Receptor subtypes mediating renal actions of calcitonin gene-related peptide.

We previously reported that the renal arterial infusions of non-hypotensive doses of calcitonin gene-related peptide (CGRP) caused renal vasodilatation and increases in glomerular filtration rate at a low dose, but renal vasoconstriction, natriuresis and kaliuresis at a high dose. In the present study, we examined the effects of the specific CGRP1 receptor antagonist (CGRP-(8-37) (1 and 10 nmol/kg) and the putative CGRP receptor antagonist, [Tyr(0)]CGRP-(28-37)(3 and 30 nmol/kg), on the renal vascular and tubular effects of CGRP in inactin-anaesthetized Sprague-Dawley rats. Renal arterial infusion of single doses of CGRP (0.3-300 pmol/kg per min) did not significantly alter mean arterial pressure or heart rate. However, during the continuous renal arterial infusion of either CGRP-(8-37) or [Tyr(0)CGRP-(28-37) incompletely inhibited the vasoconstriction but did not inhibit diuresis, natriuresis and kaliuresis elicited by a high but non-hypotensive dose of CGRP. On the basis that CGRP-(8-37) is a competitive CGRP1 receptor antagonist, our results suggest: (1) the renal vascular effect of CGRP is completely mediated via the activation of CGRP1 receptors, (2) the renal tubular effects of CGRP are not mediated via CGRP1 receptors, and (3) [Tyr(0)]CGRP-(28-37) is a CGRP1 receptor antagonist with potency and efficacy less than those of CGRP-(8-37).

Effects of calcitonin gene-related peptide receptor antagonists on renal actions of adrenomedullin.

1. Adrenomedullin is a novel vasoactive peptide which is produced in the lungs, ventricle, kidneys, heart and adrenal medulla. Adrenomedullin shows homology to calcitonin gene-related peptide (CGRP) and has similar pharmacological actions to CGRP. 2. This study examined the dose-response effects of adrenomedullin (rat, 11-50) on mean arterial pressure (MAP), heart rate (HR), renal blood flow (RBF), glomerular filtration rate (GFR) and renal tubular electrolyte excretion in Inactin-anaesthetized Sprague Dawley rats. The possible involvement of CGRP receptors in actions of adrenomedullin was also examined via renal arterial injection of a CGRP receptor antagonist, CGRP (8-37) (1 or 10 nmol kg-1) or [Tyr0]CGRP(28-37) (3 or 30 nmol kg-1), starting 15 min prior to the administration of adrenomedullin. 3. Renal arterial infusion (0.001 to 1 nmol kg-1) of adrenomedullin did not alter MAP, HR and renal K+ excretion but dose-dependently increased RBF and arterial conductance, GFR, urine flow and Na+ excretion. 4. The renal actions of adrenomedullin were not blocked by either the low or the high dose of CGRP(8-37) or [Tyr0]CGRP(28-37). 5. The results show that adrenomedullin causes renal vasodilatation, increments in GFR, diuresis and natriuresis. The renal actions of adrenomedullin are not mediated via the activation of CGRP1 receptors.

Renal vascular and tubular actions of calcitonin gene-related peptide: effect of NG-nitro-L-arginine methyl ester.

The existence of calcitonin gene-related peptide (CGRP) nerve fibers and CGRP receptors in the kidney and the coupling of the receptors to adenylyl cyclase suggest that CGRP participates in renal regulation. This study investigates the dose-effect relationship of CGRP on renal blood flow (RBF) and arterial conductance, glomerular filtration rate (GFR) and tubular excretion in Inactin-anesthetized, Sprague-Dawley rats. The contributions of endothelium-derived relaxing factor/nitric oxide in the renal actions of CGRP also were investigated via renal arterial injection of the nitric oxide synthase inhibitor, NG-nitro-L-arginine methyl ester (L-NAME, 0.5 or 5 mg/kg). Renal arterial infusion of CGRP (0.3-300 pmol/kg/min) did not affect mean arterial pressure or heart rate. Low doses of CGRP increased RBF, arterial conductance and GFR, but the highest dose reduced RBF and conductance without affecting GFR. High doses of CGRP also increased urine flow and excretions of Na+ and K+. The renal vasodilator but not the constrictor effect of CGRP was inhibited by both doses of L-NAME. The increase in GFR by the lowest dose of CGRP was attenuated by the low dose and abolished by the high dose of L-NAME. L-NAME did not inhibit the diuretic, natriuretic and kaliuretic effects elicited by high doses of CGRP. The results show that a low dose of CGRP causes renal vasodilatation via the release of endothelium-derived relaxing factor/nitric acid.

Alpha 1b-adrenoceptors mediate renal tubular sodium and water reabsorption in the rat.

1. It is known that activation of alpha 1-adrenoceptors causes renal vasoconstriction and increased tubular Na+ and water reabsorption, with the alpha 1a-subtype mediating the constrictor effect. 2. This study examines which subtype of alpha 1-adrenoceptors mediates tubular Na+ and water reabsorption in pentobarbitone-anaesthetized rats. In order to avoid systemic effects, phenylephrine (0.3 to 30 micrograms kg-1), methoxamine (0.1-10 micrograms kg-1) and vehicle were infused into the right renal artery (via the suprarenal artery) of three groups of rats. Two other groups of rats were continuously infused with the irreversible selective alpha 1b-adrenoceptor antagonist, chloroethylclonidine (3 mg kg-1 h-1) for 1 h, prior to the construction of dose-response curves to phenylephrine or methoxamine. Another group was continuously infused with the irreversible selective alpha 1a-adrenoceptor antagonist, SZL-49 (10 micrograms kg-1 h-1) for 1 h, prior to the construction of dose-response curves to phenylephrine. Mean arterial pressure (MAP), heart rate (HR), urine flow, Na+ and K+ excretion, and urine osmolality were monitored. 3. Phenylephrine and methoxamine did not affect MAP or HR but dose-dependently and significantly decreased urine flow, urine osmolality as well as Na+ excretion and, slightly increased K+ excretion, although this was significant only for phenylephrine. 4. The antidiuretic, antinatriuretic and kaliuretic effects of phenylephrine were abolished by pretreatment with chloroethylclonidine, but were not inhibited by SZL-49. The inhibitory effects of methoxamine on urine flow and Na+ excretion were also almost totally abolished by chloroethylclonidine. 5. Our results show that alpha 1b-adrenoceptors mediate renal tubular Na+ and water reabsorption.

Subtype-selective alpha-1 adrenoceptor alkylation in the rat kidney and its effect on the vascular pressor response.

Separate genes for alpha-1A and alpha-1B adrenoceptors have now been identified. Whereas alpha-1 adrenoceptors are known to mediate rat renal vasoconstriction, the relative importance of these alpha-1 adrenoceptor subtypes was unknown. We cannulated the right suprarenal artery of anesthetized male Sprague-Dawley rats to permit administration of the alpha-1A and alpha-1B alkylating antagonists, SZL-49 (SZL) and chloroethylclonidine (CEC), respectively, directly into the right kidney. Treated kidneys were homogenized to identify the doses of SZL and CEC that caused the maximum reductions in Bmax for [3H]prazosin, the relatively nonselective alpha-1 adrenoceptor antagonist. In other rats, a Doppler flow probe was placed around the right renal artery, and dose-peak response curves for boluses of the alpha-1 adrenoceptor agonist phenylephrine (PHE) were generated before and after supramaximal dosages of SZL or CEC. Renal vasoconstriction to PHE was nearly obliterated by SZL. In contrast, CEC caused only a modest rightward shift in the PHE DRC. SZL also abolished the renal vascular response to two other alpha-1 adrenoceptor agonists, cirazoline and methoxamine. Our data support the conclusion that the alpha-1 adrenoceptors at the level of the rat renal resistance vessels are predominantly alpha-1A adrenoceptors.