Roland Foulkes

Differential vasodilator profile of calcitonin gene-related peptide in porcine large and smail diameter coronary artery rings

The vasodilator profile of calcitonin gene-related peptide (CGRP) was compared in large diameter (3-4 mm outer diameter) and small diameter (less than 1 mm outer diameter) rings from porcine left anterior descending coronary arteries (LAD). CGRP relaxed both sized rings in an endothelium-independent manner but was 10 X more potent in small compared to large diameter rings. Repeated administration of CGRP to small diameter rings did not cause the development of tolerance to its effects, whereas in the large diameter rings marked tolerance developed. Pretreatment with the CGRP peptide fragment, CGRP-(8-37) antagonised the vasodilator effects of CGRP in a concentration-dependent manner, but in large diameter rings, the antagonistic potency of CGRP-(8-37) was 10 X less than that seen in the small diameter rings. This differing vasodilator profile of CGRP in small and large diameter rings of pig LADs may be related to a differential CGRP receptor distribution along their length.

Hemodynamic and tubular effects of endothelin and thromboxane in the isolated perfused rat kidney

We have investigated the effects of the endothelium-derived peptide, endothelin, and of a chemically stable analog of thromboxane (TX) A2, U46619, on the glomerular hemodynamics and tubular function of isolated, perfused rat kidneys. Endothelin (10(-11)-10(-9) M) dose dependently decreased the renal plasma flow to a significantly greater extent than it did the glomerular filtration rate. In contrast, U46619 (10(-9)-10(-7) M) had more pronounced effects on the glomerular filtration rate than on the renal plasma flow. As a consequence, the filtration fraction was increased by endothelin and decreased by U46619. Endothelin, unlike U46619, enhanced urinary Na+ excretion and reduced oxygen consumption at concentrations that greatly decreased the tubular load, thus suggesting that it has a direct effect on tubular Na+ reabsorption. Addition of the TXA2/PGH2-receptor antagonist, BM13177 (4.10(-4) M), or the cyclooxygenase inhibitor, acetylsalicylic acid (10(-3) M), to the perfusion medium failed to modify the endothelin-induced increase in Na+ excretion or the reduction in renal plasma flow, whereas acetylsalicylic acid, but not BM13177, partially prevented the decrease in the glomerular filtration rate. These results demonstrate that two contractile agonists produced by the kidney have specific and differential effects on cortical and tubular functions. Moreover, the intrarenal production of eicosanoids does not appear to play a major role in the renal effects of endothelin.

Human α-calcitonin gene-related peptide (CGRP)-(8–37), but not-(28–37), inhibits carotid vasodilator effects of human α-CGRP in vivo

Abstract Human α-calcitonin gene-related peptide-(8–37) alone (up to doses of 30 nmol kg −1 min −1 ) had no significant effects on blood pressure, heart rate or common or internal carotid haemodynamics, although it caused significant, reversible, inhibition of the hypotensive, tachycardic, and common and internal carotid vasodilator effects of human α-CGRP (0.03 nmol kg −1 min −1 ) in conscious, Long Evans rats. Human α-CGRP-(28-37) up to doses of 300 nmol kg −1 min −1 had no cardiovascular effects itself and did not influence responses to human α-CGRP. These results are consistent with the carotid haemodynamic effects of human α-CGRP being due largely to activation of the CGRP 1 -receptor subtype.

Models of adrenal regeneration hypertension in the rat.

Blood pressure was measured indirectly (using the tail-cuff method) and intra-arterially in conscious rats following one of three experimental procedures carried out in order to determine which resulted in the most marked and reproducible form of adrenal regeneration hypertension (ARH). All rats were unilaterally adrenalectomized and given NaCl solution (1%). In some rats, the remaining adrenal gland was either enucleated (AE rats) or compressed (AC rats) but both kidneys were left intact. During the fourth week after surgery, indirectly measured systolic blood pressure was higher in AE and AC rats than in sham-operated (SO) rats but, when measured intra-arterially, the magnitude of the developed hypertension was small (AC rats) or was absent altogether (AE rats). However, when a kidney was removed at the time of enucleation (AEN rats), the levels of systolic blood pressure, measured indirectly or intra-arterially, were markedly and consistently higher than in the corresponding group of uninephrectomized SO rats. The magnitude of the developed hypertension was similar in mature male and immature female AEN rats. We conclude that mature male rats, unilaterally nephro-adrenalectomized and given NaCl solution (1%), provide a marked and reproducible model of ARH.

The cardiovascular responses to sequential inhibition of alpha-adrenoceptors, the renin-angiotensin system and vasopressin in rats with adrenal regeneration hypertension.

The cardiovascular responses to selective alpha 1- and alpha 2-adrenoceptor antagonism (with prazosin and idazoxan, respectively) were assessed in rats 4 weeks after unilateral nephro-adrenalectomy, contralateral adrenal enucleation and the provision of a 1% NaCl solution as drinking fluid (AEN rats) and in sham-operated (SON) rats. Measurements were made between 0700 and 1000 h and between 1400 and 1700 h, since we have previously shown that resting blood pressures (BPs) in AEN rats are higher in the morning than in the afternoon. Following prazosin administration (morning or afternoon), BP fell to similar levels in both SON and AEN rats. Idazoxan, given 20 min after the start of prazosin infusion, caused similar transient falls in BP in all four groups of rats. Following the subsequent additional antagonism of angiotensin II (Ang II) production (with captopril) and vasopressin (V1) receptors [with d(CH2)5DAVP], BP in AEN rats studied in the morning was higher than in SON rats at that time of day, and higher than in AEN rats studied in the afternoon. These findings suggest than an additional underlying mechanism capable of increasing BP exists in AEN rats studied in the morning.

Cardiovascular and steroid responses to graded haemorrhage in rats with adrenal regeneration hypertension.

Blood pressure (BP) and plasma steroid responses to haemorrhage (2 ml + 1 ml + 1 ml at 20‐min intervals) were assessed in sham‐operated (SO) rats and in rats with adrenal regeneration hypertension (ARH). Experiments were carried out between 0700 and 1000 h (a.m.) and between 1400 and 1700 h (p.m.), because rats with ARH have BPs that are higher a.m. than p.m. There were no differences in the BP responses following haemorrhage in SO or ARH rats either a.m. or p.m., although ARH rats were unable to increase their plasma steroid levels. Pretreatment with captopril alone, d(CH2)5 DAVP alone, or captopril and d(CH2)5DAVP augmented the early hypotensive responses to haemorrhage but did not influence the later compensated levels of BP in either group of rats. There were no clear‐cut a.m. to p.m. differences in the changes in BP in any of the drug‐treated groups of SO or ARH rats. Under all conditions studied, the compensated level of systolic BP in ARH rats, 20 min after the final bleed, remained higher a.m. than p.m., indicating that this difference was not dependent on the renin‐angiotensin system and vasopressin and suggesting that the sympathetic nervous system and/or other factors might be involved.