Pressor Effect Of Phenylephrine Research Articles

α1-Adrenergic receptor regulates papillary muscle and aortic segment contractile function via modulation of store-operated Ca2+ entry in long-tailed ground squirrels Urocitellus undulatus.

The effect of phenylephrine (PE) on right ventricle papillary muscle (PM) and aortic segment (AS) contractile activity was studied in long-tailed ground squirrels Urocitellus undulatus during summer activity, torpor and interbout active (IBA) periods in comparison to rat. We found that PE (10μM) exerts positive inotropic effect on ground squirrel PM that was blocked by α1-AR inhibitor-prazosin. PE differently affected frequency dependence of PM contraction in ground squirrels and rats. PE significantly increased the force of PM contraction in summer and hibernating ground squirrels including both torpor and IBApredominantly at the range of low stimulation frequencies (0.003-0.1Hz), while in rat PM it was evident only at high stimulation frequency range (0.2-1.0Hz). Further, it was found that PE vasoconstrictor effect on AS contractility is significantly higher in ground squirrels of torpid state compared to IBA and summer periods. Overall vasoconstrictor effect of PE was significantly higher in AS of ground squirrels of all periods compared to rats. Positive inotropic effect of PE on PM along with its vasoconstrictor effect on AS of ground squirrels was not affected by pretreatment with inhibitors of L-type Ca2+ channels, or Na+/Ca2+ exchanger or Ca2+-ATPase but was completely blocked by an inhibitor of store-operated Ca2+ entry (SOCE)-2-APB, suggesting the involvement of SOCE in the mechanisms underlying PE action on ground squirrel cardiovascular system. Obtained results support an idea about the significant role of alpha1-AR in adaptive mechanisms critical for the maintaining of cardiovascular contractile function in long-tailed ground squirrel Urocitellus undulatus.

Renal and femoral venous blood flows are regulated by different mechanisms dependent on α-adrenergic receptor subtypes and nitric oxide in anesthetized rats

Venous and arterial walls are responsive to sympathetic system and circulating substances, nevertheless, very few is known about the venous blood flow regulation simultaneously to arterial vascular beds. In this study, we compared the venous and arterial blood flow regulation in visceral and muscular beds upon injection of different doses of vasoactive drugs which act in arterial vascular beds. Anesthetized adult male Wistar rats underwent to right femoral artery and vein cannulation for hemodynamic recordings and infusion of drugs. Doppler flow probes were placed around the left renal artery and vein, and left femoral artery and vein to evaluate the changes in flood flow. Phenylephrine (PHE) injection (α1-adrenergic receptor agonist) elicited vasoconstriction in all arteries and veins. Intravenous prazosin (PZS) (1mg/kg, α1-adrenergic receptor blocker) caused renal artery vasodilation, but not in the other beds. Vasoconstrictor effect of PHE was abolished by PZS in all vascular beds, except in femoral vein. Phentolamine (PTL) injection (1mg/kg, α1/α2-adrenergic receptor blocker) produced renal artery vasodilation with no change in other beds. After PTL, the vasoconstriction evoked by PHE was abolished in all vascular beds. Sodium Nitroprusside (SNP), a nitric oxide donor, elicited vasodilation in all beds, and after PTL but not post PZS injection, SNP enhanced the vasodilatory effect in femoral vein. Our findings suggest that the vasoconstriction in renal and femoral veins is mediated by different subtypes of α-adrenoceptors. The nitric oxide-dependent vasodilation in femoral vein enhances when α2-adrenoceptors are not under stimulation, but not in the other vascular beds investigated.

High‐calorie Diet Induces Vascular and Hemodynamic Abnormalities in Absence of Change in Blood Glucose or Insulin Levels: Modulation by Oral Anti‐hyperglycemic Drugs

While the effect of hyperglycemia associated with diabetes on vascular function is well‐established by experimental and clinical evidence, few studies examined the early onset vascular changes occurring within the context of diabetes development before the establishment of frank hyperglycemia. Moreover, recent clinical evidence suggests a vasculoprotective effect for anti‐hyperglycemic drugs that is not a direct consequence of their effect on blood glucose level. Thus, an early intervention with diabetic vascular complications, be it through anti‐hyperglycemic drugs or otherwise, requires an adequate understanding of the underlying pathophysiological mechanism. In this study, we used a high calorie‐fed rat model, known to develop stable fasting hyperglycemia on long‐term feeding, to study changes in vascular function prior to the development of diabetes. Rats were fed a high fat (15% saturated fat), high fructose (20%) diet for 12 weeks, at which point there was no increase in fasting serum glucose, serum insulin, nor mean arterial pressure (MAP). Aortic rings from these rats showed an increased contractile response to phenylephrine (PE) compared to rings from age‐matched control animals, with an increased sensitivity (reduced EC50). The PE‐induced contractions were resistant to Ca‐free physiological solution and appeared to be more sensitive to Rho kinase inhibition. In parallel, the hypercontractile phenotype was manifested as an increase in the pressor effect of PE upon administration in vivo with a poor reflex bradycardiac response, despite the absence of a change in basal MAP. On the other hand, aortic rings from the high‐calorie fed rats showed an impaired endothelium‐dependent relaxation in response to acetylcholine (ACh), with increased constriction with higher ACh concentrations. Cyclo‐oxygenase‐mediated relaxation appeared to be most affected in these vessels, whereas nitric oxide donor‐mediated relaxations were not affected. Both ACh‐mediated relaxation and constriction were abolished in denuded rings from high‐calorie fed rats or upon treatment with a nitric oxide synthase inhibitor. Again, the altered dilatory effect was reflected in a reduced in vivo depressor response. Histopathology and immunohistochemistry showed an increased intimal thickness of aorta from these rats together with increased TGF‐β1 and Smad 3 expression. A two‐week treatment with either pioglitazone or metformin reversed the increased contractility to PE, increased intimal thickness, and increased TGF‐β1 expression with no change in fasting serum glucose. Our results suggest that early vascular dysfunction associated with high calorie intake involve inflammatory changes that could be linked to adipose inflammation. Anti‐hyperglycemic drugs showed a possible vascular anti‐inflammatory effect that is distinct from their effect on glycemic control.Support or Funding InformationFaculty of Medicine Bridge Fund, American University of Beirut

Protective Effect of Mycophenolate Mofetil on Endothelial Function in an Aortic Allograft Model

Whether mycophenolate mofetil (MMF) can prevent the vascular endothelial dysfunction related to the administration of calcineurin inhibitor after organ transplantation remains unknown. Four groups of Lewis rats, grafted with Brown Norway donor aortic abdominal allograft, received since the transplantation cyclosporine A (CsA, 5 mg/kg/day), MMF (40 mg/kg/day), CsA+MMF, or vehicle (control) for 2 weeks. Fifteen days after transplantation, all immunosuppressive regimens were equally effective in preventing graft rejection. When compared with control rats, the endothelium-dependent relaxation to acetylcholine was reduced, and the vasoconstrictor effect of phenylephrine was enhanced in thoracic aorta of CsA-treated rats but not in rats treated with MMF alone or combined with CsA without difference for the endothelium-independent relaxation to sodium nitroprusside. The relaxation to acetylcholine was abolished by the nitric oxide (NO)-synthase inhibitor N-nitro-l-arginine in all groups. Moreover, the endothelial NO-synthase protein dimer:monomer ratio in the thoracic aorta and the plasma nitrites concentrations, an indicator of NO availability, were decreased in CsA-treated rats but not in rats treated with MMF alone or combined with CsA. This study demonstrates that MMF prevents systemic endothelial dysfunction and the enhanced sensitivity to vasoconstrictors related to CsA administration in a rat allograft aortic model through an increase in NO availability related to the improvement of endothelial NO-synthase functionality.

Hypocapnia Enhances the Pressor Effect of Phenylephrine During Isoflurane Anesthesia in Monkeys

Phenylephrine was administered to increase arterial blood pressure in 6 monkeys anesthetized with isoflurane during both normocapnia (arterial partial pressure of CO2 35 to 44 mm Hg) and hypocapnia (arterial partial pressure of CO2 23 to 29 mm Hg). The doses of phenylephrine required to increase mean blood pressure to 33% and 66% above control pressure during hypocapnia [1.7+/-0.9 and 3.1+/-1.7 microg/kg/min (mean+/-SD), respectively] were significantly less than the doses required to achieve the same changes in blood pressure during normocapnia (2.4+/-0.9 and 4.9+/-2.4 microg/kg/min, respectively, P<0.05). In patients with intracranial pathology, for whom hypocapnia is frequently induced, phenylephrine dosage may need to be appropriately reduced.

L-Arginine and Antioxidant Diet Supplementation Partially Restores Nitric Oxide-Dependent Regulation of Phenylephrine Renal Vasoconstriction in Diabetics Rats

The increase of reactive oxygen species (ROS) in diabetes potentiates the vascular effects of phenylephrine through nitric oxide (NO) impairment, facilitating the development of diabetic nephropathy. We propose that the combination of an antioxidant and L-arginine as diet supplements could prevent the increased vascular response to phenylephrine in diabetic animals. Changes in the adrenergic system play an important role in the development of vascular complications in the prediabetic condition. The vasoconstrictor effects of phenylephrine are regulated by NO, and the impairment of endothelium-dependent vasodilation in diabetes is associated with ROS. Diabetes was induced with a low dose (55 mg/kg body weight) of streptozotocin in 7-week-old rats. Diabetic rats were fed with a diet supplement containing a combination of vitamin E, vitamin C, eicosapentaenoic acid, docosahexaenoic acid, and L-arginine, and the effects on phenylephrine-induced renal vascular responses were evaluated. Phenylephrine increased the renal perfusion pressure of isolated perfused kidneys from diabetic rats compared with nondiabetic rats. This effect was associated with reduced nitrite release as well as reduced plasma tetrahydrobiopterin and increased superoxide anions in the renal tissue. Diet supplementation with a combination of L-arginine and vitamins in diabetic rats partially prevented the generation of superoxide associated with recovery of the renal release of NO and decreased phenylephrine-induced vasoconstrictor effects, compared with untreated diabetic rats. However, the administration of L-arginine or vitamins alone did not affect phenylephrine-induced vasoconstriction. Vitamin treatment alone did decrease superoxide generation. The protective mechanism of NO on the vasoconstrictor effects of phenylephrine in the kidney is lost during the development of diabetes, probably via the actions of ROS through a decrease in tetrahydrobiopterin, thus contributing to the pathogenesis of diabetic nephropathy. Restoration of this protective NO mechanism can be achieved by simultaneously stimulating NO synthesis and preventing the effects of ROS through the use of L-arginine and a combination of vitamins E and C as diet supplementation.

Effects of Thiol Chelation on α1-Adrenoceptor-Induced Vasoconstriction In Vivo

The aims of this study were to determine whether systemic injections of the lipophobic thiol chelator, para-hydroxymercurobenzoic acid (PHMBA) would reduce the vasoconstrictor responses elicited by the alpha1-adrenoceptor agonist, phenylephrine, in urethane-anesthetized rats by chelation of thiol residues in alpha1-adrenoceptors in vascular smooth muscle rather than voltage-sensitive Ca(2+)-channels (Ca(2+)VERSUS-channels). The magnitudes and durations of the vasoconstrictor responses elicited by phenylephrine were markedly reduced after the injections of PHMBA. In contrast, the maximal phenylephrine-induced responses were not affected whereas the durations of these responses were markedly attenuated after injection of the Ca(2+)VERSUS-channel blocker, nifedipine. Nifedipine elicited pronounced and sustained falls in mean arterial blood pressure and vascular resistances in PHMBA-treated rats. Moreover, the vasodilator actions of the nitric oxide-donor, sodium nitroprusside were minimally attenuated by PHMBA whereas they were markedly attenuated by nifedipine. These findings support evidence that the vasoconstrictor responses due to activation of alpha1-adrenoceptors are initiated by mobilization of intracellular pools of Ca(2+) whereas they are sustained by opening of Ca(2+)VERSUS-channels. These findings also suggest that PHMBA diminishes the vasoconstrictor effects of phenylephrine by chelation of thiol residues in alpha1-adrenoceptors rather than by blockade of Ca(2+)VERSUS-channels, and that chelation of these thiol residues prevents agonist occupation and/or activation of these receptors and subsequent mobilization of intracellular pools of Ca(2+).

NO-Dependent Mechanism of Adrenergic Reaction of Systemic Hemodynamics

Blockade of NO synthesis in narcotized rats potentiated pressor effects of phenylephrine by 55% and increased total peripheral resistance by 153%. Vasodilation caused by enhanced NO secretion modulated pressor shifts evoked by stimulation of alpha(1)-adrenoceptors with phenylephrine.

Effect of baseline vasodilation on adrenergic reactions of systemic hemodynamics.

Systemic vasodilation produced by sodium nitroprusside in various concentrations and accompanied by a decrease in baseline blood pressure was followed by progressive reduction in pressor responses to alpha-adrenoceptor agonist phenylephrine (mesatone) in rats. In a blood pressure range of below the physiological level (80-100 mm Hg), a positive linear correlation was revealed between the decrease in baseline blood pressure and pressor effect of phenylephrine.

Effect of phenylephrine injected into the nucleus tractus solitarius of Sprague–Dawley rats and spontaneously hypertensive rats

In α-chloralose-anesthetized Sprague–Dawley (SD) rats with unilateral nucleus tractus solitarius (NTS) lesions, injection of the α 1-adrenergic receptor agonist phenylephrine into the contralateral NTS dose-dependently increased arterial pressure (AP). Bunazosin (0.1 nmol) or prazosin (0.36 nmol), an α 1-adrenergic receptor antagonist, also increased AP. When injected into the NTS, pre-treatment with phenylephrine (10 nmol) or both antagonists abolished the cardiovascular effects of glutamate and acetylcholine. In contrast, pre-treatment with prazosin or methylatropine did not alter the effect of phenylephrine. Phenylephrine (30 nmol) injected into the NTS abolished aortic depressor nerve (ADN) evoked-responses. The pressor effect of phenylephrine in the NTS was exaggerated in spontaneously hypertensive rats (SHR). These results suggest that when injected into the NTS, the effect of phenylephrine may be due to a baroreflex blockade resulting from direct modulatory actions or non-specific neuronal alterations rather than stimulating the α 1-adrenergic receptor. Additionally, this effect is enhanced in SHR.

Andrographolide suppresses the expression of inducible nitric oxide synthase in macrophage and restores the vasoconstriction in rat aorta treated with lipopolysaccharide.

1. We investigated whether andrographolide, a diterpenoid lactone found at Andrographis paniculata, influences the induction of the inducible nitric oxide synthase (iNOS) in RAW264.7 cells activated by bacterial endotoxin (LPS), as well as in the rats with endotoxic shock and in aortic rings treated with LPS. 2. Incubation of RAW264.7 cells with andrographolide (1 to 50 microM) inhibited the LPS (1 microg ml(-1))-induced nitrite accumulation in concentration- and time-dependent manners. Maximum inhibition was observed when andrographolide was added together with LPS and decreased progressively as the interval between andrographolide and LPS was increased to 20 h. 3. Western blot analysis demonstrated that iNOS expression was markedly attenuated in the presence of andrographolide for 6-24 h, suggesting that andrographolide inhibited iNOS protein induction. 4. Thoracic aorta incubation with LPS (300 ng ml(-1)) for 5 h in vitro exhibited a significant decrease in the maximal contractile response to phenylephrine (10(-9)-10(-5) M). Andrographolide (30 microM) restored the contractile response to control level. 5. In anaesthetized rats, LPS (10 mg kg(-1), i.v.) caused a fall in mean arterial blood pressure (MAP) from 116+/-4 to 77+/-5mmHg. The pressor effect of phenylephrine (10 microg ml(-1), i.v.) was also significantly reduced at 30, 60, 120 and 180 min after LPS injection. In contrast, animals pretreated with andrographolide (1 mg kg(-1), i.v., 20 min prior to LPS) maintained a significantly higher MAP when compared to LPS-rats given with vehicle. Administration of andrographolide 60 min after LPS caused a increase in MAP and significantly reversed the reduction of the pressor response to phenylephrine. 6. Our results indicated that andrographolide inhibits nitrite synthesis by suppressing expression of iNOS protein in vitro. And, this inhibition of iNOS synthesis may contribute to the beneficial haemodynamic effects of andrographolide in endotoxic shock.

Attenuation of arteriolar alpha 2-adrenoceptor sensitivity during endotoxemia

It is well documented that adrenergic responses after endotoxin (ENDT) administration are greatly reduced. The hypothesis of this study is that either alpha 1- or alpha 2-receptor activity is attenuated and the other receptor type is minimally affected during ENDT shock. Reactivity of the arterioles of left cremaster muscles of male Wistar rats anesthetized with pentobarbital sodium was studied using videomicroscopy. Femoral mean arterial pressure and first-, second-, third-, and fourth-order arteriolar diameters were measured. In group I, the decreases in arteriolar diameter and half-maximal effective dose (ED50) values with increasing phenylephrine concentration (alpha 1-adrenergic receptor agonist) were similar in all four branching orders before and after ENDT. In group II, the decreases in arteriolar diameter with increasing clonidine concentrations (alpha 2-adrenergic receptor agonist) were effectively attenuated by ENDT, and ED50 values were increased above control in all four branching orders. In group III, idazoxan (alpha 2-receptor antagonist) effectively blocked the vasoconstrictor effects of clonidine but did not affect the responses to phenylephrine before or after ENDT in all four arteriolar orders. In group IV, prazosin (alpha 1-adrenergic receptor antagonist) blocked the vasoconstrictor effects of phenylephrine before and after the administration of ENDT. However, vasoconstriction due to clonidine post-ENDT even at maximal dosage (10(-3) M), was greatly attenuated in all four branching orders as in group II. It is concluded that during endotoxemia the reduced adrenergic vasoconstrictor response of cremaster muscle arterioles is the result of attenuated activity of alpha 2-adrenergic receptors with minimal if any effects on alpha 1-adrenergic receptor activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Postjunctional regulation by angiotensin II of alpha 1-adrenoceptor-mediated pressor responses in the rat.

The effects of angiotensin II on the vasopressor responses to the selective alpha 1-adrenoceptor agonist, phenylephrine, in intact and sympathectomized rats were investigated. Infusion of angiotensin II at subpressor doses significantly enhanced the pressor effects of phenylephrine in intact rats. We also found that in the chemically sympathectomized rat, where prejunctional sympathetic function is impaired, the effects of angiotensin II infusion on the pressor effects of phenylephrine were similar to those obtained in intact rats. Furthermore, pretreatment with valsartan ((S)-N-valeryl-N-([2'-(1H-tetrazol-5-yl)biphenyl-4-yl]-methyl)-val ine), a new selective angiotensin AT1 receptor antagonist, antagonized the effects of angiotensin II on phenylephrine-mediated pressor responses, whereas the administration of the selective angiotensin AT2 receptor antagonist, PD 123319 (1-[[4-(dimethylamino)-3-methylphenyl]-methyl]-5-(diphenylacetyl)- 4,5,6,7-tetrahydro-1H-imidazo[4,5-c]-pyridine-6-carboxylic acid, ditriflouroacetate, monohydrate), injected in bolus doses of 100 micrograms/kg, did not antagonize the enhancing effect of angiotensin II. Collectively, these data suggest that angiotensin II modulates the response to phenylephrine primarily at a postjunctional level through the activation of angiotensin AT1 receptors and that the suggested prejunctional facilitation mediated by angiotensin receptors is quantitatively much less important in the intact animal.

Effects of age and indomethacin on response and sensitivity of pulmonary artery to phenylephrine and to histamine in pigs

The vasoconstrictor effects of phenylephrine and histamine were investigated in isolated strips of pulmonary arteries in pigs during ageing. Interactions between phenylephrine-induced responses and arachidonic acid derivatives were also studied by incubating the blood-vessels with indomethacin. Potency (pD2 values) and maximal effects (EmaxX) recorded in 5-week-old piglets (group I, n = 5) with phenylephrine [5.71 +/- 0.17 and 0.76 +/- 0.22 g/mg of dry tissue respectively (mean +/- SEM)] were similar to values found in 12-week-old animals (group 2, n = 5) (5.49 +/- 0.30 and 1.06 +/- 0.27 g/mg of dry tissue respectively). The sensitivity and responsiveness of tissues to this agonist were significantly reduced in 26-week-old mature pigs (group 3, n = 6) as indicated by the decrease in pD2 (3.91 +/- 0.23; P < 0.01) and Emax (0.27 +/- 0.13 g/mg of dry tissue; P < 0.05) values observed in this group. Histamine (10(-3) M)-induced maximal responses (Emax) were significantly higher in group 2 (2.23 +/- 0.49 g/mg) than in group 1 (0.85 +/- 0.11 g/mg; P < 0.05) and in group 3 (0.48 +/- 0.10 g/mg; P < 0.01). In 5-week-old animals, indomethacin (3 x 10(-5) M) significantly (P < 0.05) shifted the concentration-response curve to phenylephrine to the right (0.28 log. units) and depressed contractions to this drug as shown by the significant decrease of 39.5% (P < 0.05) in Emax. This cyclo-oxygenase inhibitor had no effect in other groups.(ABSTRACT TRUNCATED AT 250 WORDS)

Potentiation of the pressor response to stress by tolbutamide in dogs.

Tolbutamide has previously been shown to amplify the pressor effects of "exogenous" catecholamines in conscious dogs, possibly due to sensitization of the alpha 1-adrenoreceptor-mediated vasoconstriction. The objective of this study was to examine if tolbutamide also amplifies the pressor effects of "endogenous" catecholamines released during psychological stress (classical Pavlovian aversive conditioning). Experiments were conducted in beta-adrenoreceptor-blocked (propranolol, 1 mg/kg, i.v.) conscious dogs (n = 4) trained in classical aversive conditioning. Conditioning was accomplished by following a tone (CS+) with a 1/2 second shock; another tone (CS-) was not followed by any shock and served as control. With saline pretreatment, aversive conditioning (i.e., CS+) increased mean arterial pressure (MAP) only by approximately 4.7% when compared to CS-, whereas with tolbutamide (45 mg/kg, i.v.) pretreatment, the increase in MAP induced by CS+ beyond what was induced by the CS- (approximately 6.2%) was significantly (p < 0.05) larger than that with saline pretreatment. In isolated canine femoral arterial segments (n = 4), the vasoconstrictor effect of phenylephrine (an alpha 1-agonist) at 5 x 10(-6) M (which was the EC50 value) was amplified by 2 x 10(-2) M of tolbutamide from 54.0 +/- 2.0% to 66.9 +/- 2.1%. In conclusion, tolbutamide amplifies the pressor effects of "endogenous" catecholamines in conscious dogs, possibly by sensitization of the alpha 1-adrenoreceptor-mediated vasoconstriction. This mechanism of action is novel and has not been reported with other agents.

The α‐ and β‐adrenoceptor blocking activities of labetalol and its RR‐SR (50:50) stereoisomers

1. We compared the alpha 1-, alpha 2- and beta 1-adrenoceptor blocking potencies of labetalol with those of its two stereoisomers (RR and SR) in pithed rats and in homogenized rat cerebral cortex and heart. 2. In pithed rats, labetalol and the RR-SR combination were given orally either at doses of 25 and 50 mg kg-1 body wt. or intravenously at doses of 1 and 5 mg kg-1 body wt. Prazosin 4 and 20 micrograms kg-1 body wt. and propranolol 1 and 5 mg kg-1 body wt., were given intravenously for comparison studies of potency at alpha 1- and beta 1-adrenoceptors, respectively. Effects were studied before and after i.v. administration of either phenylephrine (at doses which increased the mean arterial pressure by approximately 80 mmHg) or isoprenaline (at doses that increased heart rate by approximately 100 beats min-1). 3. In pithed rats, labetalol and the RR-SR combination antagonized, in a dose-dependent manner, the pressor effect of phenylephrine (P less than 0.05) and the chronotropic effect of isoprenaline (P less than 0.05). Following both oral and intravenous dosing, the RR-SR combination was twice potent as labetalol in terms of alpha 1- and beta 1-adrenoceptor antagonism at equivalent doses. 4. Labetalol and the enantiomers lacked affinity at alpha 2-adrenoceptors while at alpha 1-adrenoceptors the order of potency was prazosin much greater than RR-SR greater than labetalol. At beta 1-adrenoceptors, the affinity of the compound RR-SR was about 3 times that of labetalol.5. As labetalol is a mixture of active (RR and SR) and inactive (SS and SR) enantiomers (in terms of alpha and beta receptor actions), the combination of RR and SR may be a valuable substitute for labetalol in the treatment of systemic hypertension. Although the potential for non-specific side effects (common to all four enantiomers) could be expected to be diminished, recent reports by postmarketing surveillance indicate that the RR isomer (dilevalol) can induce liver toxicity. Interestingly, labetalol is devoid of this effect; whether the combination of RR and SR enantiomers could be of clinical importance warrants further investigation.

Differential impairment of vasodilator responsiveness of peripheral resistance and conduit vessels in humans with atherosclerosis.

The purpose of this study was to assess the effect of atherosclerosis on the regulation of limb blood flow. To examine this issue, the reactivity of resistance and conduit vessels was evaluated in 11 patients with peripheral atherosclerotic disease and six control subjects. Responsiveness of resistance vessels was measured by venous occlusion plethysmography. Responsiveness of conduit vessels was determined by quantitative angiography to measure the diameter of the superficial femoral artery. To distinguish endothelium-dependent vasodilation from that caused by direct smooth muscle relaxation, each participant received intra-arterial infusions of methacholine and nitroprusside, respectively. Flow-mediated dilation of the superficial femoral artery was determined during reactive hyperemia. Vasoconstrictor function was determined by the infusion of phenylephrine. Methacholine reduced calf vascular resistance in the control subjects but not in the patients with atherosclerosis (-64 +/- 11% versus 6 +/- 18%, p less than 0.01). Nitroprusside decreased calf vascular resistance comparably in each group (-51 +/- 5% versus -42 +/- 4%, p = NS). The vasoconstrictor effect of phenylephrine was similar in each group (105 +/- 30% versus 108 +/- 22%, p = NS). In the superficial femoral artery, the vasodilator responses to both methacholine (20 +/- 4% versus 1 +/- 4%, p less than 0.05) and nitroprusside (19 +/- 4% versus 5 +/- 4%, p less than 0.05) were blunted in the atherosclerotic patients as was the vasoconstrictive response to phenylephrine (-15 +/- 1% versus -1 +/- 5%, p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Effect of artificial respiratory volume on the cardiovascular responses to an alpha 1- and an alpha 2-adrenoceptor agonist in the air-ventilated pithed rat.

1. The effect of varying artificial respiratory volume (at a fixed rate of 54 min-1) on cardiac output, its distribution and tissue blood flows were determined with tracer microspheres in control pithed rats or during pressor responses to either the alpha 1-adrenoceptor agonist phenylephrine or the alpha 2-agonist xylazine. Phenylephrine was investigated in the presence of propranolol (3 mg kg-1). The rats were pithed under halothane anaesthesia. 2. A respiratory volume of 15 ml kg-1 produced modest hypercapnia (PaCO2 = 47 mmHg), hypoxia (PaO2 = 60 mmHg) and acidosis (pH = 7.35) relative to control animals respired at 20 ml kg-1 (PaCO2 = 32 mmHg; PaO2 = 77 mmHg; pH = 7.47). In rats respired at 15 ml kg-1, total peripheral resistance was lower, and cardiac output greater (due to increased stroke volume), than in the controls. Lowering respiratory volume reduced distribution of cardiac output to the kidneys, increased it to the large intestine and also increased blood flow through the gastrointestinal tract, skin and spleen. A respiratory volume of 30 ml kg-1 gave mild hypocapnia (PaCO2 = 19 mmHg), hyperoxia (PaO2 = 101 mmHg) and alkalosis (pH = 7.59) compared to 20 ml kg-1 but had no effect on cardiac output distribution or organ blood flow although heart rate was 29% greater at 30 ml kg-1. 3. Xylazine (500 micrograms bolus followed by 100 micrograms min-1 infusion) at all three respiratory volumes gave well-sustained mean pressor responses of 62-64 mmHg by increasing both total peripheral resistance and cardiac output (resulting from increased stroke volume). It increased the proportion of cardiac output passing to the liver, reduced that going to the spleen and gastrointestinal tract and increased cardiac, renal and hepatosplanchnic blood flows. 4. The secondary, relatively sustained, pressor effect of phenylephrine (5 micrograms bolus followed by 0.4 micrograms min-1 infusion, i.v.) varied at the 3 respiratory volumes with mean values from 32 to 53 mmHg. This response was due to both increased total peripheral resistance and cardiac output (resulting from greater stroke volumes and/or heart rates). Phenylephrine increased the proportion of cardiac output passing to the gastrointestinal tract, heart, kidneys and hepatosplanchnic bed and increased cardiac, hepatosplanchnic, renal and gastrointestinal blood flows. 5. Respiratory volume had no effect on the cardiovascular effects of xylazine. However, respiratory volume modified the effects of phenylephrine on heart rate and changed the relative contributions of stroke volume and heart rate to the increased cardiac output. It also influenced the effects of phenylephrine on cardiac output distribution to the liver, epididimides and hepatosplanchnic bed and on blood flow through skeletal muscle and the large intestine. 6. Changes in respiratory volume of air ventilated pithed rats thus influence cardiac output, its distribution and regional blood flows. Such changes can also differently influence the responses of various vascular beds to phenylephrine whilst having no effect on their responses to xylazine.

Antihypertensive effects of S9490-3, a new converting enzyme inhibitor, in the conscious spontaneously hypertensive rat.

The acute and chronic cardiovascular effects of S9490-3, a new converting enzyme inhibitor, were studied by means of a computerized analysis of the intra-aortic blood pressure recorded for 48 consecutive hours, in the conscious, unrestrained adult spontaneously hypertensive rat (SHR). The software used allowed the simultaneous study of one control and one treated animal. A single intravenous dose of S9490-3 (2 mg/kg) induced a rapid fall in systolic and diastolic blood pressure, which remained significant for 11 h. This decrease was not associated with an elevation in heart rate. A chronic oral treatment with S9490-3 (1 mg/kg/24 h for 12 days) significantly lowered systolic and diastolic blood pressure and reduced the variability of systolic blood pressure. The heart rate was slightly increased at rest (day time) but significantly elevated in the freely exercising SHR (night time). However, it must be noted that this increase remained moderate. The baroreflex sensitivity of chronically treated animals was enhanced when measured after phenylephrine but not after nitroglycerine bolus. Chronically given S9490-3 significantly reduced the pressor effect of phenylephrine and decreased the left ventricle weight.

Studies on the mechanism of action of the hypotensive effect of ketanserin.

Ketanserin, 0.01-3.0 mg/kg i.v., was found to cause a dose-related fall in blood pressure in anaesthetized rats. However, these decreases were only significant after 1 and 3 mg/kg doses. Subsequent administration of prazosin, 0.2 mg/kg i.v., had no significant effect on blood pressure. In the presence of ketanserin 3 mg/kg, plus prazosin 0.2 mg/kg, adenosine caused a significant dose-dependent fall in blood pressure in anaesthetized rats. Methysergide, 1 mg/kg i.v., significantly attenuated the blood pressure responses to serotonin in anaesthetized rats whereas ketanserin (1 and 3 mg/kg) had no overall effect on serotonin responses. Ketanserin, 1 and 3 mg/kg i.v., was found to antagonize the pressor effects of phenylephrine and reverse the pressor effects of adrenaline in anaesthetized rats. Responses to angiotensin II were not significantly affected by ketanserin. These results suggest that ketanserin lowers blood pressure in anaesthetized rats by blockade of alpha-adrenoceptors.