Aging humans and rats have a reduced renal vascular constriction response to stress, change in posture, or exercise. In this study, renal interlobar arteries from 9- (intermediate age) to 15-month-old (aging) male Wistar rats constricted less to alpha-adrenergic agonists than those of 4-month-old (young adult) rats. The reduced contraction to A61603 (alpha 1 A agonist) was similar to that to norepinephrine and phenylephrine. Therefore, it appears that the reduction in constriction is primarily related to alpha 1 A receptor stimulation. GeneChip microarray hybridization analysis of the interlobar arteries with the RAE 230A GeneChip indicated that there were no significant differences in gene expression for alpha 1 A/C, 1B, or 1D receptors between 4-month-old (young adult) and 1-year-old (aging) male Wistar rats. Competitive binding experiments (prazosin) revealed that maximal binding (Bmax, fmol/mg protein) of the alpha 1 receptors of interlobar arteries was reduced 25% by 10 months of age and 50% by 18+ months of age. Alpha 1 receptor-induced arterial constriction and prazosin binding were both down-regulated. The loss of receptor-initiated constriction likely includes down-regulation of maximum agonist binding by alpha 1 adrenergic receptors.
"It has been demonstrated that alpha adrenergic receptors are largely coupled to Gq/ 11 Gs and/or Gi types of G proteins (Fig. 3). The reduced gene expression for G alpha q in aging male rat renal arteries (Table I) could play a role in the renal vascular contraction deficit in male rats [Passmore et al., 2005]. However, this does not explain the difference between male and female rats, as the G alpha q Gene Chip expression for the female group (4–11-month-old) is not different from the aging male group (11- months-old). "
[Show abstract][Hide abstract] ABSTRACT: As human males age, a decline in baroreflex-mediated elevation of blood pressure occurs due, at least in part, to a reduction in alpha-1 adrenergic vasoconstrictor function. Alpha adrenergic constriction is mediated by guanosine triphosphate binding Protein (G Protein) coupled signaling pathways. Alpha-1 A/C, B, and D adrenergic receptor expressions, measured by GeneChip array, are not reduced during aging in renal blood vessels of male or female rats. Alpha-1 A GeneChip expression is greater, at all ages studied, in females than in males. Prazosin binding by alpha-1 adrenergic receptors is greater in young adult female rats than in young adult male rats; however, it is reduced with aging in both male and female rats. G alpha q GeneChip expression declines while expression of adrenergic receptor kinase (GRK2) and tyrosine phosphatases (TyrP) increase with aging in male rats. The declines in alpha-1 adrenergic receptor binding and G alpha q expression and also the increases in GRK2 and TyrP expression likely relate to the age-related decline of vasoconstriction in male rats. The information that the expression of alpha-1 A adrenergic receptors is greater in female rats and (GRK2) expression does not increase during aging could relate to the gender differences in vasoconstrictor function with aging. Gene therapy to ameliorate the age-related decline in renal function could possibly reduce the need for renal dialysis. Signaling pathways such as those reviewed herein may provide an outline of the molecular pathways needed to move toward successful renal gene therapy for aging individuals.
[Show abstract][Hide abstract] ABSTRACT: Age and/or gender appear to moderate alpha-adrenergic mediated constrictor mechanisms found in the interlobar arteries of the Munich Wistar rat. We have determined the extent of constriction to alpha-adrenergic receptor stimulation using norepinephrine, phenylephrine and A61603 (α1A-adrenergic receptor agonist) as a function of age and gender. Norepinephrine produced less constriction in male-derived arteries at ages greater than eight months as compared to the younger adult male (four to six months). The arteries derived from females did not demonstrate altered constriction until greater than 15 months of age. Similarly, arteries derived from the male demonstrated weaker constrictions to phenylephrine (10(-6) to 10(-3) M) at ages greater than eight months while arteries from females showed differences at greater than 15 months. In contrast, the effective concentration of norepinephrine to cause a 50% maximal constriction (EC50) was significantly less in the four to five-month-old male rats compared to the pooled data from older groups. Interestingly, four to five month old males had A61603 EC50 values similar to the 8 to 12-month and 15+ old females. These studies conclude that an age related loss of sympathetic α-adrenergic constriction of renal interlobar arteries is present in Munich Wistar rats. Furthermore, this loss, while similar along longitudinal aspects of age, is also different as a function of gender with the loss of α-adrenergic constrictor function delayed in the female when compared to the male.
Age 06/2005; 27(2):107-116. DOI:10.1007/s11357-005-1627-9 · 3.45 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: 1. The present study identifies alpha1-adrenoceptor subtype(s) involved in constrictor responses of the kidney and how ageing influences it. 2. The study was conducted on kidneys from F344BNF1 rats, which unlike F344 or Wistar rats used by many previous investigators do not exhibit glomerulonephritis at advanced age. 3. Noradrenaline (NA) and phenylephrine (PHE) (non-selective alpha1) and A61063 (selective alpha(1A)) adrenoceptor agonists elicited constriction of perfused kidneys of young and old rats. The pD2 values (index of renovascular reactivity) were significantly higher for A61603 than for either PHE or NA, and significantly decrease across age groups. 4. BMY 7378 or RS 100329, alpha(1D)- or alpha(1A)-adrenoceptor antagonists, respectively antagonized the constrictor responses and suppressed the maximal responses to all agonists in young adult rat kidneys. However, antagonism of PHE or A61063 by BMY 7378 in old rat kidneys was surmountable. 5. This study suggests that: (i) alpha(1A) and alpha(1D)-adrenoceptor subtypes mediate vasoconstriction of perfused rat kidney; (ii) alpha(1A)-adrenoceptor subtype appears to predominate in renal vasculature based on agonist relative potencies. (iii) Ageing significantly decreases alpha1-adrenoceptor-mediated vasoconstriction of rat kidney.
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