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ABSTRACT: Hemodynamic responses to histamine were investigated in the anesthetized rabbit. Intravenous injections of histamine induced dose-dependent decreases in systemic arterial pressure that were blocked by the H(1)-receptor antagonist pyrilamine but not the H(2) antagonist cimetidine. Injections of histamine and the H(1) agonist 6-[2-(4-imidazolyl)ethylamine]-N-(4-trifuormethylphenyl)-heptan ecardo xamide dimaleate (HTMT) into the hindlimb perfusion circuit increased hindlimb perfusion pressure, whereas the H(2) agonist dimaprit decreased perfusion pressure and the H(3)-receptor agonist R-(-)-alpha-methylhistamine did not alter perfusion pressure. Pyrilamine reduced hindlimb vasoconstrictor responses to histamine and HTMT but did not alter vasodilator responses to dimaprit. Cimetidine reduced the response to dimaprit but did not alter vasoconstrictor responses to histamine or HTMT. The H(3)-receptor antagonist thioperamide was without effect on responses to the histamine agonists. These data suggest the presence of H(1) and H(2) receptors and that histamine for the most part acts by stimulating H(1) receptors to produce vasoconstriction in the hindlimb vascular bed of the rabbit. Responses to histamine, HTMT, and norepinephrine were significantly enhanced by a nitric oxide synthase inhibitor at a time when vasodilator responses to dimaprit were unaltered and responses to acetylcholine were significantly reduced. Responses to histamine and the H(1) and H(2) agonists were not affected by the cyclooxygenase inhibitor meclofenamate or by ATP-sensitive K(+) channel, alpha-adrenergic, or angiotensin AT(1) receptor antagonists. The present data suggest that H(1) receptors mediate both systemic vasodepressor and hindlimb vasoconstrictor responses to histamine.
The American journal of physiology 11/1999; 277(4 Pt 2):R1179-87.
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ABSTRACT: The effects of the AT1 and AT2 receptor blockers candesartan and PD123319 on hemodynamic responses to angiotensin II (AngII) were investigated in the anesthetized rat. Injections of AngII caused dose-related increases in systemic arterial and in hindquarters perfusion pressure that were reduced by candesartan. The inhibitory effects of candesartan were insurmountable, and a vasodepressor or vasodilator response to AngII was not unmasked. The AT2 receptor antagonist PD 123319 had no effect on increases in systemic arterial and hindquarters perfusion pressure in response to AngII. The present results suggest that pressor responses to AngII are mediated by the activation of AT1 receptors, and that AT2 receptors do not appear to modulate hemodynamic responses to AngII in the anesthetized rat.
Journal of the American Society of Nephrology 02/1999; 10 Suppl 11:S95-7. · 9.66 Impact Factor
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ABSTRACT: The effects of candesartan (30 microg/kg i.v.) and PD123319 (10 mg/kg i.v.) on changes in systemic arterial pressure in response to angiotensin II (AngII) were investigated in the anesthetized mouse. Intravenous injections of AngII caused dose-related increases in systemic arterial pressure. Pressor responses to AngII were attenuated by candesartan but were not altered by PD123319. Neither candesartan nor PD123319 had a significant effect on baseline systemic arterial pressure or on the increase in arterial pressure in response to norepinephrine. The present results suggest that increases in systemic arterial pressure in response to AngII in the anesthetized mouse are mediated by AT1 receptors and that AT2 receptors do not modulate the pressor response to AngII.
Journal of the American Society of Nephrology 02/1999; 10 Suppl 11:S98-100. · 9.66 Impact Factor
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ABSTRACT: The effects of the nonpeptide angiotensin II (AngII) AT1 receptor blocker candesartan on responses to AngII were investigated in the hindquarters vascular bed of the cat. Under constant-flow conditions, injections of AngII into the hindquarters perfusion circuit elicited dose-dependent increases in perfusion pressure. Candesartan in a dose of 3 microg/kg intravenously (i.v.) decreased vasoconstrictor responses to AngII in a surmountable manner. At doses of 30 and 300 microg/kg i.v., candesartan shifted the dose-response curve to AngII to the right in an insurmountable manner, indicating an insurmountable blockade of AT1 receptors. The inhibitory effects of the larger doses of candesartan on responses to AngII were long in duration, and the AT1 receptor blocker had little effect on baseline pressures. Candesartan was without effect on vasoconstrictor responses to norepinephrine, U46619, PGF2alpha, vasopressin, BAY K8644; biphasic responses to endothelin-1; or on vasodilator responses to acetylcholine, albuterol, or levcromakalim. These results indicate that candesartan is a potent and selective angiotensin AT1 receptor blocker that can induce both surmountable and insurmountable AT1 receptor blockade and provide support for the hypothesis that there are "spare" AT1 receptors in the hindquarters vascular bed of the cat.
Journal of the American Society of Nephrology 02/1999; 10 Suppl 11:S101-3. · 9.66 Impact Factor
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ABSTRACT: The effects of the nonpeptide angiotensin II AT1 receptor antagonist candesartan on responses to angiotensin II were investigated in the hindquarters vascular bed of the cat. Under constant-flow conditions, injections of angiotensin II into the hindquarters perfusion circuit elicited dose-dependent increases in perfusion pressure. Candesartan in a dose of 3 micrograms/kg i.v. decreased vasoconstrictor responses to angiotensin II in a competitive manner. However, at doses of 10-1000 micrograms/kg i.v., candesartan shifted the dose-response curve to angiotensin II to the right in a nonparallel manner, suggesting a noncompetitive blockade. The inhibitory effects of candesartan on responses to angiotensin II were long in duration, and the AT1 receptor antagonist had little effect on baseline pressures. Candesartan was without effect on vasoconstrictor responses to norepinephrine, U46619, PGF2 alpha, and BAY K8644; on biphasic responses to endothelin-1; and on vasodilator responses to acetylcholine. Candesartan significantly attenuated hindquarters vasoconstrictor responses to angiotensin III and IV with a parallel shift at the 3 micrograms/kg iv dose and a nonparallel shift to the right at the high dose of the AT1 receptor antagonist. The results of the present study indicate that candesartan is a potent angiotensin AT1 receptor antagonist that can induce both competitive and noncompetitive blockade of responses to angiotensin II, III, and IV n the hindquarters vascular bed of the cat.
Canadian Journal of Physiology and Pharmacology 03/1998; 76(2):133-40. · 1.95 Impact Factor
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ABSTRACT: The endogenous peptides endomorphin 1 and 2 are newly isolated, potent, selective mu-opioid receptor agonists. In the present study, responses to the endomorphin peptides were investigated in the systemic vascular bed of the cat. Endomorphin 1 and 2 induced dose-related biphasic changes in systemic arterial pressure when injected in doses of 1-30 nmol/kg i.v. The biphasic responses to endomorphin 1 and 2 were characterized by an initial increase followed by a decrease in systemic arterial pressure. In terms of relative vasodepressor activity, endomorphin 1 and 2 were similar in potency and approximately 10-fold less potent than the ORL1 ligand nociceptin (orphanin FQ) in decreasing systemic arterial pressure. The biphasic arterial pressure changes in response to endomorphin 1 and 2 were inhibited by the opioid receptor antagonist naloxone in a dose of 2 mg/kg i.v. These results demonstrate that endomorphin 1 and 2 produce significant, naloxone-sensitive changes in systemic arterial pressure that are characterized by an initial increase followed by a secondary decrease in arterial pressure in the cat.
Life Sciences 02/1998; 63(9):PL131-6. · 2.53 Impact Factor
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ABSTRACT: Vasodilator responses to human adrenomedullin (hADM), a newly discovered hypotensive peptide, human calcitonin gene-related peptide-alpha (hCGRP-alpha) and hCGRP-beta, which share structural homology with hADM, were compared in the hindlimb vascular bed of the cat under constant flow conditions. Injections of hADM (0.003-1 nmol), hCGRP-alpha, and hCGRP-beta (0.003-0.3 nmol) into the perfusion circuit caused dose-related decreases in hindlimb perfusion pressure. Vasodilator responses to hCGRP-alpha and hCGRP-beta were similar in potency and duration, and the doses of hCGRP-alpha and hCGRP-beta required to reduce hindlimb perfusion pressure 40 mm Hg (ED40 mm Hg) were significantly lower than the ED40 mm Hg for hADM. The duration of the hindlimb vasodilator responses to hCGRP-alpha and hCGRP-beta were significantly longer than the duration of the response to hADM. Amylin, a peptide that shares structural homology with ADM and with CGRP, had no significant effect on hindlimb perfusion pressure when injected in doses up to 1 nmol. Decreases in hindlimb perfusion pressure in response to hADM, hCGRP-alpha, and hCGRP-beta were not altered by L-N5-(1-iminoethyl)-ornithine (L-NIO) in a dose of the nitric oxide synthase inhibitor that decreased the vasodilator response to acetylcholine or by the cyclooxygenase inhibitor, meclofenamate, in a dose that decreased the vasodilator response to archidonic acid. The present data demonstrate that hADM, hCGRP-alpha, and hCGRP-beta have potent, but relatively short-lasting, vasodilator activity, and that vasodilator responses are not dependent on the release of nitric oxide or vasodilator prostaglandins in the hindlimb vascular bed of the cat.
Molecular and Cellular Biochemistry 12/1997; 176(1-2):5-11. · 2.06 Impact Factor
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ABSTRACT: Responses to rat (r) adrenomedullin (ADM) and human (h) ADM were compared in the hindlimb vascular bed of the cat under conditions of controlled blood flow. Intra-arterial injections of rADM and hADM in doses of 0.03-1 nmol caused dose-related decreases in hindlimb perfusion pressure. In terms of relative vasodilator activity, rADM was similar to hADM. The time course of the vasodilator response and the recovery half times (T1/2) for the vasodilator response to rADM and hADM were not significantly different. Decreases in hindlimb perfusion pressure in response to rADM and hADM were not altered by the calcitonin gene-related peptide receptor antagonist, rCGRP(8-37), at the same time, vasodilator responses to calcitonin gene-related peptide (CGRP) were significantly reduced. The T1/2 of the vasodilator response to rADM and hADM were significantly greater after administration of the cAMP-selective, type IV phosphodiesterase inhibitor, rolipram. These data demonstrate that decreases in hindlimb perfusion pressure in response to rADM and hADM are similar and that vasodilator responses to rADM are not dependent on the activation of CGRP receptors in the hindlimb vascular bed of the cat. These data further suggest that decreases in hindlimb perfusion pressure in response to rADM are mediated by smooth muscle increases in cAMP levels.
Regulatory Peptides 07/1997; 70(2-3):161-5. · 2.11 Impact Factor
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ABSTRACT: Responses to proadrenomedullin NH2-terminal 20 peptide (PAMP) were investigated in the systemic and hindquarters vascular bed of the rat. Intravenous injections of PAMP and adrenomedullin (ADM) produced dose-related decreases in systemic arterial and hindquarters perfusion pressure, which were not altered by alpha-receptor or adrenergic nerve terminal blocking agents. PAMP was 100-fold less potent than ADM, and hindquarters vasodilator responses to both peptides were similar in innervated and denervated preparations. When baseline tone was increased with phenylephrine and U46619 or decreased with sodium nitroprusside, vasodilator responses to PAMP and ADM were correlated with the basal level of tone, suggesting that responses to both peptides are dependent on the baseline level of vasoconstrictor tone in the hindquarters vascular bed of the rat.
Peptides 02/1997; 18(4):513-9. · 2.43 Impact Factor
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ABSTRACT: Responses to a newly synthesized human adrenomedullin (hADM) analog, hADM (16-31), were investigated in the rat and cat. Unlike the full-sequence peptide, which has potent hypotensive activity, hADM (16-31) had pressor activity in the rat but not in the cat. Injection of hADM (16-31) in doses of 10-300 nmol/kg i.v. induced dose-dependent increases in systemic arterial pressure in the rat, and the peptide was approximately 10-fold less potent than norepinephrine when doses are compared on a nanomole basis. In contrast, injection of hADM (16-31) in doses up to 1,000 nmol/kg i.v. had no significant effect on systemic arterial pressure in the cat. Increases in systemic arterial pressure in response to hADM (16-31) in the rat were significantly reduced after administration of phentolamine or reserpine. These data suggest that increases in systemic arterial pressure in response to hADM (16-31) are mediated by release of catecholamines and activation of alpha-adrenergic receptors in the rat. These data show that hADM (16-31) has significant pressor activity and that there are marked species differences in the response to hADM (16-31).
Peptides 02/1997; 18(1):133-6. · 2.43 Impact Factor
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ABSTRACT: Responses to [Mpr14]-ADM(14-50), a novel analog of adrenomedullin, were investigated in the hindlimb vascular bed of the cat under conditions of controlled blood flow. Intraarterial injections of [Mpr14]-rADM(14-50) in doses of 0.003-1 nmol caused dose-related decreases in hindlimb perfusion pressure. In terms of relative vasodilator activity, [Mpr14]-rADM(14-50) was more potent than human synthetic adrenomedullin (hADM) in doses of 0.003-0.1 nmol. The recovery half-times (T 1/2) for the vasodilator response to [Mpr14]-rADM(14-50) were significantly greater than the recovery half-times for hADM in all doses studied. Decreases in hindlimb perfusion pressure in response to [Mpr14]-rADM(14-50) were not altered by the calcitonin gene-related peptide receptor antagonist rCGRP(8-37) at the same time vasodilator responses to calcitonin gene-related peptide were significantly reduced. The present data demonstrate that [Mpr14]-(14-50) has potent and long-lasting vasodilator activity when compared to hADM, and that vasodilator responses to [Mpr14]-rADM(14-50) are not dependent on the activation of CGRP receptors in the hindlimb vascular bed of the cat.
Life Sciences 02/1996; 59(1):PL1-7. · 2.53 Impact Factor
