to hypoxia abolished these effects in the cortex (2.1 +/- 0.2) and hypothalamus (2.1 +/- 0.2), but not in the pons (2.9 +/- 0.2). These findings suggest that NMDA receptors may play a role in the control of cerebral metabolism during hypoxia in this immature porcine model.

Animals↗

PubMed1998

Effects of isoproterenol on blood-brain barrier permeability in rats.

This study was performed to examine whether the direct topical application of isoproterenol to the cerebral cortex could modify the blood-brain barrier (BBB) permeability and whether this effect could be blocked by Timolol, a beta-adrenergic receptor antagonist without a membrane stabilizing effect. After a craniotomy in each animal, a low-dose (10(-4) M, n = 6) or a high-dose (10(-3) M, n = 6) isoproterenol patch was placed on one cortex (Ipsilateral Cortex: IC) and a normal saline patch was placed on the other cortex (Control Cortex: CC). Another 6 animals were pretreated with Timolol 1.5 mg kg(-1) i.v. before the placement of high dose isoproterenol patches. The BBB transfer coefficient (Ki) was determined using 14C-alpha-aminoisobutyric acid. Mean arterial blood pressure decreased after low- and high-dose isoproterenol patches. The low- and high-dose of isoproterenol increased Ki by 58% (IC: 5.94+/-2.02, CC: 3.77+/-1.75 microl g min(-1)) and 66% (IC: 6.97+/-3.66, CC: 4.19+/-2.48 microl g min(-1)) respectively when compared to that of the corresponding CC. Pretreatment with Timolol prevented the increase of the Ki by a high-dose of isoproterenol (IC: 5.33+/-1.88, CC: 5.66+/-1.72 microl g min(-1)). Our data demonstrate that a direct application of a beta-adrenergic receptor agonist to the brain parenchyma increased the permeability of the BBB, and that this effect could be prevented with a beta-adrenoceptor antagonist.

Adrenergic beta-Agonists↗

PubMed1998

The effects of pentobarbital on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats.

UNLABELLED: This study was performed to evaluate both the effects of pentobarbital on disruption of the blood-brain barrier (BBB) by hyperosmolar mannitol and the relationship between its effect on blood pressure and the integrity of the BBB. Under isoflurane anesthesia, rats in the control group were infused with 25% mannitol into the internal carotid artery before measuring the transfer coefficient (Ki) of 14C alpha-aminoisobutyric acid. Ten minutes before the administration of mannitol, rats received an infusion of pentobarbital: 20 mg/kg in the small-dose group and 50 mg/kg in the large-dose group. In another group of animals (hydralazine group), hydralazine was administered to maintain the mean arterial blood pressure (MAP) at 65 mm Hg during the experimental period. The MAP of the control group (113 +/- 14 mm Hg) was significantly higher (P < 0.002) than that of the small-dose pentobarbital group (78 +/- 13 mm Hg) or the large-dose pentobarbital group (68 +/- 14 mm Hg). In the control group, the Ki of the cortex ipsilateral to the mannitol injection was increased to 4.5 times that of the contralateral cortex (14.5 +/- 7.7 vs 3.2 +/- 0.6 microL x g(-1) x min(-1); P < 0.002). The Ki of the ipsilateral cortex of the small-dose pentobarbital group was 9.7 +/- 5.6 microL x g(-1) x min(-1). The Ki of the ipsilateral cortex of the large-dose pentobarbital group was 5.5 +/- 2.9 microL x g(-1) x min(-1), and lower (-9.0 microL x g(-1) x min(-1)) than that of the control animals (P < 0.05). There was no significant difference in the Ki of the contralateral cortex among any of the three groups of animals. At the same MAP, the Ki of the ipsilateral cortex of the large-dose pentobarbital group was lower (-4.3 microL x g(-1) x min(-1)) than that of the hydralazine group (9.8 +/- 4.6 microL x g(-1) x min(-1)) (P < 0.05). Pentobarbital attenuated the BBB disruption induced by hyperosmolar mannitol. This may be attributed, at least in part, to the blood pressure effect of pentobarbital. IMPLICATIONS: When the blood-brain barrier (BBB) was disrupted by a hyperosmolar solution, pentobarbital attenuated the degree of leakage of the BBB. Systemic hypotension caused by pentobarbital played a significant role in decreasing the leakage. Our study suggests that when the BBB is disrupted, pentobarbital may be effective in protecting the BBB. Furthermore, systemic blood pressure plays an important role in determining the degree of disruption.

Aminoisobutyric Acids↗

PubMed1998

Positive inotropy due to lowering cyclic GMP is also mediated by increases in cyclic AMP in control and hypertrophic hearts.

The aim of the current study was to determine if lowering myocardial cyclic GMP by guanylate cyclase inhibition would add independently to the positive inotropic effects caused by raising cyclic AMP and if these effects are modified in left ventricular hypertrophy (LVH) produced by aortic valve plication. Isoproterenol (ISO) (0.1 mg x kg(-1) x min(-1)) was infused into a branch of the left anterior descending coronary artery of seven control and eight hypertrophy open-chest anesthetized dogs. After 10 min, simultaneous infusion of methylene blue (MB) (2 mg x kg(-1) x min(-1)) was initiated at the same site. Hypertrophy increased heart weight and heart weight/body weight ratio. While both drugs increased left ventricular dP/dt(max), no additional global effects were observed in either group. Changes in regional variables followed the same pattern in both groups, i.e., ISO produced an increase that was enhanced by the addition of MB. ISO increased segment shortening, with a significant change in the control group. ISO increased regional force in both groups. The addition of MB increased force above ISO levels, with a significant change in the LVH group. ISO increased regional minute work (g x mm x min(-1)) (control, 1779 +/- 428 to 2541 +/- 500; LVH, 1157 +/- 253 to 1839 +/- 404) and O2 consumption. MB further increased regional work (control, 2993 +/- 952; LVH, 2416 +/- 853) and O2 consumption. ISO raised cyclic AMP (pmoles x g(-1)) (control, 468 +/- 41 to 580 +/- 84; LVH, 445 +/- 43 to 562 +/- 71) and had no effect on cyclic GMP (pmoles x g(-1)) (control, baseline 3.27 +/- 0.22, ISO 2.87 +/- 0.23; LVH, baseline 6.84 +/- 1.12, ISO 5.66 +/- 0.54). The addition of MB lowered cyclic GMP (control, 2.41 +/- 0.26; LVH, 3.68 +/- 0.35), but also increased cyclic AMP (control, 1021 +/- 121; LVH, 1107 +/- 134). Similar results were observed in control hearts using a specific soluble guanylate cyclase inhibitor (ODQ) in terms of changes in local work, O2 consumption, and cyclic nucleotides. Thus, at least part of the positive inotropic response to lowering cyclic GMP was mediated by changes in cyclic AMP in the current model. This was true in both control and LVH animals, although baseline cyclic GMP levels were higher, and a larger reduction in cyclic GMP was observed with MB in the LVH group.

Animals↗

PubMed1998

Increased O2 consumption and positive inotropy caused by cyclic GMP reduction are not altered after L-type calcium channel blockade.

We tested the hypothesis that increased O2 consumption and inotropy after reduction of myocardial cyclic guanosine monophosphate (cGMP) are mediated through L-type calcium channels. Anesthetized, open-chest New Zealand white rabbits were divided into four groups. Hearts were exposed to control vehicle (n = 8); LY83583 (LY, 10(-3) mol/l, guanylate cyclase inhibitor, (n = 9); nifedipine (nif, 10(-4) mol/l, L-type calcium channel blocker, n = 8), or nif+LY (n = 6). Vehicle or compound was applied topically to the epicardium for 15 min. Subepicardial (EPI) blood flow increased (from 213 +/- 22 to 323 +/- 24 ml/ min/100 g) in the presence of LY, as did subendocardial (ENDO) blood flow (from 238 +/- 20 to 333 +/- 38 ml/min/ 100 g). O2 consumption increased in the presence of LY:18.0 +/- 1.0 (EPI) and 17.0 +/- 0.6 (ENDO) ml O2/min/100 g as compared with 9.5 +/- 2.0 (EPI) and 10.6 +/- 2.5 (ENDO) in the control group. The increase in O2 consumption with LY was undiminished in the presence of nif (nif+LY group 21.0 +/- 3.0 ml O2/min/100 g EPI and 22.1 +/- 3.8 ENDO). Nif alone decreased left ventricular dP/dtmax from (2,762 +/- 197 to 2,413 +/- 316 mm Hg/s) and maximal rate of change in wall thickness (dW/dtmax from 13.5 +/- 2.0 to 9.5 +/- 0.8 mm/s), while percent change of wall thickness (from 21.3 +/- 3.3 to 31.3 +/- 7.2) and dW/dtmax (from 13.3 +/- 3.0 to 15.3 +/- 2.3 mm/s) increased in the nif+LY group. Thus, the positive O2 consumption and inotropic effects of decreasing cGMP were undiminished by nif. These results suggest that the cGMP reduction induced increases in O2 consumption and that inotropy may not be mediated through L-type calcium channels.

Aminoquinolines↗

PubMed1997

The negative functional and metabolic effects of muscarinic stimulation are enhanced by beta-adrenergic activation in control and hypertrophic dog hearts in vivo.

The aim of the current study was to determine if the effects of muscarinic stimulation on left ventricular function and metabolism are greater during beta-adrenergic activation, whether a cyclic GMP-mediated mechanism is responsible, and if this is altered by left ventricular hypertrophy (LVH) induced by aortic valve stenosis. Acetylcholine (Ach) (5 micrograms/kg/min) and/or isoproterenol (Iso) (0.1 micrograms/kg/min) was infused into a branch of the left anterior descending (LAD) artery in 8 control and 8 LVH open-chest anesthetized dogs. LVH increased heart weight, heart-to-body weight ratio and systolic left ventricular pressure. LVH reduced muscarinic receptor density (fmol/mg protein) (control: 149.2+/-18.6; LVH: 77.8+/-8.6), but not affinity. Alone, Ach had no effect on regional force, work or metabolism. Iso increased peak force (g) (control: baseline-7.4+/-0.4; Iso-12.4+/-2.2; LVH: baseline-6.7+/-0.8; Iso-16.3+/-2.7, regional work (g mm/min)) (control: baseline-1250+/-186; Iso-1813+/-409; LVH: baseline-927+/-235; Iso-1244+/-222), and O2 consumption (ml O2/min/100 g) (control: baseline-3.3+/-0.2; Iso-8.1+/-2.0; LVH: baseline-4.8+/-1.0; Iso-8.3+/-1.1). During Iso, Ach reduced segment shortening (control: Iso-14.5+/-1.2; Iso+Ach-10.5+/-1.8; LVH: Iso-10.4+/-1.5; Iso+Ach-7.6+/-1.3) and peak force (control: Iso+Ach-7.7+/-1.0; LVH: Iso+Ach-10.5+/-1.4). Ach also reduced work (control: Iso+Ach-875+/-217; LVH: Iso+Ach-776+/-180) and O2 consumption (control: Iso+Ach-3.4+/-0.7; LVH: Iso+Ach-3.6+/-0.6) in the presence of Iso. Cyclic GMP was higher in the LVH animals during all treatments and was elevated from baseline by Ach in both groups. Neither Iso nor Iso+Ach had a significant effect on cyclic GMP. Thus, the negative functional and metabolic effects of muscarinic stimulation are enhanced during beta-adrenergic activation. This does not, however, appear to be dependent on a cyclic GMP-mediated mechanism. Despite reduced number of muscarinic receptors, this response was not altered by pressure-induced cardiac hypertrophy.

Animals↗

PubMed1997

Negative metabolic effects of cyclic GMP are altered in renal hypertension induced cardiac hypertrophy.

We tested the hypothesis that increasing myocardial cyclic GMP levels would reduce myocardial O2 consumption and that renal hypertension (One Kidney-One Clip, 1K1C)-induced cardiac hypertrophy would change this relationship. Four groups of anesthetized open-chest New Zealand white rabbits (N = 26) were utilized. Either vehicle or 3-morpholinosydnonimine (SIN-1) (10(-4) M, a guanylate cyclase activator) was topically applied to the left ventricular surface of control or 1K1C rabbits. Coronary blood flow (radioactive microspheres) and O2 extraction (microspectrophotometry) were used to determine O2 consumption. Myocardial cyclic GMP levels were determined by radioimmunoassay. Guanylate cyclase activity was measured by conversion of GTP to cyclic GMP. 1K1C rabbits had a greater heart weight-to-body weight ratio (3.29 +/- 0.15) than controls (2.63 +/- 0.19). Systolic blood pressure was higher in 1K1C rabbits than in controls. In control rabbits, cyclic GMP levels (pmoles/g) were higher in SIN-1-treated (EPI: 7.5 +/- 1.6; ENDO: 8.1 +/- 1.5) than in vehicle-treated animals (EPI: 5.4 +/- 0.4; ENDO: 5.6 +/- 0.6). This effect was enhanced in 1K1C rabbits, with cyclic GMP levels in the SIN-1-treated group (EPI: 11.9 +/- 1.3; ENDO: 13.0 +/- 1.5) almost double those observed in the vehicle-treated group (EPI: 6.3 +/- 0.8; ENDO: 7.7 +/- 1.1). There were no significant differences in basal or maximally stimulated guanylate cyclase activity between controls and 1K1C rabbits. Myocardial O2 consumption (ml O2/min/100 g) was significantly less in the EPI region of control animals treated with SIN-1 (7.2 +/- 1.2) than in the same region of controls treated with vehicle (9.1 +/- 2.0). Myocardial O2 consumption was also significantly less in SIN-1-than vehicle-treated 1K1C animals (SIN-1-treated: EPI: 6.9 +/- 0.8; ENDO: 6.2 +/- 0.7; vehicle-treated: EPI: 10.0 +/- 0.8; ENDO: 12.5 +/- 3.0). There was no significant difference in O2 consumption between control and 1K1C animals after treatment with SIN-1. Thus, there was a greater elevation in cyclic GMP in 1K1C rabbits, but this did not result in a corresponding greater depression in O2 consumption. This suggests that cyclic GMP plays a role in the control of myocardial metabolism, and that the sensitivity of myocardial O2 consumption to changes in cyclic GMP is reduced by renal hypertension-induced cardiac hypertrophy.

Animals↗

PubMed1997

Local inotropic stimulation by methylene blue does not improve mechanical dysfunction due to myocardial stunning.

We tested the hypothesis that reduction of intramyocardial cyclic guanosine monophosphate (GMP) by methylene blue (MB) would improve mechanical dysfunction in stunned myocardium. Regional stunning was produced in nine open-chest anesthetized dogs by a 12-min left anterior descending coronary artery (LAD) occlusion. MB was infused into the LAD during reperfusion (1 mg/kg per min). Stunning reduced LAD force development, introduced a significant time delay between the onset of force and shortening (delay) and caused significant systolic bulging to occur. Stunning reduced systolic regional work (the integrated product of force and segment shortening during systole), but did not significantly alter regional oxygen consumption or cyclic GMP levels. MB decreased cyclic GMP (1.8 +/- 0.2 to 0.9 +/- 0.1 pmol/g) and increased peak force (36 +/- 5 to 55 +/- 10 g). However, MB increased delay (93.9 +/- 18.4 to 233 +/- 19 ms) and systolic bulging (5.9 +/- 2.1% to 9.3 +/- 2.8%) and further reduced systolic regional work (control; 4204 +/- 933 g x mm/min; stunned: 2191 +/- 542 g x mm/min; MB: 1153 +/- 516 g x mm/min). MB increased regional myocardial oxygen consumption (7.4 +/- 1.0 to 15.6 +/- 2.7 ml O2/min per 100 g). These results suggest that depressed contractility, while present in myocardial stunning, is not the primary cause of mechanical dysfunction.

Animals↗

PubMed1997

Reduced myocardial cyclic GMP increases myocardial O2 consumption in control but not renal hypertension-induced cardiac hypertrophy.

OBJECTIVES: We tested the hypothesis that a reduction in myocardial cyclic GMP would increase myocardial O2 consumption and that renal hypertension (One Kidney-One Clip, 1K1C)-induced cardiac hypertrophy would change this relationship. METHODS: Either vehicle or LY83583 (10(-3) M, a guanylate cyclase inhibitor) was topically applied to the left ventricular surface of control of 1K1C anesthetized open-chest New Zealand white rabbits (N = 38). Coronary blood flow (radioactive microspheres) and O2 extraction (microspectrophotometry) were used to determine subepicardial (EPI) and subendocardial (ENDO) O2 consumption and myocardial cyclic GMP was determined by radioimmunoassay. RESULTS: The heart weight/body weight ratio was greater in the 1K1C rabbits (3.16 +/- 0.20) than controls (2.58 +/- 0.08 g/kg). Systolic blood pressure was higher in 1K1C rabbits (116 +/- 8 mm Hg) than controls (80 +/- 6), but topical LY83583 had no significant hemodynamic effects. LY83583 significantly and similarly decreased EPI cyclic GMP in both control (7.9 +/- 1.2 to 6.0 +/- 1.0 pmol/g) and 1K1C (7.7 +/- 1.2 to 5.3 +/- 0.9) hearts and control ENDO (8.7 +/- 1.7 to 7.2 +/- 1.2) but not 1K1C ENDO (6.7 +/- 0.5 to 5.7 +/- 1.1). Myocardial O2 consumption was significantly increased in control with LY83583 (EPI 6.6 +/- 1.1 to 15.6 +/- 1.4 and ENDO 7.2 +/- 0.9 to 14.2 +/- 0.7 ml O2/min/100 g), but not in 1K1C hearts (EPI 12.1 +/- 1.0 to 12.9 +/- 1.2 or ENDO 11.4 +/- 0.7 to 12.9 +/- 0.9). CONCLUSIONS: Thus myocardial O2 consumption was only increased by LY83583 in control hearts, but LY83583 decreased cyclic GMP similarly in both the control and 1K1C EPI. This indicated, at least in the EPI, a dissociation of the inverse relationship between the myocardial level of cyclic GMP and O2 consumption in the 1K1C rabbit heart.

Aminoquinolines↗

PubMed1997

Effects of excitatory amino acids on cerebral oxygen consumption and blood flow in rat.

This investigation tested the importance of excitatory amino acids' effects on regional cerebral O2 consumption and the concomitant changes in cerebral blood flow (rCBF) in isoflurane anesthetized rats. In the glutamate or N-methyl-D-aspartate (NMDA) groups, 10(-2) M glutamate or NMDA was topically applied to the right cortex and the left cortex was used as a control. One mg/kg dizocilpine maleate (MK-801), a non-competitive NMDA receptor antagonist, was administered (iv) to the MK-801 group and saline was given to the control group. Cortical rCBF was determined using 14C-iodoantipyrine and regional O2 extraction was measured microspectrophotometrically. Cerebral O2 consumption increased 77% after glutamate (contralateral cortex: 9.0 +/- 1.1 ml O2/min/100 g, glutamate treated cortex: 15.9 +/- 3.9), while a 46% increase was observed with the same concentration of NMDA (contralateral cortex: 9.8 +/- 2.0, NMDA treated cortex: 14.3 +/- 5.5). After MK-801, the O2 consumption decreased to 37% of the control value (control cortex: 7.0 +/- 1.3, MK-801 treated cortex: 2.6 +/- 3.9). MK-801 significantly decreased cerebral O2 extraction from 7.1 +/- 1.3 ml O2/100 ml (control cortex) to 5.3 +/- 0.6 (MK-801 treated cortex). However, there was no significant difference in cerebral O2 extraction between treated and contralateral cortex in either the glutamate or NMDA groups. The increase in O2 consumption caused by glutamate or NMDA was coupled with increased rCBF. Glutamate increased rCBF from 95 +/- 5 ml/min/100 g (contralateral cortex) to 165 +/- 31 (treated cortex), while NMDA increased rCBF from 114 +/- 12 (contralateral cortex) to 178 +/- 60 (treated cortex). MK-801 decreased O2 consumption with a lesser decrease of rCBF. The rCBF was 48 +/- 9 in the MK-801 treated cortex and 99 +/- 22 in the control cortex. Some substances produced by the activation of NMDA receptors may be related to the coupling of cerebral metabolism and blood flow, since after blockade of NMDA receptors with MK-801, this relationship is uncoupled. These findings suggest that glutamatergic processes have a major effect on cerebral O2 consumption and that this is at least partly due to NMDA receptors.

Animals↗

PubMed1997

Effects of hyperosmolar mannitol on regional oxygen supply and consumption in the newborn pig.

Previous work indicated that opening the blood-brain barrier with hyperosmotic mannitol decreased local venous O2 saturation and increased cerebral O2 consumption. This study was performed to assess the vascular effect of hypertonic mannitol on oxygen supply/consumption balance in the newborn pig and to determine the role of nitric oxide in mediating the effects of mannitol. Animals were anesthetized with alpha-chloralose and mechanically ventilated to maintain their blood gases within normal range. Retrograde catheterization of the right carotid artery was performed to inject 12 ml to 25% mannitol over a 30 sec interval. In one group of animals (n = 5), the blood-brain barrier transfer coefficient (Ki) to 14C-alpha aminoisobutyric acid or 14C-urea (n = 4) was measured 12 min after mannitol. In another group of animals (n = 9), regional cerebral blood flow and small vein O2 saturation was measured using 14C-iodoantripyrine and microspectrophotometry. Similar measurements were made in other groups of animals (n = 9) after pretreatment with 10 mg kg-1 i.v. of N-omega-nitro-L-arginine methyl ester (L-NAME), 20 min before mannitol injection. The mannitol injection did not increase Ki or local cerebral O2 consumption. It resulted in a decreased small vein O2 saturation in the ipsilateral cortex (46 +/- 3%) in comparison to the contralateral cortex (55 +/- 2%). The O2 supply/consumption ratio decreased in the ipsilateral cortex in the mannitol injected animals (2.14 +/- 0.23) in comparison to the contralateral cortex (2.76 +/- 0.28). Pretreatment with L-NAME abolished this effect of mannitol (small vein O2 saturation 59 +/- 2% in ipsilateral cortex and 58 +/- 2% in the contralateral cortex; O2 supply/consumption 2.68 +/- 0.17 in the ipsilateral cortex and 2.65 +/- 0.16 in the contralateral cortex). We conclude that hypertonic mannitol adversely affects O2 supply/consumption balance, without increasing blood-brain barrier transport, and this effect is blocked by L-NAME, a nitric oxide synthase antagonist.

Aminoisobutyric Acids↗

PubMed1997

Effects of topical N-methyl-D-aspartate on blood-brain barrier permeability in the cerebral cortex of normotensive and hypertensive rats.

This study was performed to examine if blood-brain barrier (BBB) permeability could be increased by N-methyl-D-aspartate (NMDA) in the cerebral cortex, and to compare the degree of alteration of BBB permeability in normotensive and in chronic hypertensive rats. Twenty- to 22-week-old spontaneously hypertensive rats (SHR) and Wistar Kyoto rats (WKY) were anesthetized with isoflurane. After craniotomy in 7 animals in each group (SHR and WKY group), an NMDA patch (10 mM) was placed on one cortex (ipsilateral cortex: IC), and a normal saline patch was placed on the other cortex (control cortex: CC). The other 7 rats in each group were pretreated with MK-801 before placing NMDA and normal saline patches (SHR.MK-801 and WKY.MK-801 group). The BBB transfer coefficient (Ki) was determined using 14C-alpha-aminoisobutyric acid. The mean arterial pressures of the SHR and the SHR.MK-801 group were about 65% higher than those of the WKY and the WKY.MK-801 groups. In the WKY group, the Ki of the IC was significantly higher than that of the CC (IC: 10.0 +/- 2.7, CC: 6.2 +/- 2.4 microliters g-1 min-1). In the WKY.MK-801 group, the Ki was similar in both cortices (IC: 8.6 +/- 4.0, CC: 8.2 +/- 3.3). In the SHR group, the Ki of the IC was significantly higher than that of the CC (IC: 9.5 +/- 3.7, CC: 6.5 +/- 3.4), and the Ki of each cortex was similar to that of the corresponding cortex of the WKY group. In the SHR.MK-801 group, the Ki was similar in both cortices (IC: 7.2 +/- 1.5, CC: 7.1 +/- 2.7), and was also similar to those of the WKY.MK-801 group. Our data suggest that NMDA is involved in increasing BBB permeability. In chronic hypertension, the response of the BBB to NMDA is not altered when compared with normotension.

Administration, Topical↗

PubMed1997

Effects of nitric oxide on blood-brain barrier disruption caused by intracarotid injection of hyperosmolar mannitol in rats.

We performed this study to evaluate the effects of changing the level of nitric oxide (NO) on disruption of the blood-brain barrier (BBB) by hyperosmolar mannitol. Under isoflurane anesthesia, control rats (control group, n = 6) were given infusions with 25% mannitol into the internal carotid artery before measuring the transfer coefficient (Ki) of 14C-alpha-aminoisobutyric acid (14C-AIB). In the CAS group (n = 6), [3-(cis-2,6-dimethyl piperidino)-sydnonimine] (CAS 754), a NO donor, was injected to decrease the mean arterial pressure (MAP) to 55 mm Hg and in the L-NAME group (n = 6), NG-nitro-L-arginine methyl ester (L-NAME), a NO synthase inhibitor, was injected before administering mannitol. In additional control animals (control + P group, n = 6) and additional CAS 754-treated animals (CAS + P group, n = 6), phenylephrine was infused to keep MAP at 130 mm Hg during the experimental period. In the control group, with mannitol injection, the Ki of the ipsilateral cortex (IC) where mannitol was injected increased to 4.3 times that of the contralateral cortex (CC) (17.2 +/- 2.9 vs 4.0 +/- 2.6 microliters.g-1.min.1). Without blood pressure control, the Ki of the IC of the CAS group (7.0 +/- 4.5) was lower and that of the L-NAME group (26.2 +/- 12.7) was higher than that of the control animals. At the same MAP, the Ki of the IC of the CAS + P group (9.6 +/- 3.1) was significantly lower than that of the control + P group (21.3 +/- 14.5) or that of the L-NAME group. There was no significant difference in the Ki of the IC between the control + P and the L-NAME groups. In conclusion, L-NAME worsened BBB disruption induced by hyperosmolar solution, which may be due to the pressure effect of L-NAME. CAS 754 was effective in attenuating disruption of the BBB caused by hyperosmolar mannitol. This effect is apparently not due to decreased MAP.

Aminobutyrates↗

PubMed1997

Basal muscarinic activity does not impede beta-adrenergic activation in rabbit hearts in controls or thyroxine-induced cardiac hypertrophy.

We tested the hypothesis that basal myocardial muscarinic receptor activity acts as a "brake" on beta-adrenergic activation and that this effect would be greater in hearts subjected to thyroxine (T4)-induced (0.5 mg/kg for 16 days) hypertrophy due to an increase in muscarinic receptor density. Twenty control and 20 T4-treated open-chest anesthetized New Zealand white rabbits were given isoproterenol (0.5 microg/kg/min, 10 min i.v.) and/or atropine (3 mg/kg bolus). Coronary blood flow (radioactive microspheres), aortic and left ventricular (LV) pressure, and wall thickening of the LV free wall were recorded. Hearts were quickly excised and stored in liquid nitrogen. Cyclic guanosine monophosphate (GMP) and cyclic adenosine monophosphate (AMP) were determined by radioimmunoassay. T4 increased heart weight/body weight ratio, blood pressures, and the first derivative of the maximal rate of increase of LV systolic pressure (dP/dt[max]). Isoproterenol increased heart rate in both groups. Atropine had no effects on hemodynamic parameters either alone or after stimulation with isoproterenol. At this dose, atropine completely blocked the depressant effects of acetylcholine (10 microg/kg). Isoproterenol increased the maximal time derivative of wall thickening (dWT/dt[max]) in control (from 11.0 +/- 1.0 to 16.4 +/- 1.5 mm/s) but not in T4 animals. T4 increased subepicardial (EPI) and subendocardial (ENDO) coronary blood flow. Isoproterenol increased coronary flow (control: EPI, from 173 +/- 11 to 346 +/- 28 ml/min/100 g; ENDO, from 197 +/- 15 to 364 +/- 30 ml/min/100 g; T4: EPI, from 314 +/- 45 to 459 +/- 43 ml/min/100 g; ENDO, from 339 +/- 48 to 458 +/- 43 ml/min/100 g). Cyclic AMP levels were higher in T4 animals. Isoproterenol increased cyclic AMP (control: EPI, from 540 +/- 82 pmol/g to 1,096 +/- 110; ENDO, 596 +/- 58 to 1,050 +/- 145 pmol/g; T4: EPI, from 882 +/- 107 pmol/g to 1,319 +/- 222; ENDO, from 954 +/- 134 to 1 ,409 +/- 261 pmol/g). Atropine, alone or after stimulation with isoproterenol, had no effect on coronary flow or cyclic AMP in either group. Cyclic GMP levels were unaffected by T4-induced hypertrophy or by any of the treatments in either group. Thus it appears that basal muscarinic activity does not significantly influence function or signal transduction either at baseline or during beta-adrenergic stimulation in controls or in T4-induced hypertrophy.

Adrenergic beta-Agonists↗

PubMed1997

Cyclic GMP decreases cardiac myocyte oxygen consumption to a greater extent under conditions of increased metabolism.

We tested the hypothesis that the negative effects of intracellular guanosine 3',5'-cyclic monophosphate (cyclic GMP) were more profound on cardiac myocyte oxygen consumption (VO2) during increased metabolism of the myocytes. The steady state VO2 of a suspension of single myocytes isolated from hearts of New Zealand White rabbits was measured in a glass chamber by using a Clark-type oxygen electrode, and cyclic GMP was determined by using a radioimmunoassay. The cellular cyclic GMP levels were increased either by adding 3-morpholino-sydnonimine (SIN-1), a guanylate cyclase stimulator, or zaprinast (ZAP), a cyclic GMP-phosphodiesterase inhibitor, at various doses. In 0.5 mM Ca2+ medium, average VO2 was 123 +/- 8 nl/min/100,000 cells, and cyclic GMP was 35.4 +/- 9.3 fmol/100,000 cells, and these increased significantly to 182 +/- 9 nl/min/100,000 cells and 78.2 +/- 7.3 fmol/100,000 cells in 2.0 mM Ca2+. There were dose-dependent responses of the VO2 and cellular cyclic GMP levels in responding to both SIN-1 and ZAP. An inverse relation between cellular cyclic GMP level and VO2 existed in the myocytes. The regression equations for the four treatments were log(VO2) = -0.002[cyclic GMP] + 2.19, r = 0.96 for SIN-1 in low (0.5 mM) Ca2+; log(VO2) = 0.005[cyclic GMP] + 1.80, r = 0.38 for ZAP in low Ca2+; log(VO2) = -0.001 [cyclic GMP] + 2.24, r = 0.82 for SIN-1 in high (2.0 mM) Ca2+; and log(VO2) = -0.004[cyclic GMP] + 2.56, r = 0.93 for ZAP in high Ca2+. The slope of ZAP regression line was significantly more negative than that of SIN-1 with high calcium. At any given level of cyclic GMP, ZAP decreased the VO2 to a greater extent than did SIN-1 although the latter caused the maximal increase in cyclic GMP level. The reduction in VO2 caused by a corresponding increase in cellular cyclic GMP was greater in myocytes incubated with high-Ca2+ medium.

Animals↗