Aly Abdelrahman

Mechanism of the vasodilator action of calcitonin gene-related peptide in conscious rats.

1 The aim of this study was to investigate whether the hypotensive effect of rat α‐calcitonin gene‐related peptide (αCGRP) in conscious rats is mediated by endothelium‐derived nitric oxide (NO) or the opening of adenosine 5′‐triphosphate (ATP)‐sensitive potassium (KATP) channels. 2 Dose‐mean arterial pressure (MAP)‐response curves of αCGRP were examined in the presence of vehicle, phenylephrine, KATP channel antagonist glibenclamide or NO synthase inhibitors, NG‐nitro‐l‐arginine methyl ester (l‐NAME) and NG‐nitro‐d‐arginine methyl ester (d‐NAME). Dose‐MAP‐response curves for sodium nitroprusside were also constructed in the presence and absence of l‐NAME and d‐NAME. 3 αCGRP and nitroprusside produced dose‐dependent reductions in MAP which were potentiated by phenylephrine. Both l‐NAME and d‐NAME attenuated the depressor response to αCGRP but not nitroprusside. 4 Dose‐MAP‐response curves for pinacidil, a KATP‐channel activator, were also examined in the presence of glibenclamide or vehicle. Glibenclamide attenuated pinacidil‐ but not αCGRP‐induced reductions in MAP. 5 It is concluded that the hypotensive effects of αCGRP are partially mediated via endothelium‐derived NO but not via the opening of KATP channels.

Selective inhibition of pressor and haemodynamic effects of NG-nitro-L-arginine by halothane.

Summary We investigated the characteristics of inhibition by halothane of the pressor responses to NG-substituted L-arginine derivatives, nitric oxide (NO) synthase inhibitors. Intravenous (i.v.) bolus injections of NG-nitro-L-arginine (L-NNA, 1–32 mg/kg), NG-nitro-L-arginine methyl ester (L-NAME, 0.4–12.8 mg/kg), norepinephrine (NE, 0.25–8 (μg/kg) and angiotensin II (AH, 0.02–0.64 μg/kg) each caused dose-dependent pressor responses in conscious rats. Halothane attenuated responses to the highest dose of NE and AH by ~18% but completely abolished responses to L-NNA and L-NAME. The haemodynamic effects of L-NNA were further examined by the microsphere technique in two groups of conscious rats and two groups of halothane-anaesthetized rats. An i.v. bolus injection of L-NNA (16 mg/kg) in conscious rats increased mean arterial pressure (MAP) and total peripheral resistance (TPR) and reduced heart rate (HR) and cardiac output (CO). These changes were associated with reduced conductance in all vascular beds, with the greatest reduction in the lungs and the least in the liver. In halothane-anaesthetized rats, L-NNA caused significant but markedly less change in MAP, HR, TPR, and CO as compared with those in conscious rats. The vasoconstrictor effects of L-NNA were attenuated by halothane in all beds except liver and spleen, with the greatest inhibition in heart. Our results suggest that NO plays a role in maintenance of peripheral vascular resistance and that halothane selectively and “noncompetitively” inhibits the vasoconstrictor effects of NO synthase inhibitors.

Differential venous effects of isoprenaline in conscious rats

The role beta-adrenoceptors in the control of venous tone is not clear. This study examines the dose-response effects of isoprenaline, a non-selective beta-adrenoceptor agonist, on mean circulatory filling pressure (MCFP), an index of body venous tone, in conscious and unrestrained rats. Dose-response curves of isoprenaline were constructed in three groups of rats, namely, I, intact; III, pretreated with the ganglionic blocker hexamethonium; and V, pretreated with noradrenaline. Three additional groups, Groups II, IV and VI, served as time controls and were treated similar to I, III and V, respectively, except that they were given normal saline in place of isoprenaline. The infusion of isoprenaline in intact rats dose dependently decreased mean arterial pressure (MAP) and increased heart rate (HR) and MCFP while in the ganglionic-blocked rat, it caused similar effects on MAP and HR but had no significant effects on MCFP. In rats given noradrenaline, isoprenaline again decreased MAP and increased HR and, in contrast to the other two groups, it decreased MCFP. The results show that isoprenaline has variable venous effects depending on existing venous tone. It causes reflex-mediated venoconstriction under normal conditions due to its hypotensive effects and direct venodilatation when venous tone is elevated by the infusion of noradrenaline.

Regional haemodynamic effects of urocortin in the anaesthetized rat

Urocortin is an endogenous vasodilator peptide that is related to corticotrophin-releasing factor. We examined the haemodynamic effects of urocortin in thiobutabarbital-anaesthetized rats, via the triple-isotope microspheres technique. Urocortin (3 nmol/kg, i.v. bolus) reduced mean arterial pressure (-25 mm Hg) through a decrease in total peripheral resistance (-43%). This was associated with an increase in cardiac output (+24%) and vasodilatation of the following tissues: heart and stomach (approximately 300% of baseline); liver, intestine, caecum/colon, skeletal muscle and skin (approximately 200%); and testes (approximately 150%). Arterial conductances of the kidneys, spleen and brain were unaffected by urocortin. Neither the vehicle (0.9% NaCl) nor a low dose of urocortin (0.3 nmol/kg) altered any measurements. Therefore, urocortin causes generalized vasodilatation as follows: heart and stomach>liver, intestine, caecum/colon, skeletal muscle and skin>testes.

Calcitonin gene-related peptide is a venous dilator in conscious rats.

The effect of calcitonin gene-related peptide (CGRP) on body venous tone is not known. This study examines the dose-response effects of rat alpha CGRP on mean circulatory filling pressure (MCFP), an index of body venous tone, in conscious rats. Dose-response curves of CGRP were constructed in three groups of rats, namely, (I) intact, (III) rats pretreated with the ganglionic blocker hexamethonium and (V) rats pretreated with noradrenaline to raise mean arterial pressure (MAP) and MCFP. Three additional groups, (II), (IV) and (VI), served as time controls and were treated similarly to (I), (III) and (V), respectively, except that they were given saline (0.9% NaCl) in place of CGRP. The infusion of CGRP in intact rats dose dependently decreased MAP, increased heart rate (HR) and slightly reduced MCFP. In ganglionic-blocked rats, CGRP caused similar depressor responses but less tachycardia than in intact rats, however, it also slightly reduced MCFP. In rats given noradrenaline, CGRP dose dependently decreased MAP, MCFP and increased HR. The results show that CGRP has venodilator activities; its venous effect is best revealed at elevated venous tone.

Hemodynamic Changes that Accompany the Pressor Response to Propranolol in Urethane Anesthetized Rats Subjected to α-Blockade

It has been shown that a paradoxical pressor response to a beta-blocker occurs in rats given an alpha-blocker. The dual-isotope microsphere technique was used to investigate the hemodynamic changes that accompany the pressor response to propranolol in phentolamine-treated, urethane-anesthetized rats. Rats were divided into four groups (n = 8 per group): group I received 10 min of saline infusion; group II received intravenous infusion of phentolamine (300 micrograms/kg/min) for 10 min; group III received intravenous injection of propranolol (100 micrograms/kg) after 20 min of phentolamine infusion, and group IV received intravenous injection of saline after 20 min of phentolamine infusion. In groups I and IV, saline did not cause any significant hemodynamic changes. In group II, phentolamine decreased the mean arterial pressure (MAP) and total peripheral resistance (TPR) by 34 +/- 3 mm Hg and 0.28 +/- 0.07 mm Hg/min/ml, respectively. Arterial conductances in the skeletal muscle and skin were increased to 157 and 165% of control values, respectively. Cardiac output and conductances in other tissues and organs were not significantly affected. In rats given phentolamine (group III), propranolol raised MAP (+40 +/- 2 mm Hg) by increasing TPR (+0.41 +/- 0.03 mm Hg/min/ml). Vascular conductances in the skeletal muscle, skin and kidneys were decreased to 38, 57 and 69% of control values, respectively. Conductances in other tissues and organs were not significantly affected. Our results show that propranolol raised MAP by increasing flow resistance, primarily via the reversal of the vasodilator effects of phentolamine in the muscle and skin.

Analysis of the Mechanism of the Vasodepressor Effect of Urocortin in Anesthetized Rats

The aim was to examine if the depressor effect of urocortin involves activation of the nitric oxide (NO)/L-arginine pathway, production of prostanoids or opening of K+-channels. I. v. bolus urocortin (0.1–3 nmol/kg) dose-dependently decreased mean arterial pressure in thiobutabarbital-anesthetized rats. The depressor effect of urocortin was unaffected by pretreatment with NG-nitro-L-arginine methyl ester (L-NAME, inhibitor of NO synthase, i.v. bolus) or noradrenaline (i.v. infusion), which increased arterial pressure to a similar level as that produced by L-NAME. In addition, methylene blue (inhibitor of soluble guanylyl cyclase, i.v. infusion), indomethacin (cyclooxygenase inhibitor, i.v. bolus), glibenclamide (blocker of ATP-sensitive K+-channels, i.v. bolus) or tetraethylammonium (a non specific K+-channel blocker, i.v. bolus) did not affect the depressor effect of urocortin. In conclusion, the depressor effect of urocortin in anesthetized rats is not mediated via the NO/L-arginine pathway, activation of soluble guanylyl cyclase, production of prostanoids, opening of TEA sensitive K+-channels nor opening of ATP sensitive K+-channels.

Effect of Substance P on venous tone in conscious rats

Substance P is an undecapeptide that belongs to the mammalian tachykinin family. We investigated the effects of substance P on venous tone in conscious rats through measurement of mean circulatory filling pressure. The effects of substance P (10 and 30 nmol/kg, IV) and the vehicle (0.9% NaCl) on mean arterial pressure, heart rate, and mean circulatory filling pressure were examined in 2 groups each of conscious rats: rats without or with ganglionic blockade through pretreatment with mecamylamine (10 mg/kg, IV) and norepinephrine (4 μg/kg/min, IV). In the unblocked rats, both doses of substance P reduced mean arterial pressure (−19 ± 1 and −35 ± 2 mm Hg) and increased heart rate (+113 ± 14 and +115 ± 23 beats/min). The high dose of substance P also decreased mean circulatory filling pressure (−1.7 ± 0.3 mm Hg). In the ganglionic-blocked rats, both doses of substance P decreased mean arterial pressure (−48 ± 6 and −73 ± 6 mm Hg) and mean circulatory filling pressure (−2.9 ± 0.4 and −4.2 ± 0.8 mm Hg) but did not affect HR. In conclusion, substance P is a vasodilator peptide that has a prominent venodilator action.

Regional hemodynamic effects of nociceptin/orphanin FQ in the anesthetized rat

This study examined the vasodilator action of nociceptin, an endogenous opioid receptor-like ligand (ORL1), in thiobutabarbital-anesthetized rats, via the triple-isotope microspheres technique. Nociceptin (10, 30 nmol/kg, left ventricular injection) reduced mean arterial pressure (-27, -29 mm Hg), total peripheral resistance (-36, -41% of baseline) and heart rate (-8, -11% of baseline), but did not significantly affect cardiac output. The vehicle (0.9% NaCl) did not alter hemodynamics. Both doses of nociceptin caused similar changes in arterial flow and conductance of all tissues. Nociceptin increased flows to the skeletal muscle, slightly reduced flows to the caecum and colon, but did not alter flows to other organs and tissues. With flow normalized by pressure to reflect intrinsic vascular tone, nociceptin was found to increase arterial conductance of all tissues, except for the intestine, spleen, caecum and colon. Its dilator influence was greater in the skeletal muscle ( approximately 250% of baseline conductance) than the lungs, heart, liver, stomach, kidneys, skin, testes and brain (140-160% of baseline). Thus, nociceptin causes generalized vasodilatation; its greatest influence is on the skeletal muscle bed.

Possible mechanism of the vasodepressor effect of endokinin A/B in anesthetized rats

We investigated the mechanism of the vasodepressor effect of endokinin A/B. An intravenous (IV) bolus of endokinin A/B (0.05-0.3 nmol/kg) dose-dependently decreased mean arterial pressure in thiobutabarbital-anesthetized rats. The magnitude of the response was unaffected by IV pretreatment with NG-nitro-L-arginine methyl ester (L-NAME, inhibitor of nitric oxide synthase), methylene blue (inhibitor of soluble guanylyl cyclase), indomethacin (cyclooxygenase inhibitor), or tetraethylammonium (TEA, nonspecific K+ channel blocker). L-NAME reduced the half-recovery time of the vasodepressor effect of endokinin A/B relative to responses in rats pretreated with either saline or norepinephrine, which caused a similar pressor effect as did L-NAME. Methylene blue, but not TEA or indomethacin, reduced the recovery time of the vasodepressor effect of endokinin A/B. Therefore, the vasodepressor effect of endokinin A/B is mediated via the nitric oxide/L-arginine pathway and activation of soluble guanylyl cyclase but not by production of prostanoids or opening of TEA-sensitive K+ channels.