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PubMed1984

Mechanism of renin release in exercising dog.

Exercise is associated with an increase in plasma renin activity (PRA). The purpose of this study was to determine the role of the prostaglandin (PG) and adrenergic pathways in the renin release with exercise in the dog. One group of animals (n = 4) was exercised under control untreated and indomethacin- and meclofenamate- (2 mg/kg) treated conditions. A 155% increase in PRA was not influenced by PG inhibition. In a second group (n = 7) PRA was 1.22 +/- 0.32, 3.29 +/- 1.59, 6.28 +/- 2.85, and 5.30 +/- 2.00 ng ANG I X ml-1 X h-1 at rest and during light, moderate, and heavy exercise, respectively. Guanethidine treatment (15 mg/kg) decreased mean PRA by 41, 50, 70, and 73% at rest and during the three levels of exercise, respectively. In a third group (n = 5) control exercise runs were repeated after metoprolol treatment. Selective beta 1-blockade completely abolished the increment in PRA observed with exercise. These data demonstrate that the elevation of PRA during exercise in the dog is mediated by increased sympathetic nerve activity involving beta 1-receptors and that it is not dependent on alterations in PG synthesis.

Animals↗
PubMed1984

Relationship between PG and beta-adrenergic pathways to renin release in rat renal cortical slices.

The precise importance of prostaglandin (PG) in the beta-adrenergic pathway to renin release is unresolved. Thus, we examined this question using renal cortical slices from Sprague-Dawley rats incubated in Krebs-Ringer bicarbonate mixture (KRB), KRB + isoproterenol (10(-5) M, ISO), or a solution containing KRB + ISO + either propranolol (PRO, 10(-5) M) or indomethacin (IN, 10(-5) M). Media samples were assayed for renin activity, 6-keto-PGF1 alpha (the stable metabolite of PGI2), and PGE2. ISO only increased renin release 1.96-fold; modest increments in 6-keto-PGF1 alpha and PGE2 also occurred. The addition of PRO prevented these increases. In the next series of studies, ISO again increased renin, but the addition of IN failed to modify this increase in renin release. However, IN did prevent any increase in 6-keto-PGF1 alpha or PGE2. Meclofenemate (10(-5) M) provided results similar to those of IN. PGI2 was found to stimulate the release of renin in concentrations of 10(-7) M. The combination of submaximal stimulatory concentrations of PGI2 (10(-6) M, a 1.6-fold increment) and ISO (10(-6) M, a 1.7-fold increment) produced a synergistic increase in renin release (2.84-fold). These results demonstrate that renal prostaglandins do not function as essential mediators of the beta-adrenergic pathway to renin release. Rather, high concentrations of prostaglandins may increase the renin-releasing action of beta-agonists, thereby modulating the release of renin.

6-Ketoprostaglandin F1 alpha↗
PubMed1986

Angiotensin II receptor alterations during pregnancy in rabbits.

Despite activation of the renin-angiotensin system during pregnancy, renal and peripheral vascular blood flows increase, and the systemic blood pressure and the pressor response to exogenous angiotensin II (Ang II) fall. Gestational alterations in Ang II receptors could contribute to these changes. Ang II binding parameters were determined utilizing 125I-Ang II in vascular (glomeruli and mesenteric arteries) and nonvascular (adrenal glomerulosa) tissues from 24- to 28-day pregnant rabbits. Comparisons were made utilizing tissues from nonpregnant rabbits. Binding site concentrations (N) and dissociation constants (Kd) were obtained by Scatchard analyses of binding inhibition data. In glomeruli from nonpregnant and pregnant rabbits, N was 515 +/- 84 and 300 +/- 54 fmol X mg-1 protein (P less than 0.005; n = 8), respectively. Kd did not differ (P greater than 0.05). In mesenteric artery membranes from nonpregnant (n = 3) and pregnant (n = 4) rabbits, N was 304 +/- 21 and 112 +/- 23 fmol X mg-1 (P less than 0.005), respectively. Kd did not differ. Neither N nor Kd differed in adrenal glomerulosa tissues (n = 6). Meclofenamate (M) inhibits prostaglandin synthesis, reduces plasma renin activity, and enhances the pressor response to infused Ang II in pregnant rabbits. Administration of M to pregnant rabbits increased N in glomerular and in mesenteric artery membranes from 298 +/- 16 to 381 +/- 8 fmol X mg-1 (n = 3) and from 144 +/- 13 to 218 +/- 13 fmol X mg-1 (n = 4), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1981

Response of rat jejunum to angiotensin II: role of norepinephrine and prostaglandins.

At low doses, angiotensin II (AII) stimulates jejunal sodium and water absorption in the pentobarbital sodium-anesthetized rat. This response to the hormone can be blocked by cycloheximide and has a rapid onset and decay, indicating that any protein involved must have a short half-life and/or fast turnover. At high doses, AII inhibits jejunal absorption by a process that does not involve protein synthesis and has a rapid onset but slow decay. The AII-induced inhibition of water absorption can be abolished, and a net stimulation ensues after pretreatment of the animals with meclofenamate or indomethacin, suggesting that at high doses AII stimulates intestinal prostaglandin biosynthesis. The AII analogue, [Sar1,Leu8]AII, significantly stimulated jejunal water absorption and was devoid of any inhibitory response at any dose administered. Simultaneous infusion of low doses of [Sar1,Leu8]AII and AII resulted in a stimulation of water transport, while simultaneous infusion of high dose [Sar1,Leu8]AII and AII also stimulated water absorption. It is suggested that the AII analogue is a full agonist with regard to stimulation of jejunal transfer but antagonizes the inhibitory response to high doses of AII. A model consistent with these data is discussed.

Angiotensin II↗
PubMed2005

Increased myogenic tone in 7-month-old adult male but not female offspring from rat dams exposed to hypoxia during pregnancy.

Intrauterine growth restriction (IUGR) increases the risk of cardiovascular disease later in life. Vascular dysfunction occurs in adult offspring from animal models of IUGR including maternal undernutrition, but the influence of reduced fetal oxygen supply on adult vascular function is unclear. Myogenic responses, essential for vascular tone regulation, have not been evaluated in these offspring. We hypothesized that 7-mo-old offspring from hypoxic (12% O(2); H) or nutrient-restricted (40% of control; NR) rat dams would show greater myogenic responses than their 4-mo-old littermates or control (C) offspring through impaired modulation by vasodilators. Growth restriction occurred in male H (P < 0.01), male NR (P < 0.01), and female NR (P < 0.02), but not female H, offspring. Myogenic responses in mesenteric arteries from males but not females were increased at 7 mo in H (P < 0.01) and NR (P < 0.05) vs. C offspring. There was less modulation of myogenic responses after inhibition of nitric oxide synthase (P < 0.05), prostaglandin H synthase (P < 0.005), or both enzymes (P < 0.001) in arteries from 7-mo male H vs. C offspring. Thus reduced vasodilator modulation may explain elevated myogenic responses in 7-mo male H offspring. In contrast, there was increased modulation of myogenic responses in arteries from 7-mo female H vs. C or NR offspring after inhibition of both enzymes (P < 0.05). Thus increased vasodilator modulation may maintain myogenic responses in female H offspring at control levels. In summary, vascular responses in adult offspring from adverse intrauterine environments are impaired in a gender-specific, age-dependent, and maternal insult-dependent manner, with males more profoundly affected.

Animals↗
PubMed2002

Chronic hypoxia opposes pregnancy-induced increase in uterine artery vasodilator response to flow.

We tested the hypotheses that pregnancy increases the uterine artery (UA) vasodilator response to flow and that this increase is impaired under conditions of chronic hypoxia (30 days, simulated elevation 3,960 m). UA were isolated from 24 normoxic or chronically hypoxic midpregnant guinea pigs and studied with the use of pressure myography. Normoxic pregnancy increased UA flow vasodilator response and protected against a rise in wall shear stress (WSS). Chronic hypoxia opposed these effects, prompting vasoconstriction at high flow and increasing WSS above levels seen in normoxic pregnant UA. The nitric oxide synthase inhibitor N(G)-nitro-l-arginine (l-NNA) eliminated the pregnancy-associated increase in flow vasodilation in normoxic UA, suggesting that increased nitric oxide production was responsible. The considerable residual vasodilation after nitric oxide synthase and cyclooxygenase inhibition implicated endothelial-derived hyperpolarizing factor (EDHF) as an additional contributor to flow vasodilation. l-NNA increased flow vasodilation in UA from chronically hypoxic animals, suggesting that chronic hypoxia may have lowered EDHF or elevated peroxynitrite production. In conclusion, flow is an important physiological vasodilator for the acute and more chronic UA dimensional changes required to increase uteroplacental blood flow during normal pregnancy. Chronic hypoxia may be a mechanism that opposes the pregnancy-associated rise in UA flow vasodilation, thereby increasing the incidence of preeclampsia and intrauterine growth restriction at a high altitude.

Altitude↗
PubMed2003

Reduced perivascular PO2 increases nitric oxide release from endothelial cells.

Many studies have suggested that endothelial cells can act as "oxygen sensors" to large reductions in oxygen availability by increasing nitric oxide (NO) production. This study determined whether small reductions in oxygen availability enhanced NO production from in vivo intestinal arterioles, venules, and parenchymal cells. In vivo measurements of perivascular NO concentration ([NO]) were made with NO-sensitive microelectrodes during normoxic and reduced oxygen availability. During normoxia, intestinal first-order arteriolar [NO] was 397 +/- 26 nM (n = 5), paired venular [NO] was 298 +/- 34 nM (n = 5), and parenchymal cell [NO] was 138 +/- 36 nM (n = 3). During reduced oxygen availability, arteriolar and venular [NO] significantly increased to 695 +/- 79 nM (n = 5) and 534 +/- 66 nM (n = 5), respectively, whereas parenchymal [NO] remained unchanged at 144 +/- 34 nM (n = 4). During reduced oxygenation, arteriolar and venular diameters increased by 15 +/- 3% and 14 +/- 5%, respectively: NG-nitro-L-arginine methyl ester strongly suppressed the dilation to lower periarteriolar Po2. Micropipette injection of a CO2 embolus into arterioles significantly attenuated arteriolar dilation and suppressed NO release in response to reduced oxygen availability. These results indicated that in rat intestine, reduced oxygen availability increased both arteriolar and venular NO and that the main site of NO release under these conditions was from endothelial cells.

Adenosine↗
PubMed1977

Prostaglandin and histaminergic mediation of prolonged vasodilation after exercise.

An extended period of recovery of vascular resistance, far outlasting the recovery period of oxygen consumption, follows exercise of dog skeletal muscle when flow is restricted relative to the intensity of the exercise pattern. The duration of this postexercise prolonged vasodilation is graded and is related to the blood flow, duration of muscle stimulation, fatigue of the muscles, and total muscle tension development. To test whether prolonged vasodilation is mediated by prostaglandins or histamine, the prostaglandin synthetase inhibitors indomethacin or meclofenamate and the antihistamine tripelennamine were administered intravenously to anesthetized dogs between two 20-min exercise bouts of the anterior calf muscles at 4 twitches/s. Blood flow was held constant at approximately 20 ml 100 g-1 min-1, typically resulting in a venous O2 content below 2.0 ml/100 ml during exercise. The duration of vascular resistance recovery was evaluated by measuring the time at which vascular resistance returned to 90% (t90) of the recovery level (mean +/- SE). All the drugs caused a significant decline in the t90, but none reduced the recovery time to that following free-flow exercise, where the t90 is less than 1 min and the return of vascular resistance parallels the return of oxygen consumption to control. Thus, prostaglandin and/or histamine release may be at least partially responsible for prolonged vasodilation.

Animals↗
PubMed1980

Pregnancy blunts pulmonary vascular reactivity in dogs.

Pregnancy decreases systemic vascular reactivity but comparatively little is known about the effects of pregnancy on the pulmonary circulation. Pulmonary vascular resistance (PVR) during acute hypoxia was lower (P < 0.01) in eight intact anesthetized pregnant dogs compared to the same animals postpartum. Mean pulmonary arterial pressure (Ppa) and PVR during infusion of prostaglandin (PG) F2 alpha were also reduced during pregnancy. Nonpregnant female dogs (n = 5) treated with estrogen (0.001 mg x kg-1 x da-1) for 2 wk had decreased Ppa (P < 0.01) during acute hypoxia compared to control measurements, but PVR was unchanged during hypoxia and PGF2 alpha infusion. Treatment with progesterone in four dogs had no effect on pulmonary vascular reactivity to hypoxia or PGF2 alpha. Inhibition of circulating PG with meclofenamate in four dogs during pregnancy did not appear to restore pulmonary vascular reactivity. Blunted pulmonary vascular reactivity is suggested by the limited data available for women, but is not seen in pregnant cows. We conclude that pregnancy decreases pulmonary as well as systemic vascular reactivity in the dog, but the mechanism is unclear.

Animals↗
PubMed1981

Prostaglandin modulation of adrenergic vascular control during hemorrhagic shock.

This study was designed to evaluate 1) whether the initial compensatory skeletal muscle vascular constriction induced by hemorrhagic hypotension is primarily the result of increased adrenergic neural tone rather than circulating vasoconstrictor agents, and 2) whether the secondary skeletal muscle decompensatory vasodilation is caused by inhibitory action of prostaglandins on peripheral adrenergic nervous system. A constant-flow vascularly isolated double canine gracilis muscle preparation in which one muscle served as innervated control for the contralateral muscle was used. Dogs were subjected to standard stepwise hemorrhagic shock protocol. In series 1, perfusion pressures of control muscles were compared to denervated muscles with the result that innervated muscle perfusion pressures increased initially from 105 to 175 mmHg but subsequently fell significantly (P less than 0.05) to 147 mmHg. Only modest increases in perfusion pressures with no significant secondary fall were noted in denervated muscles. Series 2 compared innervated control perfusion pressures to pressures perfusing muscles pretreated with prostaglandin-synthesis inhibitor sodium meclofenamate (MCF). The MCF-treated muscle perfusion pressures rose to 260 mmHg where they remained without the secondary fall noted in control muscles. These data support the two hypotheses tested.

Animals↗
PubMed1982

Salt loading augments vascular responses to indomethacin in stroke-prone SHR.

We examined whether endogenous prostaglandins (PGs) participated in control of hindquarters vascular resistance during salt loading in stroke-prone spontaneously hypertensive rates (SHR-SP). SHR-SP and Wistar-Kyoto rats (WKY) were fed either a normal (0.3% NaCl) or high (8% NaCl) salt diet for 5 wk. High salt increased blood pressure and hindquarter vascular resistance (VR) in SHR-SP (P less than 0.01) but not in WKY. Indomethacin given intravenously increased hindquarter VR in SHR-SP during high salt as well as during normal salt (P less than 0.01) but not in either group of WKY. In SHR-SP the increase in hindquarter VR by PG synthesis inhibitors were two times greater during high salt than during normal salt (P less than 0.01). In addition, hindquarter vasodilatation by bradykinin was greater (P less than 0.05) in SHR-SP during high salt than that during normal salt, but vasodilatation by prostaglandin E1 or nitroglycerin was not different between the two groups. These results suggest that vascular synthesis of endogenous PGs was greater in SHR-SP during high salt than that during normal salt. Increased endogenous PGs may play an important role in the regulation of hindquarter VR during high salt intake in SHR-SP.

Alprostadil↗
PubMed1983

Effects of indomethacin in conscious dogs with experimental high-output heart failure.

The role of renal prostaglandins in the control of renin release and renal hemodynamic function (RHF) was studied in conscious dogs with a surgically created infrarenal aortocaval fistula, a model of high-output heart failure (HOHF). In series 1 during acute cardiac failure, indomethacin administration produced striking reductions in RHF but failed to alter the high level of plasma renin activity (PRA). In series 2, administration of indomethacin to dogs with chronic HOHF also resulted in pronounced decrements in RHF in spite of normal levels of PRA. Studies of individual animals with meclofenamate in both series 1 and 2 confirmed the findings with indomethacin with one exception; in one dog with chronic severe HOHF a very high level of PRA was present initially and fell 44% after meclofenamate. These observations indicate that in the acute and chronic phases of HOHF prostaglandins are involved in the maintenance of renal blood flow and glomerular filtration rate but do not play an essential role in the control of renin release.

Animals↗
PubMed1984

Mechanism of decreased pressor responsiveness to ANG II, NE, and vasopressin in pregnant rats.

The mechanism of decreased pressor responsiveness to pressor agents was examined serially throughout pregnancy in conscious rats. Rats, 15 and 20 days pregnant, showed marked blunting of the pressor response to graded doses of angiotensin, whereas after only 5 days of pregnancy there was a normal response and at 10 days an intermediate pressor response. A role for prior occupancy of vascular angiotensin II receptors for the blunted pressor response was made less likely by the observation that treatment with captopril to decrease endogenous angiotensin II did not improve the angiotensin II pressor response in 15-day pregnant rats. Studies of smooth muscle receptor binding of angiotensin II showed that, in pregnancy, receptor affinity and number was not changed. Inhibition of prostaglandin synthesis with meclofenamate increased the pressor response to angiotensin II toward normal in pregnant animals. The blunted vascular response in pregnancy was not specific for angiotensin since pregnant animals showed a similar decrease in the response to both norepinephrine and arginine vasopressin. Furthermore, meclofenamate increased the pressor response to norepinephrine and vasopressin in pregnant rats. We conclude that pressor hyporesponsiveness in pregnancy is not specific for angiotensin II and is not caused by alterations in vascular receptor occupancy or binding. In pregnancy there is a decreased pressor response to all three major pressor agents that is improved by inhibition of prostaglandin production.

Angiotensin II↗
PubMed1985

Effects of ouabain, low K+, and aldosterone on hypoxic pressor reactivity of rat lungs.

It can be postulated that inhibition of lung tissue Na+-K+-ATPase might potentiate hypoxic pulmonary vasoconstriction by depolarizing some excitable cell or, in contrast, that it might blunt the hypoxic response by reducing cellular metabolic rate and sensitivity to hypoxia. Thus the purpose of this study was to test in isolated rat lungs whether hypoxic pressor reactivity was related inversely or positively to Na+-K+-ATPase activity. Dose-pressor response curves to hypoxia, angiotensin II, or KCl were measured under control conditions and after exposure either to one of two inhibitors of Na+-K+-ATPase, ouabain, and low-K+ solution or to a stimulator of Na+-K+ pumping, aldosterone. Ouabain and low K+ depressed the response to hypoxia but had little effect on that to angiotensin II. The response to KCl was increased by ouabain. Aldosterone potentiated the hypoxic response. These results do not support the idea that membrane depolarization due to inhibition Na+-K+ pumping is a component of hypoxic vasoconstriction. They do suggest a positive relationship between Na+-K+-ATPase activity and hypoxic pressor reactivity and are consistent with the idea that Na+-K+-ATPase activity might influence hypoxic reactivity indirectly by altering cellular energy metabolism. It is also possible that the results were somehow due to changes in intracellular [Na+] or transmembrane Na+ gradient, rather than to changes in energy metabolism.

Aldosterone↗
PubMed1985

Effect of high doses of aspirin on pulmonary hemodynamics and lung water.

The purpose of this study was to determine if aspirin, in doses that elevate plasma salicylate concentrations to values reported in patients with salicylate-induced pulmonary edema, produce pulmonary vasoconstriction in a canine, isolated perfused left lower lung lobe (LLL) preparation. In 10 LLL's, aspirin (avg 97.8 mg/dl plasma) caused LLL arterial pressure to rise from 9.1 +/- 0.3 to 23.0 +/- 1.8 (SE) Torr. In contrast, no vascular pressure changes were observed in placebo-treated control LLL's. Sodium meclofenamate and indomethacin, structurally dissimilar cyclooxygenase inhibitors, elicited similar responses to aspirin, suggesting that a mechanism involving products of prostaglandin cyclooxygenase was involved in producing the vasoconstriction. The double-occlusion technique was used to localize the sites of the vasoconstriction. The results suggested that all three drugs caused both lobar arterial and venous tone to increase. Although high doses of aspirin produced pulmonary vasoconstriction in the isolated, perfused LLL, the aspirin-treated LLL's gained less weight and extravascular water than the control lobes.

Animals↗
PubMed1985

Adenine nucleotides, serotonin, and endothelium-dependent relaxations to platelets.

Aggregating platelets cause an endothelium-dependent relaxation of isolated contracted canine coronary arteries. The role of adenine nucleotides and of 5-hydroxytryptamine in causing this relaxation was determined. Rings of these arteries were suspended in organ chambers filled with physiological salt solution and contracted with prostaglandin F2 alpha. Adenosine diphosphate relaxed rings with intact endothelium but had no effect on endothelium-denuded rings. The relaxation was attenuated by the enzyme, apyrase, which hydrolyzes adenosine tri- and diphosphate. 5-Hydroxytryptamine (5-HT) exerted a direct contractile effect mediated by the endothelium. The latter was prevented by the 5-HT1 serotonergic antagonist, methiothepin, but not by the 5-HT2 serotonergic antagonist, ketanserin. The endothelially mediated relaxation to aggregating platelets was prevented by apyrase but not by methiothepin or ketanserin. Responses to platelets were unaltered by the inhibitor of cyclooxygenase, meclofenamate. These experiments demonstrate the key role of adenine nucleotides in mediating the endothelium-dependent relaxation of canine coronary arteries to aggregating platelets.

Adenine Nucleotides↗
PubMed1986

Meclofenamate potentiates vasoreactivity to alpha-adrenergic stimulation in chronically hypoxic guinea pigs.

The aim of this study was to examine the effect of chronic hypoxia on systemic vascular reactivity and the role of prostaglandins in modulating the vascular response to chronic hypoxia. Meclofenamate, a prostaglandin synthesis inhibitor, increased the systemic vascular resistance response to the alpha-adrenergic agonist, phenylephrine, in awake, unrestrained guinea pigs exposed for 6 wk to high altitude (3,900 m), but it did not alter the response in animals kept at low altitude (1,600 m). The systemic vascular resistance response to phenylephrine before treatment with meclofenamate was the same in high- and low-altitude animals. Meclofenamate also increased the contractile response to phenylephrine in aortic rings isolated from high- but not low-altitude animals. The systemic vascular resistance response to angiotensin II was the same in high- and low-altitude animals, and meclofenamate increased this response to the same extent in both groups. Thus chronic hypoxia appeared to enhance vascular production of dilator prostaglandins during beta-adrenergic stimulation.

Adrenergic alpha-Agonists↗