Vasodilation mediated by human PTH 1-34 in the spontaneously hypertensive rat

Abstract

Parathyroid hormone's cardiovascular effects were assessed in a model of experimental hypertension with known abnormalities of calcium metabolism. Mean arterial pressure (MAP) changes and serum ionized calcium responses were measured in the spontaneously hypertensive rat (SHR) and its normotensive control, the Wistar-Kyoto (WKY), following injections of synthetic human PTH 1-34. Six 22-wk-old SHR and six WKY were given intra-arterial serial injections (0.1-100 micrograms/kg) of hPTH 1-34. Both the SHR (P less than 0.001) and WKY (P less than 0.001) demonstrated log dose-dependent hypotensive responses that were maximal at 1 min, with recovery occurring between 15 and 30 min. The slopes, however, of the dose-response curves differed (P less than 0.01). The SHR experienced a greater maximal delta MAP [-93.7 +/- 2.4 (SHR) vs. -71.2 +/- 1.6 mmHg (WKY), P less than 0.01]. Furthermore, the duration of the hypotensive action of hPTH 1-34 was significantly longer (P less than 0.001) in the SHR. Even when corrected for base-line MAP the SHR demonstrated a significant (P = 0.025) enhancement of this vasodilator response at doses of 5 micrograms/kg and greater at time intervals between 3 and 9 min after injection. A transient decrease [2.25 +/- 0.10 (pre) vs. 2.17 +/- 0.11 meq/liter (1 min post), P less than 0.01] in serum ionized calcium occurred at 1 min. We conclude that hPTH 1-34 is a potent vasoactive peptide in both the normotensive WKY and the SHR. The greater maximal hypotensive response to hPTH 1-34 and the prolongation of this cardiovascular effect in the SHR may be an additional manifestation of this experimental animal's acknowledged abnormalities of cellular membrane calcium and phospholipid metabolism.

Mechanisms involved in the increased vascular resistance in hypertension

“…This may be due to its capacity to inhibit Na+,K+-ATPase, as reported in erythrocytes (Acceto & Weder, 1987). Paradoxically, the hormone produces vasodilation (Cross & Pang, 1980;McCarron et al, 1984). This contradictory effect is likely to be due to the fact that PTH exerts a dual action on intracellular Caz+, producing a net Ca2+ influx at lower levels of PTH (physiologic level) and a net efflux at higher concentrations (Schleiffer et al, 1979;Zemel & Sowers, 1990).…”

The role of calcium in genetic hypertension.

“…Conceivably, long-term changes in PTH levels may produce effects on blood pressure that are very different from that of the acute vasodilation and hypotension. 50 It should be noted that preliminary findings suggest that other maneuvers that increased calcium balance without reducing PO 4 balance, as was produced by the administration of 1,25 dihydroxy-vitamin D 3 51 or magnesium supplements, 52 failed to attenuate the severity of hypertension in the SHR or reduce the blood pressure in the WKY rats. 35 Initial trials in hypertensive subjects also failed to document any antihypertensive effects with 1,25 dihydroxy-vitamin D 3 administration.…”

“…3 -" produce a marked but transient vasodilation, and the hypotensive effects last only a few minutes. 50 -" 4 -…”

Calcium, Cell Function and Cell Death

“…However, many pieces of the puzzle are still unaccounted for. Not only is the PTH molecule hypotensive and vasodilatory in hypertensive models [25,26], but hypotensive effect and the hypercalcemic effects of PTH represent two separate properties of the same molecule [26], Moreover, the in vitro response of vascular smooth muscular cells to PTH is an acute decrease in cAMP content [27]. This later in vitro obser vation warrants careful scrutiny and corroboration since there are presently no reports which correlate a decrease in cAMP with vasodilation.…”